United States (12) Patent Application Publication (Io) Pub

llIIlIlllIlIlIllIlIllIllIllIIIIIIIIIIIIIIIIIIIIllllIllIlIllIlIIllIlIllIllIlIIIIIIIIIIIIIII US 20190322668Al (19) United States (12) Patent Application Publication (io) Pub. No.: US 2019/0322658 A1 Yu et aj. (43) Pub. Date: OCt. 24, 2019

(54) ANTIPROI,II(ERATION ()OMPOUNDS .AND (22) I/iied Apr. 23, 2()19 USES THEREOF Related U.S. Application Data Darmstadt (71) Applicants:Marek Patent GmbH, (DE). (60) Provisional applmduon No. 62/661,719, filed onApr. Vertex Pharmaceutieals Incorporated. 24, 2018 13oston, MA (US) Publication Classification (72) Invmltors: Henry Yu, Derma(ad( (DE); Michael Clark. 13oston, MA (US): ('uy Bemis, (51) Int. CL 13oston, MA (US); 31ichael 13oyd, CO7D 413/14 (2006.01) Boston, MA (US); Kishan .461P 35/OO (2006.01) 7/'l4 Chandupatla. Boston, lvLA (US): Philip CO7D 41 (2006 01) Collier, Boston, lvIA (I IS), Hongbo CO7D 4O3/I)4 (2006 0 1 ) Dang, Southborougb. MA (US)1 Huijun CO7D 4OI/14 (2006 ol) Dong, Arbngton. MA (US), Warren CO7D 413/94 (2006.01) Dorsch. 13oston, MA (U)): Rmsell R. CO7D 491/113 (2006.01) Iloover, Iiarvard, MA (US); Mac CO7D 491/107 (2006.01) Arthur Johnson, JR.. Derry. NH (US): (52) V.S. CL Shashank Kukarni, Walthmn. MA CPC ...... CO7D 413/14 (2013.01): dIGJP35/OO (US), Marina Penney, Acton, MA (201S.OI). CO7D 417/14 (2013.01), CO7D (US), Steven Ronkin, Boston. MA 491/197 (2013.01), CO7D 401/14 (2013.01), (US), Darin Takemoto, Belmont, iVLA CO7D 413/O4 (2013.01): CO7D 4ipl/113 (I)S), Oing Tang, Acton, MA (US): (2013.01), CO7D 4((3/O4 (2013.01) stathan D. Waul, ( ambridge, MA (US); Tiansheng Wang. ('oncord. IvLA (57) ABSTRACT (US) The present invention provides compounds of Formula 1) or phaunaceuticaily acceptable salts thereof. pharmaceutical colupositiolls thereof. and lllc(htxls oi Usc thclcof for lied(- (21) Appl. Nod 16/391,419 lug cclhlkil prollfblduvt: illsoldcrs (c.g., cduccr). US 20]9/032265[] A] Och 24, 2019

ANTIPROLIFERATION COMPOUNDS AND salts thereof. are found to lead to complete and durable USES THEREOF regression ul models 01'on-small cell lung cancer (NSCLC), myeloma, hcpdioccllular carcinoma (HCC), TECHNICAL FIELD OF THE INVENTION breast cancer. and melanoma It has also been found that the cmnpounds of the invention result in enhanced inhibition [0001] The present invention relates to compounds and of methods uscl'ul Ibr treating cellular prolilbratlvc disorders cell viability. particularly the cells v, here Wolframm (WFS I ) is Without to be (c.g.. cancer). Thc ulveniion also provides phannaccutmally overexpressed. wishing bound by any acceptable con)positions comprising compounds ofthe pres- specific theory, it is believed that the compounds of the invmliion cause calcium rclcasc Irom ilm cndoplasmic ent invention and methods ofusing said compositions in the Cal treatment of various pmhferative disorders. rciimilum (ER) via d pU!dilvc chtinncl known Bs W'iil- framin (WFSI), which induces I!R stress and the *'unfolded I3ACK(rROUNI) Oll J1 II! INVI',N'I'ION pmtein response" (IJPR) and leaiks to cell death [0006] In one aspect, the present invention provides a [0002J Cellular prolifenstive disorders comprise malignant conlpollnd of fonnUld I. and non-malignant cell populations which difibr from the surround tissue morphologically and/or genotypically. Exmnples of cellular prolifcrative disorders include. for example. sohd tumors. cancer, diabetic rctinopathy, !R')„ nlilaiiculiu nciivascUJBr svndlonlcs, nlscillln dcgcncldilon, il rheumatoid arthritis, psonasis. and endolnetriosis. Cancer ls Sg a mup of diseases involving abnormal cell proliferation ~S !R )„ with the potential to invade or spread to other parts of the body. According to Centers for Disease ('ontrol and pre- 1 anion (CDC). Cancer is thc second ion dmg cause of death in ihc United States Thcrcforc, additiolml treatmmlts for ccllUitn plohfcrdtlvc disorders Blc dcsnixi io plovldc patients with more options

SUMMARY OF THE INVENTION or a pluinnaceuiically acceptable salt thcrcof, whcrcin. 5-7 mem- [0003J It has now been found that compounds of the [0007] Ring A is ring selected from phenyl, a present invention, and pharmaceutically acceptable compo- bered saturated or partially unsaturated carbocyclic ring, sitions thereof. are usehd for treating proliferative disorders a 8-)2 mcmbcred saturated or partially unsaturated blcy- (c.g.. cancer). In one aspect, thc prcscnt lnvenuon provides clic hcierocychc ring luivulg I-2 bc!eros!orna indcpcn- 5-6 compound ol'ormula I. dently selected fmm nitmgen. oxygen, or sulfur, a nlembered heteroai'onlatic ring having 1-4 heteroatoms independently selected front nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic hetemammatic ring bavin iR 1„ 1-5 heteroatoms independently selected from nitrogen, oxygen, or sullhr, itlxg [0008J each R's independently hydrogen or (', s ali- iR 1„ phatlc; ol'0000] two R'roups are optionally taken together with their intcrvcning atoms lo form a 5-8 mcmbcrcd partially unsaturated fused carbocychc ring; [0010] each of R" is independently hydmgen, halogen, CN. NOS. ('(O)OR, C(O)NRS„NRC. NRC (O)R, NRC(O)OR, NRS(O),R, ~R, P(O)R,. SR, S(O)R, S(O) R. S(O)(NH)R, or R, or or a pharmaceutically acceptable salt thereof. wherein each [0011] two R'roups are optionally taken together to variable is as defined and described herein foml 0;

[0004] Compounds of the present invention. and phamla- [0012] each R's mdcPmxicntly hydrogen or C, 1 dli- ceuucally acceptable compositions thereof, are useful for phatlC; ol" trentmg d vanety of prolili:rauvc disorders (O.g., cancer) as [0013] two R'roups arc optionally takml togcthcr to described herein lilnn 0, [0014] two R'roups arc optionally taken together io DI!'I'AII Ol'I!R'IAIN I!D l)JiS('RIP!'ION foml ~Hi, I:MI3ODIM!1N'IS [0015] two R'roups are optionally taken together with their ultervemng atoms io filnn a 5-8 mmnbcrcd satu- I (ieneral Descnption of ('ertain I'.mbodiments of rated spirocychc ring 0-2 hcteroatonm indcpcn- the Invention haling dently selected from nitrogen, oxygen or sulfur; or [0005] It has bccn found thai the compounds ofthc present [0016] two R groups dre optionally iakcn iogcthcr widl invention, or salts ihcrcol: exhibit pronounced eilicacy ln their ultcrvcnulg atoms to form a 5-8 mcmbercd satu- nniltiple cell-hne-derived and patient-derived xenograft rated bridged bicyclic rin having 0-2 heteroatoms nlodels. Ilor example, the compounds of the invention. or independently selected front nitrogen. oxygen or sulfur; US 20]9/032265[] A] Oct. 24, 2019

[0017] each R is independently hydrogen or an optionally (O)R, NRC(O)OR, NRS(0)»R, OR, P(O)R„ subsiiluled group selected from C, r al&phatm. a 3-8 SR, S(O)R, S(O)»R. S(O)(NH)R. S(O),NR„ membered saturated or part&ally unsaturated monocyclic or R; or carbocyclic ring, phenyl. a 7-10 me&nbered saturated [0028J nvo R groups are optionally taken together to spirobicyciic heterocyclic ring having 1-2 heteroatoms fom& 0: nr independently selected from nitrogen. oxygen, or sulhir. a [0029] two R» groups are optionally taken together with 7-10 menibered saturated or partially uosnturated fused their intervenin atoms to form a 3-8 membered satu- bicyclic heterocyclic rin having 1-2 heteroatoms inde- rated spirocyclic ring having 0-2 hetematoms indepen- pendently selcclcd from nnrogcn, oxygen, or sulfur. a 4-8 ilenil)'clccu:d Iron& 11&lri&gcn, oxvgcn or sulful, membered saturated or parually unsaturated mo&x&cyclic [0030] each R is uidcpcndcntly hydrogm&. OH, or C, s betemcyclic ring having 1-2 heteroatoms independently aliphatic; or selected tn&nl n&trogen, oxygen. or sulfur, or a 5-6 mens- [003)J nvo Rs groups are optionally taken together to bered monocyclic heteroaromatic ring having 1-4 het- foml ~; or eroatoms independently selected from nitro en. oxygen, [0032] two R'oops are optionally tal en together to or sulhir: or: foml ~H,; or [0018] lwo R groups on thc same nitrogen are option- [0033] two R'roups are optionally iakcn iogcthcr w&dl ally taken together with their intervening atoms to forni their uitcrvcnuig atoms to form a 3-8 mcmbercd saiu- a 4-7 membered saturated, partially unsaturated, or mated spirocyclic ring having 0-2 heteroatoms indepen- heteroaryl ring bavin 0-3 heteroatoms. in addition to dently selected from nitrogen, oxygen or sulfur; or the nitro en. Independently selected from nitrogen, [0034] nvo R groups are optionally taken together ivith oxygml and su)i'ur, optionally subs(iiutcd w&th 1-2 oxo their intervenin atoms to form a 5-8 membered satu- groups: rated bridged bicyclic ring having 0-2 heteroatoms iudc7&endently s elec lcd Ibom nitrogen. oxygen or sulfur. [0019] X is 0 . N(R), N(S(O)»(R)) . S [0035] each R &s indc7&Ogden&ly hydrogen or an optionally S(O) . S(O), . CH,, CH(R ), or M(R')» substituted group selected from (', i ahphatic. a 3-8 niembered saturated or partially unsaturated monocyclic [0020] m is 0. l. or 2; carbocyclic ring, phenyl, a 7-10 membered saturated [WZ)J nis0,1,2,3,4or5;and sp&robicyclic heterocyclic ring hav&ng 1-2 heteroatoms [0022] p is 0, I, or 2. independently selected from nitrogen. oxygen, or sulfur. a 7-10 mcmbcrcx) saturn&cd or partially unsa&ura(cx) fuscx) [0023] In one aspect, the present invention provides a b&cycl&c heterocyclic nng ha& &ng 1-2 hcicroatoms inde- compound of formula 15 pendently selected from nitrogen, oxygen, or sulfur. a 4-8 nlembered saturated or partially unsatum»ted monocyclic heterocyclic ring having 1-2 heteroatonls independently selected from nitrogen, oxygen, or sulfur, or a 5-6 mem- (R & bered monocyclic heteroaromatic rin having 1-4 het- croatonls lndcpcndcnllv sck:cled Iron& nitrogen, oxvgcn, ol'ulful"I CI. (R. &„ [0036J nvo R groups on the same nitrogen are optionally taken together with the&r intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl rin having 0-3 heteroatoms. in addition to the nitrogen. independently selected from nitrogen, oxygen and su)(br, optionally subst&iuicd w&th 1-2 oxo groups; [IN)37J is a single bond or a douhle bond; or a phannaccut&cally accct&(able sali lhereol: wherenu [IN)38J X is 0 . N(R), N(S(O)»(R)) [0024] Rin A is nng selected from phenyl. a 5-7 mem- W'l W'I S(O), S(O)», I» . i(R ), or bered saturated or partially unsaturated carbocyclic ring, C(R )» a 8-12 membered saturated or partially unsaturated b&cy- [0039] m is 0. I. or 2; chc hcierocycl&c ruig havuig 1-2 hetcroaloms uxlepen- [IN)40J nis0,1,2,3,4or5:and dcnlly sclccted from nitrogen. or sulfur, a 5-6 oxygen, [0041] p is 0. I, or 2. membered heteroaromat&c ring having ]-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 2. ('ompounds and Definitions or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, [0042] Compounds of lhc presmlt uivmit&on Include (hose oxygen, or sulh&r: described generally herein. and are further illustmlted by the classes, subciasses, and species disclosed herein As used [WZ5J each R's independently hydrogen. or C, ali- s herein, the following definitions shall apply unless otherwise phatic optionally subst&tuted by 1-6 halogen: or indicated. For purposes of tlfis invention. the chemical [0026[ nvo R'roups are optionally taken together v ith elcmcnts arc ulcnuiied in accordance w &th the Periodic Table their intervening atonls to form a 5-8 membered par- of the Elcmcnls, CAS lars&on. Handbook of Chemistry and tially unsaturated fused carbocyclic ring: Physics, 75" Ed. Addn&o&rally, gmleral pnnc&plea of orga&uc [WZ7J each of R» is independently hydrogen, halogen, chenlistry are described in "Or anic ('hemistry". '(horns» A N, NO», A'(O)OR, C(O)NR», NR». NRC Sorrell, f)niversity Science l)ooks, Sausal&to 1999, and US 20]9/032265[] A[ Oct. 24, 2019 3

"March's Advanced Or anic Chemistry". 5d'd.. Ed Smith, M. B and March, J., Jolm Wiley gt Sons. Ncw York 2001, thc en&ire contmits of wluch are hereby incorporated by reference. [0043J 'I he tenn "aliphatic" or "aliphatic group", as used herein. means a stmight-chain (i e., unbranched) or branched. substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon the& is completely saIuratedorIhat contains onc or morc un&&s of unsa&ural ion, but w luch is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic" or *'cycloalk34"), that has a single point of attaclunent to the rest of the molecule Unless otherwise specified, aliphatic roups contain 1-6 aliphatic carbon atoms. In some embodi- C7 io ments, aliphatic groups contain 1-5 aliphatic carbon atoms. In 0&hcr embodnnmits, al&phone groups contain 1-4 aliphatic Exemplary bridged bicyclics include. carbon a&orna. In sull other cmbodimen&s, aliplri&ic groups contain 1-3 aliphatic carbon atoms. and in yet other embodinients. aliphatic groups contain 1-2 aliphatic carbon atonis. In some embodimentw "cyckialiphatic" (or "carbocycle" or "cycloalkyl**) refers to a monocyclic C UC, hydrocarbon that is completely saturated or that contains one or more umts of unsntura&ion. bu& which Is not aroma1&c. Iha1 has a suiglc pou&1 of at&achmcnt &o thc rcs& ol Ihe molcwulc. Suitable aliphatic groups include, but are not limited to, linear or branched. substituted or unsubstituted alkyl. alkenyl, alky- nyl groups and hybnds thereof such as (cycloalkyl)alkyl, ~&&H ~HH (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. ~ p [0044] As used herein. the term "bicyclic rin "or "bicyclic ring system" refers to any bicyclic ring system, i.e. cdrbocychc or hctcrocycl&c, sa&ura&cxi or having One Or more Ulllm 01 ill&satin'tl&loll. havlllg OUC Or &nolo dtoins ill Coll&i&loll O' betwcmn ihe two nngs ol thc ruig sys&em. Tluis, &he &em& SQ303 includes any permissible ring fusion. such as ortho-hised or spirocyclic As used herein, the term "heterobicyclic" is a subset oi"bicyclic'* that requires that one or more he&eros- &on&a are present in one or both rin s of the bicycle Such t'SS SS hcteroat orna may bc present at ring tune nous imd are Option- ally subs&i&utcd, and may bc sclectcd from nitrogen (uiclud- ing N-oxides), oxygen, sulfur (includuig oxidized fi&rms SO60 such as sulfones and sulfonates), 8 phosphonis (including oxidized ti&rnis such as phosphates), boron, etc. In some embodiments, a bicyclic youp has 7-12 riiig members and SO~- SO~- 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used hcrcin, thc tenn '*bridged bicychc" rei'crs &o any b&cycl&c nng system, i.c. carbocyclm or het- [0045] The remi "lower alkyl" refi:rs to a C, d straigh& or erocyclic. satura&cd or partially unsa&uraIcd. havuig at least branched alkyl group. Exemplary lower alkyl grmips are one bridge. As defined by R)PAC, a "bridge" is an methyl, ethyl, propyl. isopropyl, butyl, isobutyl. and tert- unbranched chain of atoms or an atoin or a valence bond butyl connecting tv,o bridgeheadc, where a "brid ehead** is any [0046] The tenn "lower haloalkyl** refers to a C, d straight skeletal atom of the nng system which is bonded to tl&ree or or branched alkyl group that is substituted with one or more morc sleletal atonw (excluding hydrogen). In some embodi- halogen atonuc ments. a bndged b&cyclm group has 7-12 ruig members and [0047] Thc remi "hctcroatom" means one or more of 0-4 hcicroatoms uidcpenden&ly sclecmd from mtrogcn, oxy- oxygen, sulfur, n&&rogmi, phosplx&rus, or s&l&con (uicluduig. gen, or sulfur Such bridged bicyclic groups are well knov n any oxidixed form of nitmgen. sulfur. phosphon&s, or sili- in the art and include those groups set forth below where ciilu the quatemixed fomi of any basic nitrogen or; a each group is attached to the rest of the molecule at any substitutable nitrogen of a heterocyclic ring. for example N substitutable carbon or nitrogen atom. Unless othe&wise (as ui 3.4-dihydro-2H-pyrrolyl). NH (as in pyrrolidinyl) or specified, a bndgcd b&cychc group is opt&onally subsntutcd NR (as ui ¹Ubstitu&cd pyrrolidinyl)). with onc or morc subsU&ucn&s as sc& forth for aliphatic [0048] The tenn "unsa&urdtcd". as used hcrcin, mctuw tha& groups. Additionully or altemativcly, any substitu&able nitro- d &1&0&Clv hits ill&C Or Inure Ulllm Of Ill&su&U&dt&0&1. ('I en of a brid ed bicyclic group is optionally substituted. [IN)49J As used herein. the term "bivalent s (ol' I s) I ixemplary bicyclic rings include: saturated or unsaturated. strai ht or branched, hydrocarbon US 20]9/0322658 A[ Oct. 24, 2019

chain". refers to bivalent alkylene. all enyiene, nnd all y- hydroquinolinyl, tetrahydroisoquinolinyL and pyrido[2 3- nylcnc chains that arc strmght or branched Bs deiincxl hcrcin. b]-1.4-oxazu1-3[4H)-one. A heteroaryl group may be mono- [0050] The tenn '*alkylene** rcfi:rs to a bivalent alkyl Or btcyclic. Thc tenn "hcteroaryl" may bc used interchange- mup. An "Sikylene chain" is a polymethylene group, I e., ably with the terms "heteroaryl rin," "hetemaryl gmup," or t('I ll)„, wherein n is a positive integer, preferably front "hetemammatic," any of ivhich terms include rings that are I to 6, from I to 4, from I to 3. from I to 2, or from 2 to 3. optionally substituted. The tenn "heteroaralkyl'* refers to an Asubstituted alkylene chain is a polymethyiene group in alkyl group substituted by a heteroaryl„v herein the alkyl lvhich one or more methylene hydrogen atoms are replaced and heteroaryl portions independently are optionally substi- with a substituent. Suitable substltuents uiclude those tuted. dcscnbixi below lor a substttutcx) alipliatlc group. [0056] As usixl hcrcui, the terms '*hcterocyclc,** '*hetcro- [t)t)51] 1 he term "alkenylene" refers to a bivalent alkenyl cyclyl," '*hctcrocychc radical." and "hctcrocychc nng** arc gmnp. A substituted alkenylene chain is a polymethylene used interchangeably and refer to a stable 5- to 7-membered roup containing at least one double bond in which one or monocyciic or 7-10-membered bicyclic heterocyclic moiety more hydro en atoms are replaced with a substinient. Suit- that Is either saturated or partially unsaturated, and having, able substituents include those described below for a sub- in addition to carbon atonls„one or more„preferably one to sututixi Bliphauc group. filur, hctcroatoms, as dcfincxI above. When used ul rcfcrcncc [t)t)52] As used herein. the term "cyclopropylenyl" refers to II Illlg Bttllll Of B 11CICIOCVCIC. IIIC tCml llltrogcil lllCIOIICS to a bivalent cyclopropyl roup of the following, stnicture a substituted nitrogen. As an cxiunplc, in a saturated or partially unsatunsted rinc having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen. the nitrogen nlay be N tas in 3.4-dihydro-ZH-pyrrolyl). NH (as in pyrrolidinyl). or 'NR (as In ¹ubstituted pyrrolidinyl). [0057] A heterocyclic ring can be attached to its pendant groilp Bt Bll)'cu:loatolll ol cillboil Bkllll that lcsulh ill II stable stnicture and Bny of the ring atoms can bc optionally [0053J 'the tenn "halogen" means IL ('I, l3r, or I. substituted. 1!xantples of such saturated or panially unsatu- [0054] The term '*aryl" used alone Or Bs part 01 a larger mated heterocyclic radicals include, without hniitation. tet- moiety as ui "aralkyl." "aralkoxy,** or "aryloxyalkyl." rcfcrs nshydrofuranyl, tetrahydrothiophenyl, pyrmlidinyl, piperidi- to monocyclic or blcyclic nng systems having a total Of live nyl, pyrrolinyL tetrahydroquinolinyl, to fourteen rin menlbers, w:herein at least one ring m the tetrahydroisoquinolinyl, decahydroquinolinyL oxazolidinyl, system is aromatic and wherein each ring in the systenl piperazlnyl, dioxanyl. dioxolmiyl, diazcttutyi, oxazcpmyl,

"het- contains 3 to 7 nng members. The term "aryl" may be used tluazc7tinyl, morpholinyl. and quuluclidinyl. The tcmis erocycle," "heterocyclyl." "heterocyclyl ring," "heterocyclic interchangeably with the temi "aryl ring.*'n certain embodi- radical,*'re IIICIIIS Of thC prcsctlt lllvclltloll. Btyi ICfCI'S to Bll BIOIIIB)IC gmup," "hetemcvclic moiety," and "hetemcvclic rmg system wluch uicludcs, but not lnn«cd to, phenyl, used interchangeably herein, and also include groups in biphcnyl. naphthyl, anthracyl and the hkc, wluch may bear which a heterocyclyl ring is fused to one or more aryl, one or more substituents Also included within the scope of heteroaryl. or cycloaliphatic rings. such as indolinyl, 3H-in- the term "aryi." as it is used herein, is a group in which an dolyl. cluomanyl, phcnantlmduiyl, or tctrahydroquulohnyl. aromatic ring is fused to one or more non-aromatic rings, A hetcrocyclyl group may bc mono- or blcychc. The tenn such as indanyl, phthalimidyl. naphthimidyl. phenanthndi- "hetemcyclyialkyl" refer: to an alkyl group substituted by a nyl, or tctmhydrotraphthyl. mid thc hhc. heterocyclyl, wherein the alkyl and heterocyclyl portions [t)t)55] 1 he terms "hetemaryl" and "heteroar-," used alone independently are optionally substituted or as part of a larger nloiety. eg, "heteroaralkyl." or [0058] As used herein, the temi "partially unsatumsted'* "heteroaralkoxy.** refer to groups having 5 to 10 ring atoms, refers to a ring moiety that includes at least one double or preferably 5, G. or 9 ring atoms; having 6. 10. or 14x tnple bond. The temi "partially unsatumsted** is intended to elec«rona shared ln a cychc array: and having, m addi) ion 10 encompass nngs having multiple sites of unsaturatlon, but ts Calboll Bti1111S. Irolll 011C 10 Ilvc'. 11CICltia)0111S. 111C )Crlll not uitended to include aryl or hctcroaryl molettcs, as herein '*hcteroatom" refi:rs to mtrogen. oxygml, Or sulfur, and dehned includes any oxidized form of nitrogen or sulfur. and any [Ig)59J As described herein, compounds of the invention quaternized form of a basic nitmgen I letenlaryl groups may contain "optionally substituted" moieties In gene«11, include. without limitation, thienyL hiranyl. pyrroiyl. imi- the term "substituted,'* whether preceded by the tenn dazolyl. pyrazolyl. triazolyl. tetmszolyl, oxazolyi. isoxazolyl, "optionally" or not, means that one or more hydrogens ofthe oxadiazolyl. tluazolyl, isotluazolyl, tluadlazolyl. pyndyl, dcstgnatcd moiety arc replaced with a suitable subsutucnt. pyndazuiyl, pyrimidinyl, pyrazlnyl, indohzulyl, puruiyl, Unless Otherwise tndtcatcxI, an '*opuonally substituted" naphthyridinyl, and ptenduiyl. The tcnns '*heteroaryl" and group nuly have a suitable subsutumit at each subsututablc *'heteroar-", as used herein. also include groups in which a posrtlofl Of the gl'Oup, Btld iVIMII IBOIC thatl OIIC posrtli1ll ill heteroaronlatic ring is fused to one or more aryl, cycloali- any given stmcture may be substituted with nlore than one phatic. or heterocyclyl rings, where the radical or point of substituent selected from a specified group, the substituent attaciunent is on the heteroaromatic ring. Nonlimiting may be either the sante or d«ferent at every position. cxiunples uicludc uidolyl, woindolyl, bcnzotlucnyl. bcnzo- Combinations oi'ubstitucnts envisioned by thw uivcntlon furmiyl, dibmlzofuranyl, indazolyl, benzimidazolyl, bcnztlu- are prcfcrably lhosc Ihat result in lhc formation of stable or azolyl. quulolyl, isoquinolyl, culnoluiyL phthalazinyl, qui- chemically fi:Bslble compounds. Thc tenn "stable." as uscx) nazolinyl, quinoxalinyl, 411-quinolizinyl, carbazolyl, herein, refers to compounds that are not substantially altered acridinyl, phenazinyl, phenothiazinyl. phenoxavinyl. tetra- when subjected to conditions to allow filr their production, US 20]9/0322658 A] Oct. 24, 2019

detection. and, in certain embodiments. their recovery. pun- unsubstituted 5-6-membered saturated, partially unsatu- licanon. Snd usc for onc or morc of thc purposes disclosed ra&cd, or aryl nng luiving 0-4 hctcroatoms indcpcndcnlly herc&a. sclectcd from n&trogml, oxygml, or sulfur.

[tlt)6U] I iach optional substituent on a substitutable carbon [t)U63[ When Ra is ('» aliphatic. Ra is optionally substi- is a nuinovalent substituent independently selected fmm tuted with halogen, R, -(haloR ). OH. OR halogen; (CH&)c SR', (CHI)v IOR'; 0(CH,)„ 0(haloR ). CN, C(0)OH, C(0)OR . NH„ — IR . ~ (CH,)„C(0)OR' (CHS)„CH(OR'- ),, NHR, NR I, or NO&. whcrc&n each R &s inde- (CHz)a~SR, (CH&)CSPh, wluch may be subsntutcd pcndcntly sclce&ixl from C, I aliphauc, ~H&ph, ~(CH&) w a 5 6 sa&ura ted unsatura&ed ith R: (CH&)c 0(CH )a, Ph wluch may be subsntutcd m I Ph or mcmbercd part&ally or ('I with R; ~'I I lph. which may be substituted v ith aryl ung having 0-4 heteroatonls independently selected R; (('Ilz)OSO(('Iiz)»-Pyridyl ivhich may be substi- from nitrogen, oxygen. or sulfur. and wherein each R is — nited»ith R -: NO„CN: Nc; (CH.)C,N(R )1, unsubstituted or where preceded by halo is substituted only (CH&)„N(R )C(0)R', N(R'C(S)R ': (('Hz)„ with one or more halo ens. — -&N(R )C(0)NR,, N(R'C(S)NR .. (CH&)OIN [0064] An optional substituent on a subst&tu&able nitrogen ', (R ')C(0)OR N(R ')N(R ')C(0)R, N(R")N is independently R . NR z. W'(0)R', W'(0)OR&, (R ')C(0)NR ',, N(R")N(R'C(0)OR"; (CH,)O,C A'(0)('.(0)R&. A'(0)('I I,('(0)R', S(0)zgt S(0) (0)R: W (S)R '( I lz)u s(l(0)OR '- +(. I lz)o I( (0) SNR& C(S)NR'.. C(NH)NR'„or N(R')S(0),R&; )R; (('ll )u ('(0)0)iR,; (('Ill)c 0('((J)R wherein each R's independently hydrogen, C,, aliphatic, OC(0)(CHz)c ISR SC(S)SR 'CHz)o ISC(0)R OPh. unsubst&tuted 5-6-membered ' unsubstituted or an (CH )O~C(0)NR '(S)NR C(S)SR 'C salura&ixl, partially unsaturated. or aryl nng havul 0-4 (S)SR', (CHS)(, IOC(0)NR 'z C(0)N(OR'1 )R'-, hc&crea&orna uldepcndcntly selectixl Irom n»rogen, oxygen. C(0)C(0)R, C(0)CH&('(0)R: ~(NOR )R or sulfur, or, »vo independent occurrences of R, taken (CH&)c~SSR (CH&)v IS(0) R (CH&)wsS(0) together vith their intervenin atom(s) form an unsubsti- OR''; (Cllz)c OS(0)&R; S(0)CNR; S(0) tuted 3-12-membered saturated, partially unsaturated. or (NR )R: S(0)&N ( (NR 'z)„{('I is)u IS(0)R aryl mono- or bicyclic ring having 0-4 heteroatoms inde- z)R-', N(R-)S(0)&NR „N(R -)S(0),R -: N(OR pendently selected from nitrogen. oxygen, or sulfur, wherein ': C(NH)NR',: P(0)SR P(0)R',: OP(0)R' when R's C I aliphatic, R's optionully subst&tu&cdt w&di '.,: OP(0)(OR )„S&R (C, I strmght or branched alky- halogen, R . -(ImloR ), ~H. OR, 0(lmloR ), lene)0 N(R )„or (C, I s&ra& ht or brmlched alkylmle) W'N, W'(0)OI I, i C(0)OR, NI I,, NIIR C(0)0 N(R ')z. NR „or NOC. wherein each R is independently [0061] Each R - is independently hydrogen, C,, aliphatic, selected from C,~ aliphatic. CIJ,Ph. 0(CH,),»Ph. or a CH Ph„0(CH )c &Pi CH (5 6 Inembered het- 5-6-membered sanuated. partially unsatumted, or aryl ring eroaryl ring). or a 5-6-membered saturated. partially unsatu- having 0-4 heteroatoms independently selected from nitro- ratnl, or aryl mng hav&ng 0-4 hcieroatoms uldcpcndcntly gen, oxygen, or sullur. and whcrcul each R &s unsubsututod sclci'lcd fronl nlnugcn. Cxvgcn, ol s&ill&in on no&wl&hs&end- or whcrc prccixled by halo &s subst&tuted only w&th one or ing the definition above, tv o independent occurrences of more halogens ', R taken together with their intervening atom( ~ ). form a [0065] As used herein, the term "pharmaceutically accept- 3-12-membered saturated. partially unsaturated. or aryl able salt" refers to those salts which are. w&thin the scope of mono- or bicyclic ring having 0-4 heteroatoms indepen- sound medical judgment, suitable for use u& contact w &th thc dentlyselected fmm nitrogen. oxy en. or sulhir. which may t&asues oflumlans mid lower amma la without undue &oxicny. be subsiitu&ed by a d&valcn& substi&uen& on a saturaled carbon irn&al&on. allergic response mid &hc 1&ke, and arc conuncn- atom of R" selcctcd from 0 and S, or c mh R 's surate with a reasonable benetit,'risk ratio Pharmaceutically optionally substituted with a monovalent substituent inde- acceptable salts are well knov n in the art Ilor example, ) pendently selected fmm halogen. (( I lz)„zg, -(halog ), M. Berge et al.. describe pharmaceutically acceptable salts (( I lz)&i 101 1, (( I lz)i, COR, (CI Iz)v ( I l(OR )1, in detail in J. Pharmaceutical Sciences, 1977. 66. 1-19, 0(haloR ). CN„N.„(CHS)o IC(0)R . (('Hz)„ i&corpora&cxt hcrmn by rcfcrcnce. Phannaccuncally acccp&- ,C(0)OH. (CHS)O,C(0)OR . (CH,)C,SR . (('H,) able salts ol'hc cou£s of this &nvcntion ulclude thusc c SH (CH )c &NH (CH )c NHR (CH )„oi'ndcrivcd fronl suitable n&organic rind organic acids and bases. NR, NO„S&R,. OSiR,. ~(0)SR . (C, I Exanlples of pharnlaceutically acceptable, nontoxic acid straight or branched alkylene)('(0)OR, or SSR addition salts are salts of an amino group formed ivith [0062] Each R is independently selected from (', I ali- inorganic acids such as hydrochloric acid. hydrobromic acid, phatic, CH,Ph. 0(CH )c &Ph. or a 5-6-membered satu- phosphoric acid, sulfuric acid and perchloric acid or with ratnl, partially un&atom&cd, or aryl nng havulg 0-4 hctcroa- orgatuc acids such as acetic acid, oxal&c ac&d, male&c acid, toms uldependently sclcctcd I'rom lutrogcn. oxygen, or tartaric acul. c&tnc acid. succuuc ac&d or melon&c ac&d or by sullhr. and whcrcu& each R is unsubstltu&ed or whcrc using o&hcr methods used in &hc art such as &on exchange. preceded by halo is substituted only with one or nlore Other pharmaceutically acceptable salts include adipate, halogens: or wherein an optional substituent on a saturated alginate, ascorbate, aspartate. benxenesulfonate, benzoate, carbon is a divalent substituent independently selected from bisulfate, borate. butyrate. camphomlte„camphorsulfonate, 0, S. NNR"„NNHC(0)R*. NNHC(0)OR', c&trate, cyclopentanepropionate, digluconate, dodecylsul- NNHS(0),R", NR", NOR") ~(C(R: z))z 0 . or fa&c. c&hanesulliirmtc. loons&c, fumaratc. glucohep&onatc, S(C(R"1)), S, or a d&valent subs»tumlt bozu&zid to vlc&- glyccrophosplmtc, glucolratc, hcm&sulfate, hcptanoatc, nal subst&tu&able carbons ol an '*opnoluilly substitu&ed" hcxanoa&c. hydroiodidc, 2-hydroxy-cthancsulfonatc, lacto- mup is ~)(('IV'z)z 10 . wherein each independent bionate, lactate, laurate, Iaulyi sulfate, malate, maleate, occurrence of Ra is selected from hydrogen, 0» aliphatic malonate, methanesulfimate, 2-naphtlmlenesulfimate. Oico- US 20]9/032265[] A] Oct. 24, 2019

tinate, nitrate. oleate. oxalate, palmitate. pamoate. pectlnate, I-S heteroatoms independently selected from nitrogen, persulfate, S-phenylpropionate, phosphate, pivalate. propi- oxvgen, or sulfur; onate, stearate, succinate, sulfate, tartrate, thiocyanate, [0070] each R's independently hydrogen or ali- p-(olucnesulglnatc, undccdnoa(c, valerdtc salts, and the hke. C,, phatlc;

[0066] Salts derived from appropriate bases include alkali ol'0071] (wo R'roups are optionally taken together with metal. dike)inc earth metal, ammoruum imd N (C, dalkyl)d their intervening atoms to form a 5-8 nlembered par- salts. Representative alkali or alkaline earth metal salts tially unsaturated fused carbocyclic ring; lricIUdc sodlUBI, hihlUBI, po(asslunl, calclunl, nlagncsnun, and Ihe like I'urther phmnlaceutically acceptable salts [0072] each ol' is uldepmldcntly hydrogen, halogen. include. Ivhen appropriate, nontoxic anunonium. quaternary CN. NOS. ('(O)OR, C(O)NRS„NRC. NRC anum&nium, and amine cations formed using counterions (O)R, NRC(O)OR, NRS(O)SR, ~R, P(O)R„ such Bs hahde, hydroxnle, carboxylaie. sulfate. phosphate, SR. S(O)R, S(O)IR. S(O)(NH)R, or R; or nitrate, low cralkyl su)fons(c imd aryl sullbllatc. [0073] two R ~Cups arc optionally taken togc(her (o [0067J Unless otheiwise stated, stmcnlres depicted herein form 0; are also meant to include all isomeric (e g., enantiomeric, dli- diastereomeric. Bnd geometric (or coniilrmational)) fomls of [0074] each R's mdcpmx)cntly hydrogen or C, 1 the structure„ for example. the R and S configurations for phatlc; ol" each asynunetnc center, Z and E double bond isomers. and [0075] two R'Cups arc optionally taken togc(her (o Z;md E confonnational isomers. Therefore, sulglc stcrcxt- form 0; chemical isomers as well as cnanuomcnc. dlasicreomenc, and geometric (or conformational) inixtures of the present [0076] two R'Cups arc optionally taken togc(her (o compounds are within the scope of the invention. Unless form CI I,; otherwise stated, all tautomeric forms of the compounds of [0077] two R'roups dre optionally iakcn iogcthcr WIQI the invention are wltlgn the scope of the invention. Addi- their intervening atoms Io foun a 5-8 membered satu- tionally, unless otherwise stated. structures depicted herein 0-2 arc also meant to Include compounds that dill):r only ul the rated spirocyclic ring having hetematoms indepen- presence of one or more lsotoplcally enriched aloms For dently selected from nitrogen, oxygen or sulfur; or example, compounds having the present stnlctures includiag [0078] (wo R'roups are optionally taken together with the replacement of hydmgen by deuterium Or tritium. or the 5-8 "C- their intervening atoms to form a membered satu- repLacement of a carbon by a or '-enriched carbon rated bridged bicyclic ring bavin 0-2 heteroatoms are within the scope of tlgs invention. Such compounds are independently s elec (cd Ibom nitrogen. oxygen or sulfur. useful, for example. as analytical tools, as probes in bio- loglcdl Basal's, or Bs thcrapcUnc II cn(s nl liccolikulce with [0079] each R is independently hydrogen or an optionally ihc plescnt nlvcnilon substituted group selcc(cd from C, I ahplrdtlc, a 3-8 membered saturated or partially unsatumsted monocyclic 7-10 3. Description of Exemplary Embodiments cdrbocychc ring, phenyl, a mmnbercd satura(cd) spirobicyclic hetemcyclic ring having 1-2 heteroatoms [0068] In onc aspcc(, thc prcscnt invention provides a Indcpcndcntly selccicd from nitrogen, oxygen, or sulfur, a compound of fornlula I 7-10 membered saturated or partially unsatmated fused blcyclic heterocyclic ring having 1-2 heteroatoms independently selected front nitrogen, oxygen, or sulhlr. a 4-8 membered saturated or partially unsatumsted monocyclic IR ) hctcmcyclic ring havulg 1-2 hctcroa(orna indcpcndcnily ))IX+ selected from nitrogen. oxygen. or sulfur, or a 5-6 membered monocyclic hetcroaroma(ic nng havulg 1-4 hei- IR. ) eroatoms independently selected from nitrogen. oxygen, or sullur, or. [0(NUJ two lt groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heicroaryl nn havulg 0-3 hetcroatoms, In addition to lhc nlinlgen. Uxlcpcndcntlv'ch:ctcd flout nnlogcn, oxygen and sulfur. optionally substituted with 1-2 oxo or a phannaceutically acceptable salt thereof, wherein: groups; [0069] )ting A is ring selected from phenyl. a 5-7 mens- [IN)81] X is . N(S(O),(lt)) bered saturated or partially unsaturated carbocyclic rin, 0 N(R), S(O) . CH1 . CH(R'), or a 8-12 membered saturated or partially unsaturated blcy- S(O),, C(R clm hetcrocychc nng havulg 1-2 hc(eros(orna lndcpml- )I denily sclcctcd from nltmgcn, oxygen, or sulfur, a 6-6 [0082] m ls 0, I, or 2. nlcnlbcrcil hcicrodlomiltn: ling havnlg 1-4 hciclialtonls [UU83J n is 0, I, 2. 3, 4 or rul and independently selected from nitrogen. Oxygen, or sulfur, or an 8-10 membered bicyclic heteroaroinatic ring. haviag [IN)84J p is 0, I, or 2. US 20]9/032265[] A[ Oct. 24, 2019

[0085] In one aspect, the present invention provides a bicyclic heterocyclic ring having 1-2 heteroatoms inde- compound of formula 11 pmxlcnily selccicd from nitrogen, oxygen, or sull'ur. a 4-8 membcrcd saturated or parually unsaturated monocychc hetemcyclic ring having 1-2 heteroatonis independently selected from nitmgen. oxygen, or sulfur, or a 5-6 mem- ix 1 bered monocyclic heteroaromatic rin having 1-4 heteroatoms independently selected from nitro en. oxygen, or sulfur: or: (x»)„ [0098] two R groups on the same nitmgen are option- dlly'akCII togC(lli I v Itli dll Ir ulti rvi lllllg Iitollls to loilll a 4-7 mcmbcred saturated, partially unsaturatixi, or heicroaryl nn havuig 0-3 hetcroatoms, in addition to the nitmgen, independently selected fmm nitnigen, oxygen and sulfur. optionally substituted with 1-2 oxo groups: or a phamtaceutically acceptable salt thereof. wherein: [UU99J is a single bond or a double bond; [0086J Ring A is nng selected from phenyl, a 5-7 meni- [0 I UUJ X is N(R), N(S(O)»(R)), S bered saturated or partially unsatumted carbocyclic ring, 0, S(O) . S(O),, CH, . CH(R'), or a 8-12 membered saturated or partially unsaturated bicy- C(R'), clic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen. oxy en. or sulfur. a 5-6 [0101] m is 0, I. or 2: membered hctcroaromatic ring havui 1-4 hcteroatonts [0102J nis0,1,2.3,4or5:and uidcpcndmitly sclccted from iuirogen, oxygen, or sulfur, Ol'n 8-10 IIICIIlbel'ed IOCy'CRC betel'rial'OnlatlC I"lllg liavillg [0103J p is 0, I, or 2. 1-5 heteroatoms independently selected from nitrogen, [0104J As defined enerally alxive, is a single oxygen, or sulfur; bond or a double bond. [0087] each R's Indepcndcntly hydrogen, or C, ah- [0105J In sonic enibodinients. is a single bond phatic optionally subsututcd by 1-6 halogen, or In some embodinients, is a double biond. [0088] two R'upsareoptionallytakentogetherv.ith their intervening atoms to form a 5-8 membered par- [01061 In some embodinients. = is selected from tially unsatumted fused carbocyclic rin: those depicted in Tables I, 2. and 2A„below» [0089J each of R» is independently hydrogen, halogen, [0107] As dciincd generally above, Ring A is nng selcctcxi N, NO», A'(O)OR, C(O)NR», NR». NltC A from phenyl, a s-7 membered saturated or partially unsatu- (O)R„NRC(O)OR. NRS(O)»R. OR. P(O)R„ mated carbocyclic ring. a 8-12 niembered saturated or par- SR, S(O)R. S(O)»R, S(O)(NH)R. S(O)»NR„ tially unsatumted bicyclic heterocyclic ring having 1-2 het- or R: or eroatoms independently selected from nitro en. oxy en. or two R are taken to [0090] groups optionally together sulhir. a 5-6 membered heteroammatic ring having 1-4 form 0; or hclcroaloms uidepcndcntly seleclixl lrom nitrogen, oxygen. [0091] iwo R groups arc optionally Iakcn Iogciher wiIh or sulfur, or an 8-10 membcrcd bicychc hcieroaromatic nng 3-8 Iheir intcrvmung atoms io form d membcrcd saIu- havuig 1-5 heicroaioms uidepmidcntly sclectcd from iuiro- rdicd 0-2 Indcpmi- spirocychc ring having hcteroaioms gen, oxygen. Or sulfur. dently selected from nitmgen. oxygen or sulfur: [0092] each R" is independently hydrogen. OH. or C, [01081 In some embodiments, Rin A is phenyl. In some dipl»title. Or embodiments. Ring A is a 5-7 membered saturn»ted or [UU93[ two R groups are optionally taken together to partially unsaturated carbocyclic ring. a 8-12 membered form 0; or saIuraiixl or parually unsaturated bicychc hetcrocychc nng [0094] tvso R'oops are optionally taken together to havuig 1-2 heicroaioms uidepmidcntly sclectcd from iuiro- foun CH„or gen, oxygen, or sulfur. a s-6 menibered heteroanimatic ring, 1-4 nitro- [0095] two R» mupsareoptionallytakentogetherv.ith having heteroatoms independently selected from 8-10 their intervening atoms to form a 3-8 membered satu- gen, oxy en. or sulfur. or an membered bicyclic 1-5 rated spirocyclic ring having 0-2 heteroatoms indepen- heteroaromatic ring having heteroatoms independently dently sclccicd lbom nitmgcn, oxygmi or sulfur: or selected from nitrogen, oxygen„or sulfur. [0096] two Rs groups are optionally taken together v ith [0109] In some cmbodimmits. Rin A is a 5-7 mcmbcrcd their intervening atoms to form a 5-8 membered satu- saIuraiixl or partially unsaturated carbocychc ring. In some rated bridged bicyclic ring having 0-2 heteroatoms embodiments, Ring A is a 8-12 nienibered satmated or independently selected from nitrogen, oxygen or sulfur, partially unsaturated bicyclic heterocyclic ring having 1-2 [0097] each R is independently hydrogen or an optionally heteroatoms independently selected fmm nitmgen, oxygen, substituted gmup selected from C,, aliphatic. a 3-8 or sulfur. In some embodiments. Ring A is a 5-6 membered membered saturated or partially unsaturated monocyclic hcicroaromaiic ring havuig 1-4 lu:tcroaioms indcpcndcntly carbocyclic ring, phenyl, a 7-10 membcrcd saturated sclectcd from nitrogen, oxygen. or sulfur. In some embodi- spirobmyclic hctcrocychc nng havuig 1-2 hetcroatotns ments, Ring A is an 8-10 membered bicychc hcteroaromatic independently selected from nitmgen. oxygen, or sulfur. a ring having 1-5 heteroatonis independently selected from 7-10 membered saturated or partially unsaturated fused Illti'Ogefl, (ixygeii i»i'lllfiu'. US 20]9/0322658 A[ Oct. 24, 2019

[0110] In some embodiments, Ring rt is phenyl or -colttlltllixl

L[&

wherein Rtng B is 5-7 membered partially unsaturated heterocyclic ung havutg 1-2 hetcmatonm utdependently selected from nttrogen, oxygen, or sulfur, or iting ll is b-g membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur In some embodiments. Ring B is selected from:

I-D) 'yi'0112]

In some embodiments„Rtng A is

In sonte embodiments, Ring B is

[0113] In some embodiments„Rtng A is

[0114] In some embodiments, Ring rtc is selected from

[ill 1 1] In sonte entbodiments. Ring .sr is selected from US 20]9/0322658 A] Oct. 24, 2019

-connnuml ]0118] In some embodiments, Ring A is selected front:

[0115] Ilt soirlc cillbodtnlcltts, Rlllg A Is &pl )- u

[0116] In some cmbodtmcnts, Rutg A ts selected from. [0119] In some cmbudnnents, Rin A ts C

Light [0120] In some embodiments. Ring A ts selcctcd from.

[0117] In some cmbodunents, Rutg A ts US 20 1 9/032265 JJ AJ Oct. 24, 2019 10

-conunuml -contrnucsl

NH HN

NH .)

:u I

J01221 In some embodiments. Ring A is selected from IIN ill

HN „)

Int

J01211 In some embodiments, Ring A is selected from:

Jl)1241 In some entbodiments. Ring A is selected from HN US 20 ] 9/032265 [] A[ Oct. 24, 2019

-continued v hich can aiso be in the tautomeric form:

iuz1

0 [0128] In some embodiments, Ring A is selected from those depicted in I'shies I and 2. below. [t)129J In sonic embodiments, Rmg A is selected from those depicted ui Table 2A, below. [0130] As dclincsI gcncrally above, each R's independently hydrogen or C, aliphatic: or two R'roups are HH optionally taken together with their intervening atoms to form a 5-8 membered pauially unsaturated fused carbocy- t(st clic ring. [0131] In some cmbodimmits. R's hydrogen. In some mubodunents, R's C, aliphatm. In some embodiments. :) two R'roups are optionally taken together with their 5-8 0 intervening atoms to form a membered partially unsatu- mated fused carbocyclic ring 0 [t)132J In some embodiment~. R's niethyl in some mubodunents, R's cshyl. In some embodiments, R's propyl In some cmbodimcnts, R's isopropyl. [0133] In some embodiments, R's attached to position 5 of the pyrimidine. In some embodiments, R's attached to position 6 of the pyrimidine. [t)134J In some enibodinients. two R'roups are optionally taken together v, ith their uitcrvm»ng atoms to lbrm a 5-8 [0125] In some cmbodimcuts, Ring A is membered parually unsatumtcd fused carbocychc ung. In some embodiments. nvo R'roups are optionally taken together with their intervening atoms to form a 5 membered partially unsaturated fused carbocyclic ring In soine embodinients, tsvo R'roups are optionally taken together

with their intcrvciung atoms to fonu a 6 mcmbcred partially

uusatuuttcd fuscsi carbocyclic ung. In some cmboduucnts,

two R'roups are optionally taken together with their 01'0126] intervening atoms to Ibnn a 7 membered parually unsaturated fused carbocyclic nng. In some mnboduncnts, two R'roups arc optionally Liken together with their intcrvciung In some cmbodimcuts, Ring A is atonis to ferns a 8 membered partially unsaturated fused carbocyclic ring [0135] In some embodiments, R's C, s aliphatic optionally substituted 1-6 times by halogen. In some embodiments, R's C, alkyl optionally substituted 1-6 tunes by halogen. In some cmbodimcnts. R's C, i alkyl optionally substttutcsl 1-6 umes by lluoridc. In some embodiments. R's C,, alkyl optionally substituted 1-3 times by iluoude In some embodinients, R's ~'I'z [0136] In some embodiments„R's selected from those depicted in Tabies I and 2, below. one is I. and R ~)I [0137] In some cmbodimmits, R's sclectcd lyom those dc7uctcd in Table 2A. below. [0127] [0138] As delincd generally above, each of R w indcpcn- dently hydrogen, halo en (I'. ('I, l3r, or I), ~'N. NO„ HO W'(O)OR, W'(O)NRz. NRz, NR('(O)R, NR( (0) OR. NRS(O),R, OR. P(O)Rz. SR, S(O)R, 15 (ttz)„ a S(OHR, S(O)(NH)R, or R: or two R groups are optionally taken together to Ibnn ~. [0139] In some cmbodimmits. R is hydrogen. In some embodiments, each of R is uidependcntly halogen. CN, NOz, ~'(O)OR, i C(O)NRz, NRz, NR('(O)R, NR(l(O)OR NRS(O)zR'R'(O)Rz'R' US 20 ] 9/032265 [] A[ Oct. 24, 2019 12

S(O)R„S(O)nR, S(O)(NH)R, or R; or uvo R groups -cottlttttlixl arc optionally taken logcllmr lo form O. [0140] In some embodunents. R's halogen. In some entbodiments. R's Cl. In some embodiments. R's CN. In some cmbodtmcnts, R' NOn. In some embodtmmtts, R ts C(O)OR. Iu some cmbodunents. R's ~(O)NRa. in some embodiments, R is Ngo. In sotne embodiments, lt is NR( (O)R In some embodiments, R is Nitg(O) OR In some entbodintents. R is NRS(O)alt in some embodiments, R's independently OR. In some embodiments, R is P(O)Re. In some embodiments. R's SR. In some mnboduncnls, R's S(O)R. In some mnbodt- mcnts. R is S(O)eR. Iu some cmbuduncnts, R is S(O) (Nil)R In some embodiments, R's 8 ln some embodintents. tv o It groups are optionally taken together to ferne 0 [0141] In some cmboduueuls, R is S(O)eNRa. In some embodiments, 8 is )(O)nNI In [0142] In some cmbodunculs, R ts C, r aliphatic. In some cmbodimcnts. R' a 8-8 membered saturated monocyclic carbocyclic ring In sense embodiments, R is a 7-10 mentbered saturated spirobicyclic hetemcyclic ring having 1-2 heteroatoms independently selected from nitrogen. oxygen, or sulfur. In some embodiment~, R's a 7-10 membered saturated fused bicyclic heterocyclic ring haviltg 1-2 hetcroaloms utdependenlly scltulcd from mtrogcn, oxygmt. or sullhr. In some embodtmcuts. R ts a 4-8 membered saturated ntonocyclic heterocyclic ring having 1-2 heteroatoms ,,i.k y,j, independently selected from nitrogen, oxygen, or sulfur In some entbodiments. R's a 5-0 membered monocyclic heteroaromatic ring bavin 1-4 heteroatoms independently selected from nitmgen. oxygen. or sulfur. ,.JL.',J [11141] In some enlbodintents. each R i ~ $ of independently selected from

— — — halogen lo e, CH NH . CHa Cga Yw tl~ /t'.,JL,

S —, — t'H CHn

0 ):.l]

@'~Vv ='-

o~ /t'.NJL US 2019/0322658 A1 Oct. 24, 2019 13

-00111111111:Tt

O.,

01T F

0 0 (TTT 0

v-~-- ~) TT V~.

HO OH

HO US 2019/0322658 A[ Oct. 24, 2019 14

[((144[ In snme entbodiments. R is selected from 5(0) zNHz, OCHFz. OCF,. C—=CH. 0

('"t CHz —c=('H, p 0

V [[ Y~

V~ [0145[ In some embodintents. Rz is C» aliphattc. optionally substituted 1-4 nmcs by ha)ogcn, ~H, NH„~CHn NII( (0)( I la 510)z( I Iz ol N1( I Iz)( (0)( I Is Ilt some cmbodimcnts, R ts selected from CHo ~Fz. &1lzCI Is,

Q 0

0 8~¹ US 20]9/0322658 A] Oct. 24, 2019 15

[0146] In some embodunents, R is C«aliphatic. optionally substituted 1-4 times by halogen, ~)I I, Ni la, ~)CI ls, NHC(O)Citu S(O)zCH,. COOH, COzCH, or In some embodunents, R'sCOzCzH,, N(CHz)C(O)CHv

[0151] In some embodiments„R's a 7-10 membered R's saturattxl fused btcycltc hcterocycltc ring havtng 1-2 het- [0147] In some embodunents, Cu & aliphatic. option- eroatoms independently selected from or ally substituted by a S(O)z (CH,)o s group, whereat nttrogen oxygen In some embodiments, R ts (('I Iz)e»s is optionally substituted 1-4 titnes by halogen, OH. NH„or OCHv In some embodiments, R" is C« aliphatic, opttonally substituted by a S(O)z (Cllz)o s group, vvherein (CHz)e s ts tlnsubstituted. In some embodintents. R is (', r aliphattc. optionally substituted by S(O) CH, or S(O), CH, CH, In some embodiments. R is C, s altphatic, opuonally substttutcdby S(O)z~H,. In some embodiments. R's CHz S(O)z CH,. In some cmbodimcnts. R's ~Hz S(O)z CHz CHv In some embodiments, Rz is W'Hz Cl lz S(O)zi CH, In some [0152] In some embodiments. R is a 4-6 membered mnbotlimcnts, R is S(O)z CHz CHz. In MHzMHz saturated monocyclic heterocyclic ring havmg 1-2 heteroa- some entbodiments. Rz ts selected fmm toms independently selected from nitrogen. oxygen, or sul- litr, opttotrally substituted 1-4 ttmcs by halogen, OH, CH,. OCH,. 0, or

0 o ssu S—

0 0 In sonte embodiments. R is selected front

[0148] In some embodiment~, R's unsubstituted C« aliphatic. In some cmbodtmcnts, R's ~=— CH. [0149] In some embodtments, R is a 3-6 membered saturau 0 monocyclic carbocychc ring. In some embodtments. Rz is

[0150] In some cmbodunents, R ts a 7-10 membered saturated spirobicyclic heterocyclic ring bavin 1-2 heteroatoms utdependently selected from nitmgcn or oxygen. In some entbodiments. Rz ts selected fmm US 20]9/032265[] A[ Oct. 24, 2019

continued [0154] In some embodiments. R is a 5-6 membered monocyclic hctcrouromanc nng having 1-2 hcteroatoms independently sclcctcd from rutrogcn, oxygen, or sull'ur. In D some embodiments, Rs is selected from H

[0155] In some embodiments. R ts C(O)OR, wherein R is hydmgen or ('„ i aliphatic ln some embodimentg R's i W'(O)OI I In some embodiments, R's O(O)O(,, ali- plmtic, wherein the C, s aliphatic is unsubstituted. In some embodiments. R's

[0153] In some mnbodimcnts, R's a 4-6 mcmbcred saturated ntonocyclic heterocyclic ring having 1-2 heteroatoms independently selected fntm nitrogen, oxygen. or sulfur, optionally substituted 1-4 times by halogen. OH, CH,. OCHv O. In some embodiments. R's

ln some embodiments, R is selected from [0156] In some cmbodmtents, R m ~(O)NRc, wherein each of R ts independently hydrogen, C, r ahphattc wluch ts optionally substituted by a N(CH,)s, unsubstitutcd 3-6 mentbered saturated monocyclic carbocyclic nng, or unsubstituted 4-6 mentbered saturated ntonocyclic heterocyclic ring bavin 1-2 heteroatorns independently selected from nitrogen or oxy en, or two R taken together with their intcrvmung atoms to lbrm a 4-7 mcmbcrcd saturated and umubstitutcd hcteroaryl rutg. In some mnbodiments. R ts sch:ctcd flolll US 20]9/0322658 A[ Oct. 24, 2019 [7

conunuixl [0164] In some embodinients. R's selected from

[0157] In some embodunents, Rz is C(O)NR&. w:herein tw o R taken togcthcr w &th thc&r uitcrvcmng atoms to fi&rm a 4-7 membered saturated rin having 0-3 heteroatoms. in aildiiion to the n&trogm», ndependently selected from n&tro- en, oxygen and sulfur. optionally substituted with 1-2 oxo groups. In some embod&mm&ts, R &s ~(O)NR&, where&n two R taken together with their intervening atoms to foun a 4-7 membered saturated and unsubstituted ring having 0-3 heteroatoms, &n addit&on to the nitrogen, independently selected from nitrogen. oxygen and sulfur. In some embodi- 2 ments. R &s

0 D +i&

[0158] In some embodiments. R's NR„wherein each ol' is uidcpmulcntly: [0159] hydrogen:

&s 1-2 [0160] C, & al&phat&c wh&ch optionally subst&tuted times by OH,

~@M ~a [IH651 In some embodiments, R is NI IC(O)R, wherein 1-3 R is C, &, al&phatic opuonally subsututed times by halogen, OCH„N(CH&)z, or ~H, 3-6 mcmbcrod saturated monocyclic carbocyclic ring opt&onally substituted [t)161] unsubstituted 3-6 membered saturated monocyclic 1-2 times by halogen or OH. or 4-6 membered saturated monocyclic heterocyclic ring bavin 1-2 heteroatoms inde- carbocyclic nn „ pendently selected from nitrogen, oxygen or sulfur option- [t)162] 4-6 membered saturated monocyclic heterocyclic ally substituted 1-2 umcs by halogen, OH, or ~H&. In ring having 1-2 heteroatoms independently selected from some embodiments, Rz is selected from &utrogcn or oxygen, wluch &s optionally substituted 1-2 tunes by CH&. OH. C(O)OC(CH,),. or C(O)CH,: or [0163] 6 membered monocycl&c hetcmaromatic ring bavin 1-2 heteroatoms independently selected from nitrogen, oxygen. or sulfur wh&ch is opuonally subst&tuted 1-2 tunes VJ( VJ[ by ~'l l, or Nl lz. US 20]9/0322658 A[ Och 24, 2019 18

In some embodiments. R is selected from Y~ Y[f V~

[0167[ In some embodiments. Rz is NHC(O)OR, v herein R is unsubstituted C,, aliphatic. In some embodiments. R is

[l)160] In some embodintents, R's Nl lb(O)zR, svherein R is tutsubstituted ('. s aliphatic In sense embodiments. Rz is

o s 0

[0169] In some embodintents. R is OR. svherein R is H; Cz s aliphatic op nonally substituted by a halogen. OH,

[0166] In some embodtmcnts, R ts NHC(O)R, vsheretn

R is (',, altphatic optionally substituted l-g times by lutlogen. ~CHo N(CH,)„or ~H. In some embodt- or 4-6 membered saturated monocyclic heterocyclic ring ntents. C, s aliphatic is a straight-chain (i e., unbranched) ot'ranched. having 1-2 heteroatonts independently selected from nitnz- subsututed or unsubstituted saturated hydrocar- gen or oxygen. In some embodiments„R's selected from bon chain In some embodiments, Cz s aliphatic is a stramht- OH. chain (i.e.. unbranched) or bmnched, substituted or unsubstituted hydrocarbon chain comprising a nxmocyclic hydrocarbon. In some embodiments, C,, aliphattc ts selected front yy

G US 20]9/0322658 A[ Oct. 24, 2019 19

coltthtlnxl

[0172] In some embndiments, Rz is OR, wherein R is unsubstituted C, s aliphatic. In some embodintents, R is WW('I lzi C=CI I 0 otr [0173J In some embodintents, R's P[O)R„wherein each of R is independently unsubstituted ('» aliphatic. In some embodimetus, Rz is

[0170] In some embodiments. R's OR, wherein R is (', „nliphatic optionally substituted by a halogen, OH.

Suz [0174] In some entbodintents. R is SR, wherein R is 0 unsubstituted C» aliphatic. In some embodiments, R's

( [O)NI I( i saliphatic, ('OOI I. ~ [O)OC, zaliphatic, ( N SOz( i saliphatic. or

[0175J In snme embodiments, R is S[O)R. wherein R is unsubstinrted ( i i aliphatic. In snme embodintents, R's (.)

10171] In some embodiments. Rz is selected from [0176] In some embodintents. R's S[O)zR, where R is unsubstituted C«aliphatic or 3-6 membered saturated monocyclic carbocyclic rutg. In some cmbodunents, R's sch:ctcd flolll

[0177J In sonic mnbodiments. R is S[O)[NI I)R, wherein R is tutsubstituted ('. s aliphatic In sense embodimentg R is

[0178] In some cmbodnnents. R is a group tlmt incrcascs hydroplulicity. In some emboduneuts, R is selected from the group consisting of NOz. ('10)OR, ~'10)NRz, NRz, NR('10)R, NR( [O)OR, NRS[O)zR, OR, US 2019/0322658 A1 Oct. 24, 2019 20

P(O)R„SR. S(O)R, S(O)sR, S(O)(NH)R, or a ( „s aliphattc group wheretn one or more tnethylene unit ts repLaced by C(O) . S(O), S(O), . P(O) . or P(O)s . In some embodiments, R ts a C, r aliphatic roup wherein one or more methylene unit is repLsced by C(O) . S(O), S(O)s, P(O), or P(O)s ln some embodtments, lts is a C, s aliphatic group wherein one or more methylene umt is replaced by S(O)s In some embodiments, R's selected form the group consisting of

In some embodiments. R's selected from the group con- smttng of

In some cmbodtments, R" ts selected from thc grmtp con- sisttng of US 20 ] 9/032265 [] A] Oct. 24, 2019 21

to ether with their intervening atoms to form a 3-8 membered saturated splrocyclic carbocychc nng. In some embodiments, lwo R groups arc optionally taken together with their intervening, atoms to form a 3-nlenlbered saturated spirocyclic carbocyclic rin . In sonle emlxldinlents, two Rs groups are optionally taken together with their intervening atoms to form a 4-, 6-. or 6-membered saturated spirocyclic carbocyclic ring. [0180] In some embodiments„ two R'roups are attached at the same position. In some embodiments, two R'roups are attached lo a carbon atom. In some mnboduncnts, each In some embodunents, R's selected from the group con- oftwo R groups attached to a carbon atom l ~ indcpcndcntly sisting of an optionally subsututcd C, r ahplratlc group. as descrtbcx) herein. In some embodiments, each of two R gmups attached to a carbon atom is independently unsubstituted Cl r aliphatic. In some enlbodinlents. each oftv o R'roups attached to a carbon atom is independently unsubstituted C,, all yl. In some enlbodinlents. each of tv o R groups attached lo a carbon atom is methyl. [0181] In some embodiments, R is selected from those dcpictcd in Tables I mid 2, below. [0182] In some embodiments„R's selected from those depicted in Tabie 2A. below. [0183] As defined generally above. each Rs is independently hydrogen or C, aliphatic: or: In some embodlmcnts. R w [0184J hvo Rs groups are optionally taken together to foml 0; [0NgJ hvo Rs groups are optionally taken together to form CI Is; [0186[ hvo R groups are optionally taken together lvith their intervening atoms to form a 5-8 membered satu- mated spirocyclic ring having 0-2 heteroatoms indepen- R's dently seiected front nitrogen. oxygen or sulfur: or In some embodnuents. [0 N7J hvo R groups are optionally taken together svith their intervening atonls to filrm a 5-8 membered saturated bridged bicyclic ring bavin 0-2 heteroatoms independently selected from nitmgen. oxygen or suit'ur. [0188] In some embodiments. Rs is hydmgen. In some embodiments. R's C, s aliphatict or: [0N9J hvo Rs groups are optionally taken together to foml ~; In some enlbodinlents. Rs is [0190] hvo R'oops are optionally tal en together to foml ~H,; [0191] two R'roups are optionally taken togcthcr wldl their ultcrvcnulg atoms to form a 5-8 mcmbercd saturated spirocychc ring luh ing 0-2 lmtcroatoms independently selected from nitrogen, oxygen or sulfur; or 0 [0192J hvo R groups are optionally taken together lvith their intervenin atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms In some embodnuents. R ls independently selected from nitmgen, oxy en or sulfur. [0193] In some cmbodmlents. R's C» ahphatlc. In some mubodunents, lw o R groups arc optionully taken togcthcr to filrm O. In some cmbotlimcnts, two Rs groups are optionally taken together to form ('ill In some embodiments, two Rs groups are optionally taken together with their intervening atoms to foml a 5-8 membered saturated spirocychc ring having 0-2 heteroatoms independently selected [0179] In some mnboduncnts, two R" groups arc option- from nltrogcn, oxygen or sullhr. In some cmboduucnls, two ally la 1 en together w lib (herr intcrvcmng atoms to lonn a 3-8 R groups are opuonally takml together with (herr uuerven- membered saturuted splrocychc ring havulg 0-2 hetcroatonw iug atoms lo foml a 5-8 membered saturated budged blcy- independently selected from nitrogen. oxygen or sulfur In clic ring having 1-2 heteroatoms independently selected some embodinlents, hvo R groups are optionally taken from nitrogen, oxygen or sulfilr US 20]9/032265[] A[ Oct. 24, 2019 22

[0194] In some embodiment~, R's methyl. In some embodiments. two R'coups are optionally taken together cmbodimcnts. R's ethyl. In some embodiments. R's w&1h their intcrvcnuig atoms to form u 3-mcmbcred sahiratcxi propyl. In some embodiments, R's isopropyl. spirocyclic carbocyclic rmg. [0195] In some embodiments, two R'roups are option- [0199] In some cmbodimmits, R's sclectcd lbom those dc7&tctcd I mid ally taken together with their intervening atoms to form a 5 in Tables 2, below. membered saturated spirocychc ring havuig 0-2 hcteroatonw [0200] In some embodiments, R" is selected from those independently sclccted lbom nitrogen. oxygmi or sulfur. In dcpictcd in Table 2A. below. sonic embodiments, hvo lt'roups are optionally taken [0201] As defined generally above. each R is indepen- together with their intervening atoms to fonu a 5 membered dently hydrogen or an optionally substituted group selected saturated spirocyclic ring having 0-2 oxygen atoms. In some from C, s slip!attic, a 3-S membered saturated Or partially embodiments, hi o R'&soups are optionally mken together unsaturated monocychc carbocyclic nng, phenyl, a 7-10 'ivith their lntcrvcnillg aitolus to foml menibered saturated spirobicychc heterocyclic ring having 1-2 heteroatoins independently selected from nitrogen, Oxy- gen, or sulhir, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected fmm nitmgen, oxygen, or sUlfUr, a 4-S membcrcd saturated or partially unsahiraied Q 1-2 monocyclic hctcrocychc ruig having hctcroatoms independently selected from nitmgen. Oxygen, or sulfur. or a 5-6 wiuch fonna a spirocychc ring on thc carbon atom at menibered monocyclic hetemaromatic ring having 1-4 het- position 2. eroatoms independently selected fmm nitrogen. oxygen. or sulhir: or: two R gh&ups on the same nitrogen are optionally [0196] In some embodiment~, two R'oups are option- taken together v,ith their intervenin atoms to form a 4-7 ally tel en w 1 th their intcrvcmng atoms 10 lonn a 5-8 together membered saturated, partially unsaturated, or hctcroaryl nng n&cmbcrcd saturated bndgcd bicyclic ruig having 1-2 het- havuig 0-3 hetcroatoms, in;uldition to thc rutrogcn, inde- croatonis lndcpcndcntly'clcctix! fIi&01 nitrogen and oxvgcll.

pendently selected from nitrogen. Oxygen and sulfur, option- In some embodiments, two R'mups are optionally taken ally substituted ivith 1-2 oxo groups together ivith their intervening atoms to form a saturated bridged bicyclic ring having 1-2 nitrogen atoms. ~ herein the [t)202J In some enibodiments. R is hydrogen In soine embodiments. each R is independently an optionally sub- saturated bridged bicyclic rin comprises a di membered ring R'rollps stituted group selected front Ci aliphatic, a3-8 membered and a 7 membered rin . In some embodiments, two s together with saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 7-10 n&cmbcrcd saturated spirobicyclic heterocyclic ring having 1-2 lu:tcroutoms indcpcndcnily selected from nitrogen. oxygen. or sulfur. a 7-10 niembered saturated or partially unsaturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen. oxygen. or sulfur„a 4-8 membered satumted or partially unsaturated monocyclic hetemcyclic ring having 1-2 bc!eros!orna uidcpcndcntly selcctcd from nitrogen, oxygen, or sulfur, or a 5-6 membered monocychc hctcroaromatic nng having ! -4 hetematonis independently selected optionally form from nitrogen, oxygen, or sulfur; or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated. partially unsaturated. or heteroaryl ring having 0-3 heteroatoms, in addi1&on to the nitrogen. independently sclectcd from nitrogen, oxygen and sulibr, optionally substituted with 1-2 oxo gmups [t)2()3J In some embodiments, R is an optionally substi- hited (.', s aliphatic In some embodinients. R is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic rin . In some embodiments. R In some enibodiments. R's I [0197J Oi is an optionally subshtutcd phmiyl. In some mnboduuents. R [0198] In some mnboduncnts, two R'roups are option- is mi optiormlly substituted 7-10 mmnbercd saturated spiro- ally Liken together with their intervenuig atoms to forms 3-8 bicyclic heterocyclic ring having ! -2 hetcroatoms indcpcn- membered saturated spirocychc ring having 0-2 heteroatoms dently selected from nitro en, Oxygen, or sulfur ln soine independently selected from nitrogen. oxygen or sulfur In embodiments, R is an optionally substituted 7-10 membered some embodunents, two R'oups are optionally taken saturated or partially unsaturated fused bicyclic heterocyclic to ether with their intervening atoms to fohn a 3- or ring bavin 1-2 heteroatotns independently selected from 4-mcmberix! saturuted spirocyclic rm havmg 0-2 heteroa- nitrogen, oxygen. or sulfur. In some embodimmits. R is an toms uidependently selixtcd I'rom nitrogen, oxygen or sul- optionally substihitcsl 4-S mmnbcrcd saturated or parhally fur. In some cmboihmcnts, two Rs groups arc optionally unsatunttcd monocyclic heterocyclic nng lraving 1-2 hct- taken together with their intervening atoms to ti&rm a 3- or eroatoms independently selected fmm nitrogen. oxygen. or 4-membered saturated spirocyclic carbocyclic ring. In some sulfur. In some embodiments. R is an optionally substituted US 20]9/032265[] A[ Oct. 24, 2019 23

5-6 membered monocyclic heteroaromatic ring bavin 1-4 [02Z3] In some embodiments, the present invention pro- hetcroaioms uldependently sclcctcd form nilrogen, oxygen, vides a compound of Formulae I-a or I-b: or sulfur. In some cmbodunents, two R roups on the same nitmgen are optionally taken together with their interveniag atoms to form a 1-7 membered saturated, partially unsatu- Is rated, or heteroaryl ring havmg 0-3 heteroatoms. in addition (R'.„ to the nitrogen, independently selected tbom nitrogen. oxy- II.S)g gen and sulfur. optionally substituted lvith 1-2 oxo groups. [0204] In some embodunents, R is selected from those IR1) dcpimcd in Tables I and 2, below. [0205] In some embodunents, R is selected from those dcpimcd in Table 2A, below. [0206] As defined generally above. X is 0 N(R) . N(S(O),(R)), S . S(O), S(O), CHS, CH(R'), or ~(RS)

[0207] In some embodiments. X is 0 . In some mubodimcnts, X is N(R~. In some embodiments, X is N(S(O),(R)) In sonic embodiments, X i ~ S. In some embodiments, X is S(O) In come einbodiments, X ic

S(O), . In some embodiments. X is CH, . In sotne embodiments, X is CH(R') . In come embodiments, X is M(R')s [0208] In some embodiments, X is N(S(O)s(R)) whcrcul R is C, s aliphatic In some embodiments, X is N(S(O)1CH1) In some cmbodnuenis. X is ~H or a plmrmaceutically acceptable salt thereof, wherein each (Rl), whercul R is C, i aliphatic. In some emboduncnis, of Ring A, IH, R', R', R. X, m, n. and p ic ac defined above X ic i Ol I(('I ll) In come emlxldiments, X is i C(lts) and described in embodiments herem. Ixlth singly and in 1 . tvherein R is (', s aliphatic. In some embodiments, X combination. is C(CH,)1 [0224] In seine clnbodllnt:lite thc present lnvcniloll provides a compound of Formula II: [i)209J In some enlbodiments. X ic selected fn)m those depicted in Tables I and 2. below. [0210] In some embodiments. X is selected from those depicted in Table 2A, below. As is 0. 2. R'R [0211] defined genemlly above, m I. or In come embodinlents, m is 0 In come embodi- [0212J )„ ments. m is l. In some embodiment~, m is 2. [02131 In some embodiments. m is selected from those depicted in Tables I and 2. below. iRS)r [02141 In some embodiments. m is selected from those depicted in Table 2A, below. 0 [0215] As defined genemlly above, n is 0. I, 2. 3. 4 or 5. or a pharmaccuiically acceptable salt thcreol; whereul mch of Rulg A, R', R, R'. R, n, and p is as delincd above mid [02161 In some embodunents. n ic 0. In some embodi- described in embodiments herein, both singly and in com- ments. n is I. In some embodimentc. n is 2. In some bination. enlbodiments. n is 3. In some embodiments. n is 4. In some [0225] In seine clnbodllnt:lite thc present lnvcniloll pro- w S. mubodimcnts, n vides a compound of Formulae II-a or H-b [0217] In some embodiments, n is sclcctcxi Ibom those ilt:plctcd in Tables I and 2, below. us [0218] In some embodiments, n is sclcctcxi Ibom those ilt:plctcd in Table 2A, below. [0219] As dclincd gmlcrally above. p is 0, I. or 2. iR )„ [0220] In some embodiments, p is 0. In some embodi- lncllis. p ls l. In some embodiments. p is 2. [0221] In some embodiments, p is sclcctcxi Ibom those ilt:plctcd in Tables I and 2, below. iRS)r

[02Z2J In some embodiments, p is selected from those 0 depicted in 'I'able 2A, below US 20]9/032265]] A] Oct. 24, 2019 24

-continued ]0220] In some embodiments, the present invention pro- 0 s vtdes a compound of Formula IV IV

(R'). "-~)9 or a phaunaceutically acceptable salt thereof, wherein each of Ring su R', R". R', n. and ic as defined above and or a pharmaccuttcally acceptable salt thcreol; whereut each R, p R', descubcd in cmbothmcnts hcrcut. both smgly mtd In cum- of Rutg B. R, R, R. m, n. and p is as dc(iced above mtd btnation. described in embodintents herem. both singly and in com- ]0226] In some embodiments, the present invention pro- bhlatton. vides a compound of Formula III ]0229] In some cmbodmtents, thc present Invenuon pro- a lsonnulae IV-a IV-b III vides compound of or IV s

tR )

0 0 or a pharntaceuttcally acceptable salt thereof. wherein each of R'. R"„R', R„m. n, and p is as defined above and dcscubtal in cmbothments hcretn, buth smgly and ut combmation. ]0227] In some embodunents, the present invention provides a compound of Founulae III-a or III-b: Iu s

(R )„ or a pharmaceutically acceptable salt thereof, wherein each of Rtn B. R', R, R', R, m, n, and p is as defined above and described in embodunmtts heraus. both stngly and in com- btnatton. ]0230] In some embodintents. the present Invention pro- vtdcs a compound of Formula V RI 6 R'Rs)„

(R ')1,

or a pharmaceuttcally acceptable salt Ihereol: whercut each or a pharmaccutreally acceptable salt thcreol; whereut each ol''. R', R', R, m. n, and p Is as dclincd above and of R', R, R'. R, X, n, and p Is as dclincd above and described in embodiments herein. both singly and in cont- described in embodintents hereat. both singly and in combination. bhlatton. US 20]9/0322658 A[ Oct. 24, 2019 25

[0231] In some embodiments, the present invention pro- -coiiliiiilcd vides a compound of I'orniulae V-a or V-b VI S

uib R's

or a pharmaceuticaliy acceptable salt thereof, wherein each of Ruig B. R', R', R', R. X. n, and p is as dcliued above and described in embodunmits heraus. both singly and in com- blllutloli. uib [0234] In some cmbodmients, thc present invenuon provides a compound of Formula VH .I R''I I (Ril„ or a pharmaceutically acceptable salt Ihereol: whercui each of R', R', R'. R, X. n, and p is ac defined above and dcscnbtal in cmboihments herein, both smgly and ui combination. (R's [0232] In some embodiments, thc present uivenuon provides a con)pound of I'orniula VI

VI a phanuaceutically acceptable salt thcrcol; whcrcin n's I or 2, and R is halogmi or OC, i aliphatic, and wherein each of R", R . R, R. X. and p is as defined above and IITX described in embodiments herein, Ixith singly and in combination. In some embodiments, n's l. In some embodiments. n's 2. In some embodiments. R is F. In come embodiments, R's Cl. In some cmbodunents, R is Br. In some mnbodimen(s, R's I. In some cmbodunents, R's TR'!r OCH,. In some cmboiluncnts, R is ~CsHs In some embodinients, It is 0('lls('lli('lla. In some embodimentg lt is ~)('I l(('I li]s [0235] In some embodiments, n is selected from those or a pharmaceutically acceptable salt Ihereol: whercui each depicted in tables I. 2, and 2stc below. of Ring I I, R', R, R . It, X, n, and p is as defined above and [0236] In some embodinients. R is selected from those described in embodiments herein. both singly and in com- dc3uctcd in tables l. 2, and 2A, below. bination. R'r[0237] In some cmbodmients, thc present invenuon provides a compound of Fonnulac VB-a or VH-b. [0233] In some embodunents, the present invention provides a con)pound of I'orniulae VI-a or VI-b VII:

I I 0 US 20]9/032265[] A[ Oct. 24, 2019

R'conunuml -colttlltllcd VHI I3 VII-S

H X~

...,I'Q LX

or a plmrmaceutically acceptable salt thereof, wherein each or a phaunaccutically acceptable salt thcrcol. whereui each ofRing B, R', R, R'. R", R„X. p. and n" is as detined above R', It'. R', and as defined and of It, lt, X, p. o's above and dcscrtbcvt in cmboilimcnts herein. both singly and in descubcd in cmboihmcnts hcrcut. boih smgly mid in cum- combination. bination. [0242] In some embodiments, the present invention pro- [0238] In some embodiments, the present invention provides a compound of Fomtula IX vides a compound of I'orniula VIII:

IX R'III I I.H (R I„ (R I„

IRs!, 0

or a pharmaceutically acceptable salt thereof, wherein Rc is halogen. and each of R" and n's as defined above and or a pluinnaceutically acccptablc sali dtercttf, whcrcui n" is described in embodiments herein. both singly and in com- 0. I, 2, 3, or 4, and wherein each of Ring B. R'. R'. R-'. R', buiation. R. X, and p is as delincd above mid descubed m embodi- [0243] In some cmbodmients, thc present invenuon pro- nients herein, both singly and in combination vides a compound of Fonnulac IX-a or IX-b: [0239] In some embodiments. n" is 0. In some embodinients. n" is In some enibodiments, n" i ~ 2 In some l. IX-s embodiments, n" is 3. In some embodiment~. n." is 4. [tt240J In some embodiments, o" is selected from those depicted in tables l. 2, and 2.%, below. (Ril [0241J In some embodinients, the present invention provides a compound of Formulae VIII-a or Vill-b:

R'HI-s 0 US 20]9/0322658 A] Oct. 24, 2019 27 or a pharnlaceutlcally acceptable salt thereof, wherein R's -continual halogen. and each of It and n's as defined above and described in embodiments herein. both singly und in combination. H»H ]0244] In some embodunents, the present invention pro- t ides a conlpound ol Fonuulas X, Xl, or XII:

0 H»X

H H

XI 0

XH 0 XH-1

H»H

0 or a pharmaceutically acceptable salt thereof, wherein It is xII u halogen. and each of R's as detined above and described in mubodimcnts hereul, both sulgly and ul combmation. ]0245] In some embodiments, the present invention pro- 1 ides a compound ol'Fonmdac X-a, X-b, Xl-a. Xl-b. Xll-a, or XII-b:

X» 0

or a phaunaceutically acceptable salt thereof, wherein R's halogen. and each of R's as defined above and described in embodiments herein. both singly and ul combulauon. ]0246] In some embodinlents. the present invention provides a compound of Formulae X, Xl, XII, X-a, X-b, Xl-a, Xl-b. XII-a. or XII-b. as slmlvn above„v herein R'c Ci and each ol'R is sclectcd lbom the group comlstlng of halogen te g., ('I), Nl Il/ MCI I». ('I'», US 2019/0322658 A1 Oct. 24, 2019 28

Sii OH(( H1'

W Y Ytf" YY=-- @&0 0 0

— ('OOII, S —,

6 v (Ii'

j.,Qi',JL.k g,ii .i. g,J Yw- 7- V- US 2019/0322658 A1 Oct. 24, 2019 29 y~--continued -eoitltitiuxi Y Q~A~ HO OH

HO Q

HO„, V~OH g+ Q,Jl-.g ~Q- ~'D g,~

0 - j..JL I

— — Oi.'HF Stol VH,~ . 0 c 2 c Cj — OCF — i =CH, —0— ('H — C=CHI,

0 Y ii Q'~„,g Q Y ii US 20]9/0322658 A[ Oct. 24, 2019 30

[0250] In some embodiments, the present invention provides a compound selected from those listed in I able 2. or a phamtaceutically acceptable salt thereof. [0251] In some embodtmcnts. thc prcscut utvcntton provtdes a compound sclectctl from those ltstcd ut Table 2A, or a phannaceutically acceptable salt thereof [l)252[ In some embodiments, the present invention provides a triiluoroacetate salt of compound D-I 50.

'lAlll,l. I

ot $

Y"'Y""

QY[

[0247] In some embodiments. Exemplary compounds of the tmenuon arc sct forth in Tables I and 2, below. [0248] In some embodiments. Exemplary compounds of the tmenuon arc sct forth in Table 2A, below. [0249] In some cmboduueuts, the present utventton pro- xtt vides a compound selected from those listed in Table l. or a pharntaceutically acceptable salt thereof. US 2019/0322658 A1 OcL 24, 2019 31

TABLE 1-conttnttcd TABLE t-connnucd

Exec lplIE' oillpooll t5 EXCOlpl IIX cclllpccllcl

I 4

NIII

HI I QY"'I.

I $~'"

I-P 1-14 I IIN VjV"'

I IC 114 +IV C) US 2019/0322658 A1 OcL 24, 2019 32

TABLE ! -cont!1 nmd TABLE t-connnucd

Enemplex, Canponnde Enanplnn l.omponnte 21 I-ld QV"'

I 2-

I 17

/ 0

1-24

I IP

I 0 I-2e C! US 2019/0322658 A1 OOL 24, 2019 33

TABLE 1-conttnttcd TABLE t-connnucd

EXClTlplmo' OI1lpccll t5

1-27

I I2H

+IV

I I.37

H2H

I IC US 2019/0322658 A1 OcL 24, 2019 34

TABLE 1-contnnIcd TABLE t-connnucd

Exemplex, Cmnpouede

H .I

I 44 %if

I le

I-44

HII I-4C NH

I 41

7'Y" H.H

I 4II Hen Yif I 41

0 US 2019/0322658 A1 OcL 24, 2019 35

TABLE 1-contttnmd TABLE t-connnucd

ExclTlplen' ompccll te neemplen Compounds tt I dc V

pet

7 US 2019/0322658 A1 OcL 24, 2019 36

TABLE 1 -contlpnmd TABLE t-connnucd

nxemplnn, Cmnponnds Fxemplny Cnmponnds I 66 169

1-66

1-66 Yif 0 0

(. HH I 66

1-61

lien 168

I 61 US 2019/0322658 A1 OcL 24, 2019 37

TABLE 1-conttnttcd TABLE t-connnucd

Exempiex, Cmopooode Exeolpleo' olllpooll te

1-7C

Yif 176 H.H I 71

1-77 HOH

1-72

I 73

%if 173 C), 1-79

17d %if I IIC US 2019/0322658 A1 006 24, 2019 38

TABLE 1-connmmd TABLE 1-connnucd

Fx mplary compounds I-81 H,V +1K C.V

II7N I-87

N N VII

VI I

I 88 17 0

I 88 QV

I Po 0

N H

NII

V US 2019/0322658 A1 006 24, 2019 39

TABLE 1-contllnmd TABLE t-connnucd

nuemplnx, Cmnpounde Fnemplmy Compounde

I 94 1-91 H.N C); 19

I-92

0 I 9II

I 93 NH

I 99

0 N

194

NIT2

1-91 I lnl HTN US 2019/0322658 A1 006 24, 2019 40

TABLE 3 -contntncd TABLE t-connnucd

Exec lp lop' oillpooll t5 Excolpl lip Colllpoollnl

I lc I I )7 H.N NI I

I lcl HN I-1 c8

C'I

I-nip

I leo

NH.

I IIV

N 0

I lllc

1-111 US 2019/0322658 A1 OcL 24, 2019 41

TABLE 1-contttttlcd TABLE t-connnucd

ExcolplJE' olllpooll t5 EXCOlpl IIX cclllpccllcl

I 117 Hll

I 113 HH

I 1 14 H

HIE

QiV

HH .J I 114 Yig " US 2019/0322658 A1 OOL 24, 2019 42

TABLE 1-conttnttcd TABLE t-connnucd

Exec lplIO' oillpooll t5 EXCOlpl IIV cclllpccllcl

I 127 +IV

1-128 XIII I I 3

0 1-12P

VII

1-123

VIII

11 O 0~ 1 131 0 US 2019/0322658 A1 OcL 24, 2019 43

TABLE 3-conttnttcd TABLE 3-connnucd

Exemplex, Cmnpouede ExelTlplm3' emceell te HH

I 13

XH ...) I 133 0 Cl

H ~ HH4 YiH V" I I to "i/ o / EH 1-134 $~'" 1-140

1 141

1-1" 4

NI I US 2019/0322658 A1 OcL 24, 2019 44

TABLE 1-contltnmd TABLE t-connnucd

Exanplnn I.omponntx Fx mplnry Cnnoponndx

I 14II I 143

1 144 1-144

I-lop

I 14 'xVYQ

1 141

1-144 I) I I 2

I 147 NH2

VII2 US 2019/0322658 A1 006 24, 2019 45

TABLE 1 -contnnfcd TABLE t-connnucd

0 0

/ 1 166 0 F / F NH.

NH7

1-166 ix // 0 HN~ &

C) 1-166 H.N 0 0 I 161 ix // N 116N

1-167

116

0 US 2019/0322658 A1 006 24, 2019

TABLE 1 -conttmmd TABLE t-connnucd

ExclTlplm7' Ompcc6 tx Fx mplary compounds

1-168 I 161

I 166 I 166 HN NH

I 16 I-17V . IH7 1 17N

1 I 166 0 171

1 17N

N 0

I 167 1-17" 1 17N

N 0 US 2019/0322658 A1 OcL 24, 2019 47

TABLE 3-contllnmd TABLE t-connnucd

Euanplnn l.ompounte Euemplex, Canpounde

I 173 I 17II .IH

I 17u I 17u

I Iful

1-173

Yi,

I 17e

. IHf

Cl I- Hl" I 177 US 2019/0322658 A1 OcL 24, 2019 48

TABLE 1-contntttcd TABLE t-connnucd

Exemptex, Cmopooode Exeolpleo' olllpooll te I 187

I 181 NI Il

Q NIL

I 188

NI I

I 188

XI IIO NH.

1-189

I 18

NI Ie

1-191 US 2019/0322658 A1 OcL 24, 2019 49

TABLE 1-cont)1 nmd TABLE t-connnucd

Hxanplnn I.omponntx Fx mplnry Co)nponnnx I 19 ,v 1-197

(. C, 0 1-19" 1-198

NI I)

Yin

I 199 1 199

~H.

Yi,

I 191 I I )9

Yi Yin V

1-199 I -nl US 2019/0322658 A1 OcL 24, 2019 50

TABLE 1-conttnttcd TABLE t-connnucd

ExelTlpleo' olllpooll te Exempiex, Cmopooode

I 07

P—

(. N xiii

I 204 Q~'Y" 1-209 (.

I El

1-210 US 2019/0322658 A1 OCL 24, 2019 51

TABLE 1-contlpnmd TABLE t-connnucd

Fxemplcy Compounds Exemlpl elm COIIlpollllce

I 21 I 21C

/ I 17 0 CI

Yin

I 2111

le C Q

I lip

CI I- 12

HH .JH11 Yi H US 2019/0322658 A1 OCL 24, 2019 52

TABLE 2-conttnttcd TABLE 2-connnucd

Cooopooo ts Exaoplon Exclilplcv COIIlpololco

o I 2- Cl

N N VI I2

Yi Yi,

12 I

I 22O

V I NH2 Y

I- 22 .~i 1-227 Yi, ~i

12 I YiN

1-228

12 C

N N "III

Yi US 2019/0322658 A1 OOL 24, 2019 53

TABLE 1 -contnnlcd TABLE 2-connnucd

Exemplex, Omnpouede

I- 29 12

1-234 I- 30 HJ=.

HN OI

1-2 I 3

I 231

I 'ld

0 IT

I 23

ITTN

I 237 US 2019/0322658 A1 OCL 24, 2019 54

TABLE 1 -contipnmd TABLE t-connnucd

neemplen Compounds

1-24"

1 244

I 44

I 46 41 Y

I 24 US 2019/0322658 A1 OCL 24, 2019 55

TABLE 1-contntttcd TABLE t-connnucd

Exaoplon Cooopooints yv'" RJ~—

op HJ,

HII2 H 0II 0

I-275

I- 21 I I 0 0

1-257 US 2019/0322658 A1 OCL 24, 2019

TABLE 1-contlpnmd TABLE t-connnucd

Fxemplcy Compouods Exelilpleem Colxlpo111145

O~ I 242 .J

xlll

I 249 QIY xlll

I 244

'4'OII

'o'OII US 2019/0322658 A1 OCL 24, 2019 57

TABLE 1-contltnmd TABLE t-connnucd

Esanplsn T.ompounts Esemplnn Cmnpounds

1-271

I- 67 1. 7 7 7

H.T

Yi,

76) 1-275 C) g y+E1T US 2019/0322658 A1 OcL 24, 2019 58

TABLE 1-contnnfcd TABLE t-connnocd

nxemplex, Cmupouede

I 276 I flu

Yi V

I cfn

Yi N

N Y Nile I-2flc

H2N OII

I 279

1-2 fld

YiN US 2019/0322658 A1 006 24, 2019 59

TABLE 1-conttnttcd TABLE t-connnucd

EXClTlpl777 C 071lpccll IS

I Cu NH

NI IT

I 281

VTT 87

I 288 0 Q NIH

I 287 88

N VHT US 2019/0322658 A1 OcL 24, 2019 60

TABLE 1-conttnttcd TABLE t-connnucd

Exauplon Cooopouu ts Euolilplllu COIIlpolu145

I 299

I 299 HJ, Hon

I 'luii

~'" H2N ci / 0 / $ HH

9 tt US 2019/0322658 A1 OCL 24, 2019

TABLE 1-contltnmd TABLE t-connnucd

Compounds EXClTlplm7' Olllpccll te Exemplxn

1-00TI od

1 101 I-"09

117 US 2019/0322658 A1 Oct. 24, 2019

TABLE I-continued [02531 Compounds 1-120 to 1-125 are stereoisomers of the followulg fornnlllls. rxenu&l.&z& I empeusdx

1 313

N NH C)

1 314

NH&

0 N 0 N z

I 31 C)

1-316

H 0 0

Compounds 1-120 to 1-128 can be sepamted by chrial punlicatlon (sem. for example. Example 181. Accordingly, in some cmbodlmcnls, thc present la&cation provides a sle- reoisomcr sclccled from compounds 1-120 to 1-128& or a plmrmaceutically acceptable salt thereof. HN [t)254J (:ompounds I-t f&4 to 1-157 are stereoisomers ofthe followln formulas: 1 317

NH HN O~s

Yi, C) 01 US 2019/0322658 A1 Oct. 24, 2019

-continued Compounds 1-209 and 1-210 can be separated by chrial NH punlicatton (scm for example. Example 521. Accordingly, in Hsx O~ some cmbodtmcnls, thc present tnvcntion provslcs a sle- s~ reoisomer selected from compounds 1-209 to 1-210. or a plrarmaceuticaily acceptable salt thereof. [02561 Compounds 1-211 and 1-212 are stereoicomers of the following fornnllas:

I slrrl

Its N 0

H N

Compounds 1-164 to 1-167 can be separated by clutal Compounds 1-211 and 1-212 can bc separated by clutal punlicatton (sec. I'or example. Example 41). Accordut ly, tn punlicatton (scm for example. Example 521. Accordingly, in some embodtments, the present invention provides a ste- some enlbodiments. the present invention provtdes a ste- reoisomer selected from compounds 1-164 to i-167, or a reoisomer selected fmm compounds 1-211 to 1-212. or a pharmaceutically acceptable salt thereof. phannaceuticaily acceptable salt thereof. [0255] Compounds 1-209 and 1-210 are stereoisomers of the Ibllowing formulas. 1AI II,I! 2

o-2

0 NJ „

N ttsx US 2019/0322658 A1 OCL 24, 2019

TABLE 2-contntttcd TABLE 2-connnucd

Eecooplere co&opouo ts Fceoeplery otnpocoeds

NH,

II N C 4

C nl

HoV~

C-11

XP VH7 V

C I US 2019/0322658 A1 OCL 24, 2019

TABLE 2-contttnmd TABLE 2-connnucd

Fsemplmy compnunds nnemplsn cmnpounds

C-I" C Itt

(&i

( lu

0 C'I

(. 2))

(-21 R,

0 Cl

C 17 (. 2- US 2019/0322658 A1 006 24, 2019

TABLE 2-contllnmd TABLE 2-connnucd

Fsemplmy compnunds nnemplsn cmnpounds

112 I

~yr .

C-2o

0 C-26

E NI 17

C 'I

2' N 0 0 Cl Cl US 2019/0322658 A1 OcL 24, 2019

TABLE 2-contttnmd TABLE 2-connnucd

Fyempleyy cumpuuude

H ~ C 33

(. 4u

C 3(

C'I 0 CI Help C-41

114H C 36

H / ott

C 37 US 2019/0322658 A1 OCL 24, 2019

TABLE 2-contltnmd TABLE 2-connnucd

Escmplsn: co(npoun ts Esemplcn cmnpounds

C 4(I

~ &,

0 CI

c 4o

XP HH7 H

HH ('7 US 2019/0322658 A1 OOL 24, 2019

TABLE 2-contzznmd TABLE 2-connnucd

Fnemplzuy cumpnunde nneznplen cmnp zuzde

NHz ~L+

C-ns Jl

0 ~OH

(. dl

I izN

0 OH Ci Vp Y QNHz C. N US 2019/0322658 A1 OcL 24, 2019 70

TABLE 2-connnncd TABLE 2-connnucd

Fe.eceplery etnpe&ueeIs J,

N P'EHe

I Xl. c1 0

mt US 2019/0322658 A1 OCL 24, 2019 71

TABLE 2-contnnfcd TABLE 2-connnucd

Fceceplery etnpe&ueefs ('3

'(1 ~II(

c 77

C 7(

C ffif

C-77 US 2019/0322658 A1 OCL 24, 2019 72

TABLE 2-connlnlcd TABLE 2-connnucd

Fxempcyyy onyponnds Exemplmy eompomydx

Yj- C

CR,

R. Hen C Pl

C-87 US 2019/0322658 A1 OCL 24, 2019 73

TABLE 2-contlnnmd TABLE 2-connnucd

nuempl(uy cnmpnuude Fueu(pl(re n(upn(unde

H ~ C 33 g~N Q 0

(. uu

0 Cl

(. I ul

N )II~ Ji

~0 ~ C XX ('d C lnl

C 37 ( nn Vp 0 0 C CI US 2019/0322658 A1 OCL 24, 2019 74

TABLE 2-contilnmd TABLE 2-connnucd

nxempjen cmnpcucds

('I 0 C j(jjj

'yNire

C-lop Cl ( loc

XX PNH

C 1(i(

C llil

QNHj

C 1(16 US 2019/0322658 A1 OCL 24, 2019 75

TABLE 2-cont(Et(cd TABLE 2-connnucd

EXCnlplolp oolllpollll tc Excmplolo conlpolmdx

C'-11" C-ttt( NR.,

C 11P

C-tt(

( 12O H.N

HN C ttc

C -121

0 E~

('17 C-122 US 2019/0322658 A1 OCL 24, 2019

TABLE 2-conttnttcd TABLE 2-connnucd

Eneneplnn canp coeds Eecnoplere co&nponn to Cl I OH

I H

C-12d OH H1N C IIII

..Xx

~Ho C 12P

C-12o

NI I

C-126

C I'H NR,.

NH1 US 2019/0322658 A1 OCL 24, 2019 77

TABLE 2-contlnnmd TABLE 2-connnucd

nuempleyy cnmpnunde Fueuyplery nmpnyuyde

C 13 (.1 7

PXHe

C 133 C -133

'y~H,

C-134 ( lyu

PHH,

C-137

yt FH

C-134 C 141

Hnn US 2019/0322658 A1 OcL 24, 2019 78

TABLE 2-conttnttcd TABLE 2-connnucd

EXCI1lplnp c0111pccll t5 US 2019/0322658 A1 OCL 24, 2019 79

TABLE 2-cont(Eood TABLE 2-cont(cued

Euanpta&3 co&npocucda

('1 u

'.(H2

C 1 1 ~)W

TABLE 2A

Euenaptary Conepounda

D 1 Q~E~

0 C 1(

N D 2

C) C 1(3 D 3 auQ-:;„- gN N NH US 2019/0322658 A1 OOL 24, 2019 80

TABLE 2A-con)lnucct TABLE 2A-connnucxt

Exec lp)ID' on)poco 15 Excolpl lip Conlpoollul

DO D 11

)

D lu

D 6

Ji C~ 1,1''I D-11 R,

D-7 , ~i

D 12

HO US 2019/0322658 A1 OCL 24, 2019 81

TABLE 2A-conlpnucet TABLE 2A-colulnucdt

neemplen Compounds

12 11 HIN D-III

D IP

12 ld

D-cu

12 I NJ,

HN CI D I

H,N D-ld

D 2-

HN D-17 US 2019/0322658 A1 OCL 24, 2019 82

TABLE 2A-connnucct TABLE 2A-connnucxt

ExcolplID' onlpoon l5 Excolpl lip Conlpoollul

D 17 211

D-22

D-" u

D-"1 D-26

17 2 D-27 US 2019/0322658 A1 ODL 24, 2019 83

TABLE 2A-conlpnuclt TABLE 2A-connnuc33

Exemplex, Cmnpoeede

13 II I3 33 /~o

D 34

D-39

0 CI

l3 3

HHe

D-41

D-37 US 2019/0322658 A1 OcL 24, 2019 84

TABLE 2A-con)pouch TABLE 2A-connnurd

ExclnPlllc ConlPolnlul

13 411 I) 43

H) IC I) 44 I) 44

0—

D-5u

13 2 I) 47 .J US 2019/0322658 A1 006 24, 2019 85

TABLE 2A-conrrnuc&1 TABLE 2A-conrrnuc33

Exemplex, Cmnpoeede

13 7

D 13

rro 0 ,J, D rrr Y

0 Yin

D 1

XQNrre

D 16 D 61 US 2019/0322658 A1 ODL 24, 2019

TABLE 2A-connnucct TABLE 2A-coIuInuc72

ExclnPI117 CcnlPoln165

D-62 Y I) 67

Yi,

D 67

17 6 US 2019/0322658 A1 OcL 24, 2019 87

TABLE 2A-conttnucct TABLE 2A-conttnurd

ExelTlplen' olnpeun te Exemplex, Cmnpoeede

D 71 D 76 EJ.,

Hdtc D 7 D 77

lien D-711 D 73

He. I

C'I

D-79 D-7d j,

D 71 D E1) US 2019/0322658 A1 OcL 24, 2019 88

TABLE 2A-conlpnucit TABLE 2A-con))nord

Exemplex, Ce)npouede ExelT)pleo' on)peon )5 D I)d

D Iu

„-L)

C, Q.

13 In)

D I)3

D Pi Y D PO

NH US 2019/0322658 A1 OcL 24, 2019 89

TABLE 2A-connnuc&1 TABLE 2A-coconuts US 2019/0322658 A1 OCL 24, 2019 90

TABLE 2A-conlmuc&1 TABLE 2A-conlsnuuut

Cmnpounds Esanplsn l.ompounts Esemplsn

xx~ 0 CI

H,N

HsN

NII US 2019/0322658 A1 OcL 24, 2019 91

TABLE 2A-conlpnucct TABLE 2A-connnuc33

Exemplex, Cmnpoeede D-1 1c

D lid

-, -,:cL)

D-111 0

D-112 gl

D 117

D 113

D-»d j,.

c 0 US 2019/0322658 A1 OCL 24, 2019 92

TABLE 2A-conlpnuclt TABLE 2A-connnucdt

Compounds ExclTlplen' on)peon )5 E)empleo

D-I ) D IIP gI Li e m

D I-d

D I O

D I

Dl I

D-I 6 V. &v Ci~

D I 2 Dl I US 2019/0322658 A1 Oct. 24, 2019 93

TABLE 2A-conipnuc&1 TABLE 2A-connnurd

Exempleo Cmnpoeede D-13II D 13'1

110~ =. 0 „. / H

11 D-139

D I'ld

Ci D-139

13 I le

HO~ Ci 0 0 131 yX 13 I le

0 D-137 j, D I'l2 US 2019/0322658 A1 OcL 24, 2019 94

TABLE 2A-contmuclt TABLE 2A-conttnucxt

Fxemplny Cnmponnds Exemplnz, Cmnponnds

0 D Izd HzV D 14'I "~& //

Hzug/ V

Hzn D 144 Vj- D tip C

D-14D 'rp. D 14

D 146 I H D 141

V H IxH C)

D 142 D-147

C) US 2019/0322658 A1 OcL 24, 2019 95

TABLE 2A-conlnoucct TABLE 2A-connnurd

D-14 II D I

D-149

D 144

D 149

D 144

D I I

D-I 6

I IO

D 142

D 14

II N US 2019/0322658 A1 OcL 24, 2019

TABLE 2A-conlnnuclt TABLE 2A-connnucxt

Fx mplary Cmnpmmdx ExclTlplxn' ol1lpmm 15

D 16 D 166

D-164

D 149

D-164 c

112 I D-166 p ~ D 166

D-161 D-166 US 2019/0322658 A1 OOL 24, 2019 97

TABLE 2A-connnuc&1 TABLE 2A-connnurd

Exaoplon Oooopoonns Exclilplnc COIIlpoluluo

D 167 0 17-

D-168

0 166 ~/ // 0

0 I

D 176

c-L.6

HO I'I 0 0 17

D 171

0 US 2019/0322658 A1 OCL 24, 2019 98

TABLE 2A-connnucct TABLE 2A-connnucxt

Exec lp)ID' on)poco 15 Excolpl lip Conlpoollul

D 176 D )XO

HIE

D 1)n

D 177

OH D l)C

D 17E

D )X D 179 US 2019/0322658 A1 Oct. 24, 2019 99

TABLE 2A-contmucd TABLE 2A-con(Inurn(

Fxemplny Onmponnde Hxemplnr, Cmnponnde

D lsn D IS9

D 19n D lao gl Horn+/

HO~'l D-191 D-lad Yj- (. D 19 Vj~- Vj- D-197 OH (. D 199 D-ISS

HnVQ/

d. (ieneral Methods of Pnnvidtnp the Present Con(pounds [t)257J The compounds of this Invention may be prepared or isolated in geneml hy synthetic and/or semi-synthetic US 20 ] 9/032265 [] A[ Oct. 24, 2019 100

methods known to those skilled in the art for analo ous allyl amines. amides, and the like Examples of such groups compounds and by methods descnbcd ui detail ut the include t-butyloxycarbonyl (130('). ethyloxycarbonyl, meth- Exmnples. heraus yloxycarbonyi, trichloroethyloxycarbonyl. allyloxycarbonyl [0258] In thc Schemes below, where a particular protect- (Alice), bmizyloxocarbonyl (CBZ), allyl. phthahnudc, ben- ing roup ("P(i ), leaviilg group ("I,G ). Or transforniation zyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, condition is depicted. one of ordinary skill in the art will cldoroacetyl. dichloroacctyl. tncldoroacetyl, phenylacctyl. appreciate that other protecting groups, leavin @cups. and tntluoroacetyl, benzoyl, and the like tramfonnation conditions are also suitable and are contemplated. Such groups and transformations are dcscnbcd in [0262] One ol'stall in thc art vstll appreciate that various 's functional in compounds of the invention dctm1 ui March .(dvu riced Organic Cheini rrrf r yeucriuns, groups present Mechanisms, und Sirucinre, M. B. Snuth mtd J. March, 5"':dition. such as aliphatic groups, alcohols, carboxyhc acids, esiers, Jolm Wiley 8. Sons, 2001, (:uinyrehenrive Orgunir" amides, aldehydes, haloaens and nitnles can be intercon- (' Irunsfurnuuiuns. 8 amck, 2" I idition„.lohhn Wiley verted by teclmiques weil known in the art including. but not Sons. 1999. and Prorecimg Gruuys in Orgumc Swiiiierir, T. linuted to reduction. oxidation. esterification. hydrolysis, 3"a SV, Greene and P Ci. M Wats, edition. Jolut Wiley gr partial oxidation. partial reduction. halogenation, dehydra- Sons, 1999. Ihc cntircty of each of wluch is hcrcby uicor- tion, partial hydrauon, mtd hydration. Sec, I'or example. poratcd herein by rcfi:recce. "March*s Advanced Organic ('hemistry", 5" Iid.. Ed. [0259] As used hcrcin, the pluase "leaving group" (LG) Snuth, M 13 and March..l . John Wiley di Sons. New York includes. but is not limited to, halogens (eg fluonde, 2001, the entirety of which is incorpomsted herein by refer- chloride, bromide, iodide), sulfonates (e g mesylate. tosy- ence. Such interconversions may require one or more of the late, benzenesulfimate. brosylate, nosyLste„ triflate), diazo- albremcntioncd tccluuqucs. and certain methods Ibr synthe- nium. and the lil e. slzlllg coillpollllds ol rite illicit(loll arc ilcscllbixl bc'Iow. [0260] As used herein. the phrase "oxygen protecting [0263[ In one aspect. the present invention provides a group" include~, for example. carbonyl protecting groups, method for synthesizin a compound of liormula I, or hydroxyl protecting groups, ctc. Hydroxyl protccung roups subfonnulae thereof. or a salt thereof. comprising reacting a are well known in thc ait and include fltose desvnbcd in compound of fiinnula: detail in Bra(erring (irrniyr in Orgunir,yrralrusis. 'I W. Cireene and P (I M Wuts, 3" edition..fohn Viiley E; Sons, 1999, and Philip Kociensl I, in "Protecting Ciroups*k Cieorg Thieme Veriag Stuttgart. New Yorl. 1994. the entireties of which is incorporated herem by reference. Examples of suitable hydroxyl protectuig grmips mclude, but arc not limited to. caters, allyl cthcrs, cthers, silyl a)hers, alkyl ethers. arylalkyl ethers. and alkoxyalkyl ethers I ixamples of such esters include forniates, acetates. carbonates, and sulfonates. Specific examples include formate, benzoyl for- or a salt thcrcoi; and a compound ol'ormula mate, chloroacetate. trifluoroacetate, methoxyacetate. triph- enylntethoxyacetate. p-chlorophenoxyacetate, 3-phmtylpropionatc. 4-oxopcntanoate, 4,4-(ethylencditluo) pcntanoate, pivaloate (tnmcthylacctyl), crotonatc, 4-methoxy-crotonate. benzoate, p-benzylbenroate, 2,4.6- trintethylbenzoate, carlxmates such as methyl, ')-tluorenyl- methyl. ethyl, 2„2.2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl. vinyl, allyL and p-nitrobenzyl. Examples of such silyl ethers include trimethylsiiyl. Irieth- ylsilyl. I-butylduncthylsilyl, I-butyldiphenylsilyl. Inisopro- pylsilyl. mtd other Inalkylsilyl cthers. Alkyl a)hers uiclude ntethyl. benzyl. p-methoxybenzyl. 3,)-diinethoxvbenzvl. tri- or a salt thercxsf, whcrcin each of Ruig A. RL R, R', R, X, tyl. t-butyl. allyl, and allyloxycarbonyl ethers or derivatives. m, n, and p is as detined above and described in embodi- Alkoxyalkyl ethers include acetals such as methoxymethyl, ments herein. both sin ly and in combmation. methylthiomethyl. (2-methoxyethoxy)methyl. benzyloxym- ethyl, beta-(trimethylsilyl)ethoxymethyl. and tetrahydropy- [0264] In some embodiments, the present invention pro- r;myl cthers. Examples ol'rylalkyl a(hers include bemyl, vides a compound of fomuiLs; p-mcthoxybcnzyl (MPM), 3,4-dimcthoxybcnzyl, 0-m- trobenzyl, p-nitrobenzyl. p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl [0261] Amino protecting groups are well knov n in the art and include those described in detail in Protecting (rruuyr i n Orguriic Svnrherts„T W. Cireene and P. Crk M. Wats, 3is edition. Jolm Wiley gz Sons, 1999, tmd Philip Kocienski. in '*Protecting Groups", Gcorg Thicme Verlag Stuttgart, Ncw Yorl, 1994. thc mitireuca ol'hich is uicorporated herein by or a salt thcrcof. wherein each ol'R', R, and m m as dcftncxI reference. Suitable amino protecting gmups include. but are above and described in embodiments herein, Ixith suigly and not limited to, arallylmuines. carbmuates, cyclic insides, in combination. US 20 ] 9/032265 [] A] Oct. 24, 2019 101

[0265] In some embodiments, the present invention pro- t lies d conipiiUnd of IomlUla. RL

IRI)„,

or a salt thereof, and a con)pound of fornuila

(Ri (,I or a salt thereof„wherein each of Rin II. R'. R'. R. X. n, and p is as detined above and described in embodiments herein. both singly and ui combuiauon. [0266] In one aspect, the present invention provides a met[a&d for synthesizing a compound of FonnuL1 I'. or sublbrmulac thercol; or a salt thereol; comprism rcactuig a conIpound iil IouuUia. ore salt thereof, wherein each of lt', R, It . It . R. X, p, and n's as defined above and described in embodiments herein, both singly and in combination. [0269J In some embodiments. the present Invention pui- vides a method for synthesizing a con(pound of I'onnula VIIL or a salt thereof, comprising reacting a compound of fbrnlUIK or II adit thctcof, and a conlpound of ICUUUIU.

(RI)„.

or a salt thereof, and a con)pound of fornuila

or a wilt thereof, whermn each of Ruig A, RL R, R', (R I„ R, X, m. n, aud p is as delined above and described in embodiments herein. both singly and in coni- bination. [0267J In some embodinients, the present invention provides a compound of fonmda:

( 1 5 I„. R-', H or a salt thereof, wherein each of Ring B, R', R', R', R, v X, p. and n" is as defined above and described in embodiments hcrcin, both smgly dnd in combination. [0270J In some embodimentg the present invention provides a compound of fomuiL1: ora salt thereof. wherein each ofRing i, R". R', =, R. X, n. and p is as detined above and described in cmbodimcnts hcrcui. both suigly and ui combmation. [0268] In some cmboduueuts, the present uivention pro- t ides a method for synthesizing a compound ol'onuula Vll. or a salt thereof, compusing reacting a compound of formula US 20 ] 9/032265 [] A[ Oct. 24, 2019 102

or a salt thereof, wherein each of R'nd R is as defined [0275] The term "pharmaceutically acceptable carrier, abol e mid descnbcd ul embodiments hereul, both sulgly and adluvant, or vducle" rcli:rs to a nou-toxic camel, adiuvant, hi ConlbuliltlotL or vchiclc that docs not destroy tlu: pharmacological activity [0271J In some embodinlents, the present invention pro- of the compound with which it is fonmilated Pharmaceu- vides a conlpound of fhrnlula tically acceptable carriers, adjuvants or vehicles that mav be used in the compositions of this invention include. but are not limited to, ion exchangers, alumina„alumulum stearate, lecithul. senun proteins, such as human serum albumin, IRI)„, buffer substances such as phosphates. glyculc, sorbic acid. polassium sorbatc, partial glyccnde mixtures of saturated vegetable fatty acids, lvater, salts or electrolytes, such as pmtamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloridei zinc salts. colloidal sihca. magnesium trisiiicate. polyvinyl pyrmlidone, cellulose-bused substances, polyethylene glycol. sodium car- boxymcthylccllulosc. polyacrylates. waxes, polycthylene- or a salt thcrcof', wherein each of R, R', R'. R, X, p, and polyoxypropylcnc-block polymers, polyethylene glycol and n's as defined above and described ul cmbodnnents herein, wool fat. both singly and In combination. [0276] A "pharnlaceutically acceptable derivative" means In some emlxldinlents, the [t)272] present invention pro- any non-toxic salt, ester. salt of an ester or other derivative a fornlula vides compound of of a compound of this invention that. upon administration to a recipient. is capable of providing. either directly or indi- rcctl)'. a conlpollnd of lhls hivcntion or dn activi: nlctabohlc or residue thcrcof: (R [0277] As usixl hcrcul, thc tenn '*active mctabohte or residue thereof'eans that a metabolite or residue thereof also results in cell death [t)278J Ooinpositions of the present invention may be S administered orally, parenterally, by inhalation spray, topically. rectaliy. nasally. buccally. vaginally or via an (R')„~[ implanted reservoir. The teml "parenteral*'s used herein includes subcutaneous, ullravenous. ultramuscular, ultrd- articular, intra-synovial. ultrdstcrnal, Intrathecal, intrahe- patic, intralesional and intracranial Injection or infusion or a salt thcrcof; whereul each of Ring B, R, R", R'. R, X, teclmiques. Preferably. the compositions are adniinistered n" p, and Is as defined above mid describixi in embodiments omlly. intraperitoneally or intravenously. Sterile injectable herein. both singly and ul combulauon. forms of the compositions of tlus invention may be aqueous or oleaginous suspension. These suspensions may be for- 5. Uses. Formulation and Arhninistration mula)cd according to icclnuques known ul thc art usulg suitable dispersing or w ctung agcnm and suspending agents. Pharnlaceutically Acceptable ('ompositions 'I'he sterile injectable preparation may also be a sterile [0273] According to another cmbodunent, thc invention inlectable solution or suspension in a non-toxic parenterally provides a compositiou compnsing a compound of tlus acceptable diluent or solvent. for example as a solution in invention, or a phanuaceutically acceptable derivative 13-butanediol. Atnon the acceptable velficles and solvents thereof. and a pharnlaceutically acceptable carrier, adjuvant, that may be employed are water. Ringer*s solution and or vehicle. In certain embodiments, the amount of com- isotonic sodnim chloride solution. In adihtion, stcnle, ftxcxf pound in compositions of this invention is such that Is oils arc conventionally muployed as a solvent or suspcndulg cflbcul e to cause cancer cell death in a biological sample or medium. in a patient. In certain cmboduncnis, thc mnount of com- [0270] For this purpose, any bland fixed oil may be pound ul compositious of tlus invcnlion Is such that Is employed including synthetic mono- or di-glyceudes Iiatty effective to induce I.IPR in cancer cells in a biological acids. such as oleic acid and its glyceride derivatives are sample or in a patient In certain embodiments. the anlount usehd in the preparation of injectables. as are natural phar- of compound in compositions of this invention is such tlmt maceutically-acceptable oils, such as olive oil or castor oil. is effective to induce ER stres~ in cancer cells in a biological especially in their polyoxyethylated versions. These oil sample or in a patimlt. In certain cmboduncnl1. Ihc Iuuollnt solutions or suspensiom may also contaul a long-chain of compound In compositions of tlus ulvention Is such )liat alcohol diluent or dispersant. such as carboxynlethyl cellu- is cfliwtive to ulducc calcium release from thc ER via WFSI lose or similar dispersing agents that are conlmonly used in in cancer cells m a biological sainple or in a patient. In the formulation of pharmaceutically acceptable dosage certain embodiments, a composition of this invention Is forms including emulsions and suspensions. Other com- formulated for administration to a patient in need of such monly used surfactants. such as Twemls, Spam and other conlposition. In some embodiments, a composition of tlus emulsifying agents or bloat ailabihty enhanccrs wluch are invention is fornuilated for oral administration to a patient. conunonl)'sed hl lhc nldnufdctUIC of phanndccUlicallv [0274] 'the term "patient," as used herein, means an acceptable solid, liquid. or other dosage fonna may also be animal, preferably a mammal, and most preferably a lnunan. used for the purposes of formulation US 20 ] 9/032265 [] A[ Oct. 24, 2019 103

[0280] Pharmaceutically acceptable compositions of tlus tration. Such fonnukltions may be administered with or invention may bc orally admiiustered in any orally accept- without food. In some embodiments. phannaccutically able dosage fonu including, but not limited to, capsules, acccptablc compositions ol'ins invmltion arc aihnnustcrcxi tablets. aqueous suspensions or solutions. In the case of without food In other embodiments, phannaceutically tablets for onll use. earners commonly used include lactose acceptable compositions of this invention are adnlinistered and corn starch. Lubncating agents, such as magnesium with food. steamte„are also typically added. For oml administration in [0288] The amount ofcompounds of the present invention a capsule finn, useful diluents include lactose and dried that may be combined with the carrier matenals to produce colllsttllch. Whcll BqUcoUB sUspcllsious ill c Ieqlllrcd for oldl a composition ul a sulglc dosage fiinn will vary dcpcndulg usc. thc active ingrcdicnt is combulcd with cmulsifyulg and upon thc host trcatcxl, Ihc pariicular mode ol admiiustration. suspendiim agents If desired. certain sweeteninu. tlavoring Preferably, provided compositions should be formulated so or coloring agents may also be added that a dosage of between 0.01-100 mg/kg body weight/day [0281] Alternatively. phannaceutically acceptable compo- of the inlfibitor can be administered to a patient receiving sitions ol this invention may bc admimstcrcd m lhc form of these compositions. suppositories ibr riwtal adnunistration. Thcsc can bc pre- [0289] It should also be understood that a specific dosage pared by mixing the agent with a suitable non-irritating and trcatmcnt rcgunen lor dny particular patient will depend excipient that is solid at room temperanire but liquid at rectal upon a variety ol'aciors. including Ihc Bcuvity of the tempemture and therefore v ill melt in the rectum to release specific compound employed, the age. body weight, general the drug. Such materials include cocoa butter, beeswax and health, sex. diet, time of adnlinistration, mate of excretion, polyethylene lycols. dnig combination, and the judgiuent of the treating physi- [t)282] Pharmaceutically acceptable coinpositions of tlus cian and the severity of the particular disease bemg treated. invention may also be administered topically. especially The amount of a compound of the present invention in the when the target of treatment mcludes areas or organs readily coluposition will Blso ilcpclld llpoll thc ptirtlcilhll colllpoUlu! accessible by topical application, includin diseases of the ln thC CoillpUSI(loll. eye, the skin, or the lov er intestinal tract. Suitable topical formulations arc readily prcttarcd for each ol these areas or Uses of Compounds and Phanuaceuticdlly Acceptable Orgallw ('ompositions [0283] Topical application for thc lower intestinal tract can [0290] Compounds and compositions described herein are bc cfii c (cd in a rectal suppository fomlula (i on (scc above) or gcncrally useful for treatmmlt of cellular prohfcmtive dis- in d suitable cncma fonuulation. Topicallv-trmlsdemlal orders. As pmvidcxI above, thc compounds dcscnbed herein patches may also be used have bccn found capable ol'causing calcium rclcasc from thc [0284] For topical applications, provuled phamlaceuti- eildoplasnlic reticulum (i',8) via a putative ( a channel cally acceptable compositions may be formulated in a suit- known as Wolframin (Wl'Sl ). Inducing I:I( stress and the able ointment containing the active component suspiulded or "unfolded protein response" (UPI(), and resulting cell death. dissolved in one or nlore carriers. ('arriers tbr topical [0291] In some cmbodmlents, thc present invenuon pro- adnlinistration of compounds of this invention include, but vides a method for trcatulg a cellular proliferative disorder are not limited to. mineral oil, liquid petrolatmn. white in a patient comprising administenng to said patient a pctrolatiun, propylcnc glycol, polyoxycthylcnc. polyoxypro- compound of the present invention, or a composition com- pylmle compound, emulsifying wax and waler. Altenuo prisulg said compound. In some embodiments, the present tively. provided pharnlaceutically acceptable compositions invention provides a compound of the present invention, or can be formulated m a suitable lotion or cream containing d colupositioll colnpllslllg wlli! Oolllpound. for Usc ill thc the active components suspended or dissolved in one or treatment of a cellular prohfcrative disorder Such disorders more phamlaceutically acceptable carriers. Suitable carriers are described ul detail hcrcul. In some cmboduuents, a include. but are not limited to, minemll oil. sorbimn monos- cellular proliferative disorder is a cancer characterized by tcdratc. polysorbatc 60. cetyl caters wax, cetearyl alcohol, Wolframin (WFSI) overexpression In the cancer cells. In 2-octyldodccanol. bcnzyl alcohol and waicr. some embodiments, a cancer characterized by Wolframin [0285] For ophthalmic use, provided phamlaceutically (WFSI) overexpression is selected fmm non-small cell lung dcciptdblc composiuons may be lormulatwl as nucronized cancer (NSCLC), myeloma. muluplc myeloma, hcpatocel- sUspcuslons ill lsokllllc, pH ililjUslixl slixllc willnc, or, pli'.ll lular carculonui (HCC), breast cmlccr, bladder cancer, kid- erably. as solutions in isotonic, pl I adjusted sterile salme, ney cancer, mid melanoma. In some cmboduncnts, a method either v ith or without a preservative such as benvylalkonnun for treating a cellular proliferative disorder as described chloride. Alternatively, for ophthalinic uses, the pharnlaceu- herein further comprises determining the Wolfnlinin tically acceptable compositions may be formulated in an (WFSI) expression level. In some embodiments. the Wol- ointment such as petrolatum. franun (WFS I) expression level is determined by inununo- [0286] Phannaceutically acceptable compositions of tlus histochemistry and/or microamiy probe ultmlsity. invention may also be administered by nasal aerosol or [t)292J As used herein, the terms "treatment," "treat," and inhakltion. Such compositions are prepared according to "treating,'* refer to reveisin, alleviating. delaymg the onset (CChlliqlllCS Will-kllowil ill thc Bll Ol pllarlllaCCII(ICIII folunl- of. or inhibiting the progress of a disease or disorder, or one lauon and may bc prepared as soluuons m salute. employing or more symptoms thereof, as described herein. In come benzyl alcohol or other suitable preservatives, absorption embodiments, trcauncnt nuiy bc admulistcrcd after onc or pmmoters to enhance bioavailability. fluorocarbons, and/or more symptoms hale deleloped. In other cmboduuents, other conventional solubilizing or dispersing agents. treatment may bc admimstcnxl in the Bbscncc of symptoms. [0287] Most preferably, pharmaceutically acceptableconl- Iior exanlple, treatment may be aihninistered to a susceptible positions of this invention are formulated for onll adnliins- individual prior to the onset of symptoms (e 8 . in light of a US 20 ] 9/032265 [] A[ Ock 24, 2019 104

history of symptoms and/or in light of genetic or other leukemia. cluonic leukemia. chronic myelocytic leukemia, susciplibility factors). Trcalmcnt may also bc continued chroiiic I)'Iiipliocvtic lclikcliiia). pol)'cyuliciiiid vci'ti, lvlii- aller symptoms have rcsolvcd, for exiunple to prevent or phoma (c.g., Hodgkm*s disease or non-Hodgkin's discase), delay their recurrence Waldenstrom's macro lobulinemia, niultiple myeloina, [0293] In some embodiments, thc present uivwiuon pro- heavy chain disease, and solid tumors such as sarcomas and s ides a method I'or uiducing ER stress in a patient ui aced carcinomas (e.g., fibrosarcoma. myxosarcoma, liposarcoma, thereof, comprising administering a compound of the pres- chondrosarcoma. osteogenic sarcoma. chordoma. angiosar- ent invention, or a con)position comprising said compoiuid. coma, endotheliosarcoma. Iymphangiosarcoma. Iymphan- In some embodiments, the present invention pmvides a giomidothcliowdrcomd. synoiioma, mcsothclioma. Ewing's method for inducing the "unfolded protein response" (UPR) tumor, lciomyosarcomd, rhabdomyosurcoma, colon cdrci- in a paUcnl in nixd lhercol, compusing adnunislcruig a nonla, pancreatic cancer. breast cancer. Ovarian cancer, compound of the presmil invention, or a composiuon cum- pmstate cancer, squamous cell carcinonia, basal cell carci- pusuig said compound. In some cmboduncnls, lhc present noma. adenocarcinoma, sweat gland carcinoma, sebaceous invention provides a method for causing calcium release gland carcinoma, papillary carcinoma, papillary adenocar- fmm the endoplasmic reticulum (ER) via a putative ('s cinomas. cystadenocarcinoma, medullary carcinoma. bron- channel knoivn as Wolframin (WFSI) in a patient in need chogcnic camtnoma. renal cell carcinoma, hepatonui, bile thereof. comprising adminlsterin a compound of the pres- duct carcinoma, chouocarcinoma, scminoma. embryonal ent invention„or a composition comprising said compound. carcinoma, Wilm*s tumor, cervical cancer, uterine cancer, [0294] In some embodiments, the present invention pro- testicuLsr cancer, lung carcinoma. small cell lung carcinoina, vides a compound of any one of Formulas I-'vill. or a bladder carcinoma. epithelial carcinoma, glioma, astrocy- composiuon comprising said compound, for use in cinising toma, glioblastoma multifomle (CiBM. also known as glio- calcium release lyom thc endoplasnuc rcuculum (ER) via a blastoma). medulloblastoma„cmsniopharyngioma, putative Cas channel known as Wolfrmuui (WFSI) in a cpmidymoma, pincaloma. hcnuingioblastoma, acoustic ncu- subject in need thereof In some embodiments. the present roiiia. Uligodclidroglioiiia, scliw ililiioiiia. iicUIoliblosarciiiiia. invention pnivides a conipound of any one of Iiornlulas meningioma, melmioma. neuroblastonla, and retinoblas- I-'i IH. or a composition comprising said compound. for use toma) in inducing ER stress in a subject in need thereof. In some [0299] In some embodiments. the cancer is glioma, astro- mubodimcnts, thc presmil invention provides a compound of cyloma, ghoblaslomd mulufomic (CiBM, also known as dny one of Formulas IUPIII, or a cumposuion comprising glioblastoma). medulloblastoma. craiuopharyngiomd. said compound. Ior usc in uiducin lhe '*unfolded protein cpmidymoma, pincaloma. hcnuingioblastoma, acoustic neu- response" (I.JPR) in a subject in need thereof ron)a, oligodendmglioma, sclnvannoma. Ueurofibrosarcoma, [0295] In some cmboduueuls, lhe present uivenlion pro- meningioma, melmioma. neuroblastoma, or retinoblastoma vides a coinpound of I ornlula IL or a coinposition compris- [0300] In some embodiments„ the cancer is acoustic neu- ing said compound, for use m causing, calcium release front roma. Bstrocyloma (c.g. Grade I Pilocytic Astrocylomd. the endoplasmic reticulmn (I ig) via a putative ('s+ channel Grade II Low -grade Astrocyloma, Grade IB Anaplaslic known as Wolfmsmin (WFSI) in a subject in need thereof In Astmcysomm or (irade IV (ilioblastoma ((iBM)), chor- some embodiments„ the present invention provides a com- donla, GNS lyniphoma. craniopharyngionla, brain stem pound of Formula IL or B composition composing smd ghoma. ependymoma, mixed glioma. optic nerve glioma, compound. Rir use in inducuig ER stress ui a subject in aced subependymoma. medullobhsstonm. menin ioma, meta- thereof. In some embodiments, the present invention pro- static brain tumor, oiigodendroglioma, pituitary tumors, vides a con)pound of I'ornlula I. or a composition compus- punutivc neuroectodcnndl (PNET) tumor. or scliw aiuioma. ing said con)pound. for use in inducing the "unfolded protein In some embodiments. thc cancer is a t)pc found more response*'UPR) in a subject in need thereof cmnnlonly in children than adults, such as brain stem [0296[ 'I he activity of a compound utilixed in this inven- glionla, craniopharyngionm, ependymoma, juvenile pilo- tion as an inhibitor of cell proliferation may be arwsayed in cytic astrocytoma (.)PA), medulloblastoma. optic nerve vitro or in vivo. Detailed conditions for assaying a com- ghoma. pineal tumor, primitive neuroectodemml tumors pound in this invention are set forth in the Examples below. (PNET). or rhabdoid tumor. In some embodnnents, the patient is an adult human. In some embodiments. the paiicnt Cellular Prolifcrutive Disorders is a cluld or pediatric paumil. Cancer includes, in another embodiment, ivithout [0297] The present invenuon li:dturcs methods and com- [03()IJ bil- post)tous for lhc diagnosis and pro~roars of cellular prolilt limitation. mesothelioma, hepatobilliary (hepatic and bone cancer, pancreatic cancer, skin cancer, erative disorders (e 8, cancer) and the treatment of these liary duct), disorders ('ellular proliferative disorders described herein cancer of the head or neck, cutaneous or intraocular mela- Iioiiia. Uviiilaii cdiiccl; colors cBIiccr, rccL'0 ciiiiccr, caiiccl include. e.g. cancer. obesity, and proliferation-dependent of diseases. Such disorders may be dis nosed using methods tlic diiiil rcgioii. sloiiiacli cdiiccl, gastroiiilcsliiitil (gBslric. colorectal, and duodenal), uterine cancer, carcinoma the known in the art. of fallopian tubes, carcinoma of the endometriunl. carcinoma Caliccr of the cervix. carcinoma of the vagina, carcinoma of the vulva. Hodgkin's Disease, cancer of the esophagus, cancer [0298] Cancer includes, in onc mubodimenl. v,ilhoul linu- Uf tlic sliiall iiilcsl itic. cdiiccr of llic i iidocriiic sYstciii, cBiici i taUon, leukemias (c.g., acute leukemia, acute lymphocylic Of(bc thyroid gland. cancer ol tlu: puralhyroid gland, cancer lmikcmia. acute myclocytic leukemia, acute mycloblastic Uf thc adrcital gland, sarcoma of soft Ussuc, cancer of lhe leukemia. acute proniyelocytic leukemia, acute myelomono- urethra, cancer of the penis. prostate cancer, testicuLsr can- cytic leukeinia, acute ilioilocytic leukemia, acute erytluo- cer. chronic or acute leukemia, chronic nlyeloid leukemia, US 20]9/0322658 A[ Oct. 24, 2019 105

lympinlcytic lymphomas. cancer of the bladder. cancer of colon cancer. rectal cancer. anal cancer, ovarian cancer, &hc kldncv or Urcnu, rcn&ll cell calcnninla, c&ircinonl&I iif &hc ovarian epithelial cancer, ovarian carcinoma. fallopian tube renal pcb is. non-Hodgk&ns's lymphoma, spinal ax&s tumors, cancer, papillary serous cystadenocarcinoma. uterine papil- brain stenl glioma, pituitary adenoma. adrenocortical cancer, lary serous carcinoma (UPSC). hepatocholangiocarcu&orna, all bladder cancer, n&ultiple myekmlm cholangiocarcinoma, soft t&ssue and bone synoviai sarcoma, rhabdomyosarcoma, fibrosarcoma, neuroblastoma, retinobiastoma. or a combi- osteosarcoma, chondrosarcoma. anaplasnc &hyro&d cancer. nation of one or more of the foregoi»g cancers. adrenocortical carcinoma. pancreatic cancer, pancreatic duc- [0302] In some embodiment~, the cancer is selected from tal cdrcu&orna, pancrcauc ddenocarcinoma. gl&orna, brain hcpdniccilUldr cdrcnlonul, ovdrlan cdnccl, ovallBU cplthchdl cancer, neuiofibromatosis-1 associated malignant peripheml cancer, or fallopian tube cimccr, pap&llary serous cystadc- ncrvc slmdth tumors (MPNST), Waldcnstrom's macroglobu- nocdrc&noma or u&cru&c pap&llary serous cdrculoma (UPSC), linemia, or inedulloblastoma pmstate cancer; testicular cancer; gallbladder cancer, hepatochoianglocarcino&uat soft tissue and bone svnovial [0306] In some embodiments. the cancer is selected from sarcoma; rhabdomyosarcoma; osteosarcoma: chondrosar- hepatocellular carcinoma (I IG('). hepatoblastoma. colon coma; Ewing sarcoma; anaplastic thyroid cancer: adreim- cm&cer, rectal cancer. ovarian cancer. ovarian epithelial can- corticnl adcnoma, pancrca»c cancer: pdncrcalic duclai car- cer, ovarian cdrcu&orna. fallopian tube cancer, papillary cnlonnl 0& pane&i a&le &IdcnocB&ca&on&a: g&isuolnn:sfin&ll/ serous cystadenocarcinon&a, uterine papillary serous carci- s&omach (GIST) cancer, lymphoma, squamous cell noma (UPSC), hcpa&ocholang&ocarc&noma, sof& ussuc and carcinoma of the head and neck (S('( I IN); salivary gland bone synovial sarcoma. rhabdomyosarcoma, osteosarcoma, cm&cer; glionla, or brain cancer; neurofibromatosis-I asso- anaplas&ic thyroid cancer. adrcnocorncal care&noma, pm&crc- ciated mali~ant peripheral nerve sheath tumors (MPNST), atic cancer, pancreatic ductai carcinoma. pancreatic adeno- meduliobiastoma. Waidenstrom's macro lobulinemia: or carc&noma, gliomd, ncuroiibromalos&s-I assoc&a&cd nmlig- [0303] In some embodiment~, the cancer is selected from nant peripheral nerve sheath tun&ors (MPNS'I'), hcpdtocellular care&noma (HCC), htpatoblas&orna. colon Waldenstrom's macroglobulinemia, or medulloblastoma. cancer, rectal cancer. ovarian cancer, over&an tp»hehal cancer. fallopian tube cancer. papillary serous cystadenocarcl- [0307] In some nnbodnnnlts, &hc cancer &s hcpatocciluldr noma. utenne papillary serous carcinoma (UPSG), hepato- care&noma (HCC). In some cmbodimen&s. &hc cancer &s cholangiocarcinoma, soft tissue and hone synovial sarcoma, hepatoblastoma. In some enlbodiments. the cancer is colon rhabdon&yosarcoma. osteosarcoma. Bnaplastic thyroid cm&- cancer In some embodiments, the cancer is rectal cancer. In cer. adrenocortical adenoma, pancreatic cancer. pancreatic some embodiments. the cancer is ovarian cancer. or ovarian dUCt&ll CIII Chion&B, panCICd&&C &IdcnOCBICnlonla, ghoul&I, UCU- care&noma. In some embodiments, the cancer is ovarian lofibronul&osis-I dssoc&B(cil nlallgnanl pcrlphcldl ncrvc ep&thelial cancer. In son&e embodunents. the cancer is fal- sheath tumors (MPNSI'). Waldenstmm's macroalobubne- lop&an tube cancer. In some embod&ments, the cancer is nlia. or meduiloblastoma. pap&llary serous cys&adcnocarc&noma In some embodi- the cancer u&crine serous carcinoma [(1304] In some embodin&eats, the present invention pro- ments, is papillary vides a method for treating a cancer that presents as a solid (IJPS('). In some embodiments, the cancer Is hepatochoksn- giocarcinoma. In some elnbodiments. the cancer is soft tun&on such Bs al sarconni. cafe&non&a, of lynlphonla, con&- prising the step of admirustering a disclosed compound. or tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the pimmumeu&icdlly acccptablc sall &hereoi: &o a pat&cnt &n siinlc niwd thereof Solnl tumors generally comprise an abnom&al cilnccl Is os&cosdrcomd. In cnlbixhnlcn&s, lhc t&lacer ls dnilplas&lc &h)'olid cancer. In sonu: cnlbodlmcnls, Ihc cBnccl mass of tissue tl&at typically does not include cysts or liquid is In some en&bodiments. the areas In sonic emlxldin&ents, the cancer is selected fron& adrenocortical carcinoma. renal cell carcinoma, or lndney cancer: hepatocelluiar car- cancer is pancreatic cancer. Or pancreatic ductal carcino&na adenocarci- cinoma (HCC) or hepatoblastoma. or liver cancer; meLa- In some embodiments. the cancer is pancreatic is non&a; breast cancer: colorectal carcinoma, or colorectal noma. In some embodiments. the cancer lioma. In some cancer, coliin cancer, fcc&al cdnccf, anal cancel: 1ialg cancer, embodiments. the cancer is malignant peripheral nerve such as non-snuill cell lung cancer (NSCLC) or small cell sheath tumors (MPNST). In some embodunn»s, thc cancer lun cancer (S('I ('); ovarian cancer. ovarian epithelial can- is ncuroiibromatosis-I associa&ed MPNST. In some embodi- Waldenstrom's cer. ovarian carcinoma. or fallopian tube cancer; papillary ments, the cancer is macmglobulinemia. In serous cystadenocarcinoma or uterine papillary serous car- some embodiments. the cancer is medulloblastoma cinon&a (UPSC): prostate cancer: testicular cancer: allblad- [0308] The present invention hirther features methods and der cancer; hepatochoL&mgiocarCinom: soft tissue and bone compositions for the diana&sis, pmgnosis and treatment of synov&al sarcoma, rhabdomyosarcoma, os&ex&sarcoma, chon- vlrdl-dssocla&cd cJnccls, hlchahng hunldn nnnnnlixlcli- drosarcoma, Ewu&g sarcoma, anapldsnc &hyro&d cancer, c&ency v&rus (HI&/) assoc&dtcd solid tumors, humml pap&1- adrenocortical carcinoma; pancreatic cancer; pancreatic lorna v&rus (HP) )-16 positive incurable sol&d tumors, and ductal carcinoma or pancreatic adenocarci&xmm; gastroin- adult 1&cell leukemia, ivhich is caused by human Itcell testinal/stomach (CiIST) cancer: lymphoma: squamous cell leukenna vims type I (I 111)(i) and Is a highly aggressive carcinon&a of the head and neck (SCCHN); salivary gland form of CD4+ T-cell leukemia characterized by clonal cancer; glioma, or bmin cancer; neurofibromatosis-1 asso- integration of HTL)ti in leukemic cells (See https://clini- c&dtcd malignant pcnphefdl ncrvc shee&h tumors (MPNST), cal&rials.gov/ct2ishow/study/NCT02631746), as well as Waldcnsuom's macroglobulincmia: or mixiulloblastoma. virus-assoc&&&ted &Unuirs hl gast&le cdnciu, ndsophB&yn cal [0305] In some nnboduncnts, thc cancer is selec&cd from Oil&ca&on&B, ccrvlcill cdnccn vdgurJI cancer, vidvdr canccn renal ceil carcinoma. hepatocelluksr carcinoma (I IC(:), squamous cell carcinoma of the head and neck, and Merkel hepatoblastoma, colorectal carcinoma, colorectal cancer, cell carcinoma. (See httpsapchnicaltrials.gov/ct2/show/ US 20 J 9/032265 [J A[ Oct. 24, 2019 106

snidy/NCT02488759: see also https://clinicaltrials.gov/ct2/ [0312] Phanuaceutically acceptable compositions of tlfis sho&v/study/N('1 024088(&; https://clinicaltrials.gov/ct2/ invenhon can beaihn&rustercd &o humans and other mumals show/NCT0242(i892) orally, rectally, parenterally. intracistcn&ally, &ntravaginally, intraperitonealiy, topically (as by powders, 0&ntments. or [0309] In some cmbodunen&s, the present u&venhon pro- dmps), bucally, as an oral or nasal spray, or the like, 1&dcs a mc&hod for treeing a cancer in a pa1&en& u& need depending on the severity of the disease or disorder being thereof. aihuinistering to the the comprising patient any of treated. In certain embodiments, the compounds of the compounds. salts or pharmaceutical co&npositions descnbed invention may be aihninistered orally or parentemlly at herein In some embodiments, the cancer is selected fronl dosage lcvcls oi'bou& 0.01 mg/kg to about 50 mg,'kg and the cancers described herein. In some embodiments. the prcfcrably Ihom about I mg/kg to about 25 mg/kg. 01'uit act cancer is melanoma cancer. In some embodiments. the body weight per day, one or more times a day, to obtain the cancer is breast cancer In some cmbud&mcn&s. thc cancer is des&red therapeutic efiect. lung cancer. In some cmboduncnts, fi&e cancer &s small cell [(O13J I.iquid dosage ti&mls for oral aihuinistnstion luna cm&cer (S('I (') In son&e embodiments. the cancer &s include. but are not limited to„phannaceutically acceptable non-small cell lung cancer (N)('I,('). 10 some embodinlents, ennils&ons. microemulsions„solutions, suspensions. synips the cancer &s myeloma In some embodiments. the cancer &s and ehx&rs. In add&uon to the acuvc compounds. thc liquid multiple myeloma. In some embodiments. the cancer &s ilosagc fonus univ'on&an& hu:rt dlhx:nm conunonlv used hl bladder cancer. In some embodiments, the cancer is kith&ey the ar& such as, for cxmnplc. Ua&cr or o&hcr solvcn&s, cm&ccr. In some mnbod&ments, thc cancer &s hepatoccllular solubilizing agents and emulsifiers such as ethyl alcohol, cdrcu&orna (HCC). In some embodiments. thc cm&cer &s isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl nlelanoma. In some en&bodiments. the cancer i ~ colorectal alcohol. benzyl benzoate, propylene glycol. 1.3-butylene cm&cer. In some en&bod&n&cuts. the cancer i ~ endometnal glycol, dimethylfonnamide, oils (in part&cular. cottonseed, cm&cer. In sonic embodiments, the cancer is cancer of the gro&indn&i&, con&, gcrnl. tlhvt) cds&or. Bnd scstinlc 0&ls). esoplmgus. In some embodiments, the cancer is pancreatic

glycerol, tctrahydrofuri'uryl alcohol, polyethylcnc glycols cancer. In some embodunents. the cancer is renal cell and fa&ty acul caters 01 sorb&tan, and m&xuircs &hereol. cd& cnxuua.

13estdes inert diluents, the oral compos&tions can also [0310] In some mnbod&mcn&s, the tumor is treated by include adjuvants such as &vetting agents, emulsifying and arresting further the tumor. In some embodin&ents, gmwth of 0&'ass) suspending agent~, s&veetening. fiavonng. and perfumin the tumor is treated by reducu&g the size (e.g . volume a ents. of the tumor by at least 5%. 10%. 25%. 50%. 75%, [0314] In[actable preparations. for example. sterile i»ject- 90;o or 99o/o relative to the size of the tumor prior to ablc aqueous or olcdg&nous suspens&ons may bc fora&uiatcxl treatment. In some embodiments, tumors are treated by according to thc known art usu&g su&table dispersing or rixiucu&g Ihe quanuty of Ihc tumors u& lhc patmn& by a& less& wetting agents and suspending agents 'I'he stenle &njectable 5o/o. 10!o. 25%, 50%. 75%, 90%v or 99.o relet&ve 10 thc preparation may also be a sterile ultectable solut&on sus- qum&tity of tumors pnor to treatment pension ol'inillslon 11'I a nontox&c pa&'enter,'lily'cceptable [(1311J 'I'he compounds and compositions, according to the diluent or solvent, for example„as a solution &n 1,3-butane- metlu&d of the present invention, may be administered using diol. A&nong the acceptable vehicles and solvents that may iso- any amount and any route of administration efiective for bc employed arc water. Ringer's soluuon, UdkP. and tonic sodlUU& chlorulc SUIUfion. did&non, sterile, f&xcd 0&ls lrcatulg or Icsscnulg thc sever&&Y t&1 a cell&&IBI plohfc&Bfivc hl as a d&sorder. The exact amount rcqu&rcxl w&ll vary from subjec& are conventionally employed solvent or suspending, l&or to subject. depm&du&g on thc species. age, and gm&eral medium this purpose any bland fixed oil can be condition of the subtect. the severity of the disease or employed including synthetic mono- or diglycerides In condition, the particular agent. its mode of administration, addition, fatty acids such as oleic acid are used in the and the like. Compounds of the invention are preferably preparation of injectables. fonnufilted in dosage unit form for ease of administration [0315] In[actable formulations can be sterilized. for and uniformity of dosage. The cxprcssion "dosage uni& example, by liltration tluough a bactcnal-rcta&n&ng Iiltcr. or form" as used herc&n refers to a physically discrete unit of by &ncorporating s&cnhzu&g agm&ts &n the I'onn of stcnlc solid agent appropria&c lor &1m pa&icnt Io be treatcib It w&ll be cmupositions lvhich can be dissolved or dispersed in sterile understood. however, that the total daily usage of the con&- water or other sterile injectable nled&um pnor to use pounds and composit&ons of the present invention v ill be [t)31&5] In order to prolong the eifect of a compound ofthe decided by the attending phys&cian within the scope of sound present invention, it is often desirable to slow the absorption medical judgment. The specific effective dose level for any of the compound from subcutaneous or intramuscular injec- paruculdr patim&t or organism w &11 dcpm&d upon a vancty of t&on. Tlus may bc accomplished by the usc of a liquid factors u&cludu&g the dwordcr beu&g treated and fi&escvcrity suspm&s&on Of crys&all&nc or &Umirphous matcnal with poor of &hc dlsordcl', thc Bctlvnv 01 &hc spci'1(&c conlpoUnd wa&cr solub&hty. Thc rate oi'bsorpuon of thc compound employed: the specihc compos&tion employed: the age, body then depends upon its rate of dissolution that, in turn, &nay weiaht, eneral health, sex and diet of the patient; the time depend upon crystal size and crystalline form Alternatively, of administration. route ofadministration, and rate of excre- delayed absorption of a parenterally administered compound tion of the spec&fic compound employed; the duration of the form &s accomplished by dissolving or suspending the com- trcaimm&t: drugs used in combinahun or coincxlcntal w&lh pound &n an o&1 vehicle. Injec&able depot forms are made by thc spec&lic compound employed, dnd hkc factors well fi&rming micme&mdpsulc ma&ncaa oi'hc compound u& bio- known &n thc medical arts The term '*pa&icnt", as used dcgradablc polymers such as polylactule-polyglycol&dc. herein. means an animal, prefensbly a mammal, and most Depending upon the mtio ot compound to polymer and the prefembly a ln&man nature of the particular polymer employed, the mate of US 20]9/0322658 A[ Oct. 24, 2019 107

compound release can be controlled. Examples of other opaclfying agents and can also be of a composition that they biodegradable polymers include poly(orthoesters) mid poly reiciisc thc active hlglcdlt:nt(s) only', or pl'cfclcntlallvt hl B (anhydndes). Depot In)cctablc I'ormulatlons are also pre- certain part oi the ultcstinal tract, opuonally. In a delayed pared by entnlpping the compound in liposomes or nucro- manner I ixamples of embedding compositions that can be enntlsions that are compatible with body tissues. used include polymeric substances and waxes [0317J (:ompositions filr rectal or vaginal administration [0321] Dosage forms for topical or transdermal adminis- are preferably suppositories which can be prepared by tration of a compound of this invention include ointments, mixing the compounds of this invention with suimbie non- pastes. cream~. lotions. gels, pov,ders, solutions. sprays, irnuitulg cxctplcnts or camera such as cocoa butler, poly- inhalmlts or patches. 11&c aetna componmlt is adnuxod cthylcne glycol or a suppository wax which are solid at under stcnle conditions with a pharmaccuticdlly acccptablc ambient tcmperaturc but hquid at body tempcralure and carrier and any needed preservatw cs or buifi:rs as may bc therefore melt In the rectunl or vaginal cavity and release the required Ophthalntic formulation. ear drops, and eye du)ps active compound are also contemplated as being within the scope of this [t)310] Solid dosage forms for oral administration include invention. Additionally. the present invention contemplates capsules. tablets, pills, powders. and granules. In such solid the use of transdemlal patches. which have the added dosage fonna. the active compound is mixed w:ith at least advantage ofprovnlmg controlled dchvcry of a compound to one ulert. pharmaccuttcdlly acceptable cxclpimlt or carrier the body. Such dosage fonna can bc made by dissolvulg or such as sodium citratc or dicalcium phosphate and/or a) dispensing Ihe compound in thc proper nuxhum. Absorption fillers or extenders such as starches. Llctose, sucrose, glu- enhancers can also be used Io increase the flux of the cose, mannitol, and sthcic acid. b) binders such as, fiir cmnpound across the skin. 'I'he rate can be contlolled by example, carlxixymethylcellulose. alginates, gelatin. poly- either providin a rate controlling membmne or by dispers- vinyipyrrolidinone. sucrose. and acacia. c) humectants such ing the compound in a polymer matrix or gel as glycerol. d) disintegratmg agents such as agar-1 ar, [0322] In some embodiment. the invention relates to a cdlclonl ctilbonB)c. potato ol tdploca slat'ch. Idguuc acid, method oi'nduculg ER stress in a biologtcdl sample com- ceruim sthcates, and sodium carbonate, c) solulion retarding pnstng thc step of contactmg said biological sample with a agents such as paraflin, f) absorption accelerators such as compound of this invention. or a conlposition comprising, quaternary amnlonium compounds, g) wetting agents such said compound as. for example, cetyl alcohol and glycerol nxinostearate, h) [0323[ In some embodiment, the imentton relates to a absorbents such as 11olin and bentonite clay, and i) lubri- method of inducing the "unfolded pmtein response" (UPR) cants such as talc, calcium stearate. magnesium steamte, in a biolo ical sample comprising the step of contacting said sohd polyethylcnc glycols. soihum lauryl suit'dlc, and nux- biolo ical sample with a conlpound of tins invention. or a turcs thercofi In thc case ol'apsules. tablets mid pills, the composition compnsulg said compound dosaae form may also conlprise butfering agents [0324] In certain cmbodimcnts, thc Invenuon relates to a [0319[ Solid compositions of a similar type may also be method oi'ausing calcium release from the cndoplasmic employed as fillers m soft and hard-filled gelatin capsules reticulum (IIR) via a putative ( as channel known as VVO)- using such excipients as lactose or milk sugar as well as hi h framm ()VFS I ) in a biological siunple conlprising the step of molecular wei ht polyethylene glycols and the like. The contacting said biological sample with a compoluld of this solid dosa e fiinns of tablets, dra ees. capsules. pills. and invention, or a composition comprising said compound. gl'inluliw ciul bc pl'epBrcd with coatnl s Bnd shells silch ils [0325] The term "biological sample**, as used herein, mlieric coatings and other coatings well known in thc lncliides. w i)built hnllttitltui. cell col liil'cs or cxtldc'hcrctif, I'hey phanuaceutical formulating art may optionally con- blopsicd matcnal obtauled Irom a manunal or extracts tain opacih in agents and can also be of a composition that thereof; and blood, saliva, urine, feces. Senlen, tears. or other they release the active ingredient(s) only, or preferentially. in body Ihiids or extracts thereof a certain part of the intestinal tract. optionally, in a delayed manner. Examples of embeddin compositions that can be Co-Adnunistration ol'Addluonal Thcrapeuuc Agents used include polymemc substances Imd waxes. Solid compositions of a similar type may also bc mnployed as Iillcrs [0326] Dcpcndin upon the particular condition, or dis- in soft and hard-tilled gelatin capsules using such exciptents ease, to be treated. additional therapeutic agents that are as lactose or milk sugar as well as high nxilecular v eight normally adininistered to treat that condition, may also be polyethylene glycols and the lil e. present In the compositions ofthis invention. As used herein, [0320] The active compounds can also be in micm-encap- additional therapeutic agents that are nomlally administered sulated form v,ith one or more excipients as noted above. to treat a particular disease, or condition, are known as Thc solid doss e forms of tablets, dragees, capsules, pills, "appropriate for the disease, or condition, being treated." dnd granules can bc prcparcd with coatings and shells such [0327] In some cmbodmlents, thc present invenuon pro- ds en)eric coatings, release conlrollulg coaungs and other vides a method of treeing a disclosed discase or condition coatings ivell known in the pharmaceutical tbnnulating art. comprising administering to a patient m need thereof an ln such solid dosage forms the active cotnpound mav be etfective mnount of a conlpound disclosed herein or a aihnixed ivith at least one mert diluent such as sucrose, phannaceutically acceptable salt thereof and co-administer- lactose or starch. Such dosage forms may also comprise, as in simultaneously or sequentially an efl'ective amount of is nomlal practice. additional substances ofller tlrul Inert onc or more additional therapeutic agents, such as those dllucnts. e.g., tabletulg lubncants mid ofller tablcting aids described herein. In some mnboduncnts, thc method such II nlilgnt:S1unl stctiratc Bnd nuclocrvslalhnc cellillosc. In includes co-adnunlstcnng onc additional therapeutic d cnt. the case of capsules. tablets and pills, the dosage forms may In some embodiments, the nlethod mcludes co-administer- also comprise butfering agents. 'I'hey may optionally contain ing two additional therapeutic 1 ants. In sonic embodiments, US 20]9/0322658 A[ Oct. 24, 2019 108

the combination of the disclosed compound and the addi- eca). an a onistic hexameric C)ITR-hgand molecule with a tional iherapeunc agmlt or agents acts synergistically. human IgGI Fc donuiin. in advanced so)xi timiors [0328] In some embodiments, the additional therapeutic (NCT02583)65). dgcnt ls sclcctixl Irolu an utmtunostuuulatoty Ihcldpeufic [0334] Other checkpoint inlubitors that may bc used in thc compound. In some embodiments, die unmunostunulatory present invention include uiduciblc T-cell co-sumulator therapeutic compound is ac)ected from clotuzunuib, mifa- (ICOS, also known as CD278) agolusts ICOS agonists Gist munide. an agonist or activator of a toll-like receptor, or an are being studied in clinical trials include Ml:DI-570 (Med- activator of RORyt iinnmne), an agonistic anti-I( OS antibody, in lymphonias [0329] In some cmboduncnts, thc medlod I'urlhcr com- (NCT02520791): (JSK3359609 (Merck & Co.). an agonistic prises administering to said patient a third therapeutic agent, anti-ICOS antibody, in Phase I (NCT02723955); ITX-2011 such as an immune checkpoint inhibitor in some embodi- (Jounce Therapeutics), an agomstic anu-ICOS antibody, in ments. the method comprises administering to the patient in Pliase I (NCT02904226). need thereof tluee thempeutic agents selected Ibom a com- [0335] Other checkpoint inhibitors that may be used in the pound disclosed herein or a phannaceuticdlly accepuiblc sall present uiventlon uicludc killer IgG-like receptor (KIR) Ihereol, an immunosumulatory Iherapcullc compound. and inhibitors. KIR inlubitors that are bmng studied in cliiucal dn immune checkpouit ullubitor. tnals include lirilumab (IPH2102/BMS-986015, Innatc [0330] Other checkpoint inlubitors that may bc used ui the Pharma/Bristol-Myers Squibb). an anti-KIR antibody. in present uiventlon include OX40 agoiusts. OX40 agomsts leukennas (N('101687387. N("I()23')')917, N('I'02481297, that are beiim studied in clinical trials include Pli-04518600/ NCT02599649), multiple myeloma (NCT02252263). and Pli-8600 (Ptizer). an agonistic anti-OX40 antilxidy. in meta- lymphoma (NCT01 392370)t IPH2101 (I-7F9. Iiuiate static kidney cancer (N('1'03092856) and advanced cancers Plianna) in myeloma (NCT01222286 and NCT01217203), and neoplasms (NCT02554812: NCT05082566), and IPH4102 (huiatc Plmmui). an anu-KIR anubody that GSK3174998 (Merck & Co.), an agonistic anti-OX40 anti- binds Io three domauis of Ihc long cytoplasmic tml body. in Phase I cancer trails (NCT02S28357); MED10562 (KIRJDI,2). in lymphoma (N("102593045) (Mcxlinununc/AstraZcncca), mi agoiustlc anti-OX40 anti- [0336] Other checkpoint inlubitors that may bc used in thc body. in advanced solid tumors (N("I'0023183')4 and present invention inchide ('l)47 inhibitors of mteraction N('T02705482); Mill))6469, an agonistic anti-OX40 anti- between Cl)47 and signal regulatory protein alpha (SIRPa) body (Medimmune/Astra/eneca), in patients ivith colorectal ('l)47/SIRPa inhibitors tliat are being studied in clinical cancer (NCT02559024). breast cancer (NCT018(i2900), tnals include ALX-148 (Aiexo Therapeutics). an antagonis- head and neck cancer (NCT02274155) and metastatic pros- tic variant of (SIRPa) that binds to CD47 and prevents tate cnnccr (NCT01303705): imd BMS-986178 (Bnstol- CD47/SIRPS-media(cd signaling, ln pliasc I Mycrs Squibb) an agonistic anti-OX40 mitibody, in (NCT030)32)8), TTI-621 (SIRPS-Fc, Trillium Therapeu- advanced cancers (N('f02737475) tics), a soluble reconlbinant fusion protein created by linking [0331] Other chcckpouit ulhibitors 01st may bc used in thc the N-terminal (.'1)47-binding domain of SIRPa with the I'c pn:sent lllvciltloll include CD137 (also call&xi 4-IBB) ago- doniam of lnunan Ig(il. acts by binding hunian ('D47, and nists. ('D137 agonists that are being studied in clinical tnals preventing it from delivering its "do not eat*'ignal to include utomilunlab (Pli-050825(i6, Pfizer) an agonistic macrophages. is in clinical trials in Phase I (NCT02890368 anti-('D137 antibody„ in difiuse lar e B-cell lymphorna and NCT026G3518), CC-90002 (Celgmlc), an anu-CD47 (NCT02951156) and in advanced cancers and neophlsms antibody, in leukennas (NCT02641002), and HuSF9-G4 (NCT02554812 and NCT05082566); urelumab (BMS- (liorty Seven, Inc.). in colorectal neoplasms and solid 663513. Bristol-Mycrs Squibb), an agomstic anu-CD137 tumors (N("f02953782). acute nlyeloid leukemia antibody, ui mclmloma mid skui cancer (NCT02652455) and (N(''02678338) and lymphoma (N(yl'02953509) lioblastoma and gliosarcoma (N("I'02658981) [0337] Other checkpoint inhibitors that may be used in the [0332] Other chcckpouit ulhibitors 01st may bc used in thc present mvention include ( l)73 inhibitors. ('1)73 inhibitors prcscnt invention ulcludc CD27 agonists. CD27 agomsts that are being studied in clinical trials include Mill)19447 that are being studied in clinical trials include varlilumab (Medimmune), an anti-CD73 antibody. in solid tumors (Cl)X-1127, ('elldex 'I'herapeutics) an agonistic anti-('D27 (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), antibody„ in squamous cell head and neck cancer. ovarian an mlti-CD73 anubody. ui solid tumors (NCT02754141). carcinonla, colorectal cancer, renal cell cancer. and glioblas- [0338] Other checkpoint inhibitors that may be used in the toma (NCT02335918): lymphomas (NCT01460134): and present invention include agonists of stinuilator of interferon gllomd and astrocytoma (NCT02924038). genes protein (STING. also known as transmcmbranc pro- [0333] Other checkpoint inhibitors that may be used in the tcul 173, or TMEM173). Agoiusts of STING that arc beuig pn:sent ulvcntl oil uu:litic glilcocolllcold-unlaced Ilinlor studied in clinical trials include MK-1454 (Merck & ('o.). an nixrosls factor receptor (GITR) agorusts. GITR agonists that agonistic synthetic cyclic dimicleotide, in lymphoma dre being studtcxt ul clinical tnals include TRX518 (Leap (NCT03010176); and ADU-S)00 (MIW815. Aduro Bio- 'I'henlpeutics). an agonistic anti-(il'I'R antibody. in malig- tec)t/Novaltis). an agonistic synthetic cyclic dinucleotide, in nant melamlma and other maligimnt solid tumors Phase I (NCT02675439 and NCT03172936) (NCT01239134 and NCT02628574); (.IWN323 (Novartis), [0339] Other checkpoint inhibitors that may be used in the an agonistic anti-CHTR antibody. in solid tumors and lym- present mvention include CSFIR inlfibitors CSFIR inhibi- phoma (NCT 02740270), INCAGN01876 (Incyte/Agmlus), tors that arc being stuthcxl ul clinical trials include pcxtdar- an agomstic anti-C)ITR antibody, in advanced cancers tuub (PLX3397, Plcxxlkon), a CSFIR small molecule (NCT02697S91 and NCT0312G110): MK-4166 (Mcrck & inhibitor, in colorcctal cancer. pancrcauc cancer. metastatic ('o ), an aaonistic anti-()11 K antibody. in solid tumors and advanced cancers (NC'I 02777710) and nielanoma, non- (NC'102132754) and Mill)H1873 (MedimimuieiAstra/en- small cell lung cancer. squmnous cell head and neck cancer, US 20 ] 9/032265 [] A[ Oct. 24, 2019 109

astrointestinal stmmal tumor (C)IST) and ovarian cancer that may be used in the present invention is recombinant (NCT02452424), aud IMC-CS4 (LY3022855, L&lly), an human u&terlcukul 12 (rhIL-12). Another su&table IL-15 anti-CSF-IR m&t&body. u& pancrcauc cancer based inuuunothcrapcuuc is hctcrod&mcnc IL-15 (hc&IL-I 5, (NC'I 03153410), melanoma (NC I'03101254), and solid Novaitis/Admune), a fusion complex composed of a syn- tumors (NC1 027189 H ); and l3),/945 (4-[2((1R,2tt)-2-hy- thet&c form of endogenous 11,-15 complexed to the soluble droxycyclohexylamino)-benzothiazol-6-yloxyl]-pyriihne-2- IL-15 binding protein IL-13 receptor alpha chain (ILI 5:sIL- carboxylic acid &uethyla&Bide. Novartis). an orally avaiLable 15RA), which has been tested in Phase I clinical trials for inhibitor of CSFIR, in advanced solid tumors melanoma, renal cell carcinonm. non-small cell lung cancer (NCT02829723). dlld hCad illul 1&CCk agua&nous CCII CarC&1&olua [0340J Other checkpoint inhibitors that may be used in the (NCT02452268). Rccombu&ant luunau &ntcrlculon 12 (rldL- present invention include NKG2A receptor inl»b&tora. 12) has been tested in the chnic for many oncological NKO2A receptor inhibitors that are heing studied in clinical indications, for example, as a therapy for lyn&phoma (NM- trials include monalizumab (IPH2201. Innate Phanna). Bn IL-12. Ne&unedicines, Inc )„(NCT02544724 and dnt&-NKG2A ant&body. u& head and nock neoplasnw NCT02542124). (NCT02643550) und chroiuc lymphocytic leukemia [0349] In some cmbodimm&ts. thc PI3K u&lubitor is (N('1 02557516). selected from idelalisib, alpelisib. taselisib, pictilis&b, copan- [0341] In some embodiments, the imnnme checkpoint lis&b, duvelisib, Pt)IL309, or 'it)R1202 inhibitor is selected from nivolumab. pembrolizumab, ip&li- [0350] In another aspect, the present invention provides a mumab, aiclumab, durvalumab, atczohzumab, or pidil&- method of treating cancer ul a pat&cnt u& need thereol. zllludb. wherein said method comprises aihn&nwtcring to saul paiient [0342] In another aspect. the present im en&ion pmvides a a compound disclosed herein or a pharmaceut&cally accept- metluld of treating cancer in a patient in need thereof, able salt thereof in combination w&th one or more additional w barmn sa&d nu thod composes adnunislcnng to sa&d pat&wit therapeutic agents selected from B platinum-based therapeu- d compound d&sclosixl herein or a phanuaccuucally accept- tic. a taxane. a nucleoside inhibitor„or a themspeutic agent able salt thereof &n comb&nat&on w&th onc or more additional that interferes with normal DNA synthesis. protein synthe- therapemic agents selected from an indoleamine (2.3)-d&- s&s, cell replication, or will od&cruise &nh&b&t rapnlly prolil- oxygenase (IIX)) inhibitor, a Poly ADV ribose polymerase eraung cells. (PARP) inhibitor, a histone deacetylase (HDAC) inlgbitor. a [0351] In some embodinlents. the platinum-based thera- CDK4/(:DK6 inhibitor, or a phosphatidylinositol 3 kinase peutic is selected from cisplatin. carboplatin. oxaliplatin, (P13K) inlubitor. nixlaplatin, picoplatin. or satraplat&n [t)343] In some enlbodinlents. the IDO inhibitor is selected [0352[ In some embodiments. the taxane is selected from fmm epacadostat, indoximod, capmanitib. (iDC-091'), pacl&taxel, docetaxel. albumin-bound paclitaxel. cabavi- PF-06840003, BMS:F001287, Phy906&/KD108, or Bn taxel. or SID530. enzyme that breaks dov n I ynurenine. [0353] In some embodiments. thc thcrapcutic agent thai [0344] In some embod&ments, ihe PARP &ulubitor is iuterli:rcs w 1th normal DNA synthes&s, protmn synthes&s, cell selected from olaparib, n&caparib. niraparib„ iniparib, tala- replication, or will othe&wise interfere with the replication of zoparib, or veliparib nspidiy proliferating cells is selected fron& trabectedin, [0345] In some embod&ments, the HDAC mlubitor &s mechlorethamine. vincristine„ temozolonude. cytarabine, sclcctcd from vonnostat, rom&dcpsin. pdnobuxlslat. bclimls- lonulstine. azacitidine. omacetaxine mepesuccinate, aspara- tat. entinostat. or chidanl&de gllldsC Eru'&B)il C/ir/'Sill&//u lai, Crib&ill&i &l&Csvkl&C, CiipBCC- [0346] In some cmbodimenis, the CDK 4/6 &ulubitor &s tru&c, bcndanu&stine, &xabcpilone, uclacdb&nc, cloral'abu&c, sclccted Ibom palboc&cl&b, nbocicl&b, dbemacicl&b or tnlac&- tniluridinc, or t&pirac&1. clib [0354] In some embodiments. the method further com- [0347] In some cmboduncnts, the method further comprises administering to said patient a third therapeutic agent, pnscs ddnun&stcnug to saul patient a third lhcrapeulic agent, such as an inununc chcckpou&t inlub&tor. In some embodi- such as an immune checkpoint inhibitor ln some embodi- meuls, the method comprises admin&stenng to the patient in mentg the method conlprises admiilistering to the patient in nimd thcrcof &luce therapeutic agents sclccted from a com- need thereof tluee therapeutic agents selected from B compound disclosed herein or a pharmaceutically acceptable salt pound disclosed herein or a phamlaceutically Bccepmble salt thereof, a second therapeutic agent selected from a platinum- thereof, a second themspeut&c agent selected from Bn based therapeutic, a taxane. a nucleoside &niubitor, or a indolc;munc (2,3) &hoxygcnasc (IDO) udubitor, a Poly ADP thempeutic agent that interferes with normal DNA synthesis, r&bose polymcrasc (PARP) &nlubitor, a lustonc dw&cetylase protc&n synlhesis, cell replicaiion, or w &ll othe&wise inlub&1 (I IDA(') inh&bitor, a ('DK4/('DK6 inhibitor, or a phospha- rapnlly prohficndting cells. Bnd a th&rd thcrapcutic agcnl tidylinositol 3 kinase (P13K) inhibitor, and a third therapeu- selcctcd from an u&ununc chccl pou&t &niub&tor. tic agent selected fmm an inunune checkpoint inhibitor In [0355] In some cmbodm&ants. the inunuue chcckpou&t some embodiments, the immune checkpoint inhibitor &s inhibitor &s sclcctcd from nivolumab, pcmbrol&zumab, &p&li- selected from nivolumab. pembroliz&unab, ipilimumab. ave- nn&mab, aveiumab, durvahuuab, atezol&zun&ab, or pidili- lumab, dur& alumub, atczohzumab. or pnhlizumab. zuluBb. [0348] Another inumulostinudatory thempeutic that may [0356] In some embod&ments. any onc ol'hc lbrcgoulg be used u& thc present invention &s recombu&ant human methods further comprises the step of obtain&ng a biological intcrleuku& 15 (rhIL-15). rhIL-15 has bccn tested in the san&pie fmm the patient m&d measuring the amount of a cli&uc as a tlu:rapy for melanoma imd renal cell carcinoma disease-related biomarker. (NC'I 01021059 and NC1 01369888) and 1eukemias [t)357J In some enlbodiments. the biological sample is a (NC'102689453) Another immunostinn&hstory therapeutic blood sample US 20 ] 9/032265 [] A] Oct. 24, 2019 110

[0358] In some embodiments. the disease-related bio- tora useful in the present invention include everolimus markcr Is selcctcd lyom circulatulg CDS+ T cells or the ratio (Afinitooge, Novanis). tcmslrolimus (Tonsclg, Plizer): and ol'CDS+ T cells.Trcg cells. slrolimus (Rapamunog, Plizcr). [0359] In onc aspect, thc prcscnt invention provides a [0363] In some embodiments. the additional therapeutic nlethod of treating an advanced cancer, coinprising admin- a ent is a Poly ADP ribose poiymemse (PARP) mhibitor. istering a compound disclosed herein or a pharmaceutically Approved PARP inhibitors usefiii in the present invention acceptable salt thereof or pharmaceutical composition include olaparib (Lynparzaub. AstraZmleca), rucapanb (Rub- thereof. either as a sin le a ent (monotherapy), or in com- raca'8, Clovis Oiwology). mid niraparib (Zc)ulaJt. Tesaro). bmdiion with a chmnothcrapcutic, a targeted thcrapculic, Other VARV inhibitors heinz snidied which niay be used in such as a kioasc ulhibitor, andior an imnnulomoilulatory the present invention include talazoparib (Ml)V3800/13MN thcrapv. sUch as dn uunltlllc chcckpohlt ulhlbltom In solnc 673/LT00673. Medivation/Pfizer/Biomarin); veliparib embodiments, the Imniune checkpoint inhibitor is an anti- (ABT-888. AbbVie): and B(IB-290 (BeiC)ene, Inc.). body to Vl)-1. VD-I binds to the progranuned cell death I [0364] In some cmboihments. the additional therapeutic receptor (PD-I) to prevent the receptor thorn binding to the agent is a phosphatidylinositol 3 kinase (Vl)K) inhibitor inhibitory ligand PDL-I, thus overridiilg the ability of Approved V13K inhibitors useful in the present invention Illinois to SUppl'css thi: host dnit-(UIIliir unnlUUI: lcspoilsc. include ldelalisib (Zydelig'8. (Jiiead). Other PI3K inhibitors [0360] In some mnboduncnts. (he addluoixil thcrapcutic being studied vvlfich may be used in the present invention dgcnt Is II hnlasc hlhlbltol or VEGF-R antdgonist. Approved include alpeiisib (BYL719. Novartis): taselisib (GDC-0032, Vl:Cil'nhibitors and kinase inhibitors useful in the present Geneutcch/Roche), pictilisib (GDC-0941, Gcncn)IOIV invention include bevaciziuliab (Avastin)C. Cieneilteclv Roche); copanlisib (BAY806946, Bayer), duvelislb (lbr- Roche) an anti-Vl:Cil'onoclooal antibody: ramucinnnab merly IVI-145, Infinity Vharmaceuticals); VOR309 (Viqur (Cyramzag. Eli Lilly). an anti-VEGFR-2 antibody and 'I'herapeutics, Svvitzerland): and 'I'CiR1202 (filrmerly ziv-afiibercept„also known as VEGF Trap (Zaitmpiii, RP5230. TC) Therapeutics). Rcgmlcron/Sanoli). VEGFR Inlubltors, such as regorafcnib [t)365J In some embodiments. the additional themspeutic (Sui argo'8, Bayer), vandetmub (Caprclsag, AstraZcncwa), agent is a proteasome inhibitor Approved proteasome axitinib (Inlytaig. Vhzer); and leovatinib (I,envintat L Eiisai), inhibitors useful in the present invention include bortezomib Raf inhibitors, such as sorafenib (Nexavarg, 13ayer A(i and (Velcade'x( Takeda): carhlzomib (Kyprolis'8, Amgen): and Onyx): dabrafenib (Tahnlarza Novartisj; and vemurafeiub ixazonub (Ninlarorgi, Takcda). (Zeiborafg. Cienentech/Roche); MEK inhibitors, such as [0366] In some embodiments. the additional therapeutic cobimetanib (Cotellic 81 Exelexis/Genentech/Roche); tram- a ent ls a histone deacetyiase (HDAC) inhibitor. Approved ctiiub (Mclomst,X, Novartls): Bcr-Abl tyrosule hulase HDAC ullubitors useful in thc prcscnt invention include inhibitors, such as unatu»b (Glccvitmss Novartis). niloumb vonnostat (Zofinzafb. Marek 81 Co.), romidcpsln (Istodaxgt, (Tasigna)z, Novartis), dasatinib (Sptyce))L 13ristolMyersS- ('elgenej; panobinostat (liaryihlktts Novartisj; and belioostat quibb); bosutinib 0)osufif')tc Pfizer); and ponatinib (ln- (13eleodaq)t, Spectnuu Vhannaceuticals) Other I I DAO clusig'Xx Ariad Vharmaceuticals); lier2 and 1gilig inlubi- inhibitors being studied which may be used in the present tors, such as gefitlnib (Iressatu, AstraZeneca): erlotlnib invention include entinostat (SNDX-275„Syndax Pharma- (Tarceeva Sh Cienentech/Roche/Astellas): lapatinib (Tyk- ceutlcals) (NCT00866333); and chidamide (Epidaza'x. HBI- crb'a) Novarlis), afatinlb (Ciilotrifg, Boeluulgcr Ingelheuu), 8000, Clupscreen Bioscicnccs. Clunu). osimcrunib (targeting activated EGFR. Tagnssox. Astra- [0367] In some embodiments. the additional therapeutic Zeneca): and brigatimb (Alunbrigat. Ariad Pharmaceuti- a ent is a CDK inhibitor. such as a CDK 4/6 mhibitor. cals); c-Met and Vl:(il'R2 inhibitors, such as cabozanitib Approved CD K 4/6 ulhi bit ors u acl'ul In thc present ulv cut lou ((:ometriqtr. I:xelexish and nniltikinase inhibitors. such as include palbociclib (Ibrancc , Plizer), and riboclclib sunitinib (Sutentg. Pfizer); pazopanib (Votrientah Novar- (Kisqafidth Novartis). Other ( l)K 4/6 inhibitors beuig stud- tis): ALK inhibitors, such as crizotinib (Xalkori'ii. Pfizer), ied v hich inay be used in the present invention include cintinib (Zykadtattb, Novartls), and dlcvuiub (Alecenzdis, abenlaciclib (l,y2835219. ) ili I.illy); and trilaciclib ((il'I'2Y, Gcnentcch/Roche), Brutou's tyrosine hindse ulhlbitors, such Cil Themtpeutics). as ibruunib (Imbnivicdg, Phanuacychcs/Jmlssen). and Flt3 [t)368J In sonic enlbodinlents. the additional therapeutic receptor inhibitors, such as nlidostaurin (Rydaptn( Novar- a ent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. tis). IDO inlubitors bein studied which may be used in the [0361] Other lonase inhibitors and VEGF-R antagonists present invention include epacadostat (INCB024360, that are in development and may be used in the present Incytc); indoxlmod (NLG-8 1 S9. NewLulk Genetics Corpo- invention include tivozanib (Aveo Phannaecuticais); vata- ration); capmarutlb (INC280, Novarus), GDC-0919 (Genen- laiub (Bayer/Novurtis), lucitaiub (Clovis Oncology), dovi- teclv'Roche); Pli-06840(X)3 (Pfize); 13MS I'001287 (13ristol- uiub (TK1258, Novarus): Cluauarub (Clupscrecn Biosci- Myers Squibb): Vhy906,'KD108 (Vhytoceutica), and an ences): ('I.V-11981 (('ephalon); linifanib (Abbott enzyme that breaks down kynurenine (Kynase, Kyn Thera- I aboratories): neratinib (I IKI-272. Puma 13iotechnology), peutics). radotinib (Supectg. IY5511. II-Yang Phannaceuticals, S. [t)369J In sonic enlbodinlents. the additional therapeutic Korea); nixoiitinib (Jal )fig. Incyse Corporation); PTC299 a ent is a growth factor antagonist. such as an antagonist of (PTC Therapeutics)t CP-547,632 (Pfizer); foretinib (Exel- platelet-derived growth factor (PDCiF). or epidermal growth cxls, GldxoSmitld(linc), quizaruiub (Daiirlu Sankyo) and factor (EGF) or its receptor (EGFR). Approved PDGF motcsamb ( Atn en/Takeda) antagonists which mdy bc used ul Ihc prcscnt ulvcntlon [0362] In some mnboduncnts. (he addluoixil thcrapcutic include olaratumab (Lartrui OI(b: Eli Lllly) Approved EGFR agent is an mq OR inhibitor, which inhibits cell proliferation, antagonists which mav be used ul the present invention angiogenesis and glucose uptake Approved m'I OR inlubi- include cetuximab (I:rbituxg, I ili l,illy); necitumumab (Vor- US 20]9/032265[] A[ Oct. 24, 2019

trazzmgk Eli Lilly). panitumumab (Vectibix'i)L Am en): and studied vvlfich may be used in the present invention include osimertinib (targeting activated EGFR, Tagnsso'e'. Astra- pixmitrone (Pixuvrvac CTI Biophanna) Zclic:ca). [0379] In some cmbochments. the additional therapeutic [0370] In some mnboduncnts, the addiuoixil thcrapcutic agent is a nuclcosidc uthibiior, or other thcrapcutic that agent is an aromatase inhibitor. Approved aromatase inlubi- interfere with nomiai DNA synthesis, protein synthesis. cell tors ivhich may be used in the present invention include replication, or will otherwise inhibit mupidly proliferating exemestane (Ammasiniik Pfizer): anactazole (Arimidex',Iu, cells. Such nucleoside inhibitors or other therapeutics AstraZeneca) and letmzole (FemarafX, Novartis). include trabectedin (guanidine alkylating agent. Yondelic'x, [0371] In some embodiments, the additional therapeutic Jmisscn Oncology), mcchloretluuniue (alkylatuig agent. Val- agent is an antagonist of the hedgehog padtway. Approvcxt cldor'M Aktclion Pharmaceuticals); vincustinc (Oncovuia., luxigchog pathway inhibitors which may be usccl in thc Eli Lilly; Vuicasargc Teia Ptmrmaceuucals, Marqibo.a.. present invention include sonidegib (OdoinznWC Sun Phar- 'I'alon 1'herapeutics): temozoloniide (prodmg to atkytating maceutical s); and vismodegib (I irivedgeg, Cienmitech), agent 5-(3-methyltriazen-I-yl)-imidazole-4-carboxamide both for treatment of basal cell carcinoma (MTIC) Temodarak Merck & Co.), cytamubine injection [0372] In some embodiment~, the additional therapeutic (amwC, antimetabolic cytidine analog, Pfizer); lonuistine agent is a folic acid inhibitor. Approved folic acid inhibitors (alkylating agent, CecN(M, Bristol-Mycrs Squibb, Gleo- useful in tlm prcscnt uivcntion uiclude pemctrexed (Al- sttnectcc NextSource Bioteclmology): azaciudinc (pyruniduie imia'tii. Eli Lilly). nuclcoside analog ol'yticluie, Vtdazait, Cclgene), omacetaxine mepesuccinate (cephalotaxine ester) (protein syn- [0373] In some mnboduncnts, the addiuoixil thcrapcutic thesis inhibitor, Synribo'13c 'I'eva Phannaceuticals); aspam- agent is a I ('hemokine receptor 4 (I'I R-I) inhibitor. I'C'134 ginase Erii inin c/irvsnii/hemi (enzyme for depletion of inhibitors being studied that may be useful in the present Etsparg. Lundbeck; Erwinazeim, EIJSA invention include mogamulizumab (Poteligeok, Kyowa asparagine. Pharma); cnbului mesylatc (microtubulc uihibitor, tubulin- Hakko Kirin. Iapan). bascd antinutotic, Halaven'tii, Eisai), cabazitaxel (nucrotu- [0374] In some mnboduncnts, the addiuoixil thcrapcutic bulc uihibitor, tubulin-based antumtotic, Jcvtanag, Sanoli- agent is an isocitratc dehydrogcnasc (IDH) inlnb«or. IDH Aventis); capacetrine (thymidylate synthase inhibitor, inhibitors being studied which may be used in the present Xetodagz Cienentech); bencLsmustine (bifunctional mechlo- NC" invention include Ati120 (I:elgene: I'02/&77922): AC)221 rethamine derivative, believed to form interstrand DNA (Celgene, NCT02677922: NCT02577406); BAY1436032 cross-links, Treanda'8, Cephalon/Teva): ixabepilone (semi- (Bayer. NCT02746081): IDH306 (Novartis, synthetic analog of cpotlulone B, microtubulc inhibitor, NCT02987010). tubuhn-based imunntouc. Ixcmpru , Bnstol-Mycrs [0375] In some embodiments, the additional therapeutic Squibb); nelambine (prodrug of dcxixygumiosuic tumlog, agent is an arginase mhibitor Arginase inhibitors beiag nucleoside metabolic inhibitor. Armnnonm, Novartis); clo- studied which may be used in the present invention include mnfabme (prodrug of ribonucleotide reductase inhibitor, AEB 1102 (pegylated recombinant arginase, Ae lea Bio- competitive inhibitor of deoxycytidine. Ctotagtt, Sanofi- therapeutics), cvhich is being studied in Phase I clinical tools Aventis): and trifiuridine and tipiracil (thymidine-based for acute myeloul lcukcmia and myelodysplastic syndrome nucleoside analog and thymidine phosphorylace inhibitor, (NCT02732184) and solxl tumors (NCT02661234), and Lonsurt'RL Tinho Oncology). I 13-1158 (('aiithemu 13iosciences). [0380] In some embodiments. thc additional therapeutic [0376] In some embodiments, the additional therapeutic agent is a platinum-based themupeuttc. also referred to as agent is a glutaminase inhibitor. Glutaminase inhibitors platins. Platins cause cross-licking of I)N.&. such that they being studied wluch may bc used in the present invmition inhibit DNA repair ancgor DNA synthesis, mostly in mupidly include CB-839 (Calithera Bioscicnces). repmducing cells, such as cancer cells. Approved platinum- [(3377J In some embodiments, the additional therapeutic based therapeutics which may be used in the present inven- agent is an antibody that binds to tumor antigens, that is, tion include cisplaun (Ptatinolctu, Bnstol-Mycrs Squibb), proteins expressed on the cell surface of rumor cells. carboplatin (Paraplatin8, Bristol-Myers Squibb: also, Tcva, Approved antibodies that bind to tumor anti ens which may Plizcrk oxaliplatui (Eloxitui,ii Sanoli-Avmitis), and neCk- bc used in thc present uivmition uiclude ntuximab platin (Aqupta)c, Shiononi). Other platinuni-based therapeu- (Rttuxau , Geuentcclt/Btogenidcc), ofatunuunab (anti- tics which have undergone clinical testing and may be used I D20. Atzerradcv CilaxoSmithKlinek obinutuzumab (anti- in the present invention include picoplatin (Poniard Plta- I D20. Ciazyvaig. Cienentech), ibrituinoinab (anti-I'D20 and maceuticals): and satraplatin (JM-216. Agennix). Yitrimn-90, Zevalin30 Spectnun Pharmaceuticals); daratu- [0381] In some embodiments. the additional therapeutic mumab (anti-CD38, Darzalex',as Janssen Biotech), dinunix- agmit is a taxanc compouncl. wluch causes disniption of imab (anti-glycolipid CiD2, Unituxintik United Thempeu- microtubules, wluch arc cssenual lbr cell division. Approved ucs), uastuzumab (anti-HER2, Herccptuig. Gcnmitcmh), taxane compounds which nmy be used in the present inven- ado-uastuzumub mntaminc (anti-HER2, fused to cmtansuie, tion include paclitaxel (1axoltiv 13ristol-Myers Squibb), Kadcyta'13c (ienentech), and pertuzumab (anti-llliR2. Per- docetaxel (Taxoteregtga. Sanoti-Aventist Docefrezg. Siui jetaam (ienentech); and brentuximab vedotin (anti-I'D30- Pharmaceutical), albuniin-bound paclitaxel (Abraxaneg; dnig conjugate. Adcetrism, Seattle Cienetics) Abraxis/Celgene). and cabazitaxel (Jevtaua!tt, Sanofi-Aven- [0378] In some mnboduncnts, the addiuoixil thcrapcutic tis). Otlmr taxanecompounds which have uudcrgonc clinical agent is a topoisomcrasc inlubitor. Approved topoisomcrase tcstuig and may bc uscxl in thc present uivmition include inhibitors useful ui thc present invention uiclude irinotcman SID530 (SK I heniicals. I:o.) (NC TOO')31008) (Oniv3 desi. Mernniack Pharmaceuticals); topotecan (I tyca- [13382J In some embodiments. the additional themupeutic nitinti, (ilaxoSmithKline) 1opoisoinerase inhibitors beiag agent is an inhibitor of anti-apoptotic proteins, such as US 20 ] 9/032265 [] A[ Oct. 24, 2019 112

BCL-2. Approved anti-apoptotics which may be used In the Additional Co-Administered Therapeutic Agents Targeted present invention include venetocLsx (I/enclextag, Abbl/ie/ 'I'herapeutics and Immunomodulatory Dnigs Genentech)t and blinatumomab (Blincyto 8. Amgen). Other lherapeulic agents largetulg apoplonc pmlculs v,iuch imvc [0388] In some embodiments. thc additional thcrapeuuc undcrgonc climcal tcsuug and may be used ul lhc presmll agent is selected from a targeted therapeutic or inununo- invmlllon include navltoclax (ABT-263, Abbott), a BCL-2 modulatory drug. Adjuvant therapies with targeted thera- inhibitor (N("I 02079740) pCUtlCS or lfulullnonlodllhlloci'fllgs 8,'IVC Shown pl'OUIISlng, efi'activeness [0383J In some embodinlents, the present invention pro- when administered alone but are limited by the vides a method of treating prostate cancer comprising dcvelopnlcnt ol tUBIOI UUIUUnllv liver lane or cvdslon ol lhc adnlinistering to a patient in need thereof an efiective inunune response. il hi'rchl B ph'lnuBcciitl- dnlounl of conlpound disclosed iu [0389] In some embodiments. thc prcscut ulvcntion pro- cally dcccplablc salt thcrcof or plmnuaceutlcal composition vides a method of treating cancer, such as a cancer described thereof in combination with an additional therapeutic agent hcrcin, compnsing admmislenng to a patient ui aced thcrcof that interferes with the synthesis or activity of androgens. an efi'ective amount of a compound disclosed herein or a ed andmgen receptor inhibitors useful in the present Apprm phannaceuticaily acceptable salt thereof or pharmaceutical invention include enzalutamide (Xtandi sb Aste)Lss/Medlva- thereof in combination with an additional thera- tion); approved inhibitors of androgen synthesis include composition peutic a ent such as a targeted therapeutic or an imnumo- ablralerone (Zytlgag, Ccnlocor/Ortho), approved antagonist modulatory dnig. In some mnbodunmits, lhc unmunomodu- ol'onadou hormone (GURH) rcccp1or (dega- opln-re)casing latory thcrapcuuc spccilically induces apoptosls ol'umor ralix, ilirma ong, llerring Phannaceuticals). cells Appmved imnnulomodulatory therapeutics which Inay [0384] In some embodiments, the additional therapeutic be used in the present imention include pomalidomide agent is a selective estrogen receptor modulator (SERM), (Poma)yst'fc, Cei ene); lenalidomide (Revlimld'8. Celgene); which interferes with the synthesis or activity of estrogens. in enol mebutate (Picato SL LEO Pharma). Approved SERMs useful in the present invention include [0390] In other cmbodimmlts, lhe unmunomodulaiory raloxlli:nc (Evistag, Eh Lllly). thcrBpeU(lc Is B cilnccl vdcchuv hl sonic cnlbodhucnls, lhc [0385] In some embodiments, the additional therapeutic cancer vaccine is selected fmm sipuleucel-1'Pmvcngeat, agent is an inhibitor of hone resorption An approved thera- Dendreou/3:a)Cant Phannaceuticals), wluch has been peutic lvhich inhibits hone resorption is Denosumab approved for treatnlent of asymptomatic, or minimally (Xgevacu, Amgen). an antibody that binds to RANKL, symptomatic metastatic castrate-resistant (hormone-refrac- prevents binding to Its receptor RANK. found on the surface tory) prostate cancer: and talinlo ene laherparepvec (Imly- ol'stcoclasts, their precursors, and ostcxtclast-hkc giant glcst BIOVcx/Amgcn. previously known as T-3:EC), cilia, wluch medlalcs bone pathoio y ul solid Umlors wllh gcnellcdllv'lodlficd oncolvllc vudl lhcrBpv Iipprovcd lol osseous metastases. Other approvixi thcrapculics that udubll treatment ol'nrcscclablc cutam:ous, subcutaneous and bone resorption include bisphosphonates, such as zoledronic nodal lesions in nlelanonm. In some enlbodiments. the acid (/ometaig. Novartis) additional therapeutic agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (Pex- [0386] In some embodiment~, the additional therapeutic ak'ec/JX-594. Sillaien/formerly Iennerex Biotherapeutics), agent is an inhibitor of interaction between the two primary a lhymidine klnase- (TK-) delicicnt vaccinia virus cn i- p53 suppressor proteins, MDMX and MDM2. Inhibitors of nimrcd lo cxprcss CiM-CSF, for hcpaloccllular carculonui p53 suppression proteins being studmd which may be used (NCT02SG2755) and mclmloma (NCT00429312), pelarco- in the present invention include AI,RN-6924 (Aileron), a rep (Reo)ysin)rs Onco))ties i3iotech), a variant ofrespiratory stapled peptide that equipotently binds to and disnlpts the enteric orphan virus (reovinis) which does not replicate in interaction of MDMX and MDM2 with p53. ALRN-6924 Is cells that are not RAS-activated. in numerou~ cancers, currently being evaluated in clinical trials for the treatment including colorectal cancer (NCT01622543): prostate can- of AML„advanced myelodysplastic syndrome (MDS) and cer (NCT01619813), head and neck squiunous cell cancer pcriphcral T-cell lymphoma (PTCL) (NCT02909972, (NCTO)166542), pancreatic adcnocarculoma NCT02264613). I NCT00998322), imd non-small cell lung cancer (NSCLC) [0387J In some embodiments, the additional therapeutic (N(71'0861627); enadenotucirev (N(i-348. PsiOxus, tbr- agent is an inhibitor of transforming grov th factor-beta merly knov;n as ('oloAdl), an adenovirus en@neared to (T(JF-beta or TCiF[3). Inhibitors of TCiF-beta proteins being express a full length ('DSO and an antibody fragment studied which may be used in the present invention include specific for the T-cell receptor CD3 protein. in ovarian NIS793 (Novartls), au Bnn-TGF-beta dnnbody bemg tested cancer (NCT0202S117); metastatic or advanced epithchai ul lhc chute lor Ircdtmcnl of villlous cBnccls. hicllidulg tumors such as ln colorimta1 cmlcer. bladder cancer, head and breast. lung, hepatocellular, colorimuil. pancreatic, prostate nimk squamous cell carcinoma and salivary gland cancer and renal cancer (N('T 029471/15) In some embodiments, (N(''02636036); ONCOS-102 (1argovax/formerly Oncos), the inhibitor of 'I (ilnbeta pmteins is fresolimumab an adenovinis engineered ul express (iM-( Sl, in nlelanoina (CiC1008: Sanoh-Cienzyme). which is being, studied for (NCT0300367G): and peritoneal disease. colorectal cancer meianonla (NCT00923169); renal cell carcinolna or ovarian cancer (NCT02963831), CiL-ONCI (Cil 3BIh68/ (NCT00356460), and non-small cell lun cancer GLI/-)8153. Gcnclux GmbH). vaccinia viruses cnginccrcx) (NCT02581787). Additionally, ul some embodiments, the to cxprcss beta-galaclosidasc (beta- dl)/beta-glucoronidase additional therapeutic agent is a TGF-beui trap, such as or beta-gal/human sodium iodide symporler (hNIS), respec- described in ('onnolly et al (2012) lnt'I .I 13iological tively, were studied in peritoneal carcinomatosis Sciences 8:964-978 (N(71'01443260); fallopian tube cancer, ovarian cancer US 20 ] 9/032265 [] A[ Oct. 24, 2019 113

(NCT 02759588)1 or CC10070 (Cold Genesys), an adenovi- MDX1106 and BMS-936558)„has shown potential to rus m&gineercd to cxprcss Glvi-CSF, in bladder cancer in&prove the overall survival in patients with RC(':ho had (NCT02365818). expenenced disease progression during or after prior anti- [0391J In some embodiments, the additional therapeutic d&lg&ogcn&c thcrapv. agent is selected fron& .IX-929 (Sillale&Vformerly .Iennerex In some embod&ments. thc prcscut u&vcntion pro- Biotherapeutics), a TK- and vaccinia growth factor-deficient [0396] vides a nðod treatinu cancer, such as a cancer described vaccinia virus entmneered to express cytosine deuminase, of herein, comprising administerinu to a patient in need thereof &vhich is able to convert the prodrug 5-fiuoroc)tosine to the it &onal ancomposeii'ective &ti amount of a compound d&&closed herein or a cytotox&c drug 5-Jluorouracih TGOJ m&d TG02 (Tar ovax/ formerly Oncos). pcpt&de-based immunod&erapy agents tar- phannaceuticaily acceptable salt thereof or pharmaceutical geted for difficult-to-treat RAS mutationst and 'JIUI-123 on thereof in combination with an add thera- pc<u: agent s&ich ils il u&1&nut&i&st&a&UJB&o&y drUg, sUch Bs Bn ('I II I'3iothempeut&cs). an engineered adenovims desig- nated: Ad5/3-EZF-delta24-hTNF(I-IRES-hJL20: und VSV- immune checkpoint mlnbitor. In some embodiments. thc compound and the checkpoint inhibitor are administered (JP (ViraTherapeutics) a vesicular stomatitis vinis (VSV) sin&ultaneously or sequentially In annie embodiments, a engineered to express the glycoprotein ((.&P) of lymphocytic compound disclosed herein is administered prior to the chor&omeningit&s v&rus (LCMV). which can bc further m&g&- in&t&al dosing with the inunune checkpoint inhibitor. In neared to express antigcns designed Io rmsc an ant&gmi- specihc ('Dg 'I'ell response certain embodiments. the inunune checkpo&nt inhibitor is adnuiustcrcd to thc init&al dosu&g w&th thc compound [0392J In some embodiments, the present invention con&- pnor prises administering to said patient a compound disclosed ihscloscd hc&c'ln. herein or a pharmaceutically acceptable salt thereof in [(3397J In certain embodiments, the &mniune checkpoint con&bination &vith a T-cell engineered to express a chimeric inhibitor is selected fmm a Pl)-1 antagonist, a Pl)-1,1 dnt&gcn receptor, or CAR. Thc T-cells engineered to express antagonist. or a CTLA-4 ants onist. In some embodiments, such chimcnc m&t&gm& rcccptor arc rcfcrrcd to as a CAR-T a compound disclosed herein or a pharmaceut&cally accept- cells. able salt thereof is administered in combinat&on with [03931 CARs have been constructed that consist of bind- n&volunuib (anti-PD-I antibody, Opd&voii3, Bnstol-Mycrs ing domains, v,hich may be derived from natural ligands, Squ&bb); pembrolizumdb (anti-PD-I antibody, Kcytrudagt, single chain variable frag&aunts (scFv) dcnvcd Ibom mono- Merck 8; Co.): ipilimumab (anti-(Jl'I.A-4 antibody. Yer- clonal dnt&bod&cs spec&lic R&r cell-surfacean1&gens, Iuscd to voy Jt, 13ristol-Myers Squibb), durvaluniab (anti-pl)-1,1 endodomains that are the funct&onal end of the 'I&cell recep- antibody. Imtinziah AstraZeneca); or atezolizumab (anti- tor (1('R). such as the ('D3-zeta signaling domain front PD-L I antibody, Tecentriquu, Cienentech). TCRs, winch is capable of generating an activation signal in [0398] Other &nuuunc checkpou&1 inlub&tora su&table Ior T lymplu&cytes Upon antigen binding, such CARs hnk to usc in thc prcsm&1 &menuon include REGN2810 (Regen- endogenous si naling pathways in the eflector cell and eron), an anti-PD-I antibody tcstcd &n paucnts with basal generate aclivauug s&gnals sim&lar tu Ihose im1&a&cd by the cell carcinoma (N(fl'03132636); NS('I,('N("I'03088540); TCR complex. cutaneous squamous cell carcinoma (N('T02760498); lym- [0394] For example, in annie embodiments the ('AR-T phoma (NCT02(151662): and melanoma (NCT03002376); cell is one of those described in U.S. Pat. No. 8.906.682 pidilizumab (CureTech). also known as CT-011. an antibody (June; hereby incorporated by reference in its entirety), that binds to PD-I, u& cli&ucal tnals Ibr ddlbse large B-cell winch dismloscs CAR-T cells m& mixred to compnse an lymphoma and nu&lnple myeloma, avclumab (Bavcncio.s.. extracellular domuu& havu&g an anugen hindu&g dome&n Piizcr/Mcrck KGaA), also known as MSB0010718C). B (such as a don&ain that binds to ('l)19). fused to an intrac- fully hiunan Ig(il anti-Pl)-I I antibody, in clinical trials fbr elluiar signaling don&ain of the T cell antigen receptor non-small cell huig cancer. Merkel cell carcinon&a meso- con&plex zeta cha&n (such as CD3 zeta). When expressed in thel&orna. solid tumors. renal cancer. ovarian cancer. bladder the T ceiL the CAR is able to redirect antigen recognition cm&cer, head and neck cancer. and gastric cancer: and based on the antigen binding specificity. In the case of PDR001 (Novarns), an u&lnbitory aut&body that bu&ds to CD19. the ant&gcn &s cxprcsscd on malignant B cells. Over PD-J, u& cl&n&cal u&als for non-small cell lung cancer, 200 clu&ical trials arc currently u& progress employing melanoma, tnplc ncgdtivc breast cuncer aud advanced or ( AR-1 in a &vide range of &nd&cations. [https: Vclinicaltnals. metastatic solid tumors. 1'remelimumab (CP-675.206; Astm- gov,'ct2&resultsvterm ch&n&eric+antigen+receptorsg:pg IJ. zeneca) is a fully human monoclonal antibodv against CTLA-4 Ji&r Additional ('o-Administered Therapeutic that has been in studied in clinical trials a number of indications, including: mesothelioma. colorectal Aue&its In&munostin&ulatory I )rugs cancer, kuh&cy cancer. breast cancer, lung cancer m&d non- [0395] In some mnboduncnts, tlm add&t&o&ml therapeutic snulll cell JUng cancer, pdnc&ciltlc ductdl Bdcnocil&cinii&t&a. dgeni is dn &nunuuost&mulatory drug. For exmnplc, annbod- pancreatic cancer, gcm& cell cm&cer, squamous cell cancer of ies blocking the PD-I and PI&-1,1 inhibitory axi ~ can unleash the head and neck, hepatocellular carcinoma. prostate can- activated tumor-reactive 'I'ells and have been shown in cer, endometrial cancer. metastatic cancer in the liver, liver clinical trials to induce durable anti-tumor responses in cm&cer, large B-cell lymphoma. ovanan cancer. cervical increasing numbers of tumor histologies, including sotne cm&cer, metastatic anaplastic thyroid cancer, urothelial can- tumor types thut convcnuonally have noi been considered cer. Fallopian tube cancer. muhiplc myeloma, bladder can- immunotherapy scnsit&vc Sec, c.g., Ohazak&. T. ct al. (2013) cer. sofi I&ssuc sarcoma. Bnd melanoma AC)EN-1884 (Age- Ndt. hnmunol. 14. 1212-1218, Zou ct Bl. (2016) Sci. Trm&sl. nus) is an ant&-CTLA4 dnt&body tlmt &s bc&ng studied in Med. 8 'I'he anti-PD-I antibody oivolumab (Opd&vo)e, Phase I clinical trials for advanced solid tumors 13ristol-Myers Squibb. also known as ONO-4538, (N( 7 I'02694822) US 20]9/032265[] A[ Ock 24, 2019 114

[0399] Another paradigm for inunune-stimuL«tion is the [0405] Other immune-oncology a ents that may be used in usc of oncolyt&c v&ruses In some embodiments, the present the prcscnt u&vm&&ion in comb&nano« w&th a compound invention provides a method I'or treaiing a pat&ent by adnun- d&scloscd herc&n include urclumab (BMS-663513. Bristol- istering a compound disclosed herein or a pharmaceutically Myers Squibb). an m&ti-(1)137 n&onoclonal ant&body; varli- acceptable salt thereof or pharmaceutical composition lumab (CDX-1127. ('elldex Therapeutics), an anti-( D27 dtereof in combination w&th an inununostimulatory rherapy monoclonal antibody; BMS-986178 (Bristol-Myers such as oncolytic vi«ises. Approved immunostimulatory Squibb). an anti-OX40 monoclonal antibody: lirilumab oncolytic viruses w hich may be uced in the present invenrion (IPH2102/BMS-986015. Innate Phanna„Bristol-Myers include talunogcnc lahcrparcpvcc (live. attcnuatcxl herpes Squibb), m& anii-KIR monoclonal anubody: monalizumab simplex virus, Imlyg&crxh A&ngen). (IPH2201, Innatc Pharma. AsuaZcncca) m& m&ti-NKG2A [0400] In some mnboduncnts, ihe add&uo&xil thcrapcuiic monoclonal m&tibody: andecaliximab ((18-5745. Ci&lead )ci- agent &s m& activator of rcuno&c ac&d receptor-rclatcd orphan ences), an anti-MMP9 antibody; MK-4166 (Merck 8; ('o ), rcxcptor 7 (RORyt). RORyt &s a trruwcnpt&on I'actor with kcy an anti-CiITR monoclonal antibody. roles in the diiferentiation and maintenance of 'I'ype 17 [0406] Other additional therapeutic a ents that may be effecto subsets of ('D4+ (1'h17) and ('Dg+ ('I'c17) 1 cells, used &n the present invention include glembatumumab vedo- as well as the differentiation of IL-17 expressi&ig innate t&n-monomcthyl aunstatm E (MMAE) (Celldcx), m& anii- inunune cell subpopulations such as NK cells. An activator glycoprotein NMB (gpNMB) antibody (CROII) linked to of ROR/t, that is being stud&ed which may be used in the the cytotoxic MMAE. gpNMB is a protc&n ovcrcxprcsscd by prcscnt invention &s LYC-55716 (Lyccm), which is currm&tly nn<iple tumor types associated &vith cancer cells'bility to bc&ng cv aluatcd u& clu»cal &naia I'or thc trcatmcnt of sol&d metastasize. tumors (N( T02929862) [t)407J A compound of the current invention may also be [0401] In some mnboduncnts, ihe add&uo&xil thcrapcuiic used to advantage in combination with other ant&prolifera- agent is an agon&st or act&vator of a tull-like receptor (TLR). tive compounds. Such antiproliferative compounds include, Suitable acr&vators of 'I'I.ks include an agonist or activator but are not limited to checkpou&t uih&b&tora, aromatasc of 11 R9 such as SD-101 (Dynavax) SD-101 i ~ an inunu- inh&b&tora, ant&csuogens: topoisomcrasc I uih&biiors, topui- nostinn&latory CpCi which is bein ctudied for B-cell. folh- somerase I I inhibitors; n&icrotubule act&ve compounds: alky- cuLcr and other lymphomas (N('T02254772). Agonists or lating compounds: histone deacetylase inhibitors; com- am«a&ore of TLR8 wh&ch may bc used in the presm&i pounds which induce ceil d&fferentiation processes; invm&t&on include motol&mod (VTX-2337, Vcn«Rx Pham&a- cyclooxygenase inlubitors: MMP inh&bitors; mTOR inhibi- ceuucals) wh&ch &s being stud&cd lbr squamous cell cancer of tors, antineopiastic antimetabolites, platin compounds: com- the head and neck (N('I'02124850) and ovarian cancer pounds target&ng/dccreasu&g a protcu& or 1&p&d k&nasa activ&ty (N('1 02431559). and further ant&-ang&ogcn&c compounds: compounds wluch [il402J Other checkpoint inhibitors that may be used in the target, decrease or inhibit rhe activity of a protein or lipid present invention include inhibitors of 'I&cell immunoglobu- phosphatase; gonadorelin agonists; anti-androgens; methio- lin mucin contaming protein-3 fl'iM-3) 'I'IM-3 iinhibitors nine aminopeptidase inhibitors; n&atrix metalloproteinase that may be used in the present invention include TSR-022, inhib&tora; bisphosplu&nates: biological responce modifiers; LY33213(i7 and MBG453. TSR-022 (Tesaro) is an anti- antiprohferative antibodies, hepamnase inhibitor: inlfibi- TIM-3 antibody &vh&ch &s being studied u& sob&1 tium&rs tors ol Rds oncogcn&c &sofon&&s; telo«&cruse n&h&b&to&s, pro- (NCT02817633). LY3321367 (El& L&lly) &s m& ant&-TIM-3 tcasomc inlubitors, compounds used u& thc treauncni of antibody which is be&ng studied in solid tumors hematologic malignancies: compounds which target, (N('1 03099109). MI3(i453 (Novartis) is an antirI'IM-3 anti- decrease or inhibit the activity of I<-3, Iisp90 inhibitors body which is be&ng studied in advanced malignancies such as 17-AA(i (17-allylaminogeldanmnycin, (NCT02608268). NSC330507). 17-DMAG (17-dimethylaminoethylamino- [0403] Other checkpo&nt mhibitorc that may be used in the 17-demethoxy-geldanamycin. NSC707545). IPI-504, present invention include inhibitors of T cell inununorecep- CNFI 010, CNF2024, CNF1010 from Conforms Therapeu- tor with Ig and ITIM domains, or TIGIT, rm mumu&e t&cs; icmozolomnle (Tcmodal,i)); ku&esu& sp&ndle protein rcxcptor on carta&n T cells and NK cells. TIGIT mlubitors inhib&tora, such as SB715992 or SB743921 from GlaxoS- that may be used in the present invention include 13MS- nutl&Kline, or pentamidine/chlorpromazu&e fn&m ( o&nbina- 986207 (13ristol-Myers Squibb). an anti- fi(il'I'onoclonal toRx; MliK inhibitors such as ARRY142886 from Array antibody (NCT02913313): OMP-313M32 (Oncomed): and BioPhunna, AZds244 from AstraZeneca, PD181461 from anti-TIGIT monoclonal ant&body (NCT03119428). Pfizer und leucovorin. [0404] Checl point inhibitors that may be used in the [0408] The term "checkpoint inhib&tor'* as used herein prcscnt u&vcnuou also include uih&bitors of Lymplx&cytc rclatcs to agents useful &n prcveuuug cancer cells lrom Activauon Ciene-3 (LACi-3). LAG-3 inlub«ors that may bc avonl&ng thc immune systmn of the patwnt One ofthc major used u& the prcscnt u&vcniion include BMS-986016 and meehan&sms of anti-tun&or imn&unity subversion is known as RliCiN3767 and IMP321 l)MS-986016 (13ristol-Myers "'I-cell exhaustion,*'hich results from chronic exposure to )quibb). an anti-I A(i-3 antibody, is being studied in glio- antigens that has led to up-regukction of inhibitory receptors. blastoma and gliosarcoma (NC:T02658981). RE(iN37C&7 These inhibitory receptors serve as immune checkpointc in (Regeneron). is also an anti-LACi-3 antibody, and is being order to prevent uncontrolled immune reactions stud&cxI u& mal&gunne&es (NCT03005782). IMP321 (Inunu- [0409] PD-I and co-inhib&tory rcccpiors such as cytotox&c tcp S.A.) is an LAG-3-Ig I'us&on prutcin, beu&g studwd &n T-lymphocyte ant&gcn 4 (CTLA-4, B aud T Lymphocyie melanoma (NCT02676869), adcnocarcinoma Attenuator (BTLA, CD272), T cell Immunoglobulin and (NC'I 02614833): and metastatic breast cancer Mucin domain-3 ('I'in&-3), I.yn&phocyte Act&vation (iene-3 (NC'I 00349934) (I ag-3; CD223), and others are often referred to as a US 20]9/032265]] A] Ock 24, 2019 115

checkpoint regulators. They act as molecular "gatekeepers** ]0413] In some embodiments. the checl point mhibitor is that allow cxtraccllular uilormauon Io dictate whether cell sclectcd from Ihc group consistuig ol'mnbrolizumab (MK- cvclc progress&oil Blld otllcr llltracellillBr sigl&Blllllg pro- 347S), nivolumab (BMS-936558), pidilizumab (CT-011), cesses should proceed. AMP-224, MDX-1105. Ml&DI4736, MPDI 3280A. 13MS- ]0410] In one aspect„ the checl point inhibitor is a biologic 936559, ipiliinumab. Jirlumab. IPII2101, pembroliinuuab therapeutic or a small molecule. In another aspect, the (Keytiuda',tt). and tremelinumtab. chcckpouit inhibitor is a monoclonal anubody, a hununuzcd ]0414] i he term "ammatase inhibitor" as used herein antibody, a fully human antibody, d fusion pro(cia or a relates to a compound which inhibits estrogen production, combuiation Ilmrcof. In a further aspect, Ihe checkpoint for instance. the conversion of the substrates androstene- inhibitor inhibits a checkpoint pn&tain selected from C"I I,A- dione and testosten&ne to estrone and estradiol, respectively. 4, PDI,J, PD1,2, PDI, 137-113. 137-114, 13'I J,A, HVIIM, The tenn includes, but is not limited Io steroxls, especmlly TIM3, OAL9. LACJ3, V1STS. KIR, 2B4. CD160. CCJEN- atamcstane, cxcmcstane and lormestunc Bnd, in particular, 15049. CHK I„CHK2, A2aR, B-7 family ligands or a nou-steroids. especially dnunoglutctlumidc, roglctlunudc, comburdtion thercol; Iu au addiuonal aspect. the checkpoint pyndoglutethimide, trilostane, testolactone, ketokonan&le, inhibitor interacts with a hgand of a checkpoint protein vorozole, fadrozole, anastrozole and letrozole Iixemestaoe sclcctcd from CTLA-4, PDLI, PDL2, PDI, B7-H3. B7-H4, is marketed under the trade name Aromasin™. Formestane 131'I A. I IVI IM, 11M3, (IAI,9, I,A(&3, VIS'I'A. KIR, 2134, is marketed under the trade name Lentaron™. Fadrozole is ( D160, ( (il&N-15049, ('I IK l. ( I IK2, A2aR, 13-7 faniily marl eted under the trade name Afema™. Anastrozole is ligands or a combination thereof. In an aspect. the check- markctcd under Ihc trade nmnc Anmidcx&M Letrozolc is point inhibitor is an immunostimulatory agent. a T cell markctcd under Ihc trade names Fcmara™ or Famer&M. growth lector, un intcrleukin, an antibody, a vaccuic or a Anunoglutethimide is marketed under the trade name Orim- combuiation thereof. Iu a further aspect, Ihc intcrleu)un is etenmv' combination of the invention comprising a che- IL-7 or IL-IS. In a spccilic aspixm Ihe uitcrleukui is glyco- motherapeutic agent ivlgch is an ammatase inlgbitor is sylated 11.-7 In an additional aspect, the vaccine is a particulariy useful for the treatment of hormone receptor dendritic cell (D(') vaccine positive tumors, such as breast tumors. ]0411] C:heckpoint inhibitors include any agent that blocks ]0415] The term "antiestrogen" as used herein relates to a or mlnbits ui a statmucdlly sigiulicani mmuicr. thc inhibitory compound vvhich ants onizes the eifect of estro ens at the pathways of the immune system. Such inhibitors may cstrogcn rcccptor lcvcl. The tenn includes. but is not limited include small molecule mhibitors or may include antibodies, to tatnoxifcn. fulvestrant. raloxifbnc and raloxilbnc hydro- or antigen binding fragments thereof. that bind to and block cldorxlc. Tamoxifcn is nuirkctxxJ under thc tmdc name or inhibit immune checkpoint receptors or antibodies that Nolvadex™ Raloxifene hydrochloride is marketed under bind to and blocl or inhibit imnume checl point receptor the tm&de naine Itvistamu 1&ulvestrant can be administered li ands. Illustmstive checl point molecules tlmt may be tar- under the trade name Fasiodex&M. A combination of the gctxxl li&r blockuig or inhibiuon include, but are not lmuted invention comprising a chemothemspeutic a ent wlgch is an to. CTLA-4, PDLJ, PDL2, PDI. B7-H3, B7-H4. BTL.A, dllllcstrogcit B pdrticuldrlv I&Bc(Ill for tile Ircatlllcllt of csiro- I IVI:M. (IAI,9. I A(13, J1M3. VISIA. KIR, 2B4 (belongs to gcn rixcptor positive tumors, such as breast tumors. the ( l)2 family of niolecules and is expressed on all NK. (8, ]0416] The term "anti-androgen" as used herein relates to and menu&ry CD8'(x]3) T cells), CD160 (also referred to as any substance &xhtch is capable of inhibiting thc biological BY55), CCJEN-15049, CHK I and CHK2 kinases. A2aR, CJTECtS Ol dlldl'OgCillC 1&oitiiollcs ill&0 ll&Cludcs, but is llx&t and various B-7 family ligands. B7 family ligands include, linuted to, bicalutaniide (('asodex&M) 'I'he tenn "gonad- but arc not ltmitxxJ to, B7-1, B7-2, B7-DC, B7-HJ, B7-H2, orelin agonist** as used herein includes, but is not limited to B7-H3, B7-H4, B7-H5, B7-H6 mid B7-H7. Checkpoint abarelix, goserelin mid oserelin acetate Cioserelin can be inhibitors include antibodies, or antigen binding fragnients administered under the tmsde name Zoladex™. thereof. other binding proteins, biologic therapeutics, or ]0417] The term "topoisomerase I inhibitor" as used small molecules, that bmd to and block or inhibit the activity herein includes. but is not limited to topotecan. imatecan, of one or more of CTLA-4. PDLI. PDI 2. PDI. BTLA, iruiotccan, camptotluvian and its analogues. 9-iutrocamp- HVEM. TIM3, CJAL9, LACI3. VISTA, KIR, 2B4, C'D 160 tothccin and the macromolxvular camptothccui conpi aie dnd COEN-15049 Illustrative inumuie chcckpouit uilubi- PNIJ-166148. Irinotecan can be administered, e.g in the tors include Trcmclimumab (CTLA-4 blocking tmtibody), form as it is marketed, e g. under the trademark ('amp- anti-OX40, PD-I.I monoclonal Antibody (Anti-137-111, tosar&M. Topotecan is marketed under the trade name Hyca- MIIDI4736), MK-3475 (PD-I blocker), Nivolumab (anti- mptin™. PDI antibody), ('T-011 (anti-PDI antibody), 13Y55 mono- ]0418] The term "topoisomerase II inhibitor*'s used clonal antibody, AMP224 (anti-PDLI antibody). BMS- hcrcin includes, but is noi loni(cd Io the antluacycluies such 93(i559 (anti-PDLI antibody), MPLDL3280A (anti-PDLI as doxorubicin (uicluduig liposomal I'onnulauon, such as antibody), MSB0010718C (anti-PDLJ muibody). and ipili- Caclyx™). daunorubicin. cpirubicui. &rktrubtcu& mid ncmo- mumab (anti-CTLA-4 chcckpouit inhibitor). Chcckpouit nibicin, the anthraquinones niitoxantrone and losoxantrone, include, but are not limited to PD-I pmtein ligands I, and the podophillotoxines etoposide and teniposide. I itopo- PD-I 2, 137-113, 137-114, CD28, ('Dg(i aod 'I'JM-3 side is marketed under the trade name Etopophos™. Teni- ]0412] In certain embodiments. the inunune checkpoint poside is marketed under the trade name VM 26-Bristol inhibitor is selcctxxJ from a PD-I antdgomst, a PD-Ll Doxorubicin is markctcd under Ihc trade name Acnblastin antagomst. and a CTLA-4 antagonist ln some mnbodi- or Adnamycup&C Epirubicin is markctcd under thc irate mcnts. Ihc chcckpouit inlubitor is selcctcd lrom Ihc roup name Famiorubicin&M. Idanibmui is marketed. under Ihe consisting of nivolumab (Opdivoat). ipiliinumab (Yer- trade name Xavedos'M Mitoxantrone is marketed under the voy)x), and pembroliinunab (Keytrudag). trade name Novantron US 20 ] 9/032265 [] A[ Ock 24, 2019 116

[0419] The tern& "micmtubule active agent** relates to kinases. v,luch are part of the PDCiFR family. such as nucrouibule stubilizuig, micmtubulc dcstabilizing com- compounds which target. decrease or mhibit the activity of pounds and microtublui polymenzatiun inlubitors including, the c-Kit receptor tyrosine kinase family. especially com- but not limited to taxanes, such as paclitaxel and docetaxel, pounds wluch inlubit thc c-Kit receptor, such as imatinib. i) vince alkaloidg such as vinblastine or vinblastine sulfate, compounds tar etin, decreasing or inlgbiting the activity of vincristine or vincristine sulfate, and vinorelbine; discoder- members of thc c-Abl Ihnuly, their gene-fusion products derivatives molidest cochicine and epothilones and thereof. [e g. B('R-Abl kinase) and mutants, such as compounds Paclitaxel is marketed under the trade name Taxop . Doc- which target decrcasc or inlubit thc activity of c-Abl Iiunily ctaxcl is marl ctcd under thc trade &mme Taxotere™. Vin- men&hers and their gene fission products. such as an N-phe- blasune su lib te is marketed under the trade nmne V uiblastin nyl-2-pyrimidine-aminc den& ative, such as nuaunib or rulo- R P&s& Vincnstine sulfate is marketed under the trade name tinib Pi)180970, AG957: NSG 680410; Iiarmistin™. [AMN107); PD173955 from ParkeDavis; or dasatinib [BMS-354825): j) [0420] The tern& "alkylating ageni'* as used herein compounds targeting, decreasiim or inhibitmg the activity of includes. but is not limited to, cyclophosphamide, ifosf- men&hers of the protein kinase ('PK(') and Raf family of amide. melphalan or nitrosourea [B('NU or Ciliadel). Gyclo- scone/threonine kinases, menibers of the Ml &K, SR(', .IAK/ phosphaniide is marketed under the trade name Cyclostinrch pan-JAK, FAK. PDKI. PKB/Akt, Ras/MAPK. P13K, SYK, Ifosfamide is marketed under the tmde name Holoxan™. TYIC2, BTK and TEG family„and/or members ofthe cyclin- 1 he term "histone deacetylase inhibitors" [t)421] or dcpendent kirmsc Ibmily [CDK) includuig staurosponne "HDAG inhibitors** which relates to compounds inhibit the dcrivativcs. such as nudostaunn, cxamplcs of further com- which histone deacetylase and possess antiproliferative pounds include U('N-OI, safingol. l3AY 43-9006, l3ryostatin acu& ity. This includes, but is not lunitcd to. suberoylanilide I, Penfosine; llmofosine: RO 318220 and RO 320432; (IO ilvilroxilllilc ticlil [SABA). 6976; Isis 3521: I Y333531,&I,Y379196: isochinolme com- [04221 The tern& "antineoplastic antimetabolite" includes, pounds: FTIs; PD184352 or Qs&N697 [a PI3K inhibitor) or but is not lumted to, 5-Iluorouracil or 5-FU, capecitabinc, AT7519 (GDK inlubitor); k) compounds tar eting. decreas- gcmcitabuie, DNA dcmethylating compounds, such as ing or inlubiting thc activity of proteus-tyrosine kinasc 5-azacytidine and decitabine, methotrexate and edatrexate, inhibitors. such as compounds wluch target, dccrcasc or and folic acid antagonists such as pemetrexed ('apecitabine iilllibit the activity ot protein-tyrosine kinase inllibitors is marketed under the trade name Xeloda»& (iemcitabine is include imatinib niesylate [Gleevec'u) or tyrphostin such as marketed under the trade name Gemzar™. 'I'yrphostin A23&RG-50810: A(i 99; 1yrphostin A(i 213; [0423] The term "platin compound'* as used herein Tyrphostin ACJ 1748: Tyrplu&stm ACi 490: Tyrphostin B44; includes. but is not limited to. carboplatin. cis-platin, cis- Tyrphostin B44 [+) enantiomer, Tyrphostin ACi 555; ACi platuium mid oxuliplatin. Garboplaun can be admiiustcrcxk 494, Tyrphostin AG 556, AG957 and adaphosun (4-[[[2.5- c.g., in thc fomi as it is markctixi, e.g. under thc trademark dihydroxyphenyl)methyl]amino]-benzoic acid admnaniyl ('arboplat&s& Oxaliplatin can be administered. e g. in the ester, NSC 680410, adaphostin); I) compounds targetuig, form as it is marketed. e 8 under the trademark I iloxatin'v. decreasing or inhibiting the activity of the epidermal growth [(1424[ 'I he term "compounds targeting/decreasing. a pro- factor family of receptor tyrosine kinases 0:Cii'R, iirbB2, tein or lipid kinase activity: or a protein or lipid phosphamse ErbB3. ErbB4 as lu&mo- or heterodimers) and their mutants, activity: or further anti-angiogenic compounds" as used such as compounds wluch tar et, decrease or inhibit the hcrmn includes, but is uot lunitcd to. protein tyrosine iuimsc activity of thc epidermal growth I'actor riwcptor family arc anil/or serine aud/or duconinc lunase inhibitors or hpid especially compounds, proteuis or anuboihcs which inhibit kmasc inlubitors. such as a) compounds targeung. tlecreas- members ol'the EGF receptor tyrosinc kinasc I'emily, such as ing or inhibiting the activity of the platelet-derived growth I:(iF receptor, I irbl32, I irbH3 and I irbH4 or bind to 11GI'r factor-receptors 1 PI Xil '8), such as compounds which target, I:(iF related ligands, ('P 358774, XD 183'J. /M 105180; decrease or inhibit the activity of PDGFR. especially com- trastuzumab [Herceptinr"). cetuximab [Erbituxr"). Iressa, pounds which inhibit the PDCiF receptor, such as an N-phe- Tarcevm OSI-774, G1-1033„EKB-569, GW-2016, El.l, nyl-2-pyrinudinc-umine denvative, such as imatuub, E2.4, E2.5, E6.2. E6.4, E2.11, E63 or E7.6.3, and 7H-pyr- SU101. SU6668 und CiFB-ill, b) compounds uugcting, rolo-[2.3-d]pynmiduie derivatnes, m) compounds targct- dcwrcasing or inhibiting thc activity ul thc Iibroblast growth iug, dccrcasing or inhibiung the acuvity of thc c-Met recep- factor-receptors tli(il&R), c) compounds targetina, decreas- tor, such as con£s which target. decrease or inhibit the ing or inhibiting the activity of the insulin-like growth factor activity of c-Met. especially con£s which inhibit the receptor I [ICiF-IR). such as compounds which mr et, kinase activity of c-Met receptor. or antibodies that target the decrease or inhibit the activity of I(iF-IR. especially com- extmcellular domain of c-Met or bind to HCiF, n) compounds which inhibit thc kuiasc acuvity ofIGF-I recc7&tor, or pounds targctuig, decreasing or udubiung the kinasc activity ant&bod&ca that target thc extracellular domain of IGF-I of ouc or more JAK I'emily members 1JAKI/JAK2/JAK3/ riweptor or its growth factors, d) compounds targeting, TYK2 and/or pan-IAK), uicluduig but not lunitcd to PRT- decreasin or inhibiting the activity of the 'I'rk receptor 062070, SI3-1578, baricitinib. pacritinib, momelotinib, tyrosine kinase faniily, or ephrin B4 inhibitors; e) con&- VX-509, A/l)-1480, 'I'(i-101348, tofacitinib. and nixoli- pounds targeting, decreasing or inlgbiting the activity of the tinib: o) compounds targeting, decreasin or inhibiting the Axl receptor tyrosine kinase family: f) compounds mrgetin, kinase acti& ity of PI3 kinase (P13K) includin but not dcwrcasing or inhibituig thc activity of the Rct receptor limited to ATIJ-027, SF-1126. DS-7423, PBI-05204, GSK- tyrosine kinasc, g) compounds targetmg, decrcasmg or 2126458, ZSTK-474. buparlisib. pictrclisib, PF-4691502, inhibiung tlu: activity of thc K&FSCFR rcwcptor tyrosiue BYL-719, dactolisib, XL-147, XL-765. aud idclalisib: and, kinase, such as imatinib: h) compounds targeting, decreasing and qj coinpounds tar crine. decreasing or inhibiting the or inhibiting the activity of the ('-kit receptor tyrosine sigaahng effects of hedgehog protein [I Ih) or smoothened US 20]9/032265[] A[ Oct. 24, 2019 117

receptor (SMO) pathways, including but not limited to unrelated to protein or lipid kinase inhibition e.g. thalido- cyclop;mumy vismodcgib, itmconazolc, erismode &b, and nudc (Tlmlomuffu) and TNP-470. I PI-926 (saride ub). [0434] Examples ofproteasome inhibitors usefi&1 for use in [0425] The term "PI3K inhibitor" as used herein includes, combuxation with compounds of the invention include, but but is not limited to compounds bavin. inhibitory activity arc not h&xx&tcsI to bortczom&b, d&sul(iram, cp&gallocatechin- against one or more enzymes in the phocphatidylinositol-3- 3-gallatc (EGCG), salinospomxxx&dc A, carlilzonub, ONX- k&nasa family, includ&ng, but not limited to P13Kib PI3K7, 0912, (Tip-18770, and MI.N')708 P13KG. P13KJ', P13K-C2&x, PI3K-C2[3, P13K-C27, Yps34, [0435] Compounds which target, dccrcasc or uxlubit the p110-&x. I fffk p110fn p110-&X p85-u. p85-[3, p55-7, p150, pl act&vity ol'a protcux or lip&d phosphattmc area g. inhib&tora p101, and p87 I:xamples of PI3K inhibitors useful in tlus of phosphatasc I, phospluitasc 2A. or CDC25, such as invention include but are not limited to ATU-027. SF-112C&, okada&c acid or a derivative thereof DS-7423, PBI-05204, CISK-2126458, ZSTK-474, buparlisib, pictrelisib„PF-4G91502, BYL-719, dactolisib. XL-147, [(3436J Compounds xvhich induce cell differentiation pa&- ceases include, but are not limited to, retinoic acid. &x- 0& XL-765. and idclalisib & &- [0426J 'I he term "13cl-2 inhibitor" as used herein includes, b-tocopherol or &x- or b-t&xcotrienoj. but is not limited to compounds having inhibitory activity [0437] The term cyclooxygenase inhibitor as used herein against B-cell lymphoma 2 protein (Bcl-2). including but not includes. but is not limited to, Cox-2 &nh&bitorc, 5-alkyl limited to ABT-199. ABT-731, ABT-737. apogossypol, subst&tuted 2-arylaminophenyiacetic acid and derivatives, Ascenta's pau-Bcl-2 uxlub&tora. curcunun (and analogs such as cclecoxib (Cclebrex™). rofecoxib (Vioxx™), etori- thereol). dual Bcl-2/Bcl-xL uxh&bi&ore (lnlimty Phamxaceu- cox&b. valdecoxib or a 5-alkyl-2-arylam&nophenylacct&c ticals&Novartis Pharmaceut&eels). Cienasense ((1313')), acid, such as 5-nxethyl-2-(2mchloro-6mfluoroanilino)phenyl HA14-I (and analogs thereof; see WO2008118802). navi- acetic acid. Iumiracoxib tociax (and analogs thereof. see U.S. Pat. No. 7.390,799), [(3438J I he term "bisphosphonates" as used herein NH-I (Shenayng Pharmaceutical University). Cbatocjax includes. but is not limited to. etridonic, clodronic, (and analogs thereof, see WO200410G328). S-001 (Cr'loria tiludronic. pamidnxnic, alendronic. ibandmnic. ricedronic Pluirmaccuticals), TW sencs compounds (U&uv. of M&clu- and zoledronic acid. Etridonic acid is marketed under the gan), and venetoclax. In some embodiments the Bcl-2 trade name Dxlronclrck Clodromc ac&d is markctcd under In embodi- inhibitor is a snxall molecule therapeutic some the triulc name Boncfos™. Tiludron&c ac&d is markc&cdj nxents the 13cl-2 inhibitor is a peptidomimetic under the tmcde nanxe Skelid™. Pamidronic ac&d is marketed "BTK &nlub&tor" [0427] The term as used here&n uxcludes, under the trade nanxe Aredia&c&. Alendronic ac&d is marketed bui &s not linutcd to compounds lmvuxg inhib&tory act&v&ty under the trade name Fosamaxrvo Ibandronic acid is mar- agamst Bruton's Tyros&nc Kuxasc (BTK), includmg, but not keted under the trade name Bondranatrvo Risedronic acid is limited to AVI -292 and ibu&tinib marl eted under the trade name Actonel™. Zoledronic acid [0428] The tenn "SYK inhibitor" as used herein includes, is markctcd under the trade usmc Zomcta™. Thc tenn bui &s not linutcd to compounds lmvuxg inhib&tory act&v&ty "mTOR uxh&b&tora" rclatcs to compounds wh&ch inhib&t thc agamst splemx tyrosu&e kuxasc (SYK), mcluduxg but not manxmalian target of rapamycin (mTOR) and which possess lim&tcd to PRT-062070, R-343, R-333, Excellmr, PRT- antiprohfemctive activity such as s&mlimus (Rapannu&e&t), 062607. and fostanxatm&b everolinnls (Certicanr"), CCI-779 and ABT578. [0429] Further examples of BTK inhibitory compounds, [(3439J the term "heparanase inhibitor" as used herein and condit&ons trcatablc such compounds in combumtion by refers to compounds xvhich target„decrease or inhibit hepa- with compounds of tlus invention can be found ux rin sulfate degradation. The tern& includes„but is not limited WO2008039218 and W02011090760, thc cnt&rety of wluch to, Pl-88. The tenn "biolog&cal rcsponsc mod&lier'* as uscdj are incorporated herein reference by here&n rcfcrs to a lymphokuxc or &ntcrfi:rona. [0430] Further examples of SYK inhibitory compounds, and condit&ons trcatablc by such compounds in combumtion [0440] The term "&nlubitor of Ras oncogm»c &soforms", I K-Ras. as with compounds of tlus invention can be found ux such as I-Ras, or N-Ras, used herein refers to WO2003063794, WO2005007623, and WO2006078846, cmnpounds which target. decrease or inhib&t the oncogenic the entirety of which are incorporated herein by reference act&vity of Ras; for exanxple, a "famesyl transferase inhibitor" such as L-744832„DK8C3557 or R115777 [0431] Further cxmnplcs of P13K uxh&bitory compounds, (Zamestra™). The tenn "telomemsse inlgbitor" ac used and conditions treatable by such compounds in combination hcrcin rcfcrs to compounds which targcL decrease or inlub&t with compounds of this im ention can be found in thc activity ol telomcrase. Compounds wluch targcL VVO200401&)&)73 WO200408&)&)25 W(32007016176. U S. decrease inhibit the activity telomerase are Pat. No. 8.138,347, WO2002088112, WO2007084786, or of especially )VO2007129161, WO2006122806, WO2005113554, and compounds which inhibit the telomerase receptor, such as tclonlcstath& WO2007044729 the cnt&rcty ol'hich arc incorporated he&cut bv Iclblcxxcc. [(344 IJ I he term "methionine aminopeptidase &nh&bitor*'as

[0432] Further examples of )AK inhibitory compounds, used herein refers to compounds v, hich tar et, decrease or and cond&tions treatable by such compounds in comb&nation inhib&t the activity of metluonine aminopept&dase. Com- with compounds of tlus invcnlion can be I'ound &n pounds which target. decrease or &nh&b&t thc activ&ty ol'etluonuxc VVO2009114512. WO200810&P)43, WO2007053452, anunopepudasc uxclude, but arc uot l&xuitcdl to, VVO2000142246, and WO2007070514, the entirety of bcngamidc or a dern au& c ther&a&f. which are incorporated herem by reibrence. [0442] The term "protcasomc inhib&tor" as uscdl herein [(3433J I'urther anti-angiogenic co&npounds include con&- refers to compoxuxds which tar et, decrease or inhibit the pounds havuxg another mechanis&n for their activity. e g. act&vity of the proteasome. ('ompounds which target, US 20]9/0322658 A[ Oct. 24, 2019 118

decrease or inlubit the activity of the proteasome include, inhibitors include MS275, SAHA. FK228 (formerly bur are not linutcd io, Boriezomib (Vclcade™) and MLN FR901228). Tnchostatin A and compounds disclosed ur U S. 341. Pat. No. 6 5S2 OGS uicluduxg. but not lunrted to, N hydroxy-

[0443] The term "matnx metalloproteinase inhibitor" or 3-[4-[[[2-(2-methyl-111-indol-3-yl)-ethylJ-aniino J methyl] ("MMP'* inhibitor) as used herein includes, but is not limited phenyl[-2E-2-propenamide, or a pharmaceutically accept- to, collagen peptidomimetic and nonpeptidomimetic inlubi- able salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl) /)2- tors. iciracyclurc dcrivairvcs, c.g. hydroxamaic pcprridonrr- (IH-urdol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- mcirc inhibitor batrmastat and its orally broavmiablc aixr- propenunide, or a pharmaceutically acceptable salt thereof, logue marinxastat (1313-251(x), prinomastat (AC)3340), especially ihe lactate sali. Somatosiauu rcccptor miiagonisis nxetastar (NS('83551) 13MS-279251, 13AY 12-9566, as used herein rcibr io compounds which target, treat or TAA211, MMI270B or AA)996. inhibit the somatostatin receptor such as octreotide. and [0444] The tenn **compounds used in ihe trcaimcnt of SOM230 Tumor cell danxaging approaches refer to henuaologrc malignancies" as used hcrcrn uxcludcs, but rs appmaches such as ionizing radiation. The term "ionizin not limited to. I'MS-like tyrosine kinase inhibitors. which radiation" referred to above and hereinafter means ionizing are compounds targeting, decreasing or inhibiting the activ- radiation that occurs as either electromagnetic rays (such as ity of FMS-like tymsine kinase receptors (Fit-3R): inter- X-rays mid ganuna rays) or particles (such as alpha and bcia feron, 143-D-srabinohrransylcytosine (ara-c) and bisulfan, particles). Ionizuxg rarhaiion rs provuled rn, bui noi fimircd) and ALK inhibitors, which are compounds wlflch mr et, to, radiation therapy and is knov n in the art See I lellman, drmrease or ndubrt auaplasirc lymphuma lunasc. Principles of Radiation 1herapy. ('ancer, in Principles and 4m [0445] Compounds v hich tar et, decrease or inhibit the Pnxctice of Oncology, Devita et ai., I ids, lidition, Vixl. I, acus rty of FMS-like iyrosinc kinasc rcmeprors (Fit-3R) are pp. 248-275 (1993). especially compounds, proteins or aiuibodres wluch udubit [0450J Also included are I:IXI binders and ribonucleotide mcmbcrs of thc Fli-3R receptor kinasc Iiumiy, simh as reductase inhibitors. The temx "EDCI binders'* as used herein PK('412, midostauun, a staurosporine derivative, SII11248 refers to a class of imnurnosuppressants that modulates and Ml /¹18 lymphocyte recirculation, such as FTY720. The term "ribo- [r)446] 1 he terna "I ISP90 inhibitors" as used herein nuclcotulc rcductasc rnlubiiors" refers io pyrimiduxc or includes. but is not linxited to. compounds targeting, decreas- punnc nucleosidc analogs uicludrn . but not limited to, ing or inhibiting the intrinsic ATPase activity of IISP90, fludanxbine and/or cytosine arabinoside (ara-('). 6-thiogua- degrading, targeting, decreasing or inhibiting the HSP90 nine, 5-fluorouracil. cladribine, 6-mercaptopurine (espe- client proteins via the ubir)uitin proteosome pathway. Com- cially in combination with ara-C against ALL) and/or pen- pounds targeting, decreasing or udubuing the mtrumic tostatin Ribonucleotide reductase inlubitors are especially ATPase activity oi'SP90 arc cspccially compounds. pro- hydroxyurea or 2-hydroxy-HT-isoindole-l.3-dione deriva- teins or antibodies which inhibit the AI'Pase activity of tives I ISP90. such as 17-allylamino, 17-dernethoxygeldanamycin [0451] Also included are in particular those compounds, (17AACi). a eldananxycin derivative; other geldanamycin proierns or monoclonal anubodu:s of VECiF such as 1-(4- reLated compounds) mdicicol and HDAC inhibitors. chloromulino)-4-(4-pyridylmcthyl)phthalazinc or a phanna- [r)447] 1he tenn "sntiprohferative antibodies" as used ccu1rcally acceptable sali ihercoi', I-(4-chloroanrluio)-4-(4- herein includes. but is not limited to. trastuzumab (Hercep- pyndylmethyl)phthalazine succinate: Angrostatin'u; tinrvfl), Trastuzumab-DMI, erbitux. bevacizumab (Avas- I:ndostathr'™ anthranilic acid amides; /D419(? /ds474; tinrvfl), rinrximab (Rituxang), PROCi4553 (anti-CD40) and SU5416i SU(i6G8; bevacizumab: or anti-VEC)F antibodies 2C4 Anubody. By anuboihcs is meant intact monoclorml or anti-VEC)F receptor antibodies. such as rlurMAb and antibodies. polycloual antibodies, multrspimrlic antibodies RHUFab, VEGF aptamcr such as Macugon, FLT-4 uihibi- formed from at least 2 intact antibodies. and antibodies tors, FLT-3 inlubiiors. VEGFR-2 IgGI anubody, Angiozymc fra nxents so long as they exhibit the desired biological (RPI 4610) mid Bcvacizumab (Avastur™). activity [0452] Photodynamic therapy as used) herein rcibrs io [r)448] I'or the treatment of acute myeloid leukenria therapy which uses crriarn chemicals known as photosen- (AM),), compounds of the current invention can be used in sriizrng compounds io trcai or prcvcnt cancers. Examples of combination with standard leukemia thempies. especially in photodynamic therapy include treatment with compounds, combination with therapies used for the treatment of AML. such as Visudyne'M and porfimer sodium In particuLsr, compounds of the current invention can be [0453J Angiostatic sremids as used herein refers to com- adnunistcred rn combrrmtron witlx for cxmuplc. famcsyl pounds which block or inhibit angiogenesis, such as, e.g,, tralxsiclase llllxlbluirs alxd/ol oilier drugs ilscfill fixr rile anecortave. triamcinolone, hydrocortisone, 11-rx-epihydro- treatment of AMI, such as Daunonrbicin. Adriamvcin, cotisol. cortexolone, 17o.-ydroxyprogesteronee. corticoster- Ara-(. VP-16. ')eniposide, Mitoxantrone, Idarubicin, Car- one, desoxycorticosterone. testosterone. estrone and dexam- boplatinum and PKC412. crhasonc. [r)449] Other anti-leukemic compounds include, for [0454] Implants containing corticosteroids refers to com- example. Anx-C, a pyrimidine anakxg, which is the 2ualpha- pounds, such as ihiocinoione and dexamethasone. hydroxy ribose (arabinoside) derivative of deoxycytichne. [0455] Other chemotherapeutic compounds include, but Also included is the purine analog of hypoxanthine. 6-mer- are not limited to, plant alkaloids. hormonal compoxuxds and capiopuunc (6-MP) mid fludarabuic phosphate. Compounds antagonists, biological response modrlicrs, prcfi:rably lym- winch target, decrcrmc or uihrbit activity of hisionc dcace1y- phokuics or urtcrfi:rona. mxiisensc oligouucleoirdcs or oli- lasc (HDAC) inhibitors such as sodium butvrate mxrl sub- gouucleoiidc dcrivauica, shRNA or srRNA, or miscella- eroyianilide hydroxamic acid (SAI IA) inhibit the activity of neous compounds or compounds with other or unknown the enzymes known as histone deacetylases. Specitic I IDAC mechanism of action US 20]9/032265[] A[ Oct. 24, 2019 119

[0456] The structure ofthe active compounds identified by compositions a dosage of bei»een 0.01-1,000 pg/kg body code numbers, gcncuc or trade names may betaken from the wc&ghgday ofthc add&tional thcrapeuuc agent cau be aihnin- actual edition of thc standard compend&um *'The Marek istercd. index" or from databases. e g. Patents International (e g. [0463] Thc amount ol'addnional therapcut&c agent prcscnt IMS World Publications) iu thc compos&I&ons of this &ment&ou w&ll bc no more than [0457] A compound ol'hc currcni invention may also bc thc amount that would normally be adm&nistcred in a com- used in combination w&th known therapeutic processes. for position comprising that therapeutic agent as the only active example. Ihe administration of hormones or radiation. In agent Preferably the an&ount of additional therapeutic agent certain emlx&din&ents, a provided coinpound is used as a in the presentiy disclosed compositions will ran e from radiosensitizer. especially for the treatment of nm&ors which aboUt 50",s to 100'&I& of the amount normally present in a exhibit poor sensitivity to radiotherapy. con&poli&un& coulpllsulg Ihdl &&gent tis thc univ lhc&dpcUI&- acuvc agent. [0458J Acompoundofthecurrentinventioncanbeadmin- cally istered alone or in combination with one or more other [0464] The compounds of Ilus &nventiou, or phannaccuii- therapeutic compounds. possible combination therapy mk- cal compositions thereof. may also be incorporated into ing ihe Ionn ol lixed combu&a&ious ur thc ddnunislration of cmupositions fi&r coatin an implantable n&edical device, compound ol'hc u&vcnuou and onc or more other thcra- such as prostheses. artihcial valves, vascular grafts. stents pcuuc compounds beu&g staggered or g&vcn u&dcpcndcntly and catheters. Vascular stents, for example. have been used of one another. or the con&bined administnltion of fixed to overcome restenosis (re-narrow ing of the vessel wall after combinations and one or more other therapeutic compounds. iu)ury). However, paucnts us&ng stcnts or other implantablc A compound of the current invention can besides or in dcv&ces risk clot R&rmauon or platclct act&vauon. Thcsc addition be administered especially for tumor therapy in umvanted etfects nmy be prevented or nutigated by pre- combu&at&on w&th chcmothcrapy, rad&OQ&erapy. &nununo- coatmg the device with a phaunaceutically acceptable com- thcrapy. phototherapy, surg&cal &ntcrvcntion, or a combuxi- position comprising a kinase inhibitor hnplantable devices &vith a invention uon of these Long-Icon therapy is equally poss&ble as &s coated compound of this are another adjuvant therapy in the context of other treatment strategies, embodiment of the present invention. as described above. Other possible treatments are therapy to maintain the patient*s status after tmnor regression, or even I!XIIMPI,II&I( A'I'ION chenu&preventive thempy. for example in patients at nsk. Gcncral Syntheuc Methods [I)459] 1 hose additional agents may be administered separately from an inventive compound-containi»g composition, [0465] The Ibllowing cxdmplcs are &ntm&dcd Io illustraie as part of a multiple dosage regimen. Alternatively. &hose the invention and are not to be construed as being limitations agents may be part of a single doss e fi&rm, mixed together thereon. 1)nless other&vise stated. one or more tm&tomeric w I lb d coulpoUud of this a&vent&on ul &I &nigh: coulposifiou. forms of coinpounds of the examples descubed hereinafter II'admi&ustered us purt of a multiple dosage rcgunc, Q&c Iwo may be prepared in sin& and/or isolated. All tautomeric fom&s active agents may be submitted sinndtaneously, sequentially ofcompounds ofthe examples described hereafier should be or &vi thin a period oftime fron& one another nouually &vithin considered Io bc disclosed. Tempcrutures are g&vcn in five hours from one another. dcgrccs cm&tigrade. If not mentioned othcrw&sc. all cvapo- [I)460] As used herein, the term "combination," "con&- nltions are performed under reduced pressure, preferably bined." and related terms refers to the sinn<aneous or between about 15 mm I lg and 100 mn& I lg ( 20-133 mbar) sequential adm&nistration of therapeutic agents iil accor- 'I'he structure of final products, intermediates and starting, dance with tins invention For example. a compound of the materials is conhrmed by standard analytical method~. e present invention may be administered with another them- m&croanalysis and spectroscopic chamcteristics. e g.. MS, peutw. agent sunultancously or scqucntially ul separate un&I IR, NbIR. Abbrev&ations used are those convent&onal u& Ihe dowigc foluls or togo&he& ul a sul h: uu&I dosage Ibnu. d&t. Accordingly. the present invention provides a single unit [0466] All startu&g nuiterials. bu&ldu&g blocks, rcagcnts, dosaue form comprising a compound of the current inven- acids, bases, dehydmting auents. Solvents, and catalysts tion. an additional therapeutic agent, and a pharmaceutically ut&ized to synthesis the compounds of the present invention acceptable carrier, adjuvant, or vehicle. are either conunercially available or can be produced by [0461] The amount of both an inventive compound and organic synthesis metlu&ds kno&vn to one of ordinary skill in additional therapeutic agent (in those compositions which the art (Houben/Weyl 4th Ed. 1952, Methods of Organic comprise an add&t&oual thcrapcutic a cnt as dcscnbcd above) Synthesis. Thicme, Volume 21). Further, thc compounds of Ihat mdy be comb u&cd w &Ih Ihe earner matcuals Io produce thc plcscul a&vent&on cdu bc produced by'rgauu: svulhcs&s single dosage form w&ll vary dc3&cnd&ng upon Ihc host methods knovu& to one of ordinary skill in the art as shown treated and the particular mode of administration Prefer- in the follov;ing examples ably. compositions ofthis invention should be formulated so that a dosage of between 0.01-100 mg/kg body wei ht/day Abbre& is&iona of an inventive compound can be administered. [0467] equ&v or eq. molar cquivalcnts [0462] In those compositions which comprise an addi- [0468] o&n. ovenught uonal thcrapmit&c ugcnt, that adduional therapcuuc agent [l)469J rt: room temperature and Ihc compound of th&s invention may acl svnerg&slically. [l)470J IIV ultra violet Thcrcforc. thc amount of additional thcrapcuuc a ent &n such composit&ons &vill be less than that required in a [l)471 J IIPISO high pressure liquid chromatography n&onotherapy utilizing only that therapeutic agent In such [l)472J Rt: retention time US 20]9/032265[] A[ Och 24, 2019 120

[0473] LCMS or LC-MS: liquid chromatography-(nasa I spcciluillciiy NMR: magnetic resonance [0474] nuclear Synthetic Schcmc 1. (R) N-(3-(4-(2-amino-6- [t)475] ('( column chromatogmphy methylpyrimidin-4-yl)-1,4-oxazepan-)-yl)-4-chloro- [(3476J 'I I,( thin layer chmmatography phenyi)acetamide (Ci) 1-10 and (S) N-(3-(4-(2- [04'77] sat. satumtcd mnino-6-methylpyriniidin-4-yl)-1,4-oxazepan-3-yl)- [0478] aq aqueous 4-chlorophenyl)acetamide (7) 1-15 [(3479J Ac: acetyl [t)480] DCM'ichloromethane [0510J [0481] DCE. dichloroctlianc [0482] DEA: diethylamine [0483] DMF; dunethylformamide [0484J DMSO diniethylsulfoxide [0485] ACN or McCN acetonitnle [0486] DIPEA: diisopropylethyliunine [0487] EA or EtOAc: ethyl acetate ('xample[t)488] 13INAP: ( )-2,2ul3is(diphenylplmsphino)-1. I ubi- 0 naphthalene 'I SO [(3489J I (A: triethylamine [0490] THF: tctrahydrofuran [0491] TBS: tert-butyldimethylsilyl [(3492J KI IMI)S potassiuni hexamethyl disilylazide [t)493] 1 f tnihioroniethanesulfonate [0494] Ms mcthancsulfonyl [04951 NBS: N-bromosuccmimide (. (. [t)496] VI I petroleum ether [0497J 'I IiA: tnfluoroacetic acid [0498] FA formic acid [0499] MMPP ma nesium monoperoxyphthahste [0500J I IAI'U 1-[13is(diniethylamino)methylene]-111-1.2, 3-triazolo[4.5-b]pyridinium 3-oxide Hexafluorophos- phate [0501] Cy: cyclohexyl [(3502J 'lob toluene (. [0503] DMP Dess-Martin pcnoduianc [0504] IBX: 2-iodoxybenzoic acid [0505] PMB: p-methoxybenzyl [t)506] SIAM: [2-(1rimethylsilyl)ethoxyJmethvl [0507] XPhos or X-Phos. 2-Dtcyciohcxyiphospluno-2',41 6ntriisopropylbiphenyl [0508] Oenerul Inl'onnaiion. [0509] All evaporations were carried out in vacuo with a rotary et apomtor. Analytical samples were dried in vacuo (1-5 nunHg) at rt. Thin layer cluomatography (TLC) was pcrformcxl on silica gcl plates. spots were visiralized by UV C, light (214 and 254 nm) Purification by column and flash chromatoaraphy was carried out using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All 'H NMR spectra were recorded on a Bruiker 400 (400 MHz) spcciromctcr. 'H chemical slufts are reported ui 6 i elues ui paris pcr million (ppm) with thc deutera (cd solvmii as the intenral standard. Data are reported as Ibllows chemical shift, niultiplicity (s singlet. d doublet, t triplet, q quartet, br broad. m multiplet). coupling constant (I Ix), integration (i.e. number of protons). LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 (nasa spectrometer with elccirospmy ionization and except as (. othcrwisc indicated, the gcncral LCMS condition was as follows. Waters X Budge Ci 8 column (SO nuna4.6 nmis3 5 iun), Iilov Rate 2 0 nil dmin, the column temperature: 40" US 20 1 9/032265 JJ AJ Oct. 24, 2019 121

-continued Formation of (+/— )-tert-butyl 3-(2-chloro-5-nitrophenyl)-1,4-oxazcpanc-4-carboxylate (2)

105121 A mixture of 3-(2-chloro-5-nitm-phenyl)-1,4-ox- tt 8 azcpauc (0.50 g. 1.93 nuuol) and triethyhunu&e (0.27 mL, 1.94 nunol) in THF (7 mL) was added ih-ten-butyldicar- bonate (0.42 g, I 93 mmol) 'I'he reaction n&ixture was stirred overnight at room temperature '11&e react&on mixture was diluted mto aqueous saturated NI Id('I solution and extracted with dichloromethane. The or an&c phase was passed throu h a phase separator funnel and concentrated in i acuo. Thc crude residue was purilied by sil&cd gcl chromatography 0 using a 40 g ISCO Gold colunm (0-20% EtOAc,'CH&CI& 0 gradient) to give 376 mn of the desired product as an off-v hite solid: I JSI-MS m,'z cele. 356.1139. found 356/82 (M+I)+ Retention time 0 92 minutes tt 8

Formation of tert-butyl 3-(3-am&no-2-chlorophenyl)- 1,4-oxazcpanc-4-carboxylate (3)

105131 A suspension of tert-butyl 3-(2-chloro-5-nitro-phenyl)-1,4-oxazepanc-4-carboxylate (I 98 g, 5.55 nunol), NHdCJ (1.20 g, 22.43 nunol) and zinc (2.00 g, 30.58 nunol) was s&irred &n 2% TPGS-750-M &n water (50 mL).75''or The reaction mixture was stirred vigorously and heated to 23 hours The mixn&re was diluted into aqueous saturated NaHCO& solution and extracted with dichloromethane. The organic phase was dried (MSSOd), tiltered and concentrated 4 2-chloro-5-nitrobenzaldehyde. (a) A mol sieves, CH&CJ,, iu vacuo. Thc crude residue was punlied via s&lien gel 2.6-1utidine, Cu(OTJ)„hcxatluoroisopropanol, (b) CH&CJ„ ninon&atogmphy wnh 80 g isco colunm us&ng 10-50% (20% c) Boc,O. Et&N. THF: (d) zinc, NH GL 2%TPCr'S-750-Min MeOH~H&CI&/CHcCJ& grad&cnt) to aflbrd 2 grmns of water 75'.: (c)AcCJ, Et N. CH Cls, (f) TFk CH Cls. (g) des&red prnduct as a light yellov solid that was used without 2-amino-4-chloro-6-methylpyrimidine, NMP. 150'd (h) further purification; I:SI-MS nffz cele 35(i 1139. found SFC clural separation 227 14 (M-Boc) . Retention time: 0.64 minutes.

— Format&on oi'+/ — )-3-(2-chloro-5-&utrophcnyl)-1,4- Fonnauon of (+/ )-tert-butyl 3-(5-acctamalo-2- chlorophenyl)-1.4-oxazepane-4-carboxylate ox;&zcpane (I) (4) Jt)514J Tn a solution of tert-butyl 3-(5-anuno-2-chion&- 105111 To a solut&on of 3-(tributylstannylmethoxy)propan- phenyl)-1.4-oxazepane-4-carboxylate„3„(0.25 8, 0.69 I-amu&e (3 06 g. 8.09 nunol) in anhydrous dmhlorometlru&c mmol) and triethylamine (0.15 mL. 1.04 mmol) in dichlo- (15 mL) was added 2-chloro-5-n&trobcnzaldehyde (1.50 g, romcthane (3 mL) was added dropw&se a solution of acetyl 8.08 mmol) follow cd by 4 A molecular s&aves. The mixture chlor&dc (0.05 mL, 0.75 nuuol) in dichloromethanc (I mL). was stirred ovenught at room ten&perature, filtered to ren&ove Thc reaction nux&urc was s&irred at room tempera&urc Ibr I the sieves. and d&luted with dichloro&nethane (75 m[,) In a hour. I he mixture was quenched by adding aqueous satu- separate flask containin hexafiuoroisopropanol (22 mL) mated Nalff'Os solution and extracted mice with dichlo- was added 2,6-1ut&dine (0.94 mL, 8.10 mmol) followed by mmethane. The combined organic phases v ere filtered Cu(OTf)i (2.93 g, 8.10 nunol). The mixture v, as st&rrcd for through a phase separator and concentrated in vacuo. The I un&nc so Jut&on v, &n hour then thc prepared above as added c&tuh: &csuluc wds pu&lficd v&d s&lud gcl ch&on&atog&'t&phv one poruon. Thc redcnou was stirred ovenugh& at room w&th 40 g &sco GOLD column using 0-30% (20% McOH temperature 'I'he n&ixture was diluted with 150 ml 2 I of CH&CJ&,'CH&CI&) grad&ent to afl'ord 185 mg of a wlutc solid, aqueous autumn&ed Nail('Os solution and 10% ammon&un& clean by I..(.'MS IJSI-MS m,'z cele 36815. found 369.42 hydroxide. After stirring for 20 minute~, the or anic layer (M+I)+ Retention time 0 8 nunutes &vas removed and washed v ith aqueous san&rated NaHCO., solution. then bone The organic was passed tluough layer Fonuat&on of (+/ — )-N-(4-cJ&lorn-3-(J,4-oxazc7&an-3- phase separator I'uiu&cl and concentrated u& vacuo. Punfi- yl)phenyl)acct;unule (5) cat&on by rei crsc phase s&hca gcl chromatography usu&g an IS('0 100 grmn c18-sq column running with 0 2% for- 105151 Io a solution of tert-butyl 3-(5-acetamido-2- mic acid&11&O and 0 2% formic acid/('I I&CN to afiiird 700 clfloro-phenyl)-1,4-oxazepane-4-carboxylate, 4. (0 18 g, m of the desired product as omsnge-red residue wlfich was 0.47 nunol) in dichloromethane (2 mL) was added trifluo- used witluiut further purification: 'H NMR (d6-DMSO) 8 macetic acid (1.5 mL). Stirred react&on mixture at room 8.48 (0, J=2.9 Hz, IH), 8.11 (dd, J=8.8, 2.9 Hz. IH), 7.73 (d, tcmpcrature Ibr 30 mmu&es and then concentrated u& vacuo. I H). 4.38-4.21 (m, I H). 3.90-3.66 (m. 3H). 3.34 (dd, J=1 2 4, The rcsulue was d&lutcd w&th dichloro&methane and ncutral- 8.5 Hz. IH), 3.18-2.86 (m, 2H), 1.95-1.84 (m, 2H), ESI-MS izcd w ith aqueous saturated NaHCO, solution. Thc orga&uc nfiz cele. 256 06146, found 257 13 (M+ I) Retention time pl&ase ivss passed through a phase separator and the resulting 0 52 n&imites filtmste was concentmted in vacuo to afford 70 n&g of pmduct US 20[9/032265[] A[ Och 24, 2019 122

as white solid that was used without ihrther purificat&on -cont&n&axl ESI-MS m/z cele. 268 09, found 269.20 (M+I ) . Retention tin&e 0.5 mim&tes: 'll NMR (400 Mi lz, IJMSO-d6) &S 10 04 (s, ill), 7 72 (d,.l 2 6 I IX, lli), 7 61(dd..l 8 7, 2 711z. 111), 7.29 1=8.7 Hz, 4.18 J=9.2. 3.1 Hz. IH), (d, IH), (dd, Vl(ac 3.90-3.73 (m, 2H), 3.67 (dt, J=11.9, 6.5 Hz, IH), 3.20 (dd, %if 1=12.2. 9.1 Hz, IH). 3.07 (s, IH), 2.94-2.80 (m. IH), 2.70-2.57 (m, IH). 2.02 (s. 3H), 1.91-1.80 (m. 2H). lionnation of N-(3-(4-(2-amino-6-methylpyrimidin- 4-vl)-1,4-oxdzcpan-3-)'I)-4-chio& iiphcnj'1)ace&annie (R)-isomer (6) and (S)-&somcr (7) (. [t)516] qo a solution of N-[4-chloro-3-(1,4-oxazepan-3-yl) phenyl]acctamidc. 5, (0 067 g. 0.224 nunol) in NMP (3 mL) was added 4-chloro-6-methyl-pyrunnlux-2-amine (0.040 g, (+/ —)-N-(4-(4-(2-amino-6-methylpynmidin-1-yl)-1, 0.279 num&1). The reaction mixture was heated to 150" C. for 4-oxazepa&x-3-yI)-3-cldorophenyl)Beets&&tide 1-141 18 hours. The mixture was cooled to room temperature and loaded directly onto a 50 8 IS('0 c18-aq column and purified [0519] high tcmpcrature (360 K) 'H NMR (400 MHz, 'I'I&A/I by reverse phase nu&nmg with 0 1% l&O and 0 1% DMSO-d6) &1 9 77 (s. IH). 7 77 (s, 111), 7 35 (m, 111), 7.21 TFA/CH&CN. Thc pure fmcuons werc concentrated &n (d, .I 8.0 I lz. H Ij. 5 56 (s, 111). 5.43 (s. 211). 5 36-5 30 (m, BcUC. Thl: rcs&dUC wBB d&IU&ix! U&th d&chio&on&cth'u&c, ncx&- i 111), 4.63-4 59 (n&. IH). 4.05 (m, HI), 3 87 (m, II I), tralized with aqueous satumted NaHCOc solution. The 3.75-3.48 (m, 3H), 2.02 (s, 3H), 2.00 (s. 3H). 1.78-1.74 (m, organic phase was passed through a phase separator and 2H). ESI-MS m/z calc. 375.13„ found 37(U27 (M+I) . concentrated in vacuo to afFord 69 of light orange solid mg Rctcnt&on t&mc. 0.55 nnnutcs. higi& tempemxture (3(&0 K) 'I I NMR (d6-DMSO) 6 9.75 (s, [0520] Racemic material was submitted for SFC clfiral IH). 7.72-7.39 (m, 3H). 7.43-7.18 (m, IH). 5.64-5.19 (m, 3H), 4.85-4.45 (m. IH), 4 31-4.07 (m. IH). 4.04-3.84 (m, &cpa&'&t&on. I H), 3.80-3 28 (m, 3H), 3 02 (s, 3H). 2.00 (s. 3H). 1.91-1.72 [0521] Peak A: (R) N-(4-(4-(2-anuno-Cmmethylpyrimi- (m, 2H); ESI-MS n&/z cele. 375.15, found 37631 (M+I) . din-4-yl)-1.4-oxazepan-3-yl)-3-chlorophenyl)acetamide (8) lxetention time 056 nunutes. 1be race&nic mixture was [ix]o= — 1949 (c=4.1 mg/0.8 mL McOH), h&gh tcmperaturc submitted to chimsl SI&('urification to obtain the individual (360 K) 'H NOIR (400 MHz. DMSO-d6) o 9.83 (s, IH). cndnt&on&c&s. 7.99-7.73 (m, IH), 7.54-733 (m. IH). 7.34-7.12 (m. IH). [0517] Peak A (R) N-[3-[4-(2-tmuno-6-methyl-pynnu- 5 83-5.23 (m, 411), ANN-4 54 (m. 111). 4 28-4 02 (m. II I), din-4-yl)-1.4-oxazepan-3-yl]-4-chloro-phenyl]acetamide 4 07-3.85 (m, 111), 3 85-3 45 (m. 311). 2 20-1 93 (m. Cil I), 'H hi h tempemsture (360 K) NMR (400 MHz. DMSO-dCi) 1.95-1.65 (m, 2H): ESI-MS nu'z calc 375.15. foxuxd 376.31 8 9 70 (s 111) 7.5(& (dd, .I N.(i. 2 6 I im 111), 7 50 (d..l 2 6 (M+I) Retention time: 0.55 minutes 1-310. I lz. 111), 7 31 .I 8 7 I lz, I I I. 5 55 (s, I I I). 5 44 (s. 211), (d, [l)522J Peak H (S)—N (4-(4-(2-am&no-C&-nðylpyrimi- 534 IH). 4 67 1=15.1 Hz, IH). 4.13 1=13.S. 5 0 (s, (d, (dd, din-4-yl)-1.4-oxazepan-3-yl)-3-chlorophenyl)acetamide (9) Hz. IH). 3.92-3 85 IH), 3.67 (dd. J=13.5, 10.2 Hz, IH), (m, [ix]m=+13.75 (c=4.3 mg/0.8 mL MeOH); high temperature 3.63-3.49 (nx. I H), 3.40 (q, J=7 0 Hz. I H), 1.99 (d. J=4.4 Hz, (360 K) 'H NMR (400 MHX. DMSO-d6) o 9.79 (s, IH), 7.77 6H). 1.84-1.73 (m, 2H); ESI-MS m/z calc. 375.14, found J=2.2 Hz, IH), 7.35 J=8.7, 2.1 Hz, IH). 7.21 37(& 27 (M+I)+ Retention time: 0.56 mim&tes. (d, (dd, (d. .I 8.5 I Iz, 111), 5 61 (d..l 39.5 1lz, 111). 5 46 (s. 211), 5.34 [051NJ Peak 13 (S) N-P-[1-(2-amino-6-methyl-pyrim&- dn&-4-VI)-1.4-ox&&zcpan-3-vl]-4-chio&0-phcnj'1]Bee&annie (s, 111), 4.62 (s, lli), 4.08 (dd. I 13 4 5 2 I IX 111) 389 (d .I 123 IIZ, 3 7N-3 47 311), 2.01 8.1 IIZ, Cil higi& ten&perature (360 K) 'I I NMR (400 MI Iz. DMSO-d6) IH), (m. (d..l I), 1.83-1.46 (m, 2H): ESI-MS nu'z calc 375.15. foxuxd 376.31 &S 9 71 (s. 111), 7 56 (dd, .I N.CU 2 6 lit. 111). 7 50 (d..l 2 6 1-162. Hz. IH)„731 (d. 1=8.7 Hz, IH. 5.55 (s, IH), 5.44 (s. 2H), (M+I) Retention time; 0.55 minutes 534 (s. Hq). 4 CI7 (d„1=15.1 Hz. IH), 4.13 (dd. 1=13.5. 5 0 &U Hz. IH), 3.95-3.86 (m, IH), 3.67 (dd, 1=13.S, 10.2 Hz, IH), 3.63-3.49 (m, I H), 3.40 (q, J=7.0 Hz, IH), 1.99 (d. J=4.4 Hz, 6H). 1.84-1 73 (m, 2H), ESI-IvIS nx/z calr.. 375.14, fbund 2". Yif 376 27 (M+ I) Retention time: 0 56 minutes. [&x]&, +41 'I'he following analogs were prepared according to Synthetic Scheme I: (.

(S) N-(4-(4-(2-amino-6-nu:thylpyrun&d&n-4-yl)-1, 4-oxazcpan-3-yl)-3-chloroplmnyl)propionamide (10) 1-204

[0523] Peak 8 from SFC ch&ral scpamt&on: 99.8% cc, 'H NMR (400 MHz, McOD) 6 7.83 (s, IH), 7.40 (dd, 1=8.S. 2.1 I lz. 111), 7.23 (d, .I 8 5 IIX, 111). 6.()1-4 90 (br s, 311), 4 31-4.23 (m, 111), 4.04 (d, I 8.4 Hz, I I I), 3 79-3 5N (m, US 20[9/032265[] A[ Oct. 24, 2019 123

3H), 2.39 (rb 1=7.6 Hz„2H), 2.10 (s. 3H). 2.00-1.78 (m. 2H), (S) N-(4-(4-(2-amino-6-ntethylpyrimidtn-4-yl)-1, 1.24-1.16 (m. 3H). ESI-MS m/4 cele. 389.2. found 390 4 4-oxazcpan-3-yl)-3-chloroplmnyl)propionamide (13) (M+I) . Rctenuon time. 0 58 mimitcs. 1-197

11 [0526] Peak 13 from Sl'('hiral separation: 99.4% ee; 'l I NMR (400 MHz, MeOD) 6 7.75 (s. I H), 7 38-7 31 (m. I H), 7.12 (d. 1=8.5 Hz, IH). 5.43 (s. 3H), 4.15 (dd, J=I3.8, 4.9 Hz, IH), 3.91 (d, 1=9.0 Hz, IH). 3.68-3.45 (m, 3H), 1.97 (s. 3H), I 75 (dd. J=41.1, 11.5 Hz. 2H), 1.17 (dd, J=7 7, 4.S Hz. 2H), 0.94 (dd, 1=7.7. 4.5 Hz. 2H), ESI-MS nt/z cele. 417.2. found 418.3 (M+I) . Retention time 0 56 minutes

H ~ (S) N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l. 4-oxazepan-3-yl)-3-chlorophenyl)propioniunide (11) 1-207

[t)524] Peak 13 fmm SI'('hiral separation: 99 8% ee, heated (3(iOK) 'I I NMR (400 Ml lz, d6-IJMSO) 8 10 03 (s, I H), 7.80 (d„J=2.0 Hz. IH), 7.37 (dd, J=8.5, 2.1 Hz. IH), 7.21 (d. J=8 JHz. I H). 5.56 (s. IH), 5.4(i (s, 2H). 533 (s, I H), 4.63 (d„J=14.1 Hz. I H), 4.08 (dd. J=13.5, 5.0 Hz. IH), 14 3.89 (d. J=12 0 Hz. IH), 3.70 (dd, J=13yh 10.2 Hz, IH), 3.66-3.50 (m. 2H), 2.00 (s. 3H), 1.76-1.72 (m. 3H), 0.83-0. 75 (m, 411), I:SI-MS m/z cele. 401.2. tiiund 402.3 (M+I)'. Retention time: 0 59 minutes

Hix H (.) 0

(+/ — )-N-[4-[4-(2-amino-6-methyl-pyrimidu1-4-yl)-l, 4-oxazcpmt-3-yl]-3-chloro-phenyl]-2-methoxy-acetantide (12) 1-192

[0525] heated (360K) 'H NMR (400 MHz. MeOD) 8 7.74 (s, lit). 7.35 (d, J=8.5 Hz, IH), 7.12 (d. J=8.5 Hz. I H), 5.50 (br s. 3H). 4.14 (dd. J=13.6, S.l Hz. IH), 3.91 (s. 3H), 3.68-3.43 (m, 3H), 3 35 (s, 3H), 1.97 (s, 3H), 1.7S (m. 2H), ESI-MS m/z cele. 405.2, found 406.3 (M+I) . Retention time 0.56 minutes (+/ — )-N-[S-[4-(2-amino-6-methyl-pyruntdtn-4-yl)-1, 13 4-oxazcpan-3-yl]-4-chloro-2-lluoro-phenyl]acct- anudc (14) I-8S Hix [0527] 'H NMR (300 Miqz. CDCI.,) 8 8.36 (d, 1=8.2 Hz, IH), 7.51 (s. IH), 7.18 (tld, J=19.2, 10.3 Hz, IH), 6.02-5.77 (m, IH), S.28-S.09 (m, IH). 4.28 (db J=13.7, 5.1 Hz, IH). 4 20-3.95 (m, 211), 3 84-3 49 (m. 411). 2 42-2 27 (m. 311), 2 22 (d,.l 0 1) ilz, 31 I), 203-1.82 (m, 211); I:SI-MS m/z calc 393 I, found 394.1 (M+I)'. Retention tune: 0.59 minutes. [0528] Racmnic ma(anal ssas submitted for SEC clural separation. conditions 20x2&0 mm IC column, mobile plmse: 40% MeOI I (5 mM Amntonia), 60% COs US 20[9/032265[] A[ Och 24, 2019 124

[0529] Peak A: N-[5-[(3R)-4-(2-amino-6-methyl-pyrinu- (300 MHz. Chloroform-d) 6 7.02 (d. 1=10.9 Hz. IH), 6.45 dtn-4-yl)-1.4-oxazcpan-3-yl]-4-chloro-2-fluoro-plmnyl]ac- (d, J=9.0 Hz, IH), 5.56 (s. IH), 4.9S (s, 3H), 4.30 (dd, ' ctanudc (15) NMR (300 MH% Metlmnol-d4) 6 8.00 (d, J=13.6, S.O Hx, IH). 4.10 (dd, J=I0 8, 6.6 Hx, I H), 3.83-3. 802 I lz, 111). 7 33 (d, .I 10.4 I lz, 111), S.t)5 (~, 211), 4 28 39 (m, 511), 3.10 (qd, .I 7.1, 5 2 llz, 211), 2.17 (s. 311), (dd. 1 13 6. 5 I I lz. 111), 4 05 (dd..t 12 0. 4 5 Hz, 111), 2 09-1.91 (m, 111), 1.89-1.76 (m. 111). I 24 (d, J 7 2 I iz, 3.88-3.54 (m, 3H). 2.15 (s, 3H), 2.12 (s. 3H), 1.90 (d. J=i8 8 3H): ESI-MS nt/z cele. 379.2„ found 379 8 (M+I)'. Reten- Hz, 2H): ESI-MS m/z calc. 393.1. found 394.1 (M+I) . tion time; 0,66 minutes. Retention time: 0.59 minutes; Optical rotatiotu 5 mg/I mL of McOH. C=l. [xx]=-62.24'. 1-270. I:xample 2 [0530J Peak H N-[5-[(3 S)-4-(2-amino-6-methyl-pyrimtdin-4-yl)-1.4-nxazepan-3-vlJ-4-chloro-2-fluorn-phenvlJac- Syntheuc Scheme 2. (+/ — )-4-(3-(2-chloro-4-(mcth- etamide (16): 'H NMR (300 MHz, Methanol-d4) 6 8.00 (d, ylsulfonyl)phenyl)-1.4-oxazepan-4-yl)-6-mcthylpy- 1=8.2 Hz„ IH). 7.33 (d, 3=I 0.4 Hz. IH), 5.65 (s. 2H), 4.28 nmidut-2-tunine (19) 1-66 (dd. J=13.6, S.l Hx, IH), 4.05 (dd, J=12.0, 4.5 Hz, IH), [l)532J 3.88-3.54 (m. 3H). 2.15 (s, 3H), 2.12 (s. 3H). 1.90 (d, J=18 8 Hz. 2H); ESI-MS nt/z cele. 393.1, Ibund 394.2 (M+I) . Optical rotation 5 mg/I ml. of MeOII, (', [rxJ 59 6". 1-271.

1178 (,

Yxif x',xs~// 4

Hxx C. ts

Hx7 8 Yi

(+/ — )-4-[3-[2-chlnro-5-(ethyiamino)-4-fluorn-phe- - (.) nyl] I „4-ox azepan-4-yl] -6-methyl-pyrimidin-2- amtne (17) 1-272

[0531J 'In a solution of N-[5-[4-(2-amino-6-methyl-pyrintidin-4-yl)-1.4-oxazepan-3-yl]-4-chloro-2-fluoro-phenyl] Yif acetantide. 14. (0.05 g. 0.12 nunol) in tetrahydrofuran (5 mL) was added htluum alununum hydride (0.08 mL of 2 M, 0.16 nunnl) in THE. The cloudy solution was surrcxl at room tempcraturc ovcmight. Adxhuonal htiuum alununum hydride (0 10 ml ) was added and the reactinn mixture was heated to 60''verntght 'Ihe mixture xvas diluted v ith (. water (0.25 mL) and stirred for 10 minutes. Dichlorotneth- 21 ane (10 mL) was added and the resulting white solid was liltcrcd mtd washed with dtchloromcthmte. Thc combutcd orgatuc phases werc conccntratcd ut vacuo. Tlm resulting (a) 4 A mol stcvcs, 2-cltioro-4-(mcthylsulfonyl)bcnzaldc- restdue was punlitxl by sthca gel cinematography usutg a 4 hydc, CH,CIx, (b) 2.6-1utidutc, Cu(OTI)„hcxafluorotsoPro- IS('0 colmnn eluting a 0-10'%eOIUdichlnrnmethane panol, ('.I la('I,: c) 2-aminn-4-chlnrn-6-methylpyrimidine, radient to provtde destred pntduct as white solid: 'I I NMI( NMP, 150'; (d) Sis( chiral separation US 20 ] 9/032265 [J A[ Ock 24, 2019

125

Fomtation of (+/-)-3-(2-chloro-4-(methylsulfimyl) 396 10. found 397,16i (M+I) . Retention time: 0.57 minutes; — plmnyl)-1,4-oxazcpanc (18) [ JD 71.67 (c 54 nigii 5 ml. MeOII) 1-67 [0533] To a solution oi'3-(tnbuiylsiannylmcthoxy)propan-mme [0537] Peak B: (S)-4-(3-(2-chioro-4-(methylsulfonyl)phe- I-amuie (2.69 g, 7.11 mmol) in diclfloromeihane (11 mL) nyl)-1,4-oxavepan-4-yl)-6-methylpyrimidm-2-amine (21), was added 2-chloro-5-methylsulfonyl-benzaldehyde (I 00 heated 'H NMR (360K) (400 MHz. DMSO-d6) 6 7.94 (d, 'I 8,. 4.57 mmol) followed by 4 angstrom molecular sieves he J=2.0 Hz, IH), 7.80 (dd. J=8.1, 2.0 Hz. IH), 7.56 (d, J=8.2 mixture was stirred for 14 h. filtered to remove the sieves Hz. I H), 5.72-5.63 (m, IH), 5.ti3-5.52 (m. IH), 5.43 (s. 2H), and washed and diluted with dichloromethane (50 mL). 4.S8-4.37 (m, IH), 4.14 (dii. J=13 5, 4 8 Hz, IH). 3.97-3.8S 1 ). (m, ill), 3 N5-3 Gi4 (m, 211). 3.57 (dt. I 12 4. 7.4 I lz, II I), [0534] In a scparaic flask containuig hexafluoroisopropanol (15 mL) was added 2,6-1utxlinc (0.53 mL. 4.S8 nunol) 3.21 (s. 3H), 2.03 (s. 3H), 1.90-1.70 (m. 2H), ESI-MS m/z 16 fii1 loived by ( u(01 f) s ( I . 65 g, 4 56 I'he mixture was cele. 396.10, tiiund 397 (M+I)+ Retention tune: 0.56 stirred for I h. then the imine solution prepared above was muiutes: [ ]D=+58.36 (c=5.3 m /1.5 mL MeOH). I-G8. added in one portion. The reaction was stirred overnight at [I)538J I he folloivin analo s v ere according to Synthetic The mixture was diluted with 2: I mixture roon)temperature. Scheme 2: oi'aquixius saturated NaHCO, solution and 10% ammonnim hyiiroxiiic. Afler stirnng for 10 mimiies, ihe orgamc layer was rcmovtxl and washed with aqueous saturated NaHCO, solution, then brine 'I he organic layer was passed through a phase separator funnel and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography usin an ISCO 100 gram c I 8-aq colunut nut- nmg with formic acid/HsO and formic acid/CH,CN grad&- i:lli. Tlii: rcsniui: was illliiieil wliil illcliltiroilleiiiilllc, ncuirahzed with aqueous saturated NaHCOi solution. Thc organic phase was passed thmugh a phase separator and concentrated in vacuo to afford 688 mg, of desired product 'H NMR (400 MHz, DMSO-d6) 6 7.93 (dd, 1=1.6. 0.7 Hz, 7.90-7 87 4.31 J=8.7, 3.3 Hz. 0 IH), (m, 2H), (dd. IH), 3.92-3.77 3.71 i=I 2.2. 6.2 I 3.35-3.27 (m. 2H), (dt, Hz, H), HH (m, IH). 3.26 (s. 3H), 3.10 (di, J=13.7. 5.1 Hz, IH). 2.89 (di, J=13.3. 6.4 Hz, 2H), 1.93-1.81 (m. 2H). ESI-MS m/z cele. 289 05396, found 290 05 (M+ IF. Itetention time: 0 5 minutes.

lion)sation of (l&)-4-(3-(2-chloro-1-(inethylsultioayl) phenyl)-1,4-oxazepan-4-yl)-6-inethylpyrimidin-2- amine (20) 1-67 and (S)-4-(3-(2-chloro-4-(methylsuifonyl)phenyl)-1.4-oxazepan-4-yI)-6- methylpyrimidm-2-amine (21) I-tig (It)-4-(2-(2-fluoro-5-methoxyphenyl)azepan-I-yl)-6- [0535] To a solution oi'-(2-chloro-4-(mcthylsulfonyl) mcthylpynmidui-2-mnine (22) 1-26 and (S)-4-(2-(2- phenyl)-1.4-oxazepane. IN. (0 67 8, 2 31 mmol) in NMP fluoro-5-methoxyphenyl)azepan-I -yl)-6-methylpy- (7 5 mi,) was added 4-chloro-6-methyl-pyrimidin-2-aniine rimidin-2-amine 1-27 (0.40 g. 2.79 mmol). The reaction mixture was heated to (23) 150" C. overnight The mixture wns cooled to room tem- Tlie racemic mixture v as synthesized in the smne perature mid loaded directly onto a 100 g ISCO clg-aq [l)539J colunui and purilicd by reverse phase runnuig with 0.1% fasluon and then submitted to chiral SFC purification to TFA/H 0 and 0.1% TFA/CH,CN. The pure fractions werc obtain the individual enantiomers: concentrated in vacuo I'he resulting residue ives diluted Peak A: 98.6% ee: hi+ temperature (3GO K) 'H NMR (400 with dichloroniethane, neutrahzed with aqueous saturated MI Iz DMSO-d6) 8 7 10-6.i/4 (m. 211). 6 N4 (dd, .I 9.5. 2 8 NaHCOs solution. The mixture was passed tltrough a phase Hz. I H), 5.59 (s. I H). 5.54-5.29 (m„3H), 4.70-4.47 (m. IH), separator and the organic phase concentmted in vacuo to 4.16 J=13.2, 5.1 Hz. I 3.99-3.77 3.72-3.40 afibrd 550 mg oi'esired product. The racemic nuxture was (dd, H), (m, 4H), 2.00 1.86-1.61 ]"=-34.12 submitted for SFC clural purification to afliird 155 mg of (m, 3H). (s, 3H), (m. 2H); [ (c=19 1-26 siercoisomcr A and 153 mg of sicrcoisomcr B. mg/3 mL MiqJH). [t)536] Peak A (R)-1-(3-(2-chion)-4-(methylsulfonyl)phe- Peak B: 97.4% ee: hi+ temperature (3GO K) 'H NMR (400 nyI)-1.4-oxazepan-4-yl)-G-methylpyrimidin-2-cmice (20), MHz. DMSO-d6) 6 7.08-6.93 (m, 2H), 6.84 (dd, J=9.4. 2.8 heated 'H NMR (360K) (400 MHz. DMSO-d6) 6 7.97 (t, I lz. 111), 5.59 (s, 111). 5.48 (s. 211), 5 41-5 31 (m, 111), J=1.9 Hz. IH). 7.84 (di, J=8.2, 1.9 Hz, IH), 7.60 (dd, J=8 I, 4.68-4.50 (m, I H), 4.16 (dd. J=13.3, S. I Hz, I H), 3.96-3.77 2.0 Hz. IH), S.78-S.65 (m, IH), 5.65-5.51 (m, IH), 5.46 (s, (m, 4H), 3.72-3.3S (m, 3H). 2.00 (s, 3H). 1.89-1.60 (m, 2H), 2H). 4.60-4.41 (m, IH). 4.2S-4.07 (m, IH). 4.02-3.87 (m, [ ] =+40.44 (c=19 mg/3 mL McOH), ESI-MS nt/z cele. I i I). 3.85-3.68 (m, 211), 3.68-3.44 (m, 111). 3 24 (s. 311), 333 21, found 333 I N (M+I) Itetentton time 0 61 minutes 2 10-1 3/9 (m, 311). I 89-1.70 (m. 211); I'.SI-MS m,'z cele. 1-27 US 20]9/032265]] A] Oct. 24, 2019 126

(+/— )-4-13-(G-chloro-1,3-benzodioxo1-5-yl)-1,4-ox- 24 azepan-4-yl]-6-methyl-pyrinttdin-2-amine (26) 1-113

]0542] heated (360K) 'l l NMlt (400 Mlis, DMSO-d6) tb 7.00 (s, IH). 6.79 (s, IH), 6.09 (s. 2H), 6 01 (s, 2H), 5.73 (s, 111), 5 37 (s, H I), 4 C&8-4 50 (nt, H I), 4 05 (dd..i 13 6, 4 9 Hz. IH), 3.93-3.51 (m. 413). 2.09 (s. 3H), 1.78 (p. J=4.5, 3.9 Hz. 2H); ESI-MS nt/z cele. 362.1, found 363.0 (M+I) . Retentton time; 0.71 minutes.

4-(3-(2-chloro-5-nitrophenyl)-1,4-oxazepan-4-yl)-6- methylpyrimtdm-2-amine (24) 1-72 0

]t)540] high tentperature (360 K) 'll NMR (400 Milz, DMSO-d6) 8 8.14-8.01 (m, 2H). 7.73 (d. J=8.7 Hz. IH), 5.73 (s. IH). 5.68-5.53 (m, I H), 544 (s, 2H), 4.56-4.39 (m, IH), 4.12 (dd, J=13.6, 4.8 Hz, IH), 3.95-3.69 (m, 3H), 3 68-3 53 (nt. II I), 2 04 (s, 311). I 85-1 73 (tn„211); I 'tSI-MS m,'z cele. 363 11. found 364 16 (M+I)+ Retention time 0 61 minutes.

zs (+/ — )-4-(3-(2-chloro-6-1luorophmtyl)-1,4-oxazcpan- 4-yl)-6-methylpyrintidin-2-amine (27) 1-59

]0543] 'H NMR (400 MHz, DMSO-d6) (heated 360K) 6 7 30 (td, .I 3 8, 2 7 iiz, 2H), 7 10 (ddd..i 11 3. 6.1. 341)x, IH). 5.71 (s. IH), 5.54 (dd, J=10.6, 5 (I Hz. IH), 5.41 (s, 211), 4 48 (d, J 15 6 I lz. IH). 4.00-3 88 (m, 311). 3 71 (dd, J=15.6. 11.2 Hz, IH), 3.53 (td, J=12.1, 3.1 Hz. I H), 2.02 (s, 3H), I 82-1.57 (m, 2H). ESI-MS m/z cele. 336.12. found 337 0 (M+I) Retention time 0 7 ntmutes

(+,' )-4-13-(2-chloro-4-nitm-phenyl)-1,4-oxazepan- 4-yl]-6-methyl-pyrimidin-2-amine (25) 1-125

]0541] high temperature (360 K) 'H NMR (400 MHz, DMSO-d6) 6 8.22 (d, J=2 3 Hz IH), 8.08 (dd, J=8.6. 2.4 Hz, IH), 7.58 (d, J=8.6 Hz, IH), 5.G9 (s. IH), 5.59 (dd, J=9 9, 4 7 I Iz, 111). 5 41 (s. 21 I), 4 46 (d..i 157 I lz., I I I), 4 14 (dd, 1 13 5. 4 8 I lz, 111), 3 90 (dt, .I 11 5, 3 6 I la, 111), 3 77 (ddd, 1=16.3, 13.0. 8 2 Hz, 3H). 3.63-3.53 (m, IH). 2.03 (s. 3H), 1.85-1.77 (m, 2H): ESI-MS m/z cele. 363.11. found 364.25 (M+I ) . Retention time: 0 6 minutes.

(+/ — )-4-(3-(2-chloro-4-(JH-pyrazol-l-yl)plmnyl)-l, 4-oxazepan-4-yl)-6-methylpyrimtdtn-2-mntnc (28) Itsg 1-133 0 ]0544] 'll NMI& (400 Ml lz, I JMSO-d6) (heated 360K) 6 8.42 (d. 1=2.5 Hz, IH), 7.91 (d, 1=2.3 Hz. IH), 7.79-7.67 (m, 2H). 7.43 (d, J=8.5 Hz. IH), 6.51 (dd, J=2.6. 1.8 Hz. IH), 6.06 (s. 2H), 5.80 (s, IH), 5.54 (d, J=7.6 Hz, IH), 4.58 (d, J=15.2 Hz, IH), 4.15 (dd. J=13.5, 4.9 Hz, IH). 3.96-3.80 (m, 2H), 3 80-3.69 (m, IH). 3.68-3.55 (m, IH), 2 09 (s, 3H), I 88-1.75 (m, 2H): I!SI-MS m/z cele 384 15, found 385 0 (M+I)+ ltetention time 0 72 ntinutes US 20 1 9/032265 [J A[ Oct. 24, 2019 127

-con/banal tl NQ

N ()7 37 33 la I I 8

4 ~ . N

(+/ — )-4-(3-(4-bromo-2-chlorophenyl)-1,4-oxazepan- 4-yl)-6-methylpyrimidin-2-amine (31) 1-194 (8)-4-(3-(5-chloro-2-methoxyphenyl)-I „3-oxazepan- 4-yl)-6-mcthylpyrunldul-2-aminc (29) 1-131 [0547J hi8h temperature (360 K) 'll NMR (400 Mllz, DMSO-d6) 6 7.70 (d. 1=2.1 Hz. I H). 7.52 (dd, J=8.4. 2.1 Hz, 111), 7 31 .I 6 8 I 4 15 1 13 6. 5 111), [0545J 'I I NMIJ (400 Milt. IJMso-dGi) Oteated 360K) 75 (t, lz, 31)). (dd, 01lz. 7.29 (dd. J=8.8. 2.7 Hz, IH). 7.11 (d, J=2.7 Hz. IH), 7.07 (d, 3.96-3.72 (nl. 3H), 3.64 (s, IH). 2.25 (s, 3H). 1.85 (s, 2H); 1 KS llz 111) 697 (s 211) 5.95 (d .I 353 llz 111) 555 ESI-MS mlz cele. 396.0, found 397.0 (M+I) . Rctcntlon (s, IH), 4.55 (s. I H). 4.17 (dd. J=13.4, 5.2 Hz. IH). 3.87 (s, time: 0.64 minutes. 4i I). 3 82-3 68 (m, 211), 3.57 (ddd..t 12.2„8 3, 5 7 I lz. 111), [05481 Racmnic matenal txas submitted for SEC clural 2.19 (s. 3H). 1.79 (h. J=3.9 Hz, 2H). ESI-MS nt/z cole. sepal'ltlon. 348.14. found 349.0 (M+ I) . Rctenuon umc: 0.72 numltcs. [05491 Peak A. ESI-MS m/z cele. 396.0, found 39RO (M+I)+ Retention time 0.8 minutes, (R)-1-(3-(1-bmmo-2- (S)-4-(3-(5-chloro-2-nlethoxyphenyl)-1,4-oxazepan- cldorophcnyl)-1,4-oxazcpml-4-yl)-6-mcthylpynmldul-2- 4-yl)-6-methylpyrimidin-2-amine (30) 1-132 amine (32). 1-200 'H [0546J 'I I NMIJ (400 Milt. IJMso-dGi) Oteated 360K) 75 [05501 Peak B: NMR(400 MHz, DMSO-dG) 67.69 (d, 7.29 (dd, 1=8.8. 2.7 Hz. I H). 7.11 (d, J=2.7 Hz, IH), 7.07 (d, 1=2.0 Hz. IH), 7.50 (dd, J=8.4, 2.1 Hz. IH), 7.29 (d. J=84 5.S9 J=8.8 Hz, IH)7 6.97 (s7 2H), 5.95 (d, J=3S.3 Hz. IH), S.55 Hz. IH), 6.87 (s, 3H), 6.01 (s. IH), (s, IH), 4.49 (d, (s, IH), 4.55 (s. I H). 4.17 (dd. J=13.4, 5.2 Hz. IH). 3.87 (s, J=14.9 Hz, IH), 4.13 (dd. J=13.6, 4.9 Hz, IH). 3.91-3.78 (m, J=12.2. 4H). 3.82-3 68 (m, 2H), 3.S7 (ddd7 J=12.27 8.3, 5.7 Hz, IH), 3H), 3.62 (ddd, 9.4. 4.9 Hz, IH), 2.19 (s, 4H), 1.82 (dp. 1 10 I, 3 67. 3 I I )z, 211): I:S I-MS m/z cele 39/7 0, found 2 19 (s. 311). I 79 (h, .I 3.9 I is, 211); I'.SI-MS m/z cele. 397 0 (M+I)+ i&etention time 0 8 minutes; [etJ +79 9 (c I, 348.14. found 349.0 (M+ I) . Rctenuon umc: 0.72 numltcs. MeOH) 7.1 m /mix (S)-4-(3-(4-bromo-2-chhlrophenyl)-1, 4-oxazepan-4-yl)-6-methylpyrinudin-2-amine (33). 1-201 lrlx HlN Br US 20]9/0322658 A] Och 24, 2019 128

4-[(3S)-3-(5-bromo-2-chloro-phenyl)-1.4-oxazepan- 1.91 (d, 1=10.7 Hz. 2H), 1.(i(i (s. IH), 1.63 (s, 3H). 1.50-1.33 4-yl]-6-methyl-pyrinudin-2-tmune 1-245 (m, 2H), ESI-MS m/z cele. 316 15, Ibuud 317.2 (M+I) .

Rctcntton time. 0.8 mututcs. [0551] 'l l NMR (300 Mlis. DMS(&dC&) 8 7.47 (nt, 3H),

[0554] The racemic mixture vvas separated by Analytical 6.52 (brs, Hq). 5 99 (brs. IH), 3.90 (m. 4H), 3.6(i (br. 2H), Chtral HPLC (AD-H. 4.6xl00 nuu, 40% MeOH. 5 mM 250 (s, 3H). 1.89 (m, 2H), ESJ-MS nt/z cele. 39Cc03. found 68'c=0.5. anunonia. 60% CO„at 5 ml/min )socratic iniectton 10 uM 397.01 (M+I) Rctenuon umc: 0.65 mtnutes; [&x]o=+66 iu I mg/mL methatx&1. 120 bar. UV 254 nM). RT Peak A MeOH). 0.432 min, cc 97.2%, Peal B at 0479 mtn. Examplc3 [0555] Peak W: 2.10 v. 97.2% ee, optical rotation: [ ]~=— 0.096 (c=1.04. MeOH); 'H NMR (400 MHz. CDCls) 6 7.36 Synthetic Schmnc 3. (R)-4-(2-(2-citiorophcnyl)azc- (s, I H), 7.17 (s, 3H). 5.81 (s. I H), 5.44 (s, I H), 4 90 (s, I H), pan-I-yl)-6-mcthylpynmtdut-2-amuse and (S)-4-(2- 4.68 (s, 2H), 4.03-3.20 (m. IH). 2 63-2 43 (m, I Hj, 2.11 (s, (2-chlorophenyljazepan-I -yl)-Ci-methylpyrimidin-2- 3H), 2 02 (s. IH), 1.97-1.82 (m. 2H), 1.76-1.51 (m, 2H), alllule) I 51-1.31 (tn. 21 I); I:SI-MS mtz cele 316 15, found 317.24 (M+I)+ Retention time 0.83 minutes (R)-4-(2-(2-chlonu [0552] phenyl)azepan-I-yl)-6-methylpyrunidin-2-amine (35) 1-13. [0556[ Peak 13 2 09 g, 96% ee; optical rotation: [ ]o +I 373 (c I 02, MeOII): 'll NMR (4(X) Milz, ('D(qs) 8 1.46-151 (m. 2H). 1.72-1.53 (nt. 2H). I 96-1 82 (m. 2H), 2.04 (d. J=18.8 Hz, IH), 259-2.05 (m„3H). 2.61-2.42 (m, JH), 4 08-3.22 (m, IH), 4.72 (s. 2H), 4.89 (s. IH), 5.43 (s, JH), S.82 (s, IH), 7.16 (s, 3H), 7.35 (s, JH): ESI-IvIS m/z cele. 316.15, found 317.2 (M+I) Rctenuon ume: 0.82 nunutes. (S)-4-(2-(2-chlomphenyl)azepan- I -yl)-6-methyl- pynnndin-2-an)inc (36) 1-14

[0557[ I he following analogs v ere prepared according to Synthetic Scheme 3

Hsu

ttx

H Hg

(a) 2-amino-4-chloro-6-ntethylpyritnidine, nl3uOI I. 2(X)" C., microwave: (b) Chiral HPLC separation

Fomutttou of (+/ — )-(2-(2-citionrphcnyl)azcpvan-I- yl)-6-mcthylpyrimidin-2-anunc (34) (R)-4-(2-(2-methoxyphenyl)azepan-I -yl)-6-methyl- A suspenston 4-chloro-6-methyl-pyrimidin-2- [0553] of pyrimidin-2-amine (37) I-l I and (S)-4-(2-(2- anunc DL02 g, 21 03 mmol), 2-(2-chlorophenyl)azcpanc mcthoxyphenyl)azcpan-I-yl)-6-mcthylpynmidut-2- (3.99 g, 19.01 nunol) tn u-butanol (15 mL) was scaled in a anunc (38) 1-12 microwave tube and irradiated at 200" ( for 2 hours 'the crude mixture was concentrated in vacuo and diluted v ith [0558] Peak A from SFC chiral separation: 'H NMR (400 aqueous saturated KHCOs solution and extracted nvice with MHz. CDCJ,) 8 7.01 (dd. J=118.6, 38.8 Hz. 4H). 5.60 (2 s. dichloromethane. The organic phase was concentrated in I H), S.24-4.44 (m, 3H), 3.82 (s. 3H). 3.32 (dd. J=63.S. 46.9 t acuo. Thc rcstdue st as then rccrystalltzed from tsopropanol I lz, Ill), 2.49 (2 s, 1 i I). 2 30-1 91 (m, 311), I 94-0 56 (m, and ether to allbrd 3 61 g ofracemtc product. 'H NMR (400 911); ltSI-MS m,'z cele 312 20. found 313 13 (M+I) MHz. CDCI,) 8 757 (d. J=8.S Hz, IH), 7.16 (d, J=13.9 Hz, Retentton time: 0.78 minutes. (38) 1-12 ' 3i I). 5 47 (s, 111). 43)1 (s, 111), 4 57 (s, 211). 3 32 (s, 111), [0559] Peak 13 front Sl'( chiral separatton l NMR (400 2 58-2.45 (m, ill), 2 17 (d, J 22.1 I is. 211), 2 03 (s. 111), MI Iz, CD(.'Is) 6 9 (B-6 27 (m. 411), 5.59 (2 s, 111), 5.29-4.3(& US 20[9/032265[] A[ Oct. 24, 2019 129

(m, 3H)„3.82 (s. 3H). 3 54-2 79 (m. I H), 2.33 (d. 1=61.8 Hz, (s, IH). 2.58 (s. 3H), 2.38 (d, J=17.3 Hz, IH), 2.02 (d. J=6.2 IH). 2.00 (s, 3H), 1.93-0.44 (m, 10H), ESI-MS m/z cele. Hz. 3H). 1.96-1.81 (m. 2H)„1.72 (d„J=6.7 Hz. IH). 1.62- 312.12, found 313.13 (M+I) . Rctcntton umc. 0.8 mmutes. I 50 (m, 111), I 50-1 27 (m, 211); ESI-MS nv'z cele 328.17, (37) 1-11 found 329 11 (M+I)+ ltetention time 0 75 minutes

H48

tt 8 (+/-)-4-methyl-6-(2-(2-(methyl)phenyl)azepan-I-yl) pyrimidin-2-amine (44) 1-6 [0563] 'H NMR (400 MHz. Methanol-d4) o 7.19-6.99 (m, 4H), 2.46 (s. 3H), 2.27 (ddd, J=14 3, 8.4, 5.1 Hz, IH). 2.22-1.96 (m. 4H). 1.95-1.82 (nt. 3H). I 81-1 (i8 (m. IH), 1.59 (d, J=12.0 Hz. IH). 1.42 (dtt. J=23.7, 12.2. 6 3 Hz. 2H); I:SI-MS m/z cele. 296 20, found 297.14 (M+I)+ Retention time 0 74 minutes.

(R)-4-(2-(2-bmmo)azepan-I-yl)-6-methylpyrimichn- 2-amine (41) 1-2 and (S)-4-(2-(2-bromo)azepan-I- yl)-6-methylpyrimidin-2-amine (42) 1-3 ct [0560] Peak A from SFC chiral sepamtion: 'H NMR (400 MHz. CDCIs) 6 7.46 (d. J=7.4 Hz, IH), 7.08 (d, J=42.6 Hz, 3H). 5395-5.43 (m, IH). S.34 (s. IH), 4.77 (d, J=37.2 Hz, 3H). 3.98-3.08 (m, 2H), 2.46-2.32 (m. IH). 2.08 (d. J=40 4 I lz,. 31 I), 13)4 (s, 111). I Sr)-I 75 (m, 211). I 65-1 44 (m. 21 I), I 42-1.26 (m. 211): IcSI-MS m/2 cele 360.09, found 361 12 (M+I) . Retentton time: 0.91 minute~. (41) 1-2. [0561] Peak B from SFC clural separation: 'H NMR (400 (+/-)-4-(2-(2,4-dichlorophenyl)azepan-l -yl)-6-meth- MHz. CDCls) 6 7.46 (s, IH), 6.99 (I, J=70.7 Hz, 3H), vlpvrimidin-2-antine (45) I-l 6.02-5.47 IH). S 21 J=62.8 Hz, 4H), 4.78 (d. J=17 2 (m, (t, 'H Hz. IH). 3.96-3.17 (m. 2H), 2.48-2.33 (m, IH). 2.27-2.03 [0564] NMR (400 MHz. McOD) o 7.71-7.07 (m, 3H), (m, 311), 13)6-1 72 (m, 31i), ).68-).42 (m„211). I 42-1 23 6.53-5.02 (m, 2H), 4.28-3.43 (m, 2H), 2 66-2 37 (m, IH), s 2 17-1 ESI-MS (m, 211); IISI-MS nv'z cele 360.09, found 36i 12 (M+I) . 2 25 (2 311), 28 (m, 711); m/z cele 350 11, Retention time: 0.93 minutes. (42) 1-3. found 351 11 (M+I)+ ltetention time 3 13 minutes

II48

(+/ — )-4-methyl-6-(2-phenylazepan-I -yl)pyrimtdin-2- amine (45) 1-4 (+/— )-4-methyl-G-(2-(2-(methyltldo)phenyl)azepan- [0565] 'H NMR (400 MHz. McOD) o 7.48-7.17 (m, 5H), I-yl)pyrimtdin-2-amine (43) 1-5 639-5.94 (2 s, IH), 4.0)-3.36 (m, IH). 2.S2 (td, J=I4.5. 6.2 [0562] 'll NMIt (400 Mliz, MeOD) 6 733 (d,.i 78 Ilz„ Ilz. 111), 2.27 (d, .I 61 I Ilz. 311). 204-1 79 (Ill, 411), I i I). 7.23 (4, 111). 7.08 (d. J 5 7 I lz, 211), 5 45 (s, 111), 3 41 I 76-1.05 (m, 311). US 20]9/032265[] A[ Och 24, 2019 130

-colttlltluxl CI HH

bHz

SH, HzP (+/-)-4-(2-(2-chlorophenyl)azepan-I-yl)-6-isopropy- lpynmidin-2-imnne 1-16 [0566] 'H NMR (400 MHz, DMSO-d6) 6 7.47-7.34 (m, 111), 7 34-7 17 (m, 311), 5 57 (s, 111), 5 46 (s, 21 I), 5 21 (s, ill), 4 55 (d, .I 14 ') Ilz. 111). 3 55 340 (m„ ill), 2 57 2 52 (m, I I I). 2.34 (ddd..l 13 8. 8.1. 5 0 I lz, I I I), 1.98 (t..l 11 2 Hz. IH). 1.92-1.64 (m. 3H). 1.61-1.18 (m, 3H). 1.08 (d, (.) 47 1=6.9 Hz, 3H). I 04 (d. J=(i.9 Hz, 3H): ESI-MS nt/z found 345. (a) zinc, NHoCJ, 2o/o TPGS-750-M in mater, 7S'., (b) SFC clural scparauon

Formation ol'R)-4-(3-(5-amino-2-chlorophenyl)-1, 4-oxazcpan-4-yl)-6-mcthylpyrimtdut-2-atntnc (47) and (S)-4-(3-(5-amino-2-chlorophenyl)-1.4-oxazepan-4-yl)-6-methylpyrimidin-2-anune (48) [0569] 4-f3-(2-chloro-5-mtro-phenyl)-1,4-oxazcpan-4- yl]-6-methyl-pynnndm-2-amino, 24. (1.00 g, 2.7S nunol), NI Io(.'I (0 31 g, 5 85 mmol) and /n (0 87 8, 13 36 nunol) mere stirred in 2'/ I'P(iS-750-M in water (28 mi,) The reaction mixture was stirred vigorously and heated to 75" C. for 24 hours. The mixture ives cooled to room temperature — )-4-(2-(2-chlorophcnyl)azcpim-I-yl)-6-ethylpy- (+/ and diluted into aqueous saturated NaHCOs solution and nnudin-2-amine 1-17 dtclfioromctlmnc. Thc org;mic phase mas dncxI (MgSOo). [0567[ 'l l NMR (4(X) Ml lz, DMSO-d(i) 6 745-7.32 (nt, liltcrcd and concentrated ut 4 acuo. The crude rcsxluc was IH). 7.28-7 13 (m. 3H), 5.56 (4, IH). 5.41 (o, 2H), 5.21 (d, punfied via silica gel chromato raphy with 40 g isco (iOI,I) 1=12.0 Hz. IH). 4.49 (d. J=14.7 Hz, IH), 3.51-338 (m. I H), coltultn imsll'lg 0 50 / (20% MeOI I ( I I ( Iz/( I I ( Iz) to 2.52-2.49 (m, IH). 2.38-2.22 (m. 3H), 2.01-I.Ci4 (m. 2H), afibrd 390 mg of compound 4Ci as a racemic mixture. The 1.59-1.21 (m, 4H). 1.03 (t, J=7.5 Hz, 3H). ESI-MS nt/z racemic mixture vvas submitted for SFC chimsl sepamstion: found 331. prepped at 50%v IPX, 30;o Hexanes„0.2'/o dtethylamine on .4zD-H to alford thc individual stcreoisomcrs. llxatnple 4 [0570[ Peak A 9')0o pure by chiral I IPI (1 (8)-4-f3-(5- amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-py- — Synthetic Schmnc 4. (+/ )-4-(3-(5-iumno-2-chloro- rimidin-2-amine (47): lugh tempemsture (360 K) 'H NMR phcnyl)-1,4-oxazcpmt-4-yl)-6-methylpyrunnlut-2- (400 MHz, DMSO-d6) 6 7.01 (d. J=8.5 Hz, IH). 6.52 (d, 1-71 anune (4G) J=2.7 Hz, IH), G.47 (dd, J=8.5, 2.7 Hz. JH), 5.SJ (s. IH), [0568] 5.43 (s, 2H), S.26-5.10 (m. I H), 4.94 (s, 2H), 4.82-4.64 (m, 111), 4.10 (dd, .I 13 5, 5 0 I Iso 111), 3 95-3 84 (m, I I I), tt.x 3 69-3.46 (m, 311), I 99 (s, 211). 1.82-1 65 (m, 2i I) I!SI-MS m/z cele. 333.14, found 334.26 (M+I) . Retention time:

0.51 minutes; [ [ =-118.67 (c=12 mg/4 mL MeOH). 1-8G. [0571[ Peak l3 993)% pure by clural I IPI.(1 (S)-4-[3-(5- amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (48): lugh tempemsture (360 K) 'H NMR (400 MHz, DMSO-d6) 8 7.01 (dd. J=8.5, J.S Hz, IH), 6.52 (d, J=2 5 Hz. IH), 6.47 (dt. J=8.5, 2.1 Hz, JH), S Sl (s, IH), 5.44 (s, 2H), S.26-5.07 (m. I H), 4.94 (s, 2H), 4.84-4.66 (m, 111), 4 11 (ddd..l 13.4. 5.0. I 5 1lz. 111), 3 97-3 84 (m, I I I), 3 69-3.42 (m, 311), 2 05-1 ')2 (m, 311). I 83-1 66 (m. 211) US 20 ] 9/032265 [] A[ Oct. 24, 2019 131

ESI-MS nl z calc. 333.14. found 334.26 (M+I) . Retention -con/banal ume. 0.51 mulutcs, [ ] =+175 (c=g mg/4 mL McOH). 1-87. [0572] The Ihllowlng mlalog was prcparnl accordm to Synthetic Schcmc 4.

Hln C);'i'Y"'

~N .~O/ / HH

(+,' )-4-[3-(4-amino-2-chloro-phenyl)-1,4-oxazepan- 1-296 4-ylJ-6-methyl-pyrimidin-2-amine (4')) 1-140

[t)573] high tenlperature (360 K) 'll NMR (400 Milz, (a) Methanesulfonyl chloride, NEti„THFI (b) SFC chiral DMSO-d6) 6 7.01 (m„3H). 6.G5 (d, J=2.3 Hz, IH). Ci.52 (dd, si pin allen 1=8.5, 2.3 Hz. IH)„5.95 (br s, IH), 549-53Ci (m. 2H), 4.70-4.49 (m. IH), 4.04 (dd, 1=13.S. 5.0 Hz, IH), 3.83 (dd, llormation of (+/— )-3-(2-chloro-5-nltrophenyl)-1,4- J=10.4. 5.8 Hz, 2H). 3.7S-3.58 (m, 3H), 2.19 (6, 3H), oxazepane (50) 1-139 1.86-1.75 (m. 2H). ESI-MS mlz cele. 333.14, found 334.26 (M+I) . Itetentton time 0 51 mimltes [0575] To a solution of 4-[3-(4-amino-2-chloro-phenyl)- 1.4-oxazepan-4-yl[-6-methyl-pyrimidln-2-amine, 49, (0.034 (O.OSO Example 5 g, 0.103 nunol) and lricthylannnc mL, 0360 nunol) iu THF (1.5 mL) vvas added nu:thancsulfonyl chlonde (0.009 mL, 0.113 nunol). The reaction mixture ssas stttrcdI Synthetic Scheme S. — )-N-[4-[4-(2-anulxi-6- (+/ overnight at room tempemture An additional 5 ul. of methyl-pyrimidin-4-yl)-1,4-oxarepen-3-yIJ-3- methmlesulfonyl chloride ives added After 20 minutes the chloro-phenylJmethanesulfonamide 1-139. 1-179. reaction mixture was concentrated in vacuo Puritication and 1-296 was carried out on a reverse phase 50 g ISCO clg-at) column, runnulg v lth 0.1% TFA/HsO mid 0 1% TFA/ [0574] CH,CN. Thc pure fracuons werc conccntratcd ul vacuo and then dissolved ln McOH and passixl tluough two SPE bicarbonate cartridges (A iieet Stratospheres 100 mg/Ci lnl,) arranged in series and concentrated to give 7 3 mg of the desired product: high temperature (3GO K) 'H NMR (400 MHz. DMSO-d6) 6 9. 97-9. 5 5 (br s„ I H). 7.25-7.21 (m, 2H), 7.09 (dd, J=8.5, 2.1 Hz. IH). 5.59 (s. IH), 5.42 (6, 2H). 5.36 (s, IH), 4.60 (d. J=13.2 Hz. IH). 4.08 (dd. J=13.5, S.O Hz, IH), 3 88 (d. J=12.3 Hz. IH), 3.70 (dd, J=13.S, 10.2 Hz, 111). 3.66-3.50 (m, 311), 2.01 (s, 311), I 76 (6, 311); I'SI-MS nv'z cele. 411.11, found 412 24 (M+I )+ ltetention time 0.5/l nunntes. 4s [0576] Chiral HPLC separation afforded individual enantiomers Hlx ' [0577] Peak A: NMR (400 MHz, DMSO-d6) 6 9.6G (s, Xlt IH), 7 28-7.23 (m, 2H). 7.13 (dd. J=8.5, 2.2 Hz. IH), S.59 (s, 111), 5 46 (6, 211), 5 39 (s, 111), 4 59 (d, .I 149 1iz. II I), 4 09 (dd,.l 13.5, 5 011z,. II I) 3.93-3 85 (m, 111), 3 71 (dd, J=13.5. 10.1 Hz. IH), 3.66-3.49 (m. 2H). 2.99 (s. 3H). 2.01 (s, 3H). 1.81-1.70 (m. 2H). 1-179 [0578] Peak B. 'H NMR (400 MHz, DMSO-d6) 6 7.33- 7.22 (m, 2H), 7.13 (dd, J=8.5, 2.2 Hz, IH), 5.59 (6, IH), 5 46 6(l (s 211) 5 44-5 34 (m 111) 4.5i) (d .I 15 2 I lz 111) 4.0i) (dd. 1 134, 50 Ilz„ ill) 393-384 (m, 111), 3.71 (dd, US 20 ] 9/032265 [] A[ Och 24, 2019 132

1=13.5, 10.1 Hz. IH). 3.67-3.49 (m, 2H), 2.99 (s. 3H). 2.01 [0581] The followin analogs &vere prepared according to (s, 311). 1.77 (ddt, .I 10 2, 8 0, 3.4 Ilv, 211) 1-296 Synthetic Scheme 6:

Iixa&upie 6&

Synthetic Scheme 6 (+/ — )-N-[4-[4-(2-amino-6- I I 8 methyl-pyrimidin-4-yl)-I 4-oxazepan-3-yl]-3- chloro-phenylJmethanesultima&nide (5]) 1-282

[0579]

(3R) N-(4-(4-(2-amino-6-mcthylpynnnd&n-4-yl)-1, 4-oxazepan-3-yl)-3-chiorophenyl)-tetmhydroturan- 3-carboxan&ide (52) 1-280 [0582] (racemic m&xturc on oxazepanc 3-pos&uon) 'H NMR (400 MHz, CDCI„) 8 7.74 (s, IH), 7.S4 (s. IH), 730-7.21 (m. I H). 7.13 (d. J=8.4 Hz„JH). 5.53 (s, IH), 4.66 (s, 2H). 4.29 (dd, 1=13.6, 5.0 iqz. IH). 4.10-3.97 (m, 3H), 49 3 99-3.75 (m, 211), 3 6&6&-343 (m. 311), 3 11-2.95 (m. 111), 2 32-2.22 (m, 211), 2.12 (s, 311). 2 02-1 89 (m, 111), I 80 (d, J=14.3 Hz, 3H).- ESI-MS m/z cele. 431.17, found 432.18 (M+I) Re&cut&on time. 0.57 minutes. H.N

0 HN

(a) 3-methyioxetane-3-carboxylic acid. iPr&NEt. HATU, DMF. (38) N-(4-(4-(2-amino-6-methylpyrimidin-4-vl)-1, 4-oxazcpan-3-yl)-3-cldorophcnyl)-tctrahydrofur&m- 3-carbox;mudc 1-281 Fonnauon of (+/ — )-N-(4-(4-(2-annno-6-mcthylpy- (53) rimidin-4-yl)-l,t-oxazepan-3-yl)-3-chlomphenyl)-3- [l)583J (mcemic n&ixture on oxazepane 3-position) 7.74 (s, mcthyloxetanc-3-carboxanude (Sl) 1-282 IH), 7.S4 (s. IH), 7.30-7.21 (m, IH), 7.15 (d, J=8.4 Hz, IH), 5.S3 (s. IH). 4.64 (s, 2H). 430 (dd, J=13.6, 5.0 Hz. IH). 4.11-3 99 3.95-3.79 3.(i5-3.43 (m. 3H), [0580] To a solution of 4-[3-(4-amino-2-chloro-phenyl)- (m, 3H), (m, 2H), 3.11-2.95 (m, IH), 2.32-2.19 (m„2H), 2.12 (s. 3H), 2.04-1. 1.4-oxazepan-4-yl]-6-methyl-pyrimidin-2-omine (0.05 89 (m, 111), I 87-1 72 (m, 311) - I:SI-M) m/z cele 431.17, 0.15 num&1), 3-methyloxetane-3-carboxylic acid (0.02 found 432 14 (M+I) . I&etention t&me: 0 57 num&tes. 0.16 nunol) and N.N-diisopropylethylamine (0.05 mL. 0.30 nunol) in DMF (I mL) was added N-[(dimethylamino)-I H- 1,2.3-&nazolo-[4,5-b]pyudu&-l-ylmcthylenc]-N-me&hyl- mc&hanamimum hcxailuorophosphate N o&x&dc (HATU) H N (0.08 g. 0.21 nunol). The reaction mixture was st&rrcd at room tcmperaturc ovcnught. The resulting residue was punlitxi by reverse plrase prc7&erato&y HPLC (CH,CN/0.1% TFA aq). Thc fract&ons contain&ng des&rcxl product were basitied with an aqueous saturated Nal IUD& solution wash and extracted with d&chloromethane. 'I'he organic phase was passed through a phase separator, concentrated in vacuo to 0 afford the desired product US 20]9/032265[] A[ Oct. 24, 2019 133

(+/ —)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l. 4-oxazepan-3-yl)-3-chlorophcnyl)-2,2-difluoropro- pauamxle (S4) 1-228 [0584] 'H NMR (400 MHz, CDCI.,) 6 7.91 (s, IH), 7.78 (s, IH). 736-731 (m, IH), 7 22 (d, 1=8.4 Hz, IH). 5.53 (s, I i I). 4 60 (s. 211). 4 31 (dd..l 13 I&, 5 0 I la. 211), 4 06 (6, 12 5 I lz. 111). 3 65-3 47 (rn, 411). 2 13 (s, 311). I.gr) (t, 193 Ilz, 511): ESI-MS m/z cele 425.]„ tiaund 4262 (M+I) . Retention time: 0.64 minute~.

(+/-)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1, 4-oxazcpan-3-yl]-4-chloro-phenyl]-2-(oxctau-3-yl) acctannilc (57) I-18S [0588] 'H NMR (300 Midz. Methanol-d4) o 6.07-5.93 (m, I H). 5.75 (br. 2H), 5.26 (s. 115). 4.27 (s, IH), 3.87 (br, 2H), 2.80 (m. 4H), 2.52-2.21 (m. 5H), 1.74-135 (m, 2H), 0.83 (s, 3H), 0 S6 (m, 2H); ESI-MS m/z culc. 431.2, found 432.1

(M+I) . Rctcntion time. 0.55 minutes

(+/ —)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l. 4-oxazepan-3-yl)-3-chlorophenyi)-2.2-difluoroacet- amidc (55) 1-278 [0585] 'H NMR (400 MHz, ('DCI.,) 6 7.90 (s. IH), 7.77 (s, I H), 7.35 (dd, J=g 5, 2.2 Hz. IH), 7.23 (d, J=8.4 Hz. IH), 6.01 (i. J=54.2 Hz, IH), S.53 (s. IH), 4.64 (s, 2H), 4.31 (dd, 13 I&. 4 9 I lz, 111), 4 15-4 01 (m, 111), 3.68-3 46 (m, 311), 2 13 (s, 311). 2 06-1 91 (m, 211). I 88-1 76 (m. 211); I tSI-MS ngz cele 411.1, found 412 I (M+I) Retention time: 0 6 iiiiiiiites.

I la 8 i (+/ — )-N-[3-[4-(2-amino-d-methyl-pyrimidin-4-yl)-1, 4-oxazepan-3-yl]-4-cltioro-phenyl]cyclopropanecar- boxamide (58) 1-241 [0589] hcatcd (360K) 'H NMR (300 MHz, DMSO-d6) b 0 10.38 (s, IH), 7.96 (s, 2H), 7.74-7.30 (m, 8H), 6.65 (s. IH). 5 95 (dd, .I 10 3, 5 4 I lz. I I I), 5 56 (s, II I), 5 18 (dd, .I 10 I, 4 9 I lz, 11 I). 5.10-4.93 (m, 111), 4 34-4 10 (ni. 3i I). 4 02-3 55 (m, 7H). 2.29 (s. 3H). 2.00-1 6/3 (m. GH), 0.79 (d. J=73 Hz. 6H): ESI-MS m/z caic. 401.2, found 402.2 (M+I) . Rctcntion time. 0.62 muiutes.

(+/ —)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l. 4-oxazepan-3-yl)-3-chlnrophenyl)-3-fluorotetrahy- drofurau-3-carboxamidc (56) 1-279

[0586] 'H NMR (400 MHz, CDCI,) 6 8.17 (d, J=7.9 Hz, '3, Oil I I I), 7 81 (d. J 7 8 I la. 111). 732 (td, .I 8 2 2 I la, ill), 7 20 (d..l 8 5 I la, 111), 5 53 (s. 111). 4 Gt I (s. 211). 4 30 (dd, 1=13.6, 5.0 Hz, IH). 4.19-4.02 (m, 6H). 3.68-3.49 (m, 3H), 2.77-2.56 (m, IH). 2.44-2.27 (m. IH). 2.12 (s. 3H), 2.03-1. 90 (m, IH)„1.88-1.74 (m, 2H); ESI-MS m/z cele. 449 2, found 450.1 (M+I) . Rctmition time: 0.6 minutes. [0587] The Ibllowing aualogs werc prepared according to Scheme 6 using 4-(3-(S-annno-2-chlorophenyi)-1,4-oxazcpan-4-yl)-6-methylpyrimidin-2-amine 46 as starting material US 20[9/032265[] A] Och 24, 2019 134

(S) N-[3-[(3S)-4-(2-amino-6-methyl-pyrimidin-4- 738 (d, J=8.7 Hz, IH), 5.96 (brs, 2H). 5 03 (br. 2H). 4.11 (s, yl)-1,4-ox azcp an-3-yl] -4-cbioro-phenyl] -3-hydroxy- 111), 3.94 (m, 111), 3 74-347 (m, 311), 3 33 (G, /&I I), 3 04 (s, propantunule (S9) 1-283 2H). 2.25 (s. 3H), 1.98 (br. 2H), ESI-MS n&/z cele. 418.2, [0590] Racemic material obtained usin similar procedure fi&und 419.1 (M+I) . Rctenuon time. 0.58 minutes. and then submitted for chiml HPI C purification (colunu& (OJ-H 20x250 m), mob&lc phase (80% hcxancs/20% IPA/0. 2% dicthylam&nc), flow 20 mL'nun). 0 [t)591] Peak 13 ee: 91%, [r&Jo (c 05, MeOII) +324, 'll NNIlt (300 Ml lz, Methanol-dt) GS 7 63 (d„.i 2 6 I lz. 111), HH 7.49 (d, 1=8. 8 Hz, I H). 7.35 (d, J=8.7 Hz. I H). 5.46 (br. 3H), 430 (dd„1=13.6. 5.0 Hz, IH), 4.11-3.97 (m, IH). 3.85 (t, 1=6.2 Hz. 2H), 3.79-3.48 (m, 3H), 2.53 (t, J=ti.l Hz, 2H), 2.07 (s. 3H), 1.87 (m, 2H), ESI-MS nfiz cele. 405.2, fi&und 406.2 (M+I)'. Rctenuon time. 0.58 minutes.

&T&x

(+/-)-N-[3-[4-(2-amino-6-methyl-pyrimid&n-4-yl)-1, 4-oxazcpan-3-yl]-4-chloro-plu:nyl]oxetanc-2-carboxan&ide (62) 1-184

[0595] "H NOIR (300 MHz, Methm&ol-d4) 8 8 60 (G, IH). 59-6.42 6 37-6 19 6 10 22 8 7 0 6 (m, 111), (m, 111), (dd..i 6, I lz, 111), 520(s,0 511). 4 76 (dd. 1 10 2. 5 211z,0 511). 434 (s, 0.511), 4.04 (dd, J 102. 5.0 Iiz, 0 511). 3 78 (dd, .I 9 I, N-(3-(4-(2-am&no-6-methylpyrun&du&-4-yl)-1,4-ox- 6 7 I lz, I I I). 3.48-3.29 (m, 211), 3 16-2 91 (n&. 2i I). 2 81-2 azipan-3-yl)-4-chlorophenyl)-2.2,2-trifluoroacct- 26 (m,411), I 85-1 25 (m. 211), 1.02 (s. I 511), 0 89 (d .I 0 8 1-177 anude (60) I lz, I 311), 0 61 (m, 211): IISI-MS m/z cele 417.2. found [0592] Raccmic ma&coal obtained usu&g sumlar procedure 418 0 (M+I) . Retention time; O.ti minutes and then subm&tted Ibr clural HPLC punlicauon (column (OJ-H 20x250 m), mob&lc phase (80% hcxancs/20% IPA/0. 2% diethylanune), flow 20 n&I./min) 0 OH [t)593] Peak 13 ee 99%: [n]o(c 05, MeOII)+157.3: 'll NMR (300 MHz. Methanol-d4~) 6 635 (d. J=2.5 Hz. 2H), 6.16 (d, 1=9.2 Hz. IH). 4.22 (br, IH), 3.02 (dd, 1=13./i. 5 I Hz. IH), 2.88-2.67 (m, IH). 2.SG-2.23 (m, 3H), 2.03 (m, 2H). 0.59 (m, 2H), ESI-MS nfiz cele. 429.1, found 429 9 (M+I) . Rctenuon time. 0 65 mimites.

H&S

(+/-)-N-[3-[4-(2-an&ino-G-nðyl-pyrimidu&-4-vl)-I, 4-ox azepan-3-yl] -4-chioro-phenyl] -3-hydroxy-3- methyl-bmm&amide (63) 1-251

[0596] 'H NMR (300 MHz. Methanol-d4) o 7.75 (t, .I 10011z ll I) 7 487 40 (m 111) 7 397 29 (m, 111). 6&52 (s, 0.5H). 6.08 (dd, J=10.3, 5.3 Hz. 0.5H)„5.65 (d, 1=3.3 Hz, 0 511), 5 35 (dd, .I 10 5, 5.1 I la,. 0 511), 5 20 (d, J 14.4 I is, (+/ — )-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yi)-1. 0.5H). 4.46-4.19 (m. 1.5H)„4.14-3.55 (m, 4H). 2.48 (d, 4-oxazepan-3-yl]-4-chloro-phenyl]-2-(dimethyl- J=l.4 Hz, 1.5H), 2.34 (il, J=0.8 Hz, IH), 2.21 (t, 1=0.9 Hz, tunu&o)acctamidc (61) 1-168 1.5H). 2.09 (d, 1=1.1 Hz, 113). I 47-1 21 (m, 6H), ESI-MS [11594J heated (360K) 'll NMR (300 Ml lz, DMSO-d6) 6 n&/z cele. 433.2, found 434.2 (M+I) . Rctent&on tune. O.S9 9 i)0 (s, ill). 7 73 (d, .I 8 711z, 111), 7.63 (d,.i 2 6 llz. 111), nunutes. US 20 ] 9/032265 [J A[ Oct. 24, 2019 135

Example 7 mmoi) in 2-methyl-2-propanol (14 mL) v as evacuated and backlilled with nitrogen three times i he tube w:as then Synthetic Scheme 7 (+/ — )-N-(4-(4-(2-amino-6- heated to 60" C, for 3 hours. The reaction mixture was nlethylpyrimidln-4-yl)-1,4-oxazepan-3-yi)-3-chioro- dllutcd with dichloromcthanc and w ashcd w 7th water, bone, phenyl)-2-hydroxy-2-methyipropanmnide 1-277 dried over sodium sulfate. filtered and concentrated in [0597] vacuo Thc resulting residue was puulied vul rcvcrsc phase sihca gel chromatography usin C-18 (150 g) IS( 0 column eluung with 0-90% CHsCN/H40 (tunmoluum fomlme modifier). 'Ihe pure fractions were concentrated ln vacuo, diluted with dlchloromctlmnc mid washed with water. Thc organic phases were passed through a phase separator and concentrated in vacuo to afford 207 m of desired product. 'I'he mcemic mixture was submitted for Slz('hiral purification(column-i.zz, 20x250 nun mob)le phase 20% MeOH Yi (5 mM anuuonla), 80% CO tlow 80 mL/min). N [f)599J Peak l3: 'll NMH (400 Mliz, CI)('I,) 6 8.68 (s, 111), 7.83 (s, Ill), 7 31 (dd, .I 8 4. 2 2 I lz, 111), 7 16 (d, 1=8.5 Hz. IH), 5.53 (s, IH), 4.60 (s, 2H), 4.30 (dd. J=13.6, 5.0 Hz. IH), 4.08 (d. J=15.8 Hz. IH), 3 (i4-3 45 (m. 4H), 2.12 (s, 3H), 1.80 (d, J=14.3 Hz, 4H), 1.54 ( ~ . 6H): ESI-MS nt/z cele. 419.2, I'ound 420.2 (M+I) . Rctcntlou tune. 0.58 nunc)ca.

Extunple 8

Synthetic Scheme 8; (+/-)-4-(3-(2-chlom-5-(methylsulfonyi)phenyl)-1.4-oxazepan-4-yl)-G-methylpy- ftzN umidul-2-mninc (69) 1-311

[t)600] 0 0 0 ~S ~~S

6 I)0

0 Cf 0 ('I 64 Hzx 0 ~S 0

64 H(1

(a) 2-hydroxy-2-methylpmpanamide, NaOtBu. tBuXPhos C! Pd 613. tBuOH, 60" Cz (b) SF('hirai separation 66 0 Fortnatlon of (S) N-(4-(4-(2-amino-6-methylpyrinudin-s-yl)-1,4-oxazcpan-3-yl)-3-cldorophcnyl)-2- hydroxy-2-methylpropanamidc (64) 1-276 [0598] In a microwave tube, a mixture of 4-[3-(4-bromo- 2-chloro-phenyl)-1„4-oxazepan-4-yl]-(7-methyl-pyrimidin- 2-4nnnc, 31. (0 77 g, 1.86 nunol), 2-hydroxy-2-mcthyl- propmlamide (0.45 g. 4.36 nunol), sodnun tots-butoxldc (0.56 g, 5.78 nmlol), and [2-(2-amlnophenyl)phenyl]-meth- 0 Cf yl sul fonyloxy-palladium:ditert-butyl-[2-(2,4,6-triisopropyl- 67 phenyl)phenylJphosphane (tBuXPhos Pd (13) (0.06 g, 0 08 US 20]9/032265[] A] Oct. 24, 2019 136

-continued NH4CJ solution. The aqueous phase was extracted tv'ice 0 with EtOAc. Thc combined orgtuuc plrdscs werc wttshcxI with aqueous saniratcd NaHCO, soluuou. dncxI (MgSO o ), filtered and concentrated in vacuo to give 2 5 grams of desired product as an omnge oil. 1he cnide residue was punfied via silica el chromatography w ith 40 g isco column using 0-30% EtOAc/CH2C12 gmdient to afi'ord 2.0 grams of product as a v,lute solid; ESI-MS nt/z cele. 219.99, found 221 06 (M+I) . Rctenuon time: 0.61 minutes.

Formation of m 2-cldoro-5-(mcthylsulfonyl)bcnzaldehydc (67) SO,VIc [06()3] (2-chloro-5-methylsulfonyl-phenyl)niethanol. Gi6, %if (I 00 g, 4 50 nunol) tvas dissolved in methylene chloride (23 mL). Dess-Martin periodinane (2.49 g. 5.87 mmoi) was added and the reaction mixture was stirred at room temperature for I G hours. The solution was diluted into aqueous saturat txl NBHCOS solu non Bnd extracted tw ice with EIOAc. Thc combined organic pluises werc washed with aqutmus (. saturated Nai ICOS solution, dried (MSSO4), filtered and concentrated in vacuo. 'Iiie crude residue was purified via silica gel cltromato raphy vvith 40 g isco column usin 0-20%4 EtOAc/CHBCI, gradient to aflord 7(i0 mg of desired product: 'H NMR (400 Mlqz, DMSO-dG) o 10.36 (s, IH), Yif 831 (d, J=2.4 Hz. I H). 8.20 (dd. J=84, 2.4 Hz. IH). 7.94 (d, J=8.4 Hz, IH). 3.32 (s. 3H).

Fomiation ol'-(2-chloro-5-(mcthylsull'onyi)phenyl)-1,4-oxdzcpmic (68)

a SU [0604[ io solution of3-(tributylstannylmethoxy)propan- I -mnine (0.88 g, 2.33 nmiol) in dichloromethane (G mL) was added 2-chloro-5-methylsulfonyl-benzaldehyde, 67. (0.51 g, (a) TMS-diazomethanc, toiucnc. mctlrdnol. (b) NaBH4, 233 nunol) followed by 4 A mohxular sicvcs Thc mixture MeOI h (c) Bess-Martin periodinane. dichlommethane; (d) 4 was stirred ovennght Iiltered to rcmove thc sieves, and A mol sieves. 3-((tributylstannyl)methoxy)propan-l-anune, diluted with dichloromcthanc (25 mL). CHSCI,; then 2,6-lutidine, Cu(OTfjs. hexafluoroisopropa- [0605] In a separate flask containing hexafiuoroisopropanol, CHSCI„(e) 2-amino-q-chloro-6-methylpyrimiihne, nol (7 mL) was added 2.6-1utidinc (0 28 mL, 2.39 nunol) NMP, 150" Cd (f) SFC chirai sepamtion followed by Cu(OTI)c (0.85 g. 2.34 nunol). Thc mixture was stirred lor I hour, Uien the imine solution prepared above Formation of methyl v as added in one portion. 1 he reaction was stiried for 3 days 2-chloro-5-(methylsulfonyl)benzoate (65) at roon& temperature. 'I he mixture ives diluted with 60 ml, of 2: I mixture of aqueous saturated solution and 10% [0601] To a solutiou of 2-chloro-5-mcthyisulfonyl-bmi- NaHCO, anunonium hydroxide. After stirrin for 30 minutes. the zoic acid (3 0 g. 12.8 nimol) in toluene (-15 mi ) and MeOJ I organic w as removed Bnd washed tw ice with (10 nil.) was added dropwise 'I'MS-diazomethane (10.7 ml, layer aqueous saturated NaHCO, solunon. then brute. lite orgmiic layer of 2 M in hexane, 21.4 mmol) The reaction mixture was wds pBssctl tllrougll d plitlsc st:parator hlllllcl tllltl collccll- stirred for 3 hours and the solvent was concentrated in vacuo trated in vacuo I'he resulting residue was purihed by reverse to give 3 grams ofdesired product ac tan fluffy solid that was IS('0 used without furtlmr punlication. 'H NMR (400 MHz, plmse silica gel chromato raphy using an J()0 gram c 1 8-aq colunui running with 01."!4 TFA/H,O and 0.1% DMSO-d6) 6 832 (d, J=2 3 Hc IH), 8.10 (dd, J=8.4. 2.4 Hz, TFA/CH.,CN. The fractions containing product were con- I I I), 7 90 (d..i 8 5 J lz, li I), 3 92 (s, 311), 330 (s. 611), ccntratcd in vacuo and thc residue was diluted with dichlo- Iigl-NIS m/z cele. 247 99, found 249 12 (M+]) Retention tinie 0.71 mimites. romcthane and neutralized w idi aqueous saturated NaHCOB Soliltloll. T11C OlgalllC plldst: wtIS pdssixl tllrotlgll B plulSi: 'll Formation of separator and concentrated in vacuo NMR shows desired plus additional impurity Used product with- (2-chloro-5-(mcthylsulfonyi)phenyl)mctlianol (66) product out further purification: 'H NMR (400 MHz, DMSO-dG) 6 [0602] To a suspension of methyl 2-cltloro-5-methylsul- 8.16 (d, 3=2 4 Hz. I H), 7.81 (dd. J=8.4, 2.4 Hz. IH), 7.70 (d, fonyl-benzoatc, 65, (3.0 g, 12.1 mmol) ui EtOH (45 mL) was J=8.4 Hz, IH), 7.54 (t. J=7.6 Hz. JH), 4.29 (dd. J=9.0, 3.1 added NaBH4 (1.83 g, 48.4 mmol). The reaction mixture Hz. I H), 3.91-3.76 (m, 2H), 3.76-3.63 (m. IH), 3.22 (s, 3H), was siirrcd at room tcmpcraturc fiir I hour, then imdtcd to 3.12 (dd, J=12.7, 8.7 Hz. IH), 2.89 (dt, J=13.6, 6.8 Hz, 2H), 50" C to solubilize the mixture. After 3 hours. the niixture I 93-1.78 (in. 21 I); I:SI-MS ni.'z cele 390 05, found 390.09 was quenched by slow addition into aqueous saturated (M+I)+ ltetention time 0 50 niinutes US 20]9/032265[] A[ Och 24, 2019 ]37

Formation of 4-(3-(2-chloro-5-(methylsulfonyl)phe- 1-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4-ox- nyl)-1.4-oxazepan-4-yl)-6-methylpyrimidin-2-amine azepan-3-yi)-4-chlomphenyl)pyrrolidin-2-one (72) (69) 1-119 [0606] To a solution of 3-(2-chloro-5-methylsullbnyl-phenyl)-1.4-oxazcpanc, 68, (0.200 g, O.G90 nunol) ui NMP (6 [0611] 'l I NMR (400 Ml lz. 1)MSO-d6) ij 7 76 (d, .I 2 7 mL) was added 4-cldoro-6-methyl-pyrumdin-2-aminc Hz. IH). 7.45 (dd,;1=8.7. 2.7 Hz. IH), 7.39 (d. J=8.8 Hz, 'I (0 123 a. 0.857 nimol) he reaction mixture v as heated to 111), 559 (s, ill). 5 42 (s, 311),4 (i3 (d, I 15 I I lz, lii), 4.12 150" C for 18 hours 1 he reaction mixnire was cooled to (dd. i=134, 5.0 Hz. IH), 3.91 (dt, 1=11.5, 3.8 Hz. IH), roon( temperature and loaded material directly onto a 50 '0 g 3.81-3.73 (m, 2H), 3.72-3.52 (m, 3H), 2 47-2 40 (m, 2H), IS( c I 8-aq column and purified by rei erse phase silica gel 2.08-2.01 (m. 2H), 2.00 (s. 3H)„1.80 (ddt, J=10.9. 7.5, 4.2 chromatography using a 50 grmn ISCO colunui ruiumi with Hz, 2H); ESI-MS ndz cele. 401.16. I'ound 402 0 (M+I) . TFA,'CH,CN. 0.1% TFA/HsO and 0.1% Thc Pure Iyactions Retention time 0 65 minutes were combined and conccntratcd ui vacuo. Thc residue was diluted v ith dichloromethane. neutralized with aqueous saturated Nail('Os solution, passed through a phase sepa- I:xample ') rator and the resulting organic phase was concentrated in vacuo to atford 84 mg of brown solid: high temperature (360 Synthetic Scheme 9: —)-4-(2-(2.5-dimethoxyphe- 'H (+/ K) NMR (400 MHz. DMSO-d6) 6 7.85-7.73 (m. 2H), nyl)azcpan-I-yl)-6-mcthylpyrunidin-2-amuse (77) J=gg 5.75-5.54 5.50-5.34 7.71 (d, Hz, IH). (m, 2H), (m, 1-25 2H), 4.48 (d, J=14.9 Hz, IH), 4.11 (dd, J=13.5, 4.9 Hz, IH), 3 92 3 65 (m. 311). 3 67 3 50 (m, 111), 3 18 3 11 (m. 311), [0612] 2 03 (d..i 5 4 I lz, 311), I 80 (s. 211). [0607] The mcemic mixture was submitted for SFC chiral separation: prepped at 50% IPA, 50!o Hexanes. 0.2% diethylamine on AD-H I I [0608] PeakA. (R)-4-(3-(2-cldoro-5-(mcthylsulfonyl)phe- ~O nyl)-1.4-oxazepan-4-yl)-6-mcthylpyrimidin-2-anunc (70), 96 4% ee by IIPI ('; heated (3(iOK) 'll NMR (400 Mllz„ l)MSO-d6) 6 7 81 (ddd, J 8.3. 2 3, 1.1 I is, 111), 7.78 (d, 1=2.3 Hz, IH). 7 71 (dd. J=8.3, 1.2 Hz, IH), 5.70 (s, IH), 3.62 (dd. 1=9.9. 4.8 Hz, IH). 5.43 (s, 2H). 4.48 (d, J=15 4 Hz, IH), 4.11 (dd. J=13.4, 4.9 Hz. IH). 3.97-3.(ig (m. 3H), 3.66-3.52 (m. I H), 3.16 (d, J=1.2 Hz, 3H), 2.04 (d. J=I.O Hz, 3H), 1.89-1.70 (m, 2H), ESI-MS ngz cele. 396.10, fiiund — 3')7 25 (M+I)'etention time 0.5(i mimites: [ [o 42 40 (c 5 niei2 nil. MeOI I) 1-102 [0609] Peak B (S)-4-(3-(2-chloro-5-(methylsulfonyl)phe- nyI)-1.4-oxazepan-4-yl)-G-methylpyrimidin-2-cmice (71), 98+% ee by IJPLC: heated (360K) 'H NMR (400 MHz, DMSO-d6) o 7.81 (dd, J=8.3, 2.3 Hz. IH), 7.78 (d. J=2.2 Hz, IH). 7.71 (d, J=gg Hz, IH), 5.70 (s, IH), 5.62 (ild, J=9 9, 4 ') I lz. 111). 5 42 (s, 211), 4 48 (d,.t 15.21iv, 111). 4.11 (dd, 13 5. 4.9 llz. 111), 33)4-3.70 (m. 311), 3.tiO (ddd, I 12 0, 9.5. 4.7 Hz„ IH)„3.15 (s, 3H), 2.04 (s, 3H), 1.80 (dt. J=8 3, 4.2 Hz. 2IJ)t ESI-MS m/z cele. 396.10. found 397.20 (M+I) . Retention time: 0.55 minutes: [ ]o=+77.82 (c=5 5 mg/2 mL McOH). 1-103. [0610] The following mialog was preparixl accordmg to Synthetic Scheme 8: Yif

xi i US 20]9/0322658 A[ Oct. 24, 2019 138

continued g CiOLD colUnul; 10-100%o EtOAc in hePtane) as a Pale yellow oil. 'H NMR (300 MHz. DMSO-d6) 6 7.79 (s. IH), 7.27 (t, J=84 Hz. I H). 6.67 (d, J=S.4 Hz, 2H), 5.41 (t, J=6.1 I Iz. I I I), 3 74 (1, 611). 3 69-348 (ni, 21 I), 2 31-2.1 2 (m. 21 I), I 83-1.48 (in. 41 I); I:SI-MS miz cafe 261 14, found 262.15 (M+I)'. Retention time; 0.84 minutes.

Fonna(ion of

0- o. 2-(2,5-dimetlxn yphcnyl)azepanc-I-carbaldchyde (75) 7S [(1615J I o a snlution of 7-(2.6-dimethoxyphenyl)-2.3,4.5- tetrahydroazepine-l-carbaldehyde„74, (3 00 g. 11.48 mmol) 0" (a) l)MI( PO('11. ('111('11. ('o 40" (2: (b) 2.5-dime- in MeOH (30 mL) and EtOAc (30 mL) was added HOAc (9 thoxyphenylbomnic acid. Pd(PhsP),Cls. DME. 50'z (c) mL) and Pd/C (0.24 g. 2.30 nunol) The flask was charged Pd/C, HOAc. EtOAc, MeOH: (d) EtM Br. THF, O', (e) with a hydmgen balloon aflcr pun»ng tluce (uncs wifli

2-amuio-4-1:hloro-6-mcthylpynmiduic, NMP. 150'G (f) vacUUnl. Thc nllx(Urc was stlrlcol at roonl tcnlpi:1'tl(Ulc ovcl- SFC clural separation night The mixture was filtered through cehte and evapo- mated the solvent. 'I'he resulting cnide oil was used ivithout Formation of 7-chloro-2,3.4.5-tetrahydro-lH- further purification azepine-I-carbaldehyde (73) [0613] A 3-neck 3 L round bouom tlask equipped with Fonna(ion of overhead stirrer, tempcraturc pmbe, addiuon fiumcl, nitro- (+/ — )-2-(2,5-dimcthoxyphmiyl)nzepanc (76) en inlet and reflux condenser was charged ivith DMli (3607'. nil .. 4 65 mol) in dichloroniethane (500 ml,) and stirred fiir [(1616J I o a solution of 2-(2.4-dtntethoxyphenyl)azepane- Jminutes and then cooled to 0" C. POCls (220 mL. 2.36 I-carbaldehyde, 75, (1.80 g. 6 51 nimol) m '1111 (50 inl,) mol) in dichiommethane (300 mL) was added over 60 v as added etbyfntagnesium bromide (2 21 g. 2 17 ml, of 3 minutes wlulc maintaining thc internal tcmpcrature below M solution in ether, 6.51 nunol) at 0" C. The mixture was The reaction mixture was warmed to 40'. (observed stirred at 0" C. for 3 hours. The mixture was carefully colorless solutiou birn to pale orange) stirred at this 1mn- quenched by addition of 2N NaOH solutiou and then perature for 45 niuiutes Added azepan-2-one (85 g. 751 2 extracted with EtOAc. The combined orgnnic layers were mmol) in dichloroniethane (450 ml,) over 45 minutes under washed with brine, and dried over MSSOo, filtered and 'I refiux (observed Tmax 45' ). The resultin reaction mix- cmicentrated in vacuo he crude residue was purified by ture was stirred at this tempemsture for 3 h at which time IS(.'0 eluting with methanol,'dichloromethane gradient HPLC-analysis revealed consumption ol thc suirtuig material. The reaction mixture was cooled to ambient tempera- Fomiation ol'R)-4-(2-(2,5-dimcthoxyphenyl)azc- ture. pourixl into crushixl icc (3 L) anil then allowed 1O pan-I-yl)-6-methylpynnudin-2-amine (78) and (S)- ambient temperature over 12 h. 'Ihe aqueous layer was 4-(2-(2,5-dimethoxyphenyl)azepan-l-yl)-6-methyl- separated, basihed with solid Kz('Os until pl 1 '), allowed to pyrimidin-2-an)me (79) ivann to ambient temperature and stirred at tins tempermue for 18 h. The mixture was diluted with dichloromethane (2 [(1617J I o a mixture of solids 4-chloro-6-niethyl-pyriini- L) and the orgaruc layer was separated. Aquixius layer was din-2-mnine (0.15 g, 1.02 nunol) and 2-(2„4-dimethoxyphe- cxtractcil with dichloromethanc (I L) and thc combuied nyl)azepane. 76. (0.24 g, 1.02 nunol) in a vial was added organic cxtmcts werc washed with water (100 mL). brine EIOH (2 mL). The vial was placixl on thc hot plate and 180" (200 nil ). dried over NaiSOo, filtered and concentrated hcatcd at C. without corer Ibr 2 lus. Tlm crude residue under reduced pressure I'he residue was purified by sihca was purified by silica gel chromatography 40 8 IS('0 el plUg ilsing 0% 30% ethyl acetate/heptane-which con- colunin eluting with 20%o MeOH-dichloroniethane/dichlo- tained 1%o EtoN, fractions wlfich contained desired product ronietbane gradient to afl'ord 32 mg of the desired product were collected. concentrated under reduced prcssure to 'H NMR (300 MHz, DMSO-dt;) 6 7.19 (s. 2H), 6.91 (dd, ailbrd 7-chloro-2,3,4,5-tetrahydroazcpine-l-carbaldchyde J=36.7. 8.5 Hz. IH), (x61 (s. IH). G 52-G 36 (m, 2H), 5.70 (110 g. 92%) as a clear, colorless oil. (s, IH), 4.7S (dd, J=67.0. 11.7 Hz, 2H), 3.88 (1, 3H), 3.73 (d. J=2.4 Hz. 5H). 3.G2-3.14 (m, 6H), 2.18 (d, J=39.5 Hz. SH). Formation of 7-(2.5-dimethoxyphenyl)-2,3,4.5-tetm- I 95-1.70 (m, 511), I 34 (dd, .I 41) 7, 10 8 Ifz, 311): Ikql-M) hydro-IH-azcpuie-I-carbaklchydc (74) nv'z cafe 342.21. found 34332 (M+I) Retention time 0 72 minutes. [0614] Charged a 2-ucckcd round bouom flask under nitmgen with 7-chloro-2.3,4,5-tetrahydroazepine-l-carbal- [(1618J I he racemate (4.0 ) was submitted for )Ii('epa- 4.6x100 20x250 dehyde, 73. (3 00 g. 18 80 mmolb (2,6-dimethoxyphenyl) ration (Column: I(i nmi IC, mm Mobile boronic acid (4.45 „24.44 mmol). DME (24.67 mL) and phase: 40% EtOH (5 mM Anunonia), G0% CO2 40%o EtOH mM Ammonia), 60%o to alford. bis(triphenylphosplfine)palladium(11) cltloride (0.53 g. 0 75 (5 CO„ mmol). Thc rcacuon mixture was stirrcrl ovcrm ht a! 50'. [0619] Peak A. 1.61 grams of (R)-4-(2-(2,5-dimcthoxy- Thc ntlxtilli: was illluted with water mid dmhloromcthane. phcnyl)azcpan-I-yl)-6-mcthylpyrunidin-2-amuse (78). ' Thc layers werc scparatcd through a plmse separator and the ac=98%; [ii]o (c= I .0. Mvq) H') + I I I . 98, NMR (300 MHz, organic phase was concentrated in vacuo 'I he crude residue DMSO-d6) 8 6 94 (br, 111). 6 75 (br, 111), 6.48 (s, 111), 5.81) was purified by silica gel chromatography using a IS(:0 12 (s, 311), 4 76 (bra, I I I). 3 83 (s. )I I), 3 64 (s, 311). 3 32 (bra, US 20[9/032265[] A[ Och 24, 2019 139

2H), 1.94 (br. 3H), 1.81-0.95 (m. SH): ESI-MS nt/z cele. mttted for SFC separation. SFC conditions: Column: IC, 342.21, found 343 27 (M+I ) Retention time: 0.74 minutes. 20x250 nuu, Mobtle phase. 30% McOH (5 mM Anuuonta), 1-40 70% CO,; Flow. 75 mL/muu Concentrattons —40 mg/mL [(16ZOJ Peak H I 21 grants of (S)-t-(2-(2,5-dimethnxy- (MeOH); Injection Vohune: 500 fix Wavelength 214 lttll; phcnyl)azepan-I-yl)-6-methylpyruntdut-2-mnine (79) Methnd type I socratic cc=96%: (c=1.0, MeOH) — 147.32; 'H NMR (300 [u]n [0624] Peak A: [tx]o (cW.5, McOH) +74.56, 99.4% cc MHz. DMSO-dG) o 7.56-7.10 (br, 2H). 6.89 (br, 2H), [0625] (R)-4-[2-(2-chloro-5-methoxy-phenyl)azcpan-I- 6.64-639 (nt. I H). 5.86-5.65 (m. I H), 4.83 (br, I H), 4.05 (d, yl]-6-methyl-pynnudm-2-amine (81). 'H NMR (300 MHz, 153 I lz, 0 511), 3 83 (s, 311). 3 67 (s, 311)„3 59-341 (nt, DMSO-d6) It 7.36 (d, J=S.S Hz. IH), 6.85 (d, J=8.2 Hz, IH), I 51 I). 2.22 (d. J 37 7 I is. 311). 2.00-0.94 (m. Nl I): I tSI-M) 6 62 111), 6 07 (br, 211). 4.78 (brs, 111). 3 70 311), 3.29 m'z cele. 342.21, found 343.32 (M+I) . Rctenuon time (s, (s, 0.76 mututcs. 1-4 l. (br, 211), 1.99 (s, 311), I NN-I 09 (m, NI I); I IS I-MS m/z cele [0621] The following analo s were prepared accordin to 346 16. found 347.2 (M+I) . Retention time: 0.72 mimttes. Synthetic Scheme 9: 1-135. [t)626J Peak lk [o]z, (c 05, MeOII) — 76.80; 99% ee [t)627] (8)-4-[2-(2-chloro-5-methoxy-phenyl)azepan-I- s(l ylJ-6-methyl-pyrintidin-2-mnine (82) (200 mg, 89%) 'l I NMR (300 MHz. DMSO-d6) 8 7.78 (s. IH), 73tp (m. 2H), 7.01-6.77 (m. IH), 6.62 (d, 3.0 Hz. IH), 6.49 (s, 0.5H), 5.72 J[g (dd. 1=12.5. 5.1 Hz, 0.5H)„5.33 (s. 0.5H). 5.07-4.89 (m, O.SH), 4.79 (d, 1=13.S Hz. 0.5H), 4.13 (d, J=15.3 Hz, O.SH). 3.73 (d, J=3.3 Hz, 3H). 3.57 (t, J=11.9 Hz, IH), 3.18 (s. I H). 2 2N (s, I 511), 2 15 (s. I 511), 2 05-0 97 (m, NII): IISI-MS nv'z cele 346.1(&. found 347 15 (M+I) ltetentton time 0.72 mtnutes. 1-136.

(+ — )-4-(2-(2-chloro-5-ntethoxyphenyl)azepan-I-yl)- 6-mcthylpyruntdtn-2-aminc (80) 1-117 [0622] 'H NMR (300 MHz. DMSO-d6) 8 7.77 (s. IH), Yif 7 52-7 2N (nt. 2H), 6 90 (ddd, .I 20 8, 8 8, 2 8 I lz. 111), 6 5N (s, Oli), 5 82-5 46 (m, 111). 5 03-4 69 (m. 111), 4 13 (d, J=15.2 Hz, IH), 3.58-3.25 (m, 12H). 2.28 (s, 2H), 2.04-1.08 (m, 9H), ESI-MS nt/z cele. 346.IG, li&und 347.17 (M+I) . Retcnuon time: 0.72 mtnutcs.

(+/ — )-4-[2-(2-fluoro-6-methoxy-phenyl)azepan-I- yl]-6-ntethyl-pyrimidin-2-amine (83) 1-50 Yg [0628] 'H NMR (300 Mitz, DMSO-d6) 8 7.44-G.59 (m, 5H). 5.68 (s. IH), 5.04 (d, 1=11.0 Hz„0.5H). 4.67 (d, J=I4.2 Hz. 0.5H), 3.94 (s, 3H), 3.60-3.10 (m„2H), 2.29-1.69 (m, SH), I 53-0.87 (m, 3H). ESI-MS nt/z cele. 330.19, found 331 29 (M+I) . Rctenuon time: 0.72 minutes.

)[g Yif ct 0

(R)-4-(2-(2-chloro-5-methoxyphenyl)azepan- I -yl)-6- (+t — )-4-[2-(4-ihlorophcnyl)azepan-I-yl]-6-mcthyl- methylpyrimidin-2-antine (Ni) 1-135 and (S)-4-(2- (2-chlonn5-ntethoxyphenyl)azepan-I -yl)-6-methyl- pyrtnndin-2-amnu: (1-43) pyrimidin-2-amine (8l) I-13(i [0629] 'H NMR (300 MHz, DMSO-d6) o 7.37 (d, J=8.2 [06Z3J 4-[2-(2-chloro-5-methoxy-phenyl)azepan-I-ylJ-6- I lz. 211), 7 2N (d, .I 8 3 I le, 211), 6 84 (s, 211). 5 81 (s. II I), ntethyl-pyrimidin-2-antme (450 mg, 1.28') mtnol) was sub- 4 76 (br, 111), 4 00-2 &) s) (nt. 21 I), 2 20 (s. 311) I 95-0 97 (m, US 20[9/032265[] A[ Oct. 24, 2019 140

8H); ESI-MS nt/z calc. 316.15. found 317.24 (M+I) . 2H). 5.70 (s. IH). 4.78 (dd, 1=67.0. 11 7 Hz. 2H). 3.88 (s, Retcnuon time: 0.72 mtnutcs. 3H), 3.73 (d, 1=2.4 Hz, 5H). 3.62-3.14 (m, 6H), 2.18 (d, J=39.5 Hz, 5H), 1.95-1.70 (m, SH), 134 (dd, J=49.7, 10.8 I lz. 311); I ISI-MS m,'z cele. 342.20. found 343S2 (M+11 Yif Retention time 0 72 minutes

(+/— )-4-[2-(3-chlorophenyl)azepan-I-yl]-6-methyl- pynmtdin-2-tenure (1-44) (+/ — )-4-(2-cyclopmttylazcpan-I-yl)-6-mcthylpynmt- thn-2-anunc 1-9 [0630] H NMR (300 MHz, DMSO-d6) 6 7.78-7.12 (m, 5H), 6.29 (s. 2H), 6.10-5.47 (m, IH). 4.43-'3.61 (m, IH), [0633] 4 suspmtston ol'-t:hloro-6-methyl-pyruntdut-2- 3 34-2 92 (nt. 211), 2 14 (s, 3i I). I 98-0 89 (tn„gI I); ItSI-MS anunc (0.094 g, 0.657 mmol). 2-cyclopcntylazcpmte (0.100 m,'z cele 316 15, found 317 19 (M+I) . Retention tinte g, 0 598 nunol) and 'PrsNEI (0.230 mL, 1.320 mmol) in IPA 0.72 minutes (0 6 ml,j was sealed in a nucrowave tube and irradiated at 160" (2 for 2 hours. 'I'he mixture was concentrated in vacuo and punfied by reverse phase chromatogmphy (0.1% TFA/ acetonttrile). The material was converted to HCI salt to HsS aifitrd 46 mg ol'esired product. 'H NMR (400 MHz. MeOD) 8 6.31 (2 s, IH), 5.06-4.91 (m. IH), 4.48-3.34 (m. 2H), 2.35-2.27 (m, 3H), 2.27-2.15 (m, I H), 2 02 (tid, i=16.7. 8 3 I lz, I I I), I J)2-1 15 (m. 1411). I 14-0 96 (m, 111): I igl- MS m/z caic 274.22, found 275 18 (M+I) Retention time 2.84 mtnutes.

(+/ — )-4-[2-(3-Iluorophcnyl)azepmt-I-yl]-6-methylpynmidin-2-amine 1-29

[0631] high tentperature (360 K) 'I l NMlt (400 Ml lz„ DMSO-d6) 6 7.31 (dd. J=I4 4, 7.7 Hz. IH). 7.06 (d. J=7 8 Hz, IH). (i.95 (dd. J=14.0, 5.8 Hz. 2H), 5.74 (s. I H). 5.43 (br s, 3H), 4.07 (br s, IH), 3.16 (dd. J=13.4. 11.5 Hz. IH), 2.46-235 2 04 3H). 1.88-1.62 (m. 4H), 1.62-1. (m, IH). (s, (+/— )-4-methyl-6-[2-(4-pyndyl)azepan-I-yl]pynmi- 50 (m. IH). 141-1.21 (m, 2H). ESI-MS m'z cele. 300.18, din-2-amine 1-35 found 301.21 (M+1) Itetention time 0.64 minutes [0634] ESI-MS nv'z cele. 283.18, found 284.22 (M+I) . Retention time 2 14 minutes Yif H 8

— (+/ )-4-[2-(2,4-dnncthoxyphcnyl)azepan-l -yl]-6- (+/— )-4-[2-(4-Iluorophcnyl)azepan-I-yl]-6-mcthyl- methyl-pynmtdut-2-amuse (84) 1-51 pynnndm-2-amtne 1-34

[0632] 'I I NMIt (300 Mllz. 1)MSO dd) 6 7 19 (s. 2H), [0635] high temperature (360 K) 'll NMR (400 Mlis, 6 '/I (dd, .I 36 7, 8 5 I lz, 111), 6 61 (s. I I I). ti.52-6.36 (nt, DMSO-d6) 8 7.28-7.21 (m. 211), 7 05 (m, 21 1), 5 72 (s, I I I), US 20[9/032265[] A[ Oct. 24, 2019 141

5.65 (s, 2H), 5.42 (m, 3H), 4 03 (c, IH), 3.15 (dd, J=13 3, -con)banal 11.6 Hz, IH), 244-2.34 (m, I H), 2.03 (s, 3H), 1.90-1.65 (m, (J~ o~ 4H). 1.63-1.48 (m, IH). 1.42-1.21 (m, 2H). ESI-MS m/z cele. 300 18, fbund 301 22 (M+I) Retention time 2 ')7 nlimltes

(+i — )-4-ntethyl-6-[2-(p-tolyl)azepan-I-yl]pyrinudin- 2-a)nine 1-33 [0636] high tempcraturc (360 K) 'H NMR (400 MHz, DMSO-d6) o 7.12-7.04 (m. 4H). 5.70 (s. IH). S.65 (s. 2H), 5 39 (s. 111). 5.3')-5 20 (m, I I I), 4 08 (s. 111)„3.18-3.07 (nl,

I 42-2 31 88-1 I I), 2 32 (m, 111), 2 24 (s, 1), 2 02 (s, Sl i). I 66 (a) (2,5-diinethoxy-4-pyridyl)boronic acid, Pd(ph,p)z( iz, 1.(i3-1.50 ESI-MS (m, 4H), (m. IH), 1.31 (m. 2H). nt/z calc. NaJICO„DM)i, water, 60" ('4 (c) Pd/(', formic acid, 29(i.20. found 297.25 (M+I) . Retention time: 3.07 minutes. EtOAc. MeOH: (d) nBuLi, THF, -78" C; (e) 2-amino-4- cldoro-6-methyipyrimidine. NMP. 150" Cu (Ij SFC cldral sepal'ltlou

llomlation of 7-(2,5-dimethoxy-4-pyridyl)-2,3,4.5- tetrahydroazepine-I-carbaldehyde (85) [0639] A 2-necked rb flask under nitro en v as charged with 7-chloro-2,3vks-tcuahydroazcputc-l-carbaldchydc. 73, (0.79 g, 4.95 nunol). (2.5-dinu:thoxy-4-pyridyl)boroluc acid (1.0() g, 5 46 mmol) in DMJ. (10 nil.). followed by NaJICOs (8 ml, of 1.2 M solution. 9.6 mnlol) and bis (tnphenylphosphine) palLsdium(H) chloride (0.14 g, 0.20 (+,' )-4-[2-(4-methoxypheoyl)arepen-I -yl]-(l- mmoI). Stirred overnight at 60'. Added water and dichlo- methyl-pyrimidin-2-amine 1-23 mmethane. The layers lvere separated tluouogh a phase scplllator rind thc orgtlulcs couceturalixi ltl vacuo lifter a 'H [0637] high tempcraturc (360 K) NMR (400 MHz, second extraction. Puniicauon by slhca gel chromatography DMSO-d6) o 7.12-7.04 (m. 4H). 5.70 (s. IH). S.65 (s. 2H), (40 o (JOI,D colunln; 10-100% I itOAc/heptanes gradient) 5.39-5.20 4.08 3.18-3.07 539 (s. IH). (m, IH), (s, JH), (m, afforded I g (47%) of desired product 'I I NMR (300 Ml lz, I I I), 2 42-2 32 (m, 111), 2 24 (s, 31 1), 2 02 (s, 31i). I 88-1 66 CDCls) 6 7.94 (s, IH). 7.75 (s. II(). 7.28 (d. J=l.l Hz, iH), (m, 411), 1.63-1.50 (nl. 111), I 31 (m, 211); I JSI-MS mlz calc. 6.64 (s. IH), 3.91 (s. 3H), 3.84 (s. 3H)„3.80-3.69 (m. 2H), 29(i.20. found 297.25 (M+I)'. Retention time: 3.07 minutes. 2.43-2.29 (m. 2H), 1.87 (dd. 1=8.5. 3 8 Hz, 2H), 1.71-1.64 (m, 2H), ESI-MS m/z cele. 262.13, found 263.07 (M+I) . Example 10 Rctcntton time. 0.75 nnnutcs.

Synthetic Scheme 10: (+/ —)-4-[2-(2,5-dimethoxy-4- Fonna)ion of pyridyl)azepan-I -yl]-6-methyl-pyrimidin-2-umine 2-(2,5-dimethoxy-4-pyridyl)azepane-l-carbaldehyde (88) 1-116 (86) [0638] [0640] To a soluuon of 7-(2.5-dlmcthoxy-4-pyndyl)-25L 4,S-lclrahydroazcpulc-l-carbaldchydc, 85, (1.0 g, 3.8 nunul) iu MeOH (20 mL) mid EtOAc (20 mL) was added Rlmuc acid (I 7 g, 37 0 mmol) and Pdy('40 mg, 0 4 mmol) under N, atmosphere. I'he reaction mixture was then charged ivith H, (balloon) and stirred at room temperature over night. Filtered tluough celite, the solvent was evaporated. the Qi"— remduc was punlied by sthca gel colunul (40 g) ul ISCO elutlng 0%o to 50%o EtOAc/hcplanes gmthcnt. Thc dcstrcxl fracuons were collected and evaporated to alford 1.0 grams (51%) of desired product: I,SI-MS nv'z cele 264.15, found 265 14 (M+I)+. Retention time: 0.72 minutes US 20[9/032265[] A[ Och 24, 2019 142

Formation of 2-(2.5-dimethoxy-4-pyridyl)nzepane (87) gg

[0641] To a solutiou of 2-(2,5-dimcthoxy-4-pyndyl) azepane-l-carbaldehyde, SC&, (I 00 o. 3 78 nunol) in 1111& (20 n&L) was added n-butyllithium (5.0 mL of I.C& M, 8 00 — — Yif mmol) at 7S'''he mixture was stirred at 78''or 2 hours. The reaction mixture was carehdiy quenched by the addition of McOH. To thc mixture was added 2N HCJ solution until pH=2 was achieved. The resulti»g solution was then basilicd by add&ng 6N NaOH unt&1 pH=10 was 1'he achieved. aqueous solution was extracted with litOAc gt and the comb&ncd organ&c layers werc washcil w&d& bone, dried over MgSOw filtered and concentmted in vacuo to aQi&rd 230 mg of desired product; ESI-MS m/z cele. 236.15, found 237.15 (M+I) Retention time 0.58 minutes Yig I'erma)ion of 4-[2-(2.5-dimethoxy-4-pyridyl)azepan-I-yl]-6-methyl-pyrimidin-2-amine (88) 1-116

[t)642] 1o a mixture of solids 4-chloro-6-methyl-pyrim&- din-2-mnine (0 12 8, 0 Nl mn&ol) and 2-(2.5-dimethoxy-4- pyridyl)azepane (023 8, 090 nunol) in a vial was added EtOH (2 mL) The vial v as placed on the hot phste and 0'R)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-I- heated at 160'. v ithout cover for 2 hours. The crude solid yl]-6-methyl-pyrin&idio-2-mnine (90) 1-108 was purified silica chromato in ISCO by gel raphy (40 ) [0645] SFC conditions. colunm. IC, 4 6x00 nun IC, with MeOH/d&chloromethane dichlorotneth- eluting 20% 20x250 mm: Mobile phase 4(P% IitOI I (5 n&M Ammonia), ane to aiford(x5 m ofdesiredproduct: 'H NMR(300 MHz, 60% (.0&. DMSO-d6) 6 7.85 (s. I H). 7 56 (br, 2H), 6.48 (s. 0. 5H). 6.30 [0646] Peak .A: [o]o (cW.5, MeOH) +58.56: 99% ee; (s, 0.5H), 5.69 (s. IH), 4.81 (m, IH), 3.88 (s. 3H), 3.75 (s, (R)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-I-yl]-6- methyl-pyrimidin-2-amine 'H NMR 3H). 3.61-3 25 (m, 2H), 2.28 (s. 3H), 1.99-1.07 (m, 8H), (90): (300 MHz, DMSO-d6) 6 7.31 (s. IH). 6.82 (d. J=8.9 Hz, IH). 6.54 (s. ESI-MS n&/z cele. 343.20, found 344.16 (M+I) . Retention JH), 5.76 (br, 3H), 5.00-4.37 (m, 3H), 4.01-3.81 (m, IH). ume. 0.65 nunutcs. I 95 (s, 31 I), I N6-1 29 (m. SI I). 1.21 (m, C&i I); I IS I-MS m/z [t)643] 1 he fi&lloiving analogs were prepared according to cele. 374.19, tbund 37507 (M+I)+ Retention tune: 0.75 I-1 Synthetic Scheme 10: mu&utes. 08. [0647] Peak B: [u]o (c=0.5„MeOH) -70.52, 98.4% ee; (S)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-I-yi1-6- methyl-pyrinudin-2-imunc (91): 'H NMR (300 MHz, DMSO-d6) 6 7.32 (brs. IH), 6 83 (brs, IH). 6.55 (s, IH), 5 83 (br, 311), 4 96-4 43 (n&. 211), 4 02 (br, 211). 3 17 (s, 311), I 95 (s, 311), I NC&-I 31 (m. SI I), I 26-1 15 (m, 61 I), I!SI-MS nv'z cele 374.19, found 375 12 (M+I) Retention time Yif 0.77 mim&tes. 1-109.

gz u v ou

4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-I-yl]-6- methyl-pynmidin-2-iunu&e (89) 1-104

[0644] 'H NMR (300 MHz. DMSO-d6) 6 7.78 (s. IH), 7.50-7.25 (m. 2H), 6.88 (ddd. J=20.5. 8.8. 2.8 Hz. IH), 6.68-659 (m, IH), 5 81-5 46 (m, IH), 5.09-4.72 (m. IH), 3-[I-(2-amu&o-6-methyl-pyrunidin-4-yl)azepan-2- 4.56 (m, IH). 4.13 (d, J=14 6 Hz. IH). 3.87-3.46 (m, IH), yl]-4-methoxy-phenol 1-107 2.22 (s, 3H), 2.05-1.34 (m, SH). 1.23 (d, 1=5.4 Hz, 6H), (92) ' I!SI-MS miz cele 374 19, found 375 07 (M+IF Retention [t)648] I NMR (300 Ml lz„DMSO-d6) ib 8 99 (br, 111), time 0.76 minutes 7 79 (s, 111), 7 54 (s, 111), 6 85 (dd, I 20 5, 8 7 I lz. I I I), US 20 ] 9/032265 j] A[ Oct. 24, 2019 143

6.69-6.57 (m. IH), 6.53-6.43 (m. IH), 6.31 (d, 1=2.8 Hz, (+/-)-4-methyl-6-(2-(2-ntethylpyridin-3-yl)azepan- 0.5H). 5.77 (s, 0.5H), 5.70 (s. IH). 5.09-4.S7 (m, IH). 4.00 I-yl)pyrimidin-2-amine (95) 1-24 (m, IH), 3.82 (s. 3H). 3.49 (m, IH), 2.1S (s. 3H). 1.98-1.01 [0654] 'H NMR (400 MHz, DMSO-d6) o 8.30 (d, J=4.6 (m, 811); IISI-MS ns/z cele 328.19, found 329 17 (M+I)'. Hz, IH). 742 (d, J=7.9 Hz, IH). 7.12 (dd, J=7.8, 4.7 Hz. Retention time: 0 67 minutes I H). 6.94 (s, 2H), 6.18-6.00 (m. IH)„538 (s. IH), 4.29 (s, 2H)„3 63 (s, IH), 2.63 (s, 3H), 2.32-2.22 (m. IH). 2.21 (s, 311), 2.00-1.73 (m, 311), 1.56-1.28 (nt. 411): IISI-MS m/z cele 297.2, found 298 2 (M+I) Retention time: 0.49 ttllttuli:s.

HsX st OH

4-(2-(2-thtorophenyl)azepan-I -yl)-6-methylpyrimidin-2-antine (')6) 1-36 [0655] 'H NMR (300 MHz, DMSO-d6) o 7.28 (m, 2H), G— 7.20-7.06 (m. 3H), 630 (s, 2H). 6.20-5.G2 (m. IH), 348-3. 07 (m, 211). 2.10 (brs. 311), I 98-1 18 (m, 81 I): I '.SI-M) m/z cele. 300.2. found 301.2 (M+I)'etention time: 0.7 min- (R)-3-[I-(2-amino-G-methyl-pyrimidin-4-yl)azepan- utes. 2-yl]-4-methoxy-phenol (93) 1-127

[0649] SI'('onditions column: I(', 4 6x I 00 nun I(:, I I 8 20x250 mnt; Mobile phase 30oio MeOI I (5 mM Anuuonta), Cl 70i'o ('Os. [0650] Peak A. [o]o (c=0.5, MeOH) +100.16: 87.6% ce [0651] 3-[I -(2-mnino-6-methyl-pyrimidin-4-yl)azepan-2- ylj-4-methoxy-phenol (93): 'H NMR (300 MHz. DMSO- d6) 6 8.84 (br. IH). 6.81 (s, IH), 6.55 (s. IH). 6.39 (s, I H), 5.80 (s. 2H), S.32 (s, IH), 4 74 (s. IH). 3.79 (m. 3H), 3.30 (m, 2H). 1.92 (s, 3H), I 82-0 64 (m, 8H)1 ESI-MS m/z cele. 328.19. found 329 25 (M+I) Rctcnlion lime. 0.6S mimttcs. 1-1 27. [0652] Peak Px [rx]r, (c=0.5. MeOH) — 9832: 94% ee 4-(2-(5-chloro-2-ntethoxyphenyl)azepan-I-yl)-G- [0653] 3-[I -(2-mnino-6-ntetbyl-pyrimidin-4-yl)azepan-2- mcthylpynmidut-2-amtnc 1-21 'I ylj-4-methoxy-phenol (')4y I NMR (300 Ml lz. DMSO- [0656] 'H NMR (300 MHz. DMSO-dG) 6 7.46 (brs. IH), d6) 6 R85 (br. 111), 6 82 (s, 111), 6 56 (s, 111), 6 40 (s, 111), 737-7.23 (m. 2H), 7.17-6.96 (m, 2H). 6.87 (s, 0.5H), 6.43 3.80 (s. 2H). 5 32 (s„ IH). 4.74 (s, IH). 3.79 (s, 3H). 3.30 (m, (s, 0.5H). 5.84-5.S9 (m. IH). 4.96 (d, J=I0 2 Hz, IH), 4.06 2H). 1.92 (s, 3H). 1.83-0.84 (m, 8H): ESI-MS nt/z cele. (d, J=15.4 Hz. IH), 3.88 (d, J=15.1 Hz, 3H), 3.5S (dl, 328.19. found 329.1 (M+ I) . Rclenuon umc: 0.65 numttcs. J=42.6, 12.7 Hz, IH), 2.20 (tl, J=357 Hz, 3H). 2.01-1.03 (m, 1-128. 811); IISI-MS m/z cele 346 16, found 347 23 (M+I) Retention time 0 73 minutes Yif US 20]9/032265[] A[ Oct. 24, 2019 144

4-(2-(4-chloro-2-methoxyphenyl)azepan-I-yl)-6- conthlilixl methylpyrimidin-2-amine 1-20 [0657] 'H NMR (300 MHz, DlvISO-d6) 6 7.44-6.85 (m, 6H), 639 (s. O.SH), 5 62 (s. 0.5H), 4.81 (dd, J=71.0. 12 5 Yig Hz. Iit). 4.18-3.80 (m. 4H). 3.68-3.23 (m, 4H). 2.18 (d, 1=39.0 Hz. 4H). 2 01-1 07 (m, 7H); ESI-MS nt/z calc. 346 16. tilund 347 23 (M+I)+ Retention tiine 0.74 minutes.

fuo %if Hlx Yi 0

4-(2-(4-iluoro-2-mcthoxyphenyl)azepan-i-yl)-6- mcthylpynmidul-2-aminc 1-22 0 [0658J 'I I NMR (4(X) Ml is. DMSO-dfi) !5 6.98 (dd. I 84, 6.9 Hz, IH), 6.84 (dd, J=11.2. 2.5 Hz. IH), G.61 (td. J=8 5, 2.5 Hz. IH), 5.56 (s, IH). 5.35 (s. 2H), 5.14 (s, IH). 408 (s, Yif IH). 3.36-3.26 (m, IH), 2.39-2.29 (m, IH). 1.98 (s. 3H), 1.81 (d. J=47.9 Hz. 3H), I.G9-144 (m. 2H). 1.40-1.18 (m, 2i I): IISI-MS m/z cele. 330 2, found 331 2 (M+I )+ Reten- tion time 0 67 minutes

Example 11

— Synthetic Scheme 11: (+/ )-4-(2-(2-methoxy-4- ioz (methylsulfonyl)phenyl)azepan-I-yl)-ti-methylpy- riinidnl-2-lnline (100) 1-88 [0659] (a) I-bmmo-2-metlxu y-4-methylsulfonyl-bwizenc, bis(pinocalatodiboron), Pd( ls(phsp)s. KOAc, dioxane. water. 85" ('; (6) (c) Pd/(2 formic acid. IitOAc, MeOIE (d) nl)ul i, 0 THF. -78'x (e) 2-latino-4-chloro-6-methylpyrimidine, NMP. 150'x (t) SFC chirai separation

Formation of 7-(2-methoxy-4-methylsulfonyl-phenyl)-2,3vb5-tetrahydroazepine-l-carbaldehyde (97)

[t)660J Step-1: 1'o a solution of I-bromo-2-methoxy-4- methylsulfonyl-benzene (I 00 g, 3.77 mnlol) m dioxane (50 97 ml,) was added bis(pinocalatodiboron) (I 44 g. 5 66 mmol), potassium acetate (1.11 g, 11.32 nmlol). The mixture was purged v, ith nitrogen for 15 minutes and added dichloro-bis (tnphcnylphosphorimyl)-palladnun (0.27 g, 0.37 nunol) was added Thc reaction was heated to 85'. for 18 hmirs. Thc

nuxture was diluted with I ltOAc and filtered through celite v ashing v;ith litOAc (60 mi,). 'the organic phase was concentrated in vacuo. 'I'he resulting dark brown solid was used without filrther purification [0661] Step-2: Thc above crude product was dissolved in 0 DME (30 mL). 7-chloro-2 3.4,5-tctrahydroazcputc-l-carbaldehyde, 73, (0 60 g, 3 77 mnlol) was added followed by v NaiICOl (6 3 ml, of 1.2 M solution. 7 54 mmol) 'lhe mixture was bubbled with nitro en. and Pd(dppf)CI, catalyst v as added. The fiask ives covered and heated at 80" ( 2 for 12 hours. The rcsiduc was punficd by slice gcl chromatography using (40 g ISCO column) 20% McOH-dlchloromedl- ane/dichloromethanc gradient. Thc dcsircd Iyactions were 99 collected and evaporated I'he fractions were collected and used for the next step directly. US 20]9/032265[] A] Och 24, 2019 145

Formation of 2-(2-methoxy-4-methylsuliimyl-phe- (400 MHz. DMSO-d6) 6 7.59-7.40 (m. 2H). 7 26 (d. J=8.0 nyl)azcpanc-I-carbaldehyde (98) Hz. IH), 5.64 (s, IH). 5.40 (br. 2H), 4.39 (brs, IH), 4.01 (s, 3H), 3 57-3.34 (m, IH). 3.17 (s. 3H), 2.48-2.29 (m, IH), [0662] To a solut&on of 7-(2-methoxy-4-mcthylsulfonyl- 2 03 311), 1.93-1.04 (m. NI I). I:SI-MS m/z cele 390.17, phenyl)-2.3,4,5-tetrahydroazepine-l-carbaldehyde. ')7, (s, found 391 0') (M+I) . I&etention t&me: 0 67 num&tes. (I (X) g, 3.23 n&mol) in MeOI I (10 ml.) and I:tOAc (10 ml,) was added acetic acid (I mL). Under an aunosphere of [0669J 1-99 Peak 13 [r&J&, (c 0.5, MeOII) +86.51; ee 99 nitrogen. 10"i8 Pd/C (10 mol %) was added. The reaction 6% nnxturc was 3 tunes with and then surrcd purgcxt hydrogen [0670J 4-[2-(2-nðoxy-4-nðylsulfonyl-phenyl)aze- under an aunosphcrc oi'ydrogen for 14 hours. LCMS pan-I-yiJ-6-methyl-pyrimidin-2-amine (102) 'l I NMR indicated poor convcrs&on &o dcsircd product. The mixture (400 MHz. DMSO-d6) 6 7.39 (d, J=1.6 Hz, IH). 7.36-7.26 was hltered through celite and the solvent was partially (m, IH), 7.16 (d. J=7.9 Hz. IH)„5.54 (s. IH). 5.30 (s. 2H), concentrated in vacua 1 he above procedure was repeated, 4.28 (brs, IH). 3.92 (s, 3H). 3.3S-3.20 (m, IH). 3.07 (s, 3H). except using fomuc ac&d to replace acetic acid. After over- 2.40-2.2G (m. IH), 1.93 (s. 3H). I 87-1 10 (m, 8H). ESI-IvIS was converted night stirring. the starting material to the nv'z caic 390.17. found 391 05 (M+I)'etent&on time dcs&r&xl product. The m&xture was Iiltcrcxl enough cchtc and 0 66 minutes. the filtrate was concm&&rated in vacuo. The rcsuhu&g res&duc was punlicxl by s&1&ca gcl cluomatography (40 g ISCO [0671J I he following analogs v ere prepared according to cohunn) eluting with I:tOAc/heptanes (0-75'%) gradient to Svnthetic Scheme 11 afford 760 mg of desired pn&duct: 'I I NMR (300 Mllz, CDCI&) 7& 8.20 (s. s. IH), 7.63-738 (m, 2H). 7.35-7.16 (m, I H), 5.41 (dd„1=12.3. 4.7 Hz, 0.6H). 5.00 (dd, 1=11.7. 5 G 10& Hz. 0.4H), 4.35 (d, J=13.7 Hz. 0.4H), 3.96 (s, 3H), 3.91-3.79 (m, 0.6H), 3.S6 (dd. J=14.9, 11.3 Hz. 0.6H), 3.06 (s, 3H), 3.01-2.S5 (m, 0.4H), 2.46 (m, IH), 2.19-1.17 (m, 7H). Yif Formation of 2-(2-methoxy-4-mcthylsulfonyl-phenyl)azepanc (99) [0663] To a solut&on of 2-(2-methoxy-4-mcthylsulfonyl- phenyl)azepane-I -carbaldehyde, 98, (0 76 g, 2 44 mn&ol) in MeOI I (20 ml,) was added I I('1(10 mi, of 12 M. 120 mn&ol). The mixture was heated at 100" C. for 4 hour~. The solvent was concentmsted in vacuo to aflord GOO mg of des&red product &hat was used w&thou& furtlmr punlicat&on: 'H NMR (+/—)-4-[2-(3-methoxy-4-pyndyl)azepan-I-yl]-6- (300 MHz. DMSO-d6) o 9.49 (br. 2H). 7.82 (d, J=8 0 Hz, methyl-pyrmudin-2-amu&c (103) 1-80 IH). 7.65-7 48 (m, 2H), 4.59 (1, J=9.2 Hz, IH). 3.97 (s, 3H), ' 3 27 (s, 311). 3 19-3 ()8 (n&, 211). 2 34-1 51 (n&. NI I); l&SI-MS [0672J I NMR (4(X) Ml is, l)MSO-db) &5 8 57 (d, .I 5 9 ngz cele 283 12, found 284 27 (M+I) . Retention time I Iz. II I), 8 34 (d, .I 5 3 I lz. II I), 7 62 (s, 211), 7 36 (d, .I 5 3 0.5(i minutes. Hz. I H), (i.52 (s, IH), 5. (i9 (n&. IH), 4.06 (s. 3H). 3.78-3.37 (m, 2H). 2.28 (s. 3H), 2.03-1.14 (m„8H); ESI-MS m/z calc. Formation of (+/-)-4-[2-(2-methoxy-4-methylsulfo- 313 19, I'ound 314.14 (M+I) . Retenuon tune O.S6 m&nutcs. nyl-phenyl)azepan-I-yl]-6-methyl-pyrimidin-2- am&nc (100) I-SS [0664J 'Io a m&xture of solids 4-chk&ro-6-methyl-pyrim&- din-2-an&ine (0.10 8, 0 6N n&mol) and 2-(2-metlx&xy-4-methylsulfonyl-phenyl)azepane-HCI, 99. (0.25 g, 0.78 nunol) in Yif a vial was added EtOH (2 mL). The vial was pLaced on the hot plate and heated at 170'. w&Q&out cover fbr 2 hours. Thc crude solid was puriiicd by silica cl cluomatography (40 IS('0column)eluting with 20i MeOII-dichloromethane&dichloromethane to affhrd 182 mg of desired product 'l l NMR (3(X) Mi lz, DMSO-dG) &5 7.59-7.38 (m, 211), 7 22 (s, I H), (i.06-5.23 (m„3H). 4.82 (brs. IH). 4.00 (s. 3H). 3.31 (brs, 2H), 3.22 (s, 3H), 1.94 (s. 3H). 1.87-1.01 (m. SH), ESI-MS n&/z cele. 390.17, found 391.09 (M+I) . Retention (+/— )-4-(2-(2-methoxypyridin-3-yl)azepan-I-yl)-6- nme. 0.66 nunutcs. methylpyrimidin-2-amine 1-18 [0665] The racemic mixture (182 mg) was submitted for SFC clgral separation. [0673] 'H NMR (400 MHz. DMSO-d6) o 8.00 (dd, J=4.9, [0666] SFC cond&uons. Colunm. AD-H, 4.6x100 nun 1.8 Hz, IH). 734 (dd. J=7.2, 1.6 Hz. IH)„6.8G (dd. J=7.3, Al)-II, 10x250 mm; Mob&le phase: 4()% EtOII (5 n&M 4.9 Hz, I H). 5.61 (s, IH). 5.36 (s. 2H), S.19 (s, I H). 432 (s, An&monia), 6()% ('02 I H), 3 96 (s, 3H), 3.37-3.28 (m. IH), 2.96 (s. 5H), 245-2.35 [0667] 1-98 Peak A: [o]o (c=0.5. MeOH) —7239; ee=99% (m, IH), 2.00 (s, 3H), I.SS (s. IH), 1.75 (s. 2H), 1.70-144 [0668J 4-[2-(2-methoxy-4-nðylsulf&oayl-phenyl)aze- (m, 311), 1.41-1.20 (m. 211): I ISI-MS nv'z cele 313.2. found pan-I-ylJ-6-methyl-pyrinudin-2-amine (101) 'I I NMR 314 2 (M+I) Retention time 0 61 minutes US 20 ] 9/032265 [] A[ Oct. 24, 2019 146

Example 12 v et Pd/C (0.79 g, 0.37 nunol) in ethyl acetate (25 mL) and MeOH (25 mL) was shaken overnight under 55 pci of Synthetic Scheme 12 (+/-)-4-(2-(2-ethylphenyl) hydrogen 'I'be reaction mixture was filtered thmugh ( elite azepan-I-yl)-G-methylpyrimidin-2-amine (107) 1-45 and the filter pad was rinsed with I:tOAc 'I'he filtrate was [06'74] dncd over magnesium sulfate, Iiltcred. aud couccntratcd in vacuo lo give 1.47 g light yellow oil. 'H NMR (400 MHz, DMSO-d6) 6 8.06 (d, J=55.7 Hz. IH), 7.22-7.05 (m, 4H), 5.04 (ddd, 1=106.0. 12.0, 4.9 iqz, IH), 4.13-4.00 (m. 0.5H), 3 90-3.78 (in. 11 I), 3 63-3 50 (ni. 111). 3 25-3 15 (rn. 0.511), 2 84-2.63 (m, 211), 2 22-1 66 (m. 511). I 49-1 11 (m, 611); ESI-MS miz cele. 231.2, found 232.0 (M+I) . Rctcnlion time: 1.03 minutes. Formation of (+/-)-2-(2-ethyiphenyl)azepane (IOG) Cx [0677] A solution oi'-(2-ethylphcnyl)azepanc-I-carbal- los dehyde, 105. (1.47 g, 6.35 mmoi) in MeOH (5 ml ) and concentrated HCI (3 mL of 12.1 M solution. 60 50 nunol) v as rethixed overnight The resulting mixture was concentrated to dryness, dissolved in minimal MeOI I and dropped into cold diethyl clhcr wlnle slirnng vigorously Thc rcsuh- ing white precipitate was filtered and dried to Lave 1.15 o of the desired product as an II('I salt 'H NMR (3(X) MHz, DMSO-d6) 6 9.72 (s. I H), 9.2(i (s. I H). 7 76-7 61 (m. IH), l (iS 7.41-7.18 (m, 3H). 4.43 (d, J=10.6 Hz„ IH). 3.42-3.02 (m, 2H), 2.72 (ikih J=19.3, 14.6. 7.3 Hz, 2H), 2 33-1 45 (m, 6H), 1.16 (I, J=7.5 Hz, 3H), ESI-MS nt/z cele. 203.2, found 204.0

(M+I) . Rctcnlion lime. 0.67 minutes

Yif — Fonnatron of (+/ )-4-(2-(2-cthylphcnyl)azcqtan-I- yl)-6-mclhylpynnudin-2-aminc (107) I-4S [0678] A mixture oi'-(2-cthylphmiyl)azcpanc-HCI, 106. (0.1 S g, 0.63 mmol), 4-citloro-6-methyl-pynuudin-2-anunc (0.09 g, O.G3 numil) and lnclhylaminc (0.17 mL, I 25 nunul) in NMP (2 mi ) ives stirred for S hours in a sealed tube at i it 7 150" ('I'he crude reaction mixture was purified by reverse phase silica gel cluomatography by in)ecting directly onto a 50 C18 aqueous ISCO column and elutlng with 5-50% (a) (2-clhylphcnyl)bororuc acid. PdCIs(dppi'), NaHCO... g McCN in water with 0.1% TFA Pure fractions were com- DMF, water, 85'., (b) Pd/C. I'ormic acid, ElOAc, McOH, bined, neutralized with saluralixl sodium bicarbonale, and (c) n)3uLt. THF, — 78'., (d) 2-anuno-4-chloro-6-mctltyl- extracted with EIOAc. Thc orgaiuc was over pyrimidine. NMP. 150" C: (e) )I'('hiral separation layer dned magnesium sulfate, hltered, concentrated in vacuo and Fomiation oi'-(2-cthylphcnyl)-2,3.4.5-telrahydro- lyophilized to afford 45 mg of desired product: 'l I NMR HI-azepine-I-carbaldehyde (104) (400 MHz. DMSO-d6) 8 7.18 (d, J=7.5 Hz, IH). 7.15-7.09 [0675] A mixture of 7-chloro-2.3,4,5-tetrahydroazeplne- (m, I H). 7.09-7.04 (m, 2H), 5.67 (s, I H), 5 54 (s. 2H). 5.27 1=14.8 3.54-3.40 2.88- I-carbaldehyde, 73. (I 5 g, 9 4 mmol). (2-ethylphenyl)bo- (s, IH). 453 (d. Hz„ IH). (m, IH). 2.69 2.16 (ddd, J=14.2, 8.2, 5.1 Hz, 2.01 ronic acid (1.4 g, 9.4 nunol). and PdCls(dppi) (0.4 g. 0 5 (m. 2H), IH), (s. nuuol) ui DMF (30 mL) and aqueous sauiralcd NaHCO, 3H), 1.96-1.67 (m, 3H). 1.52 (q, J=12.9, 12.4 Hz, IH). solution (10 mL) was heated with microwave irrarliation al I 4(at 33 (m, 211), I 33-1 24 (m. 411); I:SI-MS m/z calc 80" C. for 30 minutes 'I'he mixture was filtered over Celite, 310 2, found 311 0 (M+I)+ Retention time 0 84 mimites diluted with I:tOAc. and washed with water 'I'he organic [0679] The follovving analog was prepared according to layer was dried over magnesium sulfate. filtered and con- Synthetic Scheme 12: centrated in vacuo. The resulting residue was purified via silica gel ciuomatography eluting with 0-50% EtOAc/heptane. Pure fractions werc combuicd anil concmitratcd to ' afihrd 1.68 g of dcstrcxt product as a colorless oil. NMR (400 Mi is. ('IJCI,) i) 7 94 (s, 111), 7.29 (ddd, .I 7.7, 6.3, 2 2 Ilr,. IH). 7 23-7 14 (nt. 311). 5 39 (t, .I 5.7 Ilz. I II), 3 96- 3.87 (m, 2H). 2.57 (q. J=7 5 Hz. 2H). 239-2.32 (m. 2H), 1.92 (tt. J=6.2, 5.2 Hz. 2H). I 84-1.74 (m, 2H). 1.20 (t. J=7 6 Hz, 3H): ESI-MS m/z calc. 229.1. found 230.0 (M+I) . Rclenuon tines I 05 mimites.

Iiormation of (+/— )-2-(2-ethylphenyl)azepane-I- carbaldehyde (105) [0676] A mixture of 7-(2-ethylphenyl)-2„3,4.5-tetrahydro- Iil-azepine-I-carbaldehyde. 104, (I (ig o, 7.33 nunol) and US 20 1 9/032265 [J A[ Och 24, 2019 147

3-(I-(2-amino-6-methylpyrimidin-4-yl)azepan-2-yl)- Fomtation of 3-chloro-6,7-dihydro-1,4-oxazepine-4 4-fiuoro-N-mcthylbcnzanudc (108) I-5S (5H)-carbaldchyde (109) [06801 'H NMR (400 MHz, DMSO-d6) 6 8.14-8.06 (m, [0682[ Intermediate. 109. &&as prepared accordin to Syn- 1=8.5. 7.Ci2 J=7 IH). 7.71 (ddd. 5.0. 2.3 Hz. IH), (dd, 4, 2 3 theuc Schcmc 9 usmg 1,4-oxazcpan-3-onc &mtcad of aze- Hz. I H). 7.19-7.13 (m, I H), 5.80 (s, IH), 5.68 (s, 2H). S.41 pan-2-onc. (d. J=35.0 Hz, IH), 4.2S (m, IH). 3.49-3.42 (m, I H). 2.76 (d, 1 4.5 I lz, 311). 2 32 (dt, .I 14 3, 7.1 I lz, I I I). 2.0C& (s. 311), liom&ation of 3-(2-chloro-5-hydroxyphenyl)-Cx7- I 95-1 69 (m, 411). I 55 (p..l 11 5 I lz, ll I), ] 45-1 22 (nt, dihydro-1,4-oxazepine-4(511)-carbaldehyde (110) 211): I i)I-MS m/z cele 357 2, fi&und 358 0 (M+I)+ Reten- tion tinte: 0 CI7 minutes. [0683J Charged a 2-necked rb fiask under mtrogen &vith 3-chloro-6,7-dihydm-51 I-I.4-oxazepine-4-carbaldehyde, Example 13 109. (046 g, 2.80 num&l), NaHCO, (G.O mL of 1.2 M Synthetic Scheme 13: (+/ — )-3-[4-(2-amino-6- solution. 7.2 mmol) and (2-chloro-5-hydroxy-phenyl)bo- ntethyl-pyrimidin-4-yl)-1,4-oxazepnn-3-yl[-4- rontc acxl (O.SO g, 2.90 nunol) ut dtmcthoxycthaue (10 mL). chloro-phenol (112) 1-147 Thm& bis(tnphcnyl-phosplune)palladnun(II)clfioridc (0.10 g. [(1681J 0.14 nunol) was added thc reaction mixture was heated overnight at C&0''I'he mixture &vas diluted into water and dichloromethane 'I'he layers v ere separated through a phase OH separator and the organics concentrated tn vacuo afier a second extraction. Purification by sihca gel chromatography (40 g GOLD column, 10-100% EtOAc/hop(anus gmdient) " aifordcd 650 mg of dcsircd product: 'H NMR (300 MHz, CDCI&) 6 7.93 (s, IH), 7.28 (s, OH). 7.20 (d, J=8 4 Hz, IH), 681 (d,.l 2 711z, 111). 6 13 (s, 111), 425 (t,.l 5 8 llz, 211), (7~ 4 11 (t, .I C& 3 I lz. 311). 2 15 (6 1 6 2 I iz. 211); I!Si MS m/z C. cele. 253.05, found 252.29 (M+I)'. Retention time: 0.55 1OS nunntes. tlu OH Fomtation of (+/ — )-4-chloro-3-(1.4-oxazcpan-3-yl) phenol (ill)

[06841 To a cold ( — 78'.) soluuou ol'-(2-chloro-S- hydroxy-phenyl)-6,7-dfitydro-5H-1,4-oxazcpinc-4-carbaldehyde, 110. (0 65 g, 1.55 n&mol) in 'll II'10 ml.) was added n-butyllithiuin (3 ml, of 1.(& M solution, 4 80 mmol) 'lhe mixture &vas stirred at tlus temp for 50 minutes. The reaction (. mixture was quenched carefully by addition of methanol. 111 More MeOH (30 mL) was added and the solution was H&b ~ warmed to room temperature. Thc rcsultutg solution was OH Yl used directly for the next step: ESI-MS n&/z cele 225.0G, .1 found 226 08 (M+I) . Retention time: 0 54 num&tea. [06851 To the abo&e soluuon was added NaBHs (0.09 g. 238 nuuol). The mn«urc was surred at room tcmperaturc overnight 'I'he reaction was quenched by the addition of 'I MeOI I and then 2N I I('I solution he acidic solution was then basified v,ith 6N NaOH and the aqueous phase was (. extracted with EtO/kc three times. The combined organic pl&sacs w&th fiitercdI 112 were washed bnne, duad over MgSOw HH 8 HH 8 and cvaporatixb The crude product (300 mg, 77%) was "" obtautcd and us&xi directly; ESI-MS m/z cele. 227.07. found Yi Yi 228 09 (M+I) . Retention time: 0.54 minutes 8 Formauon of (+/-)-3-(4-(2-auuno-6-uðylpyrinu- dtn-4-yl)-1,4-oxazepm&-3-yl)-4-chlorophcnol (112) 1-147

[0686J I o a mixture of solids 4-chloro-6-nðyl-pyriini- din-2-amine (030 g. 2 04 mmol) and 4-chion&-3-(1,4-ox- 111. a vial was 114 azepan-3-y))phono), (1.43 g, 2.22 mmol) in added EtOH (2 mL). The vial was placed on the hot plate and heated at I GO'. without cover for 2 hours. Thc crude (a) 2.5-dunethoxyPhcnylborotuc acid, Pd(Ph&P)&CI&, DME, sohd was purilicd by silma gel colunm (40 g) ut ISCO 50'., (b) nBuLi. THF, -78'., (c) NaBHw MoOH. (d) eluung with 20% McOH-DCM/DCM gradmnt (0% B to 2-an&ino-4-chloro-6-methylpynmidine, IitOI I. 160" C; (e) 50% l3) to atford 192 mg of desired product 'I I NMR (300 Sli('himl separation MI Iz, l&MSO-d6) 6 9 80 (s. 111), 7 72 (brs, 111), 7.48-7.18 US 20]9/0322658 A[ Oct. 24, 2019 148

(m, 2H)„6.90-(i.54 (m„2.5H). 5.93 (br, 0.5H). 5.59 (s. 0.5H), -coli I lli I I ixl 5.26-5.07 (m, 0.5H), 4.99 (m. 0.5H), 4.43-4.04 (m. 1.5H), 117 3.86 (m. 3H), 3.62 (I, J=10.2 Hz, I H). 2.18 (s. 3H), 1.84 (m, 2il): iiSI-MS m/7 cate 33412. found 335.10 (M+I)'. Retention time 0 6 mimites. The racemic mixture (180 mg) ives Yif submitted to clural SFC puritication to obtain the individual enantiomers. SFC conditions: Column: Cellu- lose-2, 20x230 tmn, Mobile phase: 30% EtOH (5 mM Ammonia), 70% CO„Flow. 80 mL/min, Concentrations — 18 mg/mL (McSJH), Iniccuon Volume: 2SO pL. Wave- length 220 nm (. (1-1679) Peak A 96 8% ee [a]i, (c 0 5, MeOII) — 85 10 [0687] (R)-3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1.4- oxazepan 'H NMR(300 MHz, 3yl]4chlorophenol (113); (+/-)-4-(3-(2-chloro-5-methoxyphenyl)-1.4-oxaze- DMSO-d6) 6 9.73 (s. IH), 7.25 (d, J=8.6 Hz, I H). 6.75-6.60 pan-4-yl)-6-methylpyrimidin-2-mninc (115) 1-118 (m, 2H), 640 (s. 2H). S.OI (s, IH), 4.68-4.54 (m. IH). 4.12 (br, IH), 3.99-3.86 (m, 2H), 3.83-3.48 (m. 3H). 2.04 (brs, [0691] The racemic mixture 115 was submitted to chiral 3i I). 1.767 (m. 211): 118 I-MS nv'7 cele. 334 12, tiiund 335.11 SFC purification to obtain the individual enantiomers. (M+I) . Itetentton time 0 61 mimites [0692] SFC conditions: (:olumn: AD-H, 20x250 mm; (1-170) Peak H ')5 4% ee [o]i, (c 0 5, MeOI I) +79 40 Mobile phase: 30% IPA (3 mM Atmnonia)„70% CO,; Flovv: [06881 (S)-3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1.4- 7 S mL,'min, Conccntrauons: — 75 mg/mL (McOH): 'H Ini ection oxazepan-3-yl]-4-chloro-phenol (114): NMR (300 MHz, Volume 500 PL, Wavelength: 214 nm. 9.7S 7.2S J=8.5 6.79-6.63 DMSO-d6) 8 (s, IH), (d. Hz. IH), [0693] Peak A: v:hite solid, ce 99.4%, [o]o (c=O.S, 6.57 5.34 0.5H). S.OI (m, 2H). (s. I.SH), (brs, (brs, IH), MeOI I) — 67 96 (lt)-4-[3-(2-chloro-5-methoxy-phenyl)-1.4- 4 71-4 53 (m. 111), 4.13 (br. 111). 3 91 (m„211). 383-348 oxazepan-4-yl]-6-methyl-pyrimidin-2-atnine (116) 'I I (m, 311). 2 06 (br. 311), I 77 (m, 211); I'Sl-MS m/z calc. NMR (300 MI Iz. I JMSO-d6) 6 7 94 (s 111), 7 5&) (s, li I), 334 12. tiiund 335 10 (M+I)+ Retention tiine 0.63 minutes. 7.52-7.16 (m. IH). 7.09-6.88 (m, IH). 6.86-6.75 (m. IH), [0689] The following analo s were prepared accordin to 6.58 (s. 0.5H). 5.95 (br. 0.5H), 5.(i0 (s„0.5H). 5 17 (s, 0.5H), Synthetic Scheme 13: 4.99 (br, 0.5H), 4.22 (m, IH). 4.17-4.03 (m, O.SH). 3.88 (m. 2H), 3.75 (s, 3H), 3.61 (m, 2H), 2.23 (s, s, 3H), 1.84 (br. 2H). I:SI-MS m/z cele. 348 13, found 349.15 (M+ I) Retention 115 time: 0.64 minutes. 1-137

[0694J Peak I I: white solid, ee 99 2%, [uJo (c 0 5, MeOH) +60.08 (S)-4-[3-(2-chloro-5-methoxy-phenyl)-1.4- Yif oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (117) 'H NMR (300 hIHz, DMSO-d6) 6 7.39 (d, J=8.5 Hz. IH), 6.91 (dd, J=8.7, 3 0 Hz, IH), 6.75 (i. J=2.3 Hz, IH), 6.27 (s. 2H), 4.32 (s, IH), 4.11 (d, J=13.3 Hz, IH). 3.92 (d. J=11.8 Hc IH), 3 85-3.176 (in. 511). 3 57 (d..i 12 3 Iiz. 111). 3.25 (d..i 43 7 I lz. 111), 2.05 (s, 3il). 1.77 (s, 211); IISI-MS m/7 cate (. 348 14. foiuid 349.15 (M+I)'. Retention time 0.64 mimites. 1-138.

(+/— )-4-(3-(2-clfioro-5-methoxyphmiyl)-1,4-oxazcpan-4-yl)-ti-niethylpyrimidin-2-amine (]15) 1-118 11S [0690] 'H NMR (300 MHz, DMSO-d6) 6 7.9S (brs. IH), 7.59 (s. IH), 7 43 (dd. J=24.4, 8.7 Hz, IH), 7.07-6.88 (m, I H). 6.84-6.72 (m, I H). 6.07-S 47 (m. I H). 5.09 (dd, J=58 8, Yif 11.2 I lz„ I I I), 4 38-4 05 (m, 211), 4 01-3 48 (m. 71i), 2 2'7 (s, 3i I). 1.84 (br. 211) 11SI-MS m/7 cele. 348 13, tiiund 34'J.l I (M+I) . Retention time: 0.67 minute~.

116 (.

Yif (+/— )-4-[3-(2.5-dimethoxyphenyl)-1,4-oxazepan-4- yl]-ti-methyl-pyrimidin-2-amine (118) 1-93

[0695] 'H NMR (300 MHz. DMSO-d6) 8 7.61-7.24 (br, 2H), 7.10-6.77 (m, 2H), 6.77-642 (br, IH), S 84 (br. IH), 5.04 (br, IH), 4.22 (br. IH), 4.00-3.44 (m. 12H), 2.34-1.62 (.) (m, 311), I 75 (br, 211): I'SI-MS m/7 cele 344 18, found 345 06 (M+I)+. Retention time: 0.65 minutes US 20[9/032265[] A[ Och 24, 2019 149

cottlttttlixl l la Yif Yif (. isa Yif (. lzz 123 [0696] The racemic mtxturc was submiucd to clnral SFC punlicatton lo obtatn thc utdtvtdual cnanliomcrs. SFC conditions: ('olumn: Al)-II, 10x250 mm; Mobile phase: 30% (a) 4-cltioro-6-methyl-pyrmudin-2-anunc. EtOH, 160'.. SizC chiral purification EtOII (5 mM Ammonia), 70% (Oz. I'loxv 15 ml./ntin, (6) ('oncentrations; -40 mg/mL (MeOH): Injection Volume 100 uL; Wavelengtlx 214 nm. Formation of (+z — )-t-[3-(2-chlorophenyl)-1,4-ox- [0697] Peak A. whttc solal, ce 97.6%, [u]o (cW 5, azepan-4-yl]-Ci-methyl-pyrimidin-2-amine (121) McOH) — 96.56 (R)-4-[3-(2,5-thmcthoxyphcnyl)-1,4-oxazc- 1-19 p;m-4-yl]-6-methyl-pyrimalin-2-anunc (119). 'H NMR (400 [0700] To a mixture of solids 4-chlom-6-methyl-pyrimi- Ml lz,. l)MSO-d6) 6 6 99 (d, .I 8.9 I lz. 111), C& 84 (dd, .I 8 t), din-2-mnine (0.45 g, 3.07 nunol) and 3-(2-chlorophenyl)-1, 3 I I lz 111) 6.69 (s, 111). 6 24 (s. 311), 5 8] (s, 211). 5 46 (s, 4-oxazepane (0.(i5 3.07 nunol) in a vial v as added EtOH IH), 4.(i7 (s. IH). 4 18 (dd. J=I3.1, 5.2 Hz. IH). 3.94 (d, g, (9 mL). Thc vtal was placed on lhc hot plate and heated al 1=12.5 Hz, 211). 3.85 (s. IH), 3.77-3.66 (m. 7H), 3.(i0-3.48 160o C without cover for 2 hours. The crude solid was (m, 2H). 2.11 (s, 2H), 1.89-1.70 (m, 3H), ESI-MS m'z cele. pxmfied silica chromatogmphy m IS('0 eluting 344.18, lbund 34S.06 (M+I) Retention time. 0.65 minutes. by gel (40 g) with 20% MeOII-dichloromethane/dichlorontethane. The 1-100. destred fractions were collected and concentrated m vacua [0698] Peak B: white solid, ee 9x) Ci%; [rx]o (c 0 5, The mcemic mixnlre was submitted to chiral SFC purifica- Me()I I) +98.16: (S)-4-[3-(2,5-dimethoxyphenyl)-1.4-oxaze- tion to obtain the individual enantiomers. SFC conditions: pan-4-yl]-(i-methyl-pyrimldin-2-amine (120); 'H NMR Colunuu Ccllulosc-2, 20x250 nun, Mobile phase: 40% (400 MHz. DMSO-d6) b G.95 (d, J=8.9 Hz. IH). (i.79 (dd, EIOH (5 mM Anunorua). 60!o CO„Flow. 80 mL,'ntttt. 1=8.9. 3.1 Hz„ IH). 6.64 (d. J=3.1 Hz, IH). 5.68 (s. 2H). 5.64 ('oncentrations -30 ntg'ml (MeOI I); Wavelength 254 nm; (s, IH). 507 (s, IH), 4.65 (d, J=14.8 Hz, IH), 4.15 (dd, Method Type Isocratic J=13.3. 5.2 Hz, JH), 3.98-3.87 (m, JH), 3.82 (s, 3H), 97'!o — 3 71-3 58 (m. 211). 3 C&5 (s, 311), 3.50 (td, .I i1.5. 4 0 I lz, [0701] Peak A: cc. [xx]o (c=1.0, McOH) 16.26. ill), 2 02 (s, 311). I 75 (m, 2ii) I'SI-MS m/z calc 344 18, [0702] (R)-4-[3-(2-chlorophenyl)-1,4-oxazepan-4-yl]-6- found 345.1 (M+I)'. Retention time: 0.65 minutes. 1-101. methyl-pyrinudin-2-annnc (122): 'H NMR (300 MHz. DMSO-d6) 6 7.48 (dd. J=6.2. 3.1 Hz, JH), 7.32 (m. 3H). Example 14 6.S8 (br, 2H), 4.61 (br, 0.5H), 4.15 (br, I H), 3 93 (br, IH). 3 84-3.69 3.66-3.53 3 44 2.09 Synlheuc Schcmc 14. (+/ — )-4-[3-(2-chlorophenyl)- (m, 211), (m, 111), (m, 0 511), 1.4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (s, 311), I 78 (br, 211):

(121) J-19 ESI-MS m'z cole. 318.12, found 319.13 (M+I) . Rctcnlton time 0 C&4 minutes. 1-30. [0699] [0703] Peak Jk 89'! ec. [u] (c=1.0, MeOH) +39.92. ]0704] (S)-4-[3-(2-chlorophenyl)-1.4-oxazepan-4-yl]-6- methyl-pyrimidin-2-anline (123) 'H NMR (300 MHz, DMSO-d6) 6 7.83-7.23 (m, 6H), 6.59 (s, 0.5H), 6.00 (brs, 0.5H). 5.59 (s, 0.5H), 5.24 (brs, 0.5H), 4 98 (br. O.SH), 4.58 (br, 0 5H), 4.04 (m. 4H), 3.61 (td, J=11.3, 3.9 Hz, IH), 2.22 (br, SH), 1.84 (s. 21 1) (. ESI-MS m/z cele. 318 12, found 31'3 13 (M+I) Retention time 0 C&4 minutes. 1-31. US 20]9/032265[] A[ Oct. 24, 2019 150

[0705] The following analo s were prepared accordin to -conthulixl Svnthctic Schcmc 14. 124 H 8

(+/—)-4-[3-(2-chloro-5-pyrrolidin-l-yl-phenyl)-1.4- oxazcpan-4-yl]-6-methyl-pynmidut-2-amitm (124) 1-199 [0706] 'H NMR (300 MHz, Methanol-d4) 6 7.16 (d. J=8 8 Hz. IH). 646 (dd, J=8.8. 2.9 Hz, IH), 6.35 (d. J=2.9 Hz, 111), 5.52 (hrs, ill), 5 20 (hr, II I), 4 28 (dd, .I 13 6, 4 ') Ilz, ill), 4 03 (dd, .I 12 4, 4 8 I is, 111). 3 80 3 50 (m. 3H), 330-3.04 (m, 5H). 2.05 (s. 3H), 2.02-1.94 (m. 4H), 1.91-1. 64 (m, 2H): ESI-MS m/z calc. 387.2. found 38833 (M+I) . Retention time: 0.71 minutes. XH Q

01 (+/-)-4-(3-(2-chloro-5-morpholinophenyi)-1.4-ox- 12'2 azepan-4-yl)-6-methylpyrimidin-2-maine 1-226

[0707] 'I I NMlt (300 Mi lz, Metlmnol-d4) i) 7 29 (dd, 1=18.3, 8.8 Hz. 2H). 6.91 (ddd, J=16.6. 8.9. 2.9 Hz. IH), 6.78 (dd. 1=26 7„3.0 Hz. 0.5H), 6.48 (s. IH). 6.10 (dd, J=9.5. 5.1 Hz, O.SH). S.68 (s. IH), S.39-S.10 (m. 2H), 4.42-4.17 (m, IH), 4.09-3.S9 (m, 11H), 3.09 (1. J=4.9 Hz, 6H). 2.28 (dd, J=40.8, 0 8 Hz, 5H), 2.09-1.84 (m, 4H), ESI-MS mtz cele 403 18, found 404 21 (M+ I 0 Itetention time 0.62 minutes 0 Iixample 15

Synthetic Scheme 15 (+/— )-4-[3-[2-chloro-5-(meth 121 yltunino)phenylJ-1,4-oxazepan-4-ylJ-6-methyl-pyrimidin-2-amine (129) 1-175 H.N [0708]

0 CI

129 US 20[9/032265[] A[ Ock 24, 2019 151

(a) NaH„DMF, 0" Cq (b) bis(pinocalatodiboron). Pd(Pb.,P) ture overnight. The mixnire &&as diluted into water and ,Cls. KOAC. dioxanc, 85'x (c) nBuLi. THF, -78'.. (d) extracted twice with E(OAc. Thc comb&ncd oigaruc plmscs 2-anuno-4-chloro-6-methyl pynnudmc. McOH, 125'G (c) werc dnixl (MSSOI). E)tercx) and concentrated in vacuo to 'I'I 'A. ('l I-('I, atford 200 mg of desired pmduct that was used ivithout further purification: I:SI-MS miz cele. 340 I, found 341 2 Iiormation of tert-butyl (M+I)'. Retention time; 0.(i4 minutes. (3-bromo-4-chlorophenyl)(methyl)carbamate (125)

— [0709] To a solution of ten-butyl N-(3-bromo-4-chloro- Formation of (+/ )-tert-butyl (3-(4-(2-amino-6- mcthylpyiimidu&-4-yl)-1,4-oxazcpan-3-yl)-4-chlorophenyl)carbamate (2.00 g, 6.20 mmol) ui DMF (20 mL) was phcnyl)(methyl)carbamate (128) added NaH (030 g, 7.50 nunol) at O'. Thc nuxture was stirred 0" ( for 30 minutes Methyl iodide ml . 7 55 (047 [0713] A mixture of 4-chloro-6-methyl-pyrimidin-2- nimol) was added to the reaction inixnire. 'I'he reaction anune (0.08 g, 0.54 mmol) and tert-butyl N-[4-chloro-3-(1. mixture was diluted into water and extracted with EtOAc. 4-oxazcpan-3-yl)phenyl]-N-methyl-carbamate, 127, (0.30 g. w as concen- The organic phase dried (MSSOI). filtered and 0 77 mmol) was mixed in a small amount of metlmnol. 'I he trated in iacuo to aflbrd 1.5 ol desired product. 'H grams resulting suspension ives heated at 125" (2 in an open flask NMR MHz. 6 7.55 J=2.5 Hz, 7.40 (300 CDCII) (d, IH), (d, for 16 hours so as to allow solvent to evaporate 'lhe J=8.7 Hz, 7.24-7.12 3.25 1.48 IH), (m, IH), (1, 3H). (s, 9H), resultin soiid was dissolved in MeOH and purified by silica I:SI-MS m'z calc 3190. found 3200 (M+I) . Retention gel chromatography (40 ISCO colunm) eluting with 20% 1.06 g tinie mimites. McOH-d&chloromethanc/dichloromcthanc. Thc desircx) I)ac- tions werc co)lectcd and evaporated to alford 220 mg of I&ormation of terr-butyl (4-chion&-3-(4-forinyl-4,5.6. dcsirixl product: 'H NMR (300 MHz, DMSO-d6) b 745 7-tetrahydm-l.4-oxazepin-3-yl)phenyl)-(methyl) (d, .I 8 5 I lz, 111), 725 (d..l 8 7 I Iz, 111). 7 16 (8 111), 6&)5 (br, carbamate (12G) 211), 6 46 (br, I I I), 5 95 (br. 111). 5 11 (br, 111). 4 15 (br. 21 I), [t)71U] Step-1'I'o a solution of tert-butyl N-(3-bromo-4- 4.02-3.70 (m. 3H). 3.57 (td, 1=11.4. 4.0 Hz, IH). 3.15 (s, chloro-phenyl)-N-methyl-carbamate. 125, (I 5 a, 4 7 nunol) 3H). 2.15 (br. 3H), 1.80 (ni. 21J). 1.28 (s, 9H); ESI-MS n&/z in dioxane (75 ml ) was added bis(pinocalatodiboron) (1.5 g, cele. 447.2, fi&und 448.1 (M+I) . Re(cut&on umc: O.G8 5.9 num&1). potassium acetate (1.4 g. 14.0 nunol). To tlus lnlilutes. mixture ivas purged with nitrogen for 15 minutes and added dichloro-bis(triphcnylphosphormiyl)palled&um (03 g. 05 Iiormation of (+/ — )-4-[3-[2-chloro-5-(methylamine) mmol). Thc reaction was heated to 85'. for 18 hours The phenylJ-1,4-oxazepan-4-ylJ-G-niethyl-pynniidin-2- reaction mixture was diluted with EtOAc and tiltered amine (129) through celite with I:tOAc wash (60 ml,) 'Ihe organic phases were concentrated in vacuo 'the resulting dark [l)714J lo a solution of terr-butyl N-[3-[4-(2-amino-6- brown solid i&as used v ithout further purification: ESI-MS methyl-pyrimidin-4-yl)-),4-oxazepan-3-yl]-4-chioro-phe- n&/z cele. 3(i7.2. found 3(i7.6 (M+I) . Retention time: I 0 nyl]-N-methyl-carbamate, 128. (0.25 g. 0.53 mmol) in nilllu(Cs. dichloromethane (10 mL) was added trdluoroacetic acid [0711J Step-2 I'o the above crude product dissolved in (0.74 g, 6.49 mmol). The mixture v as stirred at room DMI! (45 ml.) was added j-chloro-6,7-dihydro-511-1.4- tcmpcrature fi&r 12 lx&urs and the solvmit evaporated in oxazepine-4-carbaldehyde. 109. (0.76 g, 4.70 mmol) fol- vacuo Thc rcsulung residue was puniiixl by rcvcrsc ISCO lowed aqueous NaHCO& mL of 1.2 M, 9.60 nmtol). eluting with 0.1% Tl'A-acetonile&0 1% 'll'A-water to afford by (8 'I Thc nuxturc was bubbled w&th iutrogen and PdC11(dppf) 183 mg of desired product I NMR (300 Ml lz, DMSOdfi) was added to thc rcacuon m&xturc. The flask wils covcii'.d 8 7.82 (s. IH), 7.49 (s. IH). 7.17 (dd, J=19.2. 8 6 Hz. IH), and heated at 80' fi&r 12 hrs 'I'he mixture was concen- 6.73-634 (m. 2H), 5.93 (dd, J=10.1, 5 4 Hz. OH), 5.16-5.07 trated in vacuo and purified by silica gel chromatography (m, OH). 5,0(u4,90 (ni. IOIJ). 4.35-4.05 (m. I H). 4.00-3.47 (40 u IS('0 column eluting with 20 i MeOI I/dichlorometh- (m, 3H), 2.62 (d. J=1.9 Hz, 3H), 2.23 (d, J=35.1 Hz, 2H). ane. The desired fmctions were collected and concentmted 1.94-1.67 (m. 2H); ESI-MS m/z cele. 347.2. I'ound 348.2 in vacuo to afford 500 mg of desired product: ESI-MS nt/z (M+I) Retention time 057 minutes 1-175 cole. 366.1. found 367.1 (M+I) . Retention time. 0.92 [0715] SFC dural separation aiforded indiv&dual n&11&utes. enact&omcrs. Column. Cellulose-2, 20x250 nun Mobile pl&ass: 30% MeOII (5 mM Amnionia), 70% ('02; I low: 80 Fonntltli&11 oi (+/— )-teit-bifivl (4-chlo10-3-(1,4-ox- ml,/min. Concentrations -40 mg/ml (MeOI I) Injection azepan-3-yl)phenyl)(methyl)carbamate (127) Volunie 250 pl, )Vavelength 220 nm; Method Type Iso- cratic [0712] To a solution of tert-butyl N-[4-chloro-3-(4- formyl-6.7-dihydro-5H-1,4-oxazepin-3-yl)phenyl]-N- [l)716J Peak A: ee 97% [ii]i, (c 0 5, MeOI I) — 296.96 'I'I 1-312 methyl-carbamate, 126, (0 40 g, I 09 minol) in II& (10 ml,) was added ni3ul i (2.1 ml, of I 6 M solution„33 nunolj at [l)717J 4-[3-[2-ch)om-5-(methylamine)phenyl]-),4-ox- -78'. The reaction mixture was stirred at -78" C. for 50 azepan-4-yl[-6-methyl-pyrimidm-2-amine (38.5 mg. 47%) minutes. To this mixture v as carefully added MeOH to I H NMR (300 MHz, Methanol-d4) 8 5. 64 (d, J=8.7 Hz. I H), quench the react&on. Addiuonal McOH (30 mL) was added 5.05-4.96 (m, 2H), 4.89 (d. J=2.8 Hz, IH), 4.13 (d. i=I.O Hz, and thc solution was warmed to room tcmpcrature. ESI-MS IH), 3.78-3.61 (m. 2H), 2.78 (ddd, J=27 I, 13.7, 5.1 Hz, m'z cele. 338.1, found 339.1 (M+I) . Rctenuon time 0 63 2H), 2.57-2.03 (m, 4H). 1.16 (s, 3H), 0.67 (d, J=0.8 Hz, 3H), niimites To this solution was added Nal3111 (007 8, I 81 0 37 (td, .I 9 I, 7 4, 4 I I lz, 311). I:SI-MS n&/z calc 347 nimol) The reaction mixture was stirred at mom tmnpera- 15128, found 348.15 (M+ I)+ Retention time 0 57 minutes US 20[9/032265[] A[ Oct. 24, 2019 152

[0718] Peak B: ee: 95.4% [0]o (c=0.5, MeOH) +254 02 (a) (2-methyi-4-methyl sulfonyl-phenyl)boronic acid, 1-178 Pd(Ph,P)CCIS, EISN. DMF, (b) Pd/C, HOAc, EtOAc, [0719] 4-[3-[2-chloro-S-(mcthylanuno)phenyl]-1,4-ox- McOH, (c) nBuL1, THF, — 78', (d) 2-amino-4-clrioro-6- azepan-4-ylJ-6-methyl-pyrimidin-2-arnine (36 0 mg, 44%) methylpyrimidine, NMP, 150" (2 I i I NMR (300 Ml lz, Methanol d4) tb 5 84 (d..l 8 6 I lz. 111), 3.29-3.07 (m, 2H). 4.21 (br, IH). 3.78 (br. 2H). 2.99 (dd, Formation of 7-(2-methyl-4-(mcthylsulfonyl)phc- 1=13.(x 5.0 Hz, IH). 2 75 (dd. 1=12.2, 4.8 Hz. IH). 2.54-2. rryl)-2,3,4.5-tctrahydro-I H-azcTtrnc- I -carbaldchydc 20 (m, 313). 1.39 (s„3H). 0.78 (s, 3H), 0.68-0.4I (m, 2H). (129) ESJ-MS m/z cele. 347.15128. found 348.15 . Rctcn- (M+I) [l)721J Charged a rb fiask under nitrogen with 7-chloro- uon time. 0.57 minutes. 2B,4,5-tetmbydmazepine-l-carbaldehyde, 73. (0 60 o, 3.76 nuuol), (2-methyl-4-methylsulibnyl-phenyl)bomnrc acid Example 16 (1.00 g, 4. 67 mmol), DMF (3.5 mL), tnethylaminc (2. S mL, 17.9 mmol) then bis(triphenylphosphine)palladium li chlo- Synthetic Scheme 1(x (+/ — )-4-methyl-6-(2-(2- ride (O.li 0.15 mmoi). The mixture v as ih»hed with methyl-4-(methylsulfonyl)phenyl)avepan-I -yl)py- g. stream of nitmgen and heated at 50" ('or 7 hours Added rimidin-2-amine 1-37 (132) v ster and extmcted twice rvith I:tOAc 'I'he combined [0720] orgastic phrlscs werc wrlslll:11 tvslr:c wrrll brlllc, dncx! (MSSOS), Iilrcred arxl conccntrarcxl ur vacuo. Thc rcsulturg residue vvas purified by coiunm chromato raphy (40 g gold JSCO column; 0-30;v EtOAc/CH,CJS radient) to afford 161 mg of desired product 'I I NMI( (400 Ml lz, DMSO-d6) 13 7 83-7 58 (m, 311). 7 57-7.33 (m, 111), 5 82-5 50 (m, 111), 3.83-3.60 (m, 2H), 3.20 (s. 3H). 239-231 (m, 2H), 2.28 (s. CX 3H), 1.87-1.73 (m. 2H). 1.73-1.62 (m. 2H): ESI-MS m/z cele. 293.1. found 294.1 (M+I) . Retention time: 0.71 rlrlrrntCS.

Formation of (+,' )-2-(2-methyl-4-(methylsulfonyl) phenyl)azepane-I-carbaldehyde (130) [0722] A mixture of 7-(2-methyl-4-mcthylsulfonyl-phenyl)-2.3.4.5-tetrahydroazepine-l-carbaldehyde. 129, (0.162 g. 0.552 nunol) and palladium on carbon (0.056, 0.52G nunol) in ethyl acetate (3 ml.). nrethanol (3 ml ) and acetic 1zv acid (I ml,) was stirred under an atnrosphere of hydrogen gas After 21 hours. thc nnxrurc was Jiltcrcd through a small pad of fiuorosrl and washed with EtOAc. Thc Iilrmrc was concentrated in vacuo to afiord 190 mg of the desired product as an oii that was used rvithout further purificatioru ESI-MS m/z cele. 295 12, found 296.17 (M+I)+ Retention time 069 minutes peak R'I'.69 (M+II) 296 is desired prodrlcr.

Formation of (+/— )-2-(2-methyl-4-(methylsulfonyl) 1311 pili:nv'1)azcprlllr: (131)

[l)723J lo a cold ( — 78" C) solution of 2-(2-methyl-4- methylsulfonyl-phenyl)azepane-I -carbaldehyde. 130, (0.170 g, 0.57G nunol) in THF (4 mL) was added n-butyl- lrthnun (0450 mL of 1.6 M solution rn hexanes. 0.720 mmol). Afier 30 minutes, added another 0.4 mL of nBuLi solution. After an additional 10 minutes„stopped reaction by slow addition of reaction mixture into water The aqueous phase was extracted rsvice with JrtOAc The combined organic phases were dncd (MSSOs), filtcrcxI and concentrated rn vacuo to ailbrd 90 mg of crude orange oil thar was 0 0 used in next step rvithout further purification: ESJ-MS m/z YIP cele. 267.13, found 268.16 (M+I)'. Retention time: 0.69 nunutes peak R1' 69 (M+I I) 296 is desired pmduct.

Formatron of (+/— )-4-methyl-6-(2-(2-methyl-4- (methylsulfonyi)phenyl)azepan-I -yl)pyrinrrdin-2- amine (132) 1-37 [0724] To a solunon oi'-(2-methyl-4-mcthyisulfonyl- 1st phenyl)azepane. 131, (0.090 g. 0 337 nunol) rn NMP (2 mL) v as added 4-CJ)Joro-6-methyl-pyrinudin-2-amine (0.048 g, 0 337 mmol) 'I'he reaction nrixture was heated reaction to US 20 ] 9/032265 [] A[ Ock 24, 2019 153

150', overnight in a sealable vial with teflon septum After Example 17 15 hours, lhc m&xturc was cooled to room temperature and loaded directly onto a I S g ISCO c I 8-aq column and purilicd Synthetic Schen&e 17: (+, — )-4-(3-(2-fluoro-4-(nð- by reverse phase silica gel chmmatography running v ith ylsulfonyl)phenyl)-1.4-oxazepan-4-yl)-6-methyi- 01'i 'FI'A,'II&O and 01% Tl&A/(:II,('N. '11&e comb&ned pyrimidin-2-amine (135) 1-60 fractions contain&ng desired product were concentmted in [0728] vacuo and the result&ng res&due was diluted with dichloromethane and neutralized with aqueous saturated Nal K'0& solution. 1'he mixture &vas passed through a phase separator and thc resulting organ&c phase was conccn&rated &n vacuo lo aflbrd 46 mg of thc dcs&rcd product as a hghl brown solid high temperature (360 K) 'H NMR (400 MHz. DMSO-d6) 7& 7.71-7.53 (m. 3H)„7 31 (d. J=8.2 Hz. IH). 5.34 (s. 2H), 4 24 (s, 111), 3.57-3 44 (m, I I I), 3 15-3 05 (&n„ I I I), 3.10 (s, 311), 2 55 (s. 311), 2 51-2 40 (m, I I I). 2 29-2 08 (m, IH), (. 2.01 (s. 3H). I 98-1 88 (m. IH), 1.88-1.59 (m. 2H), 1.59-1. 13 (m, 3H): ESI-MS m/z cele 374.18, found 375.23 (M+I) . Retcnuon time: 0.61 m&nutcs. [0725] The following analo was prepared in the sa&ne fasiflon;

$V"'. 133 (. 134 Yif

(R)-4-(2-(2-cyclopropyl-4-fluorophenyi)azepan-I- yl)-6-methylpyrimidin-2-amine 1-47 and (S)-4-(2- (2-cyclopropyl-4-tluorophcnyl)azcptm-I-yl)-6-meth- (. ylpyrnn&din-2-amu&c 1-46

[07Z6[ Peak A 'll NMR (400 Mila, l)MSO-d6) &S 706 J=8.7, 6.1 Hz, I 6.83 J=8.6, 2.8 6.69 (dd. H), (ld. Hz, IH), (a) Pd/(2 I IOAc, I &&OAc. MeOI E (b) I I('I, MeOI I, reflux; (c) (dd. J=10.7, 2.8 Hz, IH), S 63 (d. J= IS.I Hz. IH), 5.46-5.19 2-amino-4-chloro-6-methylpyrimidine. NMP, 150" (: (m, 3H), 439 (s. IH)„3.42 (dd, J=14.6. 11.1 Hz, IH). 2.33 (dt, J=14.1, 6.4 Hz. IH). 2.22 (p, J=8.3 Hz, IH). 1.99 (s, 3H), Formation of 3-(2-fluoro-4-(methylsulfonyl)phe- I 'JG I 84 (m, 111). I 84 I 60 (m, 311). I 52 (d, .I 12 7 Iiz, nyl)-6.7-dihydn&-l 4-oxazepine-4(5H)-carbaidehyde ill), 1.44-1.18 (m. 211), I 13-0 91 (m, 211), 0.78 (dtd, (133) J=13.8. 10.6, 10 0, 4.6 Hz, 2H), ESI-MS nttz fi&un&1 341.24 (M+I) . Retcnuon t&mc. 0.70 minutes: [u]o= — 12.S7 (c=21 [0729] Intcrmed&alc 132 was prcparcd to Synthcl&c mg/3 mL). Scheme 13 usu&g 2-fluoro-4-(mcthylsulfonyl)-bcnzaldehyde instead of Z-chloro-5-hydroxybenzaldehyde. [0727] Peak B: 'H NMR (400 MHz. DMSO-d6) 6 7.13- J=8.6. (i.75-(i.64 6.98 (m. IH)„(i.83 (td, 3.0 Hz. IH). (m, l&ormation of (+/— )-3-(2-fluom-4-(methylsulfonyl) I I I), 5 62 (s, I I I). 5 49-5 25 (m, 311), 4 )0 (s, I I I), 3 70 (s, phenyi)-1.4-oxazepane-4-carbaldehyde (133) I i I). 3 42 (dd, .I 14 7, 11 0 I Iz, 111), 2 41-2 25 (n&, II I), 2.28-2.11 (m, IH), 2.04-1.9S (m, 3H). 1.92 (s. IH), 1.88-1. [0730] A nuxlurc of 3-(2-fluoro-4-mclhylsulfonyl-phe- 62 (m, 3H), 1.61-144 (m. IH). 1.44-1.18 (m, 2H), 1.14-0.94 nyl)-6,7-dihydro-5H-1.4-oxazepine-4-carbaldehyde, 132, (m, 2H). 0.87-0.64 (m. 2H): ESI-MS n&/z ii&und 341.24 (0.73 g, 250 mmol), palladiun& on carbon (0.23 g. 2.18 (M+I ) . Retention time: 0.70 minutes: [m]»=+3 1.&94 (c=23 mmol) u& EtOAc ((i mL) and MeOH ((i mL) and acetic acid n&g&3 ml.) (3 ml.) v ss stirred under an atmosphere of hydmgen oas US 20]9/032265[] A[ Och 24, 2019 154

After 8 days, the reaction was stopped. The mixture was -colilllnlixl filtered through a small pad of flonisil and washed v ith EtOAc. The organic phase was ncuiralized by unslung with aqueous saturated NaIICOs solution, dried (MgSO4). hl- tcrixi and concmitratixl Iiltratc ui vacuo to aflbrd 280 mg colorless oil 'lite resulting residue was used without hirther puniicauon. Iionnation of (+/ —j-3-(2-fluoni-4-(methylsulfonyl) phenyl)-1,4-oxazcpanc (134) [0731] A solution of 3-(2-fluoro-4-inethylsulfonyl-phenyl)-1.4-oxazepanc-4-carbaldchyde, 133, (0.28, 0.93 nunol) in niethanol (6 mL) and concentrated HC) (5. 5 mL of 12.1 M. 66.55 nunol) was heated to ret'Iux Ibr2.5 hours. Thc mixture ives cooled to room temperature and diluted into water. The mixture was ncutrahzcd by aililition of aqueous saturated NaHCO„solution and then extracted three tunes 4-[3-(2.4-difluorophenyl)-1„4-oxazepan-4-yl]-6- with EtOAc. The orgm»c phase was ductl (MgSO4). filtered methyl-pyrinndin-2-amine (136) 1-58 and concentrated in vacuo to afl'ord the desired product. l!SI-MS ngz cele 274, found 274 (M+I) . Retention time [0734] high temperature (31IO K) 'H NMR (400 MHz, 0.48 minutes DMSO-d6) 6 7.3G-7.27 (m, IH), 7.13-7.05 (m, IH). 6.97 (td. Formation of (+/ — )-4-(3-(2-tluoro-4-(mefliylsulfii- J=8.2, 1.9 Hz, IH), 5.73 (s, IH). 5.58-5.50 (m, IH), 5.45 (s. nyl)phenyl)-1,4-oxazcpan-4-yl)-6-methyl-pyumidui- 211) 4 37 (d..l 15.7 liz 111) 4.10 (dd .I 12 ij 5.7117 ll I) 2-amine (135) 1-60 3 92-3 85 (m, 111), 3 78 (dd,.l 13 3, 100117, 111), 3 62-3 51 [0732] To a solution oi'3-(2-fluoro-4-mcthylsulfonyl-phe- (m, 211), 2.04 (s, 31 1). I 89-1.68 (m, 211); I ISI-MS m/7 calc nyl)-1.4-oxazepane (0 25 g. 0.81 mmol) in NMP (10 mL) 320 14. found 321.11 (M+I ) . Retention time: 0.6 minutes. w as added tricthylaminc (1.00 mL. 8.89 nunol) and The racemic mixture was submitted for SFC chiral separa- 4-chioro-6-methyl-pyrimidin-2-amine (0.13 g. 0.87 nmtol). uon. 'I'he reaction mixture was heated to 150" C After 17 hours, cooled mixture to room temperature and loaded mctenal [0735] Peak A, (R)-4-[3-(2.4-difluorophenyl)-1,4-oxazc- directly onto 1(X) 8 IS('0 cl 8-aq column and purified by pan-4-yl]-6-methyl-pyrimidin-2-amine (1378 '1').5'r'17 ee; reverse phase running with 0.1% TFA/H 0 aiid 0.1% TFr0 high temperature (3610 K) 'I I NMR (400 Ml lz, 1&MSO-d6) Oils('N Pure fractions containing desired product v ere 8 7 36-7.27 (m. IH), 7.13-7.03 (m. I H). 6.97 (td, J=8.2, 1.9 concentrated in vacuo, diluted with dichloromethane The Hz. IH). 5.73 (4, IH), 5.58-5.50 (m, IH)„5.45 (s. 2H). 4.37 mixture ives passed through a separator and the phase (d, 1 157117,. 111), 4 10 (dd..l 129, 5 7117,. 111), 392-385 was concentrated in vacuo to atfiird 69 organic phase nm of (m, 111), 3.78 (dd, .I 13.3. 10.0117, 111), 3 62-3.51 (m, 211), the desired as a brown solid temperature pmduct light high 2.04 (s. 3H), 1.89-1.68 (m, 2H), ESI-MS nt/4 cele. 320.14, (360 K) 'H NMR (400 MHz, DMSO-d6) 6 7.71-7.56 (m, found 321.13 (M+I ) . Retention time. 0.6 minutes. 1-61. 2H). 7.52-7.40 (m, IH), 5.71 (s. IH), 5.66-5.59 (m, IH), 3.40 (s. 2H)„4.32-4.16 (m. IH). 4.09 (dd, J=13.4, 5.2 Hz, [0736] Peak B, (S)-4-[3-(2.4-difluorophenyl)-1,4-oxazc- IH), 3.88-3.78 (m„ IH), 3.74 (dd. J=13eb 10.0 Hz, IH), pan-4-yl]-G-methyl-pyrimidin-2-amine (138); 99.5% ee; 'H 3 63-3.38 (m. 211), 3 11 (s. 311). 1.97 (s. 311). 1.84-1.60 (ni, high temperature (360 K) NMR (400 MHz, DMSO-d6) 211) 6 7 36-7 27 (m, 111), 7 13-7 05 (ni. 111), 63)7 (td, .I 8 2, I 9 [0733] The ibllowing mining was prcparcxl accordm to I Iz. 111), 5.73 (s. 11 Ij. 5 58-5.50 (m, 11 1), 5 45 (s. 211) 4.37 Synthetic Scheme 17: (d, J=15.7 Hz. IH), 4.10 (dd, J=12.9, 5.7 Hz, IH), 3.92-3.85 1st (m, IH), 3.78 (dd. J=13.3, 10.0 Hz, IH), 3.62-3.51 (m, 2H), 2.04 (s. 3H). 1.89-1.GS (m, 2H). ESI-MS m/z calc. 320.14, found 321.16 (M+I) . Retention time: 0.6 minutes. 1-62. 11 Xg Example 18

Synthetic Scheme 18: (+/-)-4-(3-(2-chloro-5-(methylsulfinyl)phenyl)-1.4-oxazcpan-4-yl)-6-mcthyipy- p)V nmidui-2-tunine (143) 1-110 [l)737]

0 C1 0 C1 011 r'I 0 1'1

779 140 141 US 20]9/032265]] A] Oct. 24, 2019 155

-continued

1148 (. 142 143 0 0 0 0 H.x

C) C3 C3 (.3 144 145 146 141

(a) m('Pl)A, ('lls('14. 0" C; (b) Nal)114, EtOIE (c) l)ess- to give 486 ing of desired product 'll NMR (400 Milz, Martin periodinane, CH,CI,: (d) 4 A mol sieves. 3-((tribu- DMSO-d6) 6 7.92-7.81 (m, IH). 7.69-7.53 (m, 2H). 5.58 (t, tylstannyl)methoxy)propan-l-amine, CHsCJ,: (e) 2.6-luti- J=5.6 Hz. IH). 4.62 (dt, J=5.6. 0.8 Hz. 2H). 2.74 (c. 3H); dmc. Cu(OTI)„, hcxafluoroisopropanol. CHsCJ,: (f) ESI-MS nfiz cole. 204.00, found 205.07 (M+I ) Retention 2-amuio-4-1:hloro-6-mcthylpynmiduic, NMP, 150'.. (g) time: 0.55 minutes. SFC clural separation Formation of Formation of methyl 2-chloro-5-(mmhylsullinyl)bcnzaldchydc (141) 2-chlom-5-(methylsulfinyl)benzoate (139) ]0740] (Z-chloro-5-methylsullinyl-phenyl)methanol, 140, ]0738] To a cold (O'.) solution of methyl 2-chloro-5- (0.48 g. 2.35 mmol) was dissolved in methylene chloride methylsulfanyl-benzoate (2 0 g, 9.2 nunol) ui dichloromcth- (9.6 mL). Doss-Mattut pcnodinane (I 20 g, 2. 83 nuuol) was ane (40 mL) was added 3-chloroperoxybcnzotc acid (2.1 8 arlrlcr! 411d thc reactltiii solutloli was sulrcil at roulii tclll- of 77% wiw. '3 4 mniol) 1 he reaction mixture v as slowly perature for 16 hours 'I'be solution was diluted mto aqueous warmed to room tenipemture over 3 hours. After 3 5 lxiurs, saturated NaiICOs solution and extracted twice ivith the reaction mixture was diluted into aqueous saturated ('1 1st.'Is Tiie combined organic phases were filtered through NaHCOs solution and extracted twice ivith dichlororneth- a phase separator and concentrated in vacuo. The crude ane. ('ombined organic phases were ivashed twice with residue was purified via silica gel chromatography with 40 aqueous saturatixl NaHCOs solution and thmi passed g isco colunui using 0-20% EIOAc/CHsCli gradient to tlirough a phmc separator. Thc resulun liltrate was con- alford 429) mg uf dcstrtxi product. 'H NMR (400 MHz, 'I centrated in vacua he cnide residue was purified via slice DMSO-d6) 43 10.37 (s. 111), 8 1748 15 (nt, 111), 7 99 (dd, el chromatography using an 80 o isco column using 0-30% .I 8 3, 2 311z, III), 7 87-7 83 (m. 111), 2 81 (s. 311); IISI-MS 'I litOAc,'('Jizcls gradient to atford 1.8 o as a white solid I nv'z cele 202 0, found 203 0 (M+I ), Retention time 0.59 NMR (400 Mlqz. DMSO-d6) 6 8.11 (dd, J=2.2. 0.4 Hz. I H), ilia)Utes. 7.88 (dd, J=8.3, 2.2 Hz„ IH). 7.80 (dd, 1=8.4. 04 Hz. I H), 3.90 (s. 3H), 2.80 (s, 3H), ESJ-MS ngz cele. 232.00, fiiund Fomiation of 3-(2-chloro-5-(methylsulfinyl)phenyl)- 233.08 (M+ I) . Rctmition time: 0.63 nunutes. 1,4-oxazepane (142) ]l)741] To a solution of liormation of 3-(tributylstannylmethoxy)pnipan- l-annne, 141, (0 78 a. 2 05 niniol) in dichloromethane (5 (2-chlom-5-(methylsulfinyl)phenyl)inethanol (140) mL) vvas added 2-chloro-5-methylsulfinyl-benzaldehyde ]t)739] qo a solution of methyl 2-chloro-5-rnethvlsulfinyl- (0.42 g. 1.99 mmol) followed by 4 angstmm molecular benzoate. 13'J. (0 88 8, 3 79 mmol) in EtOI I (15 ml ) was sieves. The mixture wasstirred overnight. filtered to remove added NaBiq4 (0.57 g. 15.09 mmol) in portions. The reaction thc sicvcs and washed with dichloromcthanc (20 mL). was stirred at room temperature for 30 minutes and then ]0742] In a separate flask containing hexafluoroisopropa- healed to 50' After 3 hours, the reaction nuxturc was nol (5.5 mL) was addcdI 2,6-1utidinc (0 24 mL, 2.05 nunol) quenched by slow addition into aqueous saturatcxl NaHCO, ftillowcd by Cu(OTI)c (0.72 g, 2.00 nunol) Thc mixture was solution and extracted twice with EIOAc. The combuicd stirred for I hour. Then thc inunc solution preparcdI above organic phases were ivashed w:ith aqueous saturated NI 14CJ was added in one ponion lite reaction was stirred at room solution, dried (MgSO4), filtered and concentrated in vacuo temperature After 3 days, the mixture ives diluted with I10 US 20]9/032265[] A[ Oct. 24, 2019 156

mL of 2:I aqueous saturated NaHCO., solution and 10% 2.72-2.66 (m. 3H), 2.02 (s. 31T). 1.86-1.G8 (m, 2H); ESI-MS Blllltloliiillli llvdroxldc. Aftcl stll1lng for 30 llliliilu:s. Illc nt/z cele. 380.11. found 381.22 (M+ I ) . Rctenuon time: 0.53 orgalllc JBvcr w Bs rcnlovcxI tllld w Bsllcd twice w ldt BqilLol is nunuics. 1-123. saturated Nail('0, solution. then brine I'he organic layer Example 19 was passed through a phase sepamtor funnel and concentrated in vacuo. The cnide residue, which conmins hexafhi- Synthetic Scheme 19; (+/-)-I-(3-(4-(2-amino-6- oroisopropanol. was loaded directly onto a 100 yam c I 8-Bq mcthylpyruntdut-4-yl)-1,4-oxazcttan-3-yl)-4-chloro- colunui and purification via reverse phase chromatography phcnyl)-2,2.2-tnlluoroeihan-l-ol (154) 1-134 clutuig with 0.1% TFA/HSO mid 0.1% TFA/CH.,CN Thc [0749] fractions contaiiung product Ccrc conccntralLVI ui vacuo, diluted ivith dichloroniethane and neutralized with aqueous saturated Nal I('Os solutiim. I'he mixture ives passed through a phase sepamtor and the organic filtrated was concentrated in vacuo to sword 110 ntg of desired product

ESI-MS nv'z cele. 270.06. found 271.11 (M+I) . Retention ume. 0.46 nunutcs.

Fomiation of (+/-)-3-(2-chloro-5-(methyisulfinyl) phenyl)-1,4-oxazepane (143) 0 [0743] To a solution of 3-(2-cldoro-5-mcthylsuliinyi-phenyl)-1.4-oxazepane. 142. (O.ll g. 0.40 nmtol) in NMP (5 mL) was added 4-chloro-6-methyl-pyrimidin-2-Bmine (0 08 8,. 0 52 mmol). The reaction mixture ives heated to 150" C. for 17 hours The mixture was cooled to niom temperature Bnd loaded directly onto 50 g ISCO c18-Bq colunui imd thc citldc was pilrllicd by reverse pllasL'hltlllg wltll 0.1% TFA/HSO and 0 1% TFA/CH,CN gradient. The fractions containing desired pmduct were concentrated in vacuo, (. diluted v ith dichloromethane. neutralized with aqueous saturated Nell('Os solution and the mixture was passed tluough a phase separator. lite orgaiuc phase concentrated in i acuo io ailord 50 mg of dcstrcxI product as a mixture of 4 stereoisomers; high temperature (360 K) 'H NMR (400 MHz. DMSO-d6) 8 7 69-7 48 (m, 3H), 5.66 (s. IH). 5.58- 5 50 (ni. II I), 5 43 (s, 211), 4 60-4 46 (m, 111). 4 18-4 04 (ni, 1 il). 3 95-3 85 (ni. 111). 3 85-3 66 (m, 211), 3 65 3 49 (ni, IH), 2.68 (d, J=4.9 Hz, 3H), 2.02 (d, J=2.4 Hz, 3H), 1.86-1.67 (m. 2H). ESI-MS m/z cele. 380.11, found 381.22 (M+I) . Retention time: 0.53 minute~. [0744] The mixture (34 m ) was submitted for SFC chiral separation to atford 4 stereoisomers [t)745] Peak A (144) high tempemture (360 K) 'll NMR (400 MHz, DMSO-d6) 6 7.72-7.50 (m, 3H). 5.66 (s, IH), 5.62-5.50 (m. I H). 544 (s, 2H), 4.64-4.45 (m. IH), 4.12 (dd, 1=13.3, 5.2 Hz, IH). 3.98-3.86 (m, IH). 3.84-3.49 (m, 3H), 2.69 (s„3H). 2.03 (d. J=1.6 Hz. 3H), 1.89-1.67 (m, 2H), I:SI-MS m/z cele. 380 11, found 381 22 (M+]) Retention time 0.53 minutes 1-120 [0746] Peak B. (145) high temperature (360 K) 'H NMR (400 MHz, DMSO-d6) 6 7.68-7.47 (m, 3H). 5.65 (s, IH), 5.62-3.50 (m, I H). 5.42 (s, 2H), 4.61-4.46 (m. I H). 4.13 (dd, 1=13.4, 4.9 Hz, IH). 3.99-3.66 (m, 3H). 3.64-3.47 (m, IH), 2 70-2.67 (m. 311), 2 02 (s, 311). I 85-1 69 (m. 21 I); I iS I-MS m,'z cele. 380 11. fiiund 381 22 (M+I )+ Retention time 0 53 nunutcs. 1-121 [0747] Peak C. (146) high temperature (360 K) 'H NMR (400 MHz, DMSO-d6) 6 7.68-7.47 (m. 3H). 5.65 (s, IH), 5 62-5 50 (m. 111). 5 42 (s, 21 I), 4 (ii -4 4(i (m. I I i), 4.13 (dd, I 134. 4 9 I lz, 111), 3 ')9-3 66 (m, 311), 3.64-3 47 (m, 111), 2.70-2.67 (m. 3H). 2.02 (s. 3H). 1.85-1.69 (m. 2H); ESI-MS m/z cele. 380 11. found 381.22 (M+I) . Retention time: 0.53 nunutcs. 1-122 [0748] Peak D. (147) lugh icmpcraiure (360 K) 'H NMR 7.68-7.48 (. (400 MHz, DMSO-d6) 6 (m, 3H). 5.65 (s, IH), 5 61-5.4i/ (m, 111). 5 43 (s, 211), 4 59-4 42 (m, I I I), 4.12 (dd, 13 5. 5 0 I lz, 111), 4 00-3 65 (m, 31 I), 3.(i5-3 45 (m, 11 I), US 2019/032265[[ A[ Oct. 24, 2019 157

-continued followed by Cu(OTI), (1.95 g. 5.40 numil) The mixture was stirred for I hour, then thc imine solution prepared above ('11 HO was added ln onc poruon. The reaction mixture turned from blue to oreen and the mixture ives stirred over night at room temperature 'I'he mixture was diluted with 120 ml, of 2:I aqueous saturated NaH('Os solution and 10% anuuonlU(u hydroxide. After stirring for 40 minute~„ the mixture was diluted v, ith dichloromethane (50 mL) and the organic layer wds rcnlovcd and washed Uvlcc w lib aqUcoUS satuldt(x! NaHCO( solution. 111e organic layer was passed tluough a (. phase separator funnel and concentrated in vacuo. 'lite cmde 252 residue was purified by reverse phase IS('0 using a I(k) 'F, gmm c 1 8-aq cohunn eluting with 0.1% TFA/H,O and 0.1% TFA/CHzCN, The fractions containing desired product were concentrated in vacuo, diluted with dlchloromethane. neu- trahzcd with aqucxtus sdturat(xi NaHCO1 solution mid the nuxlurc was passed tluuugh a plmse separator. Thc orgaluc plmse concentrated in vacno to atford 754 nlg of desired pmduct as a yellow oih 'l l NMR (400 Ml lz, DMSO-d(i) (5 8 23 (d,.l 23112, 111). 7 82 (dd..l 8 3, 2 2112. 111), 7 5(i (d, (. J=8.3 Hz. IH), 4.26 (dd, J=8.9, 3 2 Hz. IH). 3.87 (s, 4H), 3.84-3.78 (m. 2H), 3.72 (ddd, J=12.0, 6.7. 6.0 Hz, IH), 3.26 (dd, J=12.3, 8.9 Hz, IH), 3.10 (dt, J=13.5, S. I Hz, IH), 2.88 (ddd, J=13.0. 7.2. 5.3 Hz, 2H). 1.89 (dtd. J=7.9. 6.1, S.O Hz. Hzx 211); I(SI-MS m,'z cele 26'7 08. found 27019 (M+I) Retention time 0 53 nlimltes

I(ornlation of tert-butyl 3-(2-chlom-5-(methoxycar- bonyl)phenyl)-1,4-oxazepane-4-carboxylate (149)

[07521 A mixture of methyl 4-chloro-3-(1,4-oxazepan-3- yl)bmlzoate, 148, (0.51 g. 1.80 mmol) and tncthylanunc (0.28 mL. 2.00 nunol) ln THF (8 mL) was added tc(t- 154 butoxycarbonyl tert-butyl carbonate (0 41 8, I 90 nunol) and the nnxture was stirred overnight at room temperature 'I he 8 HO t(8 (F Itx reaction mixture v:as diluted into aqueous saturated NH4CI solution and extracted with dichlommethane. The organic phase v:as passed through a phase separator funnel and concentrated ln vacuo. Thc crude residue was purilicd by slhca gel chromatography usmg 40 ISCO colunul (0-20% EtOAc/('.I I,('ll gradient) to give 545 mg of desired pmduct as a color)assi oih 'l l NMR (400 Ml lz, l)MSO-d(i) (5 (. 1=8.2 (. 7.92-7.78 48-5.23 (m. 2H), 7.61 (d„ Hz. IH), 5 (m, 155 IH). 4.37-4.24 (m, IH), 3.90 (s. 2H), 3.86 (s. 3H), 3.76-343 (m, 3H). 1.87-1.56 (m. 213). 1.42-1.04 (m„9H): ESI-MS nt/z calc. 369.13, fouml 370.33 (M+I) . Retention ume: 0.92 (a) 4 A mol sieves. 3-((tributylstannyl)methoxy)propan-I- UUUU(es. amine. ('I lz('I,; then 2,6-lutldine. ( u(O'I'tjz„hexafluoroiso- ProPanoL CHzClzi (b) BoczO. EtlN, CHzCI.: THF: (c) Formation of tert-butyl 3-(2-chloro-S-(hydroxym- 50" 80" Dess-Martin NaBH4. EtOH, C. to Cd (d) penodi- ethyl)phenyl)-1,4-oxazcpane-4-carboxylate (150) nane, CHzClzt (e) TBAF, (CH(),SiCFU THF, O'. to rt: (I3 tnfluorodcctic acid, CHzCI,: (g) 2-amino-4-citloro-6-mcth- [07531 To a solution of tert-butyl 3-(2-chloro-5-methoxy- ylpynnudinc, NMP, 150'., (h) SFC chiral separation carbonyl-phenyl)-1,4-oxazepane-4-carboxylate. 149, (0.52 g, 1.47 nunol) in E(OH (9 mL) was mldcd NaBH4 (0.22 g. Fonna(ion of methyl 5.84 numil) ul port(orna Thc reacuon was stirred at room 4-chloro-3-(1,4-oxazcpm1-3-yl)benzoate (148) tcmperaturc liir IS nunutcs and then hcatcd to SO'. I'or 23 hours 'I'he temperature was increased to 80" (2 and stirred [0750] To a solution ol'3-(tnbutylstannylmcthoxy)propan- at this temperature for 12 hours 1 he reaction was quenched I-auuuc (2.09 g, 5.S3 uuuol) ul dlchkiroulcthzulc (14 ntL) by slow addition into aqueous saturated NaHCO, solution. was added methyl 4-chlom-3-fonnyl-benzoate (1.12 g, 5 36 The aqueous phase lvas extracted twice v ith EtOAc. The 'I'he mmol) followed by 4 angstrom molecuhzr sieves mix- combined orgaruc phases were washed with aqueous satu- ture ives stirred overnight, filtered to remove the sieves, rated NH4C) soluuon. dried (MgSO4), Iiltcred and concen- washed with dichloromethane (50 mL). trated in vacuo. The crude residue was puniied via silica gcl [0751[ In a separate flask containing, hexafluoroisopropa- chromatography lvith 40 g isco colunul using 0-60% nol (14 ml,) was added 2,6-1utidine (0 64 lnl .. 5.52 mmolj (EtOAc/('Ill('Iz) to afibrd 270 mg of desired product as a US 20[9/0322658 A[ Oct. 24, 2019 158

white solid 'H NMR (400 MHz, DMSO-d6) 8 736 (d, product that was used without further purification: ESI-MS J=N.I Hz. IH), 7.27-7.16 (m, 2H). S.28 (dt. J=11.5, S.2 Hz, nt/z cele. 309.07, I'ounii 310.17 (M+I) . Retention tune. 2H). 4.46 (d, J=5.6 Hz, 2H). 4.37-3.97 (m. IH), 3.92 (d, 0.55 nunutcs. 10 7 I lz, 211). 3 52 (dq, .I 23ak 12 7, 11.9 I lz., 311). I 72 (d, .I 2N.4 I lz, 211). 1.52-1.03 (m, 911). Fomiation of (+/-)-I-(3-(4-(2-amino-6-methylpyrunidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenyl)-2. I'ormation of tert-butyl 3-(2-chloro-5-fiirmylphe- 2,2-uifluorocthan-l-ol (I S4) nyl)-1,4-oxazepane-4-carboxylate (151) [0757] To a solution of 1-[4-chloro-3-(1,4-oxazcpmi-3-yl) [0754] tert-Butyl 3-[2-chloro-S-(hydroxymethyl)phenyl]- phenyl]-2,2.2-tufluoro-ctlumol (0.040 g. 0.129 mmol) in 1,4-oxazcpanc-4-carboxylate, 150, (0.27 g. 0.78 nunol) was NMP (I 5 ml,) ives added 4-chloro-6-methyl-pyrimidin-2- dissolved in methylene chloride (6 ml Bess-Martin perio- ) amine (0024 0.16N mntol) I'he reaction mixture was dinane (040 0 93 ntmol) was added and the reaction 8, g, heated to 150" C. for 17 hours. After cooling the mixture to solution was stirred at room temperature for 18 hours The mom temperature. the niixture was loaded directly onto 15 mixture was diluted into aqueous saturated NaHCO,.solu- ISCO clg-aq colunm and punfied reverse phase uon and exuacted twice with EtOAc. The combutnl orgtuuc g by illlllllllg with 0.1% TFA/HsO and 0.1% TFA/CHsCN. The phases were ducd filtered tmd concentrated in (MNSOs), fracuons contauung dcsircd product were couccntratcd in iacuo. The crude rcsiduc was purified via silma el cltro- vacuo, diluted with dichlommethane, neutrahzed with aque- mato raphy with a 40 isco coluinn using 0-30% I'.tOAc/ 8 ous saturated Nal I( Os solution and the ntixture w:as passed ( IfsCis) radient to afford 187 mg of desired product as a throngll a phase separator. I he orgaitic pllase concentrated in white solid: 'H NMR (400 MHz. DMSO-d(i) 8 10.02 (s, vacuo to afford 41 mg of desired pmduct heated (360K) 'H IH), 7.89-7.75 (m. 2H). 7.69 (d. J=8.7 Hz, IH). 5.50-5.26 NMR (400 MHz. DMSO-d6) 8 7.50-7.29 (m. 3H), 6.65-6.48 (m, IH), 4.43-4.11 (m, IH), 4.07-3.85 (m, 2H), 3.79-3.40 (m, I H), 5.63 (d, 1=19.0 Hz, I H), S 43 (s, 2H), S 09 (t, J=6.8 (m, 3H). 1.89-1.49 (m, 2H), 1.47-1.04 (m, 9H). ESI-MS m/z Hz, IH), 4.60 (d, J=15.2 Hz, IH), 4.19-4.0S (m, IH). cole. 339.12, Ihuud 338.54 (M+I) . Retention tune. 0.87 3 97-3.81 OI 3.78-3.47 311), 2 01 311). I 78 ntimites (m, I), (m. (s, (d, .I 5.6 Ilz. 211): IISI-MS miz cele 416 12. fiiund 417.28 (M+I )+ Retention time 0 61 minutes lionttation of terr-butyl 3-(2-chloro-5-(2.2,2-trif- hioro-I -hydroxyethyl)phenyl)-1,4-oxazepane-4-car- [I)758] I he racemic product ives submitted fiir Sli('himl boxylate (152) separation. SFC conditions: (30/'8 MeOH (5 mM ammonia) on Cellulose-2) to afford two separate mcemic products: [0755] To a cold (O'.) stirred solution of'ert-butyl 3-(2-chloro-5-fiirntyl-phenyl)-1,1-oxazepane-4-carixixy- [0759] Peak A. (S)-I-(3-(4-(2-amino-6-methylpyrimidin- 4-yl)-1.4-oxazepan-3-yl)-4-chlorophcnyl)-2,2.2-tnfluoroc- late, 151. (0 17 8, 0 48 mniol) and trimethyl(trifluorontethyl) thau-I-ol 98.5'/o HPLC heated 'H silane (0.09 nil., 0.5N mniol) in '1111'2 ini,) ives added (155), pure by (360K) NMR (400 IlfHz, DMSO-ii6) 6 7.54-750 (m. 3H), 6.56 (s, tetrabutyianunonium fluoride (0.05 mL of I M solution in 111), 5.63 .I I') 0 i lz. 111). 5 55-5 37 (nt. 311). 5.09 THF, 0.05 mmol). The reaction mixture ives stirred at O'. (d, (d, .I 7 8 I lv, III). 4 60 (d,.i 15.41lz. 111). 4.12 (dd,.l 13.4. 4 &7 for 40 muiutes and then at room tcmpcrature I'or 3 hours. Thc Hz. IH). 3.89 (d. J=11.9 Hz. IH). 3 76-3 41 3H), 2.01 mixture was then diluted with I N aq. HCI (2 ml) and stirring (m, 1.89-1.71 ESI-MS cole. was contimied for a further 3 days. I'he mixture was diluted (s, 3H). (ni. 2H). m/z 416.12268, with dichloromethane and w:ashed with aqueous saturated found 417.33 (M+I ) . Re(cation time. 0.6 minutes. 1-145. Nal I('Os ihe aqueous phase was extracted again v ith [0760] Peak 8, (R)-I-(3-(4-(2-anuno-6-methylpyrinudin- dichloromethane. The combined organic phases were fil- 4-yl)-1,4-oxazcpan-3-yl)-4-chlorophenyl)-2,2,2-tnfluoroe- tered tluough a phase separator and concentrated in vacuo. thau-l-i.l (156), 99.58/o pure by HPLC. heated (3GOK) 'H Thc resulting residue was purilicd by silica el column NMR (400 MI Iz, DMSO-d(i) iS 7.57-7.33 (nt. 311), 5.60 (s, chromatography using a 12 gmm ISCO column cluting with 111) 5.56-5 36 (m 311) 5.09 (q .I 7 4 I lz 111) 4 60 (d 0 to 20% I itOAc/(:I I,(:li gradient to affiird NO mg of desired 1=14.9 Hz, I H), 4.12 (dd, J=13.4„4.9 Hz. I H). 3. 99-3.79 (m, pmduct as a white sohd 'I I NMR (100 Mi lz. DMSO-d6) 6 IH). 3.79-3.48 (m, 3H), 2.01 (s. 3H). I 81 (d. 1=19.9 Hz, 7 5(i-7.30 (m. 311). 6 90 (s. 111), 5 13-5 13 (m. 211), 4.42-4. 2H). 1-146 07 (m, I H), 3 98-3 80 (m. 2H), 3.65-3.34 (m, 3H). 1.85-1.48 [0761] The follov ing analog was prcparixl according to (m, 2H). 1.43-1.03 (m. 9H). Synthetic Scheme 19: Formation of 1-(4-clfloro-3-(1,4-oxazcpmi-3-yl) phenyl)-2,2,2-trifluomethan-l -ol (] 53) [0756] To a solution of ten-butyl 3-[2-chioro-S-(2,2.2- tufluoro-I-hydroxy-i:thyl)phenyl]-1,4-oxazepane-4-carboxylate, 152, (008 8, 0 18 nunol) in dichloromethane (2 mf.) was added tnfluoroacetic acid (2 inl.) 'I'he reaction mixture was stirred at room temperature for one hour and concentrated in vacuo The residue was dissolved in dicblo- romctluinc and ncutralizcd by waslung with aqueous satu- ratixi NaHCO, solution. The aqueous piiasc was back cxtractcd with dichloromethanc. The combuied or anic (. phases ivere passed through a phase separator and concentrated in vacuo to afford approximately 40 mg of desired US 20 ] 9/032265 [] A[ Oct. 24, 2019 159

tert-butyl 3-(5-bmmo-2-chloro-phenyl)-1.4-ox- mmol) and (2-tert-butoxycarbonylpymnzol-3-yl)boronic acid azepanc-4-carboxylate (157) (0 53 g, 2 48 mmnl) in J.f-dioxane (7 3 ml,j and water (0.73 mL) v as added Pd(dppf)('Jz,DCM (0.20 g. 0.25 nunol) and [0762J 'I I NMR (4()0 Mliz. IJMSO-d(i) tS 7.50 (dd. I 8 5, NazCO, (0.39 3.72 mmol). Thc mixture was bubbled wifli 2.4 Hz, IH)„7.4G-733 (m, 2H). 5.38-5.14 (m. IH). 4.38-4. g, for 10 minutes and heated in the microwave at 03 (m, IH)„3.89 (d. J=12.4 Hz. 2H). 3.75-3.52 (m. 2H). 3.49 nitrogen then 105' (i. J=11.7 Hz, JH), 1.71 (d, J=32.1 Hz, 2H), 1.45-1.05 (m, for 30 nunutcs. Thc mixture was diluted into water and extracted tv,ice with iitOAc. 'I'he combined 9H). ESJ-MS nt/z cnlc. 389.04. found 390.27 (M+I) . organic Retention tiine I 0 iliinutes plmscs werc washed with brine. dncd (MgSO4), filtcrcd and concentrated in vacno. 1'he cnide material was diluted ivith Example 20 diclfloromclimnc (5 mL) and lnfluoroacclic acid (5 mL) was added to the reaction mixture. 'I'he mixture was stirred at Synlheuc Schcmc 20. (+/ — )-4-(3-(2-chloro-5-(JH- mom temperature for 30 minutes and concentrated m vacuo. pyrazo1-5-yl)phenyl)-1.4-oxazepan-q-yl)-6-methyl- 'I'he resulting residue was loaded directly onto a 15 8 IS(:0 J-157 pyrimidin-2-amine (159) c 1 8-aq column and purified by reverse phase running with [0763] 0.1% TFA7'H70 and 0.1% TFA/CHiCN.

Formation of (+/— )-4-(3-(2-chloro-S-(I H-pyrazol-S- yJ)phenyl)- I,q-oxazepan-4-yI)-6-methyl-pyrnni din- 2-ammc (159) I-I S7

[0765] To a solution of 3-[2-chloro-5-(IH-pyrazol-5-yl) phenyl]-1,4-oxazepanc. 158. (0.22, 0.50 nunol) in NMP (4.5 mL) v:as added 4-clfloro-6-methyl-pyrimidin-2-amine (0.09 g. 0.6S nunol). Thc mn«urc was heated to 150'. Ibr 18 hours. 'Iiie material ivas cooled to rooni temperature and (, loiulcd directly onto a 50 g ISCO c I 8-aq column and purificxi reverse phase runnina with 0.1% TliA/IizO and 0.1017 157 by TFA/CHzCN, The fractions containing desired product alono with an impurity were concentrated in vacua diluted v ith dichloromethane, neutralized with aqueous saturated NaHCOi solution and thc mixture was passed tluou h a phase separator. The organic phase concentrated in vacuo to afford 420 mg of dcsircd product hcalcd (360K) 'H NMR (400 Mi iz. DMSO-d6) 'I'he mixture was purified again via 11 8 silica gcl cluomalography with 40 g isco CIOLD colunui usiag 5-100%v (20% MeOI I~ Iiz('Iz/('I lz(1z) gradient to ' afliird 5 mg of desired product: NMR (heated 3 60K) (400 C. Milz, IJMSO-d6) 6 1266 (s. 111), 784-753 (m, 211), 01 lss 7.53-7.27 (m, IH), G.59 (s, IH), 5.77-5.55 (m, 2H), 5.43 (s, 3H), 4.79-4.4G (m, IH). 4.24-4.03 (m, IH). 3.98-3.84 (m, IH). 3 84-3.65 (m, 2H). 3.65-3.39 (m. IH), 2 00 (s, 3H), Il,x 1.92-1.6S (m, 2H); ESI-MS m/z cole. 384.15, found 385.32 (M+I)+ Retention time 0 57 niinutes

Example 21

Synthetic Scheme 21: (+/ —)-N-(3-(4-(2-amino-6- met hylpyrinu din-4-yl)- 1,4-ox azcp an-3-yl)-4-chloro-

phenyl)methanesulfonamide (164) 1-74 ISS ]07661 (a) (2-tert-butoxycsrbonylpyrazol-3-yl)boronic acid,105', Pd(dppf)CJz~HzC1„1,4 thoxane, water, NazCO,. FH micmivave; (b) dichloromethane. trifluoroacetic acid: (gj 2-aminn-4-chlnro-6-methylpyrimidine, NMP, 150" C.

Iionnatinn of 3-(2-chloro-5-(111-pyrazol-5-yljphe- nyl)-1,4-oxazepane (158) [0764J 'Io a suspension of tert-butyl 3-(5-bmmo-2-chlnro- 0 phenyl)-1.4-oxazepane-4-carboxylate, 157. (048 g. 089 US 20[9/032265[[ A[ Oct. 24, 2019 160

-continued continual o o 0 o HN N Yif HN Ht

0 CI

16u

[0767J (a) Cl IzSOz(1, pyridine, ('I fz('ll; (bj I ll)i Iw TI II; 50" (.'4 (c) MnOz, DMI'. ('I lz('Izt (d) 4 A mol sieves, 3-((tributylstannyl)methoxy)propan-I-amine. CH,CI,: then 2.6-lutidine, Cu(OTf)„hexafiuoroisopropanol, ('HzCI,; (e) 2-anuno-4-chloro-6-mcthylpynmulinc. NMP, 150'., (I') SFC clural separation

HO Herniation of ethyl 2-chloro-5-(methylsulfonanudo)benmate (160) [l)768J To a solution of ethyl 5-amino-2-chlom-benzoate 161 (2 95 g, 14 80 mmol) in dichloromethane (60 mf,) was added pyridine (1.32 n)L, 16.30 nunol) followed by dropwise addition of methanesulfonyl chloride (1.2(i mL, 16.30 nuuol). Thc reaction nnxturc was stirred at room 1empcra- turc lilr 22 hours. The nnxturc was diluted into aqueous HN saturatixl NHzCI solution;md extracted with E1OAc. Thc 6 organic phase was dried (MSSOs). hltered and concentrated in vacuo. 'I'he resultina residue was punfied via silica gel cluomatography lvith a 80 isco CIOLD column usin 0 0-208lv (EtOAc/CH,Clz) to afiizrd 2.6 grams of desired product. 'H NMR (400 MHz, DMSO-d6) o 10.08 (6. IH), 0 1'1 7.60 (d, J=2.7 Hz, IH). 7.54 (d, J=S.S Hz. IH), 7.38 (dd, J=8.7, 2.S Hz, 4.33 J=7.1 Hz, 1.31 162 IH), (q, 2H), 3.04 (6, 3H), (t, .I 7.1 I lz. 311); IISI-MS m,'z cafe 277 02, foluld 278.16 (M+I)+ Retention time 0 75 nlinutes

Fonna)ion of N-(4-cldoro-3-(hydroxymethyl)phe- HN nl'l)nleth;ulcsuifonanudc (I 6 I) [0769J lo a solution of ethyl 2-chloro-5-(nlethanesulfona- nudo)benzoate. 160, (I 20 g, 4 10 mnlol) in 1'I ill (20 lnl,) v as added lithium borohydride (0.26 . 11.80 mmol). The reaction was stirred at room temperature for 10 minutes and then hcatid to 50'. Ihr 8 hours and then room tcmpcrature C. fbr 3 days. The mixture was ddutixl ulto aquixlus saturatcxI NHzCI solution and exuacted twice with EtOAc. Thc com- 16'I bined organic phases were dried (Mgg06). filtered and cmlcentrated in vacuo to afliord 9(X) mg ofdesired product as 0 a white solid: 'H NMR (400 Miqz, DMSO-d6) 6 9.84 (s, IH). 7 44 (dd. J=2.8, 0.9 Hz, IH), 7 35 (d. J=8.6 Hz, IH), 7.11 (ddd, J=S.6, 2.8, 0.7 Hz. IH), 5.43 (t, J=5.6 Hz, IH). Yif 4.52 (d, J=5.4 Hz, 2H), 2.98 (6, 3H). Fomtation of N-(4-cltioro-3-formylphenyl)methanesulfonamide (162) C. [07701 To a solution of N-[4-chloro-3-(hydroxymcthyl) phenyl]methancsullhnanndc. 161, (1.8 g, 7.6 nunol) in dichloromethane (60 ml ) and DMll (10 nil.) was added manganese dioxide (109 g, 1250 mmol) 1he reaction US 20 ] 9/032265 [] A[ Oct. 24, 2019 161

mixture was stirred at room temperature for 7 hours. The NMP (4 mL) was added 4-chloro-6-methyl-pyrimidin-2- nuxlurc was diluted with dichloromcthane and Iillercd anunc (0.10 g, 0.69 nunol). The reaction mixture was hcatcxl thriiUgh d plUg of cchlc Bnd wdshcd with ihchlolonlcthllnc. to 150 C. for IG hoUIS. Tltc I'cilcllon nuxllllc wds coohx! 10 'I'he filtrate was concentnsted in vacuo The resulting nlixture room temperature and loaded directly onto 50 g IS('0 was diluted into brine and extracted twice with I itOAc 1 he c1 8-sq column and purified by reverse phase mnnmg ivith conlbined organic phases were washed with brine. dried 0.1!o TFA/HSO and 0.1% TFA/CHSCN All fractions con- (MgSOo), hltered and concentrated in vacuo. The crude tainln product were concentrated in vacuo and the resulting solid ives mostly insoluble in dichloromethane and EtOAc. residue v:as diiuted lvith dicltioromethane. neutralized with Thc sohd was ihluted with 50% EiOAc/dlchloromethanc. aqueous saturated NaHCO, solution and passed through B Thc Iiltmtc was punlicd by sihcd cl chromatography with plrdse separator. The org;mic phase was concentrated in 'I 40 g iscn coluntn usmg 0-30% I itOAc/('I Is('I gradient. he vacun to afford 233 m of desired product as a light brown fractions containing clean product was combined with the sohd. 'I'he racemic mixture was submitted for Sii('hinsl precipitate to affoird I 08 grams of ofl'-white solid: ESJ-MS sepal'ltlon. m/z calc. 232.99, found 234.03 (M+I) . Retention time [0774] Peak W: (R) N-(3-(4-(2-mnino-G-methylpvrimi- 0.69 minutes din-4-yl)-I A-oxazepan-3-yl)-4-chlorophenyl) methanesul- — fiinamidc (165), 74 mg ol'ellow sohd. [ ]n= 128.77 Formauon of N-(4-chioro-3-( 1.4-oxazeyan-3-yl) (c=3.5 mg/0.8 mL McOH). 99+!o by chlral HPLC: 98+% cc. phenyl)methanesulfooamide (] 63) 'I I NMR heated (360K) (4(N) Ml lz, DMSO-d6) (I 9.79-9.44 11 7.62-7 7.36-6 98 5.85-5.25 nil[0771] .) To a solution of 3-(tributylstannylmethoxy)propmt- (m, I), 33 (nl, 111), (m, 211), 41 4 81-4/46 I I 4 38 4 O'7 111). 3 94 411), I-smine (1.79 g. 4.73 nunol) in dichloromethane (12 mL) (m, I), (m, I), (m, (s, was added N-(4-chloro-3-fomtyl-phenyl)methanesulfona- 3.24 (s. 3H). 2.0G (s, 3H), 1.98-1.62 (m. 2H): ESJ-MS nt/z . 0.57 nudc, 162, (1.07 g. 4 58 nunol) followed bv 4 angstrom cele. 411.11. found 412.28 (M+I) Retention time: 1-160. molecular sieves. The mixture was stirred for 2 days, Iillercd minutes. tn remove the sieves, and washed with dichlnrnmethane (45 [0775] Peak Ex (S jN-(3-(4-(2-amino-6-mcthylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-t-chlorophenyl) methanesul- 65 [0772J In a separate flask containiog, hexafluoroisnpropa- fonamide (166); m of yellow sohd [ Jl, +124.74 I 98+oi nol (12 mL) was added 2,6-lutidine (0.55 mL. 4.72 mmol) (c 3 I mg/0 8 nil, MeOI I): 99+% by chiral IPI.(, ee 'H NMR heated (360K) (400 MHz. DMSO-d6) 6 9.54 (s, followed by bis(tritluoromethylsulfonyloxy)copper (1.77 g, 1=8.8, 4 7.2(1-7.03 4.89 mmol). Thc mixture was surrcd for I h. then the uninc IH). 7.36 (dd, 4 Hz, IH), (m. 2H), 5.47 J=40.2 19-4 solution prcqtarcd ubovc was added in one poruon. Thc (t. Hz. 4H), 4.58 (s, IH). 4 02 (m, IH), 3.88 (s, mixture nirned from blue tn green Mixture ives stirred for I H), 3 80-3.40 (m, 3H), 2.91 (s. 3H), 2.00 (s. 3H), 1.88-1.69 m,'z 2 days at ronm temperature 'I'he mixture was diluted v ith (m, 211); IISI-MS cele. 411.11, found 412 28 (M+I) Retention time 0 57 minutes 1-161 150 ml, of 2 I aqueous saturated Nal I('Ol snlution and 10% ammonium hydroxide. After stirring for 30 minutes. the Example 22 organic Layer was removed and washed twice with aqueous satumtixl NaHCO„solunon. Thc or imic layer was passed Synthetic Scheme 22 (+I — )-4-(2-(2-chlorophenyl)- thriiUgh d phase scpaldtor fllnncl ilnd conccnlIlltcd nl cacao. 4-(methylsuifonyl)-1.4-diazepan-l-yl)-6-methylpy- 'I'he cmde residue ives purified by reverse phase IS(:0 150 rimidin-2-amine (170) 1-28 rani clg-aq colunln running with 01% 11'A/lllO and [0776] 'I 0 I 'i TIIAI('I is('N he resulting pmduct was puritied again by reverse phase ISCO 100 gram c1 8-aq colunut nutning lvith 0.1% TFA/H,O and 0,1%o TFA/CH,('N. All fractions conniining product werc concentrated ul vacuo mid thc Sit rcsuluc was diluted with aqueous saturated NBHCOB solution and extracted three tunes with dichlornmethane and then three times with 10% MeOII/dichloromethane 'Ihe ~SBBui mixture was passed thmugh a phase separator and the v, 1(i3 Bnc (, organic phase as concentrated in vacuo to afford mg desired product ESJ-MS m/z cele. 304.06, found 305 18 Boc (M+I) . Rctenuon time. 0 51 mimitcs. LCMS still slxlwcd lsi product in aqueous phase. Thc aqueous phase was concentrated in vacuo. The resulting white solid was diluted v ith acetonitrile and stirred vigorously tilr 30 lnimnes, tiltered, washed with acetonitnle and the filtrate was cnncentrated in vacuo to affoird 500 mg ofmixture containing mostly desired product.

Formation of (R) N-(3-(4-(2-anuno-6-methylpy- rinlidin-4-yl)-1.4-oxazepan-3-yl)-t-chlnrnphenyl) methanesulfnnmnide (l(i5) and (S) N-(3-(4-(2- (, anlino-6-methylpyrimidin-4-yl)-1,4-oxazepnn-3-yi)- 4-chlomphenyl)methanesuifonamide (1(i(i) Bnc [0773J 'ln a solution of N-[4-chloro-3-(1,4-oxazepan-3-yl) tss phenylJnlethanesulfonanlide, 163, (016 g, 0 53 mnlnl) in US 20 ] 9/032265 [] A[ Oct. 24, 2019 162

continued cnide material ives purified via silica gel chromatography Nii, eluung with 0-100% EtOAc in heptane (40 g ISCO column). TLC w/iunhydnn staui was used to idenufy fractions containing desired product. Iiractions containing desired pmduct were combined and concentrated to give I 7 8 of a light omnge oil. The material was purified a second time via silica gel cluomatography eluting with 0-75% EtOAc in heptane (40 g ISCO column). Pure fractions were combined and conccntratcd to give 700 mg of thc dcsircd product as a colorless oih 'H NMR (400 MHz. CDCJ,) o 7 54 (ddd. C. I 132 77 I 8 llz 111) 736 (dd I 79 1511z 111) 7 31-7.14 (m, 211), 4 32 (dd..l 10 2, 34 J lz, 111). 4.1Y-3.YY t69 (m, 2H), 3.41-3.18 (m, 2H)„3.01-2.72 (m, 2H). 1.99-1.72 (m, 2H). 1.50 (d, 1=4.4 Hz. 9H), ESI-MS nt/z cele. 310.1, found 311.0 (M+I) . Retention time 0.71 minutes.

Formation of (+/— )-tert-butyl 4-(2-amino-6-methyl- pyrunidut-4-yl)-3-(2-cltlorophcuyl)-l,q-dtazcqtanc-I- carboxylate (168) [0780] A mixture of tert-butyl 3-(2-chlorophenyl)-I 4-diazepane-l-carboxylate, 167„(0.42 g. 1.35 nunol), 4-cltloro- 6-methyl-pynmului-2-amuse (0.19 g, 134 nunol), mid tri- ethylmnine (0.38 mL. 2.69 nunol) in NMP (6 mL) was

stirred for I day at 150'. and thmi 3 days at room temperature I'he reaction ives diluted with water and extracted with IitOAc 'I'he organic layer was dried over

maenesium sulfate, filtered. and concentrated to dryness. The crude product ives purified via silica el chromatogra- (a) 2-chlorobettzaldehyde, 4 A mol sieves, Cl lzClz then phy cluting with 0-15% MeOH in dichloromcthane. Pure 2.6-1utidine, Cu(OTf),. hexafluoroisopropanol, CH,C2:150'.. (b) fractions were combuied miii conccntratcd to give IG3 mg of 2-amino-4-chloro-6-methylpyrimidine, EtzN, NMP. desired product as a brown oih 'H NMR (400 MHz. (c) HCJ, 1,4-dioxauc, (d) mcthmiesuli'onyl chlonde, DMSO-d6) 6 7.46-7.39 (ni. 111). 7 31-7 21 (m, 311). 5.78 (s, Et,N, CHzClz. 111) 5.61 (s. 111) 5 40(s 211) 4 54 (d 1 14 9 I lz IH) 4.33 (dd. 1=14.8. 5.7 Hz. IH), 3.99 (d, 1=13 7 Hz. IH), 3.G7-3.55 Fomiation of (+/ —)-tert-butyl 3-(2-chlorophenyl)-1, (m, IH). 3.16 (dd. 1=14.9. 11.2 Hz, IH), 2.86 (t, J=I2.9 Hz, 4-diazepane-I-carboxylate (167) JH), 2.00 (s, 3H), 1.87-1.52 (m, 2H), 1.38 (s, 9H), ESI-MS nt/z cele. 417.2, I'ounii 418.0 (M+I) . Retcnuou Junc. 0.81 [07'77] To a solution oi'ert-butyl (3-anunopropyl)((tribu- illlllutcs. tylstaiuiyl)methyl)carbamate (SnAP-DA) (3.0 g. 6.3 nuuol) in anhydrous dichloroniethane (16 mi,) was added 2-chlo- Fomiation oi'+/ — )-4-(2-(2-chlorophenyl)-1,4-diaz- robenzaldehyde (0 71 nil.) followed by 4 A MY, (0 64 8) 'I he epan-I-yl)-6-methylpyrimidin-2-amine (169) hazy yellow mixture was stirred at room temperature for 2 hours then filtered throu h Celite. The filter pad was nnsed [0781] A solution of tert-butyl 4-(2-amino-6-methyl-py- with 25 niL dtcltloromethane and the filtrate was concen- rinudui-4-yl)-3-(2-chlorophcnyl)-1,4-diazcpanc-l-carboxy- oi'4 trated to dryness. late, 168. (0.08 g. 0.19 nuuol) in HCJ(3 mL M solution, 12 00 mmol) in dioxane ives stirred overnight at room [0778] In a scparatc 250 mL RB ilask containing hexallu- temperature and then concentrated to dryness The crude oroisopropanol (25 mL) was addixl 2.6-lutulme (0.73 mL, residue ives used without hirther purification JiSI-MS m/z 6 28 mmol) folloived by Cu(01'fi, (0.40 g, 6 295 mmol) cele. 317.1. found 318.0 . Retention time: 0.49 (('u(O'I'f)z was dried under hi vac for 30 ininutes and heated (M+I) llllllutes. ivith heat gun). The suspension instantly became dark blue upon addition of Cu(OTflz, The mixture was stirred at room Fomiation of (+/— )-4-(2-(2-chloropheuyl)-4-(meth- temperature for I h. ylsulfonyl)-1,4-diazepan-l -yl)-6-methylpyrimidin-2- [07'79] The iminc solution above was dissolved prcparcd amine (170) 1-28 in ihchloromethauc (100 mL) and poured directly into thc grcmiislv blue lutidinc-Cu(OTf)z-hexafluoroisopropanol [0782] To a soluuon of 4-[2-(2-chlorophenyl)-1.4-diaz- mixture The reaction turned very dark green immediately epan-I-yl]-/&-inethyl-pyrimidin-2-smine, 16'7, (0.03 o. 0.09 and was stirred overnight at room temperature 'I'he reaction mmol) and triethyiamine (0.53 ml., 038 nimol) in dichlo- was quenched with 150 mL of a 2:I mixnire of aqueous mmethane (1.9 mL) ives added dmpwise a solution of saturated sodium bicarbonate solution and 10% ammonium metlmne suifimyl chloride (0.008 mL. 0.09G9 mmol) in hyiiroxiiic. The mixture was stirred for 15 minutes and then dicldoromcthanc (1.2 mL). 11ic reaction was surrcd Iiir 5 scqtamtcd. Thc aqueous layer was extractcxI 2x150 mL nunutcs and then conccntraicd to dryness. Thc crude residue dichloromcthane. Tlm combuicd organic phases were was puniicd by silica gcl Huomatography elutuig widi washed ivith bone, dried over nmgnesium sulfate. tiltered 0-10% MeOI I in dichlommethane (4 g IS('0 colmnn) Pure and concentrated to give 13 g of an ainber colored oil. 1 he fractions were combined. concentnsted. and lyophilized to US 20[9/032265[] A[ Oct. 24, 2019 163

afl'ord 15 mg of desired product: 'H NMR (400 MHz, Hz. IH). 2.29 (s. 1.5H), 2.20 (s„1.5H), 1.83 (m, 2H); DMSO-d6) 6 7.50-7.39 (m, I H), 7.36-7.20 (m, 3H). 5.96 (s, ESI-MS ngz cele. 405.16. found 406.2 (M+I) Rctcntton 2H). 5.74 (s, IH), 4.60 (d, i=IS.2 Hz, IH), 4.21 (ddd, ttmc. 0.57 minutes. 154. 5 3, 1.2 Ilz, 111). 3.80-3.61 211), 3.28 (dd, (m, [0785] The follovnng analogs werc prepared accordutg to 154. 11.1 I 111), 3 08-3 01 111). 2 86 311). 2 08 it, (m. (s. Syn1hctic Scheme 23: (s, 3H), 1.92-1.72 (m, 2H). 1.20 (t, J=7.3 Hz. IH): ESI-MS nt/z cele. 395 I„ found 39G.O (M+I) . Retention time. 0 65 n11nutes, 11 N

Example 23 Yi N

Synthetic Scheme 23 (+/— )-N-[3-[4-(2-amino-6- ntethyl-pyrimidin-4-yl)-1,4-oxazepan-3-yi]-4- chloro-phenyl]-3-hydroxy-propanmnide (171) 1-174 It)'783] (. 46 NH 0 HN 6 'if m, (. 0 (. 172

HV 011

'if — (+/ )-N-[3-[4-(2-4mitx1-6-methyl-pyruntdtn-4-yl)-1, 4-oxazepan-3-yi]-4-chloro-phenyl]-2,2,2-trifluom- acetamide (172) 1-159

[0786] heated (360K) 'H NMR (400 MHz, DMSO-d6) 6 (. 11.12 (s. IH). 7.71 (d. J=73 iqz. 2H)„7.52 (d, J=9.1 Hz. I H), 171 7.12 (1, 2H), 6.13 (brs. IH). 5.66 (brs, IH), 4.56 (br. IH), 4.23 (dd, J=13.6, 5.1 Hz. I H), 4.01-3.75 (m, 3H), 3.72-3.57 (m, 111), 2 25 (4, 31 I), I 89 (d..l 14 5117, 211), IISI-MS m/z cele 429.12. I'ouud 43014 (M+I)+. Itetentton time: 0.68 (+/ — )-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yi)-1. uuuutes. 4-oxazepan-3-yl]-4-chloro-phenyl]-3-hydroxy-pro- was panamale (171) 1-174 [0787] The racemic mixntre submitted for SFC clfiral separation. SFC condt1tonm Colunut. IC. 20x250 nun, [0784] To a solutton ol'-[3-(5-anuno-2-chloro-phenyl)- mobile phase. 30% McOH (5 mM mnmonia). 70% CO1 1,4-oxazcpan-4-yl]-6-methyl-pyrimidu1-2-4nunc. 46, (0 22 flow, 75 mL,'nun; concentrations: —24 mg/mL (McOH), , 0.66 mmol) in DM17 (18 ntl.) was added 3-hydroxypro- intectton volume 250 plz wavelength 254 nM, method panoic acid (008 8, 0 89 nmtol). diisopropylethyl amine typt. Isocratic. (0.2(i v, 2.01 mmol) and HrkTU (0.46 g. 1.21 mmol). The [0788] Peak W: (R) N-[3-[4-(2-amino-6-methyl-pvrimi- mixture tvas stirred at room temperature iitr 10 hours The din-4-yl)-I 4-oxatepan-3-yI]-4-chloro-phenyl]-2,2.2-trif- crude nnxturc was ddutcd with EtOAc and washcdI tiucc luoro-acctamulc (173). [&1]o (cW.5, MeOH) — 159.04 (98% umcs w 1th aqueous saturated NaHCO, solutton. The orgtuuc ec), ESI-MS ndz cele. 429.1, found 431.8 (M+I)'. Rctcntton phase was dried (MSSOs), liltered and concentrated tn time 0 54 minutes. 1-176 vacuo The cntde product w:as purified by ~ ilica gel chromato raphy (40 g IS('0 column) eluting with Dt'M. 10% [l)789] Peak H'S) N-[3-[4-(2-amino-6-ntethyl-pyritni- MeOH/DCM (0% to G5% gradient) to aflitrd 54 mg (20%) din-4-yl)-I 4-oxatepan-3-yI]-4-chloro-phenyl]-2,2.2-trif- 'H NMR (300 MHz. DMSO-dG) 6 12.67 (br. IH). 10.08 (d, luort1-scetamide (174): [0]o (c=0.5„MeOH) +157 28 (99% J=14.6 Hz. IH), 7.83 (br, IH), 7.74-7.31 (m. 4H), 6.67 (s, ec), 'H NMR (300 MHz. Mctlutnol-d4) 8 635 (d, J=2.5 Hz, 0.5H). 5.95 (dd, J=10.3, 5.4 Hr, 0.5H), 5.57 (d, J=3 0 Hz, 2H), 6 16 (d, J=9.2 Hz, I H), 4.22 (br, IH), 3 02 (dd, J=13.G, 0.5H). 5.18 (dd, J=9.6, 4 7 Hz. O.SH), 5.01 (d, J=13 9 Hz, 5.1 Hz, IH). 2.88-2.67 (m, IH). 2.56-2.23 (m. 3H). 2.03 (m, H I). 463 (t, .I 59 I Jz, 211), 423 (ddd, .I 309. 13 7. 52 I lz, 211), 0.59 (nt, 21 I); I:SI-MS m/z cele 429 12, found 429.99 2i I). 4 01-3 53 (nt. 411). 2 81 (t..l 5 9 I lt, I H), 242 (t..l 6 2 (M+I)+ ltetention time 0 615 ntinutes 1-177 US 20]9/032265[] A[ Oct. 24, 2019 164

-conlhlllixl 77s

Yif C. (.

( +/ — )-N-[3-[4-(2-amino-6-methyl-pyrimiilul-4-yl)-l, C; 4-oxazepan-3-ylJ-4-chloro-phenylJ-2-(dimethyl- ts7 amino)acetamide (175) 1-168 [0790] 'H NMR (300 MHz. DMSO-d6) b 9.90 (s. IH), 7.73 (il. J=8.7 Hz, I H), 7.63 (d. J=2.6 Hz. I H), 7 38 (d, J=8 7 Hz. IH), 5.96 (brs, 2H), 5.03 (br, 2H), 4.11 (s. IH), 3.94 (m, I H). 3.74-347 (m, 3H), 3 33 (s. 6H), 3.04 (s, 2H), 2.25 (s, 3i I). I 3)8 (br. 211): 118 I-MS m/7 cele 418.] 9 filund 419 0') (M+I) . Itetentton time 0 58 mimites (.

VH VY'.S cv

HiV

(+/ — )-N-(3-(4-(2-amino-6-methylpyrimiilul-4-yl)-l, 4-oxazepan-3-yl)-4-chlorophcnyl)-2,2-dilluoroacct- amide 1-250 [0791] 'H NMR (300 MHz, Methanol-d4) 6 7.78 (dd, 1=9.2, 2.5 Hz. IH)„7.67-7.35 (m, 2H), 6.(i3-648 (m. OH), 636-5.91 (m. IH), 5.65 (d, J=I.O Hz, IH), 5.37 (dd, J=IO 2, 5.0 Hz, IH), 5.20 (d, J=14.5 Hz, IH), 4.47-4.21 (m. IH), ()7 4.12-3.53 (m, 4H), 235 (d, JW.8 Hz, IH), 2.21 (d. JW.8 Hz, 1tc 211). 13)6 (d..i 107 Ilz, 211); ESI-MS m/z cele 411 13, found 412.23 (M+I)+ Itetention time 0.62 minutes Ilxample 24 Synthetic Scheme 24: (+,' )-4-[4-(2-anmlo-6- methyl-pyrimidio-4-yl)-1,4-oxazepan-3-ylJ-3- chloro-benxonitrile (179) I-')7 [(1792J CHO / 1 St

(a) 2-citioro-4-cyanophenyiborotuc acid, Pd(Ph,P),CI„ (.7 50" DME. Cu (b) MeMSBr, DMEI (c) NaBHe MeOH: (d) lac 4-chloro-6-methyl-pyrimiilui-2-anunc., NMP. ISO'G (c) chlral Sll( chnlfnatopraph)c US 20[9/032265[] A[ Och 24, 2019 165

Formation of (+/-)-3-chloro-4-(2,5.6.7-tetrahydro-l. 1=13.6. 4.9 Hz, IH), 3.93-3.76 (m. 3H)„3 65-3 57 (m. IH), 4-oxazepin-3-yl)benzonitrile (176) 2.15 (s. 3H), 1.87-1.79 (m, 2H), ESI-MS nrz cele. 343.12, fiiund 344.15 (M+I) . Rctenuon time. 0.57 nunuics. The [0793] Intermediate 176 was prepared according to Syn- mcemic mixture ivas submitted to chiral Sli('urification to thetic Schcnu: 13 using 2-chlom-4-cymiophcnylboromc acid obtain the individual enantiomers. instead oi'-chloro-S-hydroxyphcnyl boroiuc acid. [0797] Peak A. (R)-4-[4-(2-mnino-6-methyl-pyrunidui-4- yl)-1,4-oxazepan-3-yi]-3-chloro-benxonitrile (180); &9'1%& I'ormation of (+/— )-3-chloni-4-(2,5,6.7-tetrahydro-l. 'I lz, I )M)O- 4-oxazepin-3-yl)benzonitrile (177) ee; high temperature (360 K) l NMR (400 Mi d6) 6 7 93 (d, J I 5 i lz. 111), 7 69 (dd, .I 8 1. I 6 I fz. 111), [0794J 'Io a solution of 3-chlom-4-(4-fiirmy1-6.7-dihydro- 7.48 (d. J=8.1 Hz. IH). 3.6(i (s„ 1iq). 5.54 (d, J=53 Hz, IH), 511-1.4-oxazepin-3-yl)benzonitrile, 176, (1.0 8, 3 8 mmol) 5.41 (s. 2H). 4.47 (d, J=l(i.0 Hz. I H). 4.12 (dd, 1=13.5. 4.8 in DME ((i0 mL) at — 5 to 0" ('. was added MeMgBr (2 mL Hz. IH), 3.89 (dd, J=8.5. 3.6 Hz, IH), 3.73 (ddd, J=15.2, of 2M solution in 2-MeTHF. 6.4 nunol) under nitrogen. 12.9, 7.7 Hz, 2H). 3.61-3.52 (m. I H), 2.02 (s, 3H), 1.83-1.74 After 15 minutes, thc rcacuon was quenched with IM (m, 211), ESI-MS miz cafe 343.12, found 344 17 (M+I) sodium potassium tartrate and stirrrxl vigorously ibr I hour. Retention time 0 58 minutes 1-96 Thc reaction nnxture was partially concentrated and then [0798] Peak B. (S)-4-[4-(2-mnino-6-methyl-pyrunidui-4- extracted nvice with dichlommethane The layers v ere 1'1)-1,4-oxazcpdl1-3-v'I]-3-clllolo-bclizollltillc (181), . 99% separated with the aid of a phase separator and the combined ee; high temperature (360 K) 'I l NMR (400 Mi lz, I )M)O- organics concentrated in vacuo to give the desired pmduct as d6) 6 7 93 (d, J I 5 i lz. 111), 7 69 (dd, .I 8 1. I 6 I fz. 111), a semi-solid was yellow The crude product used in the next 7.48 (d. J=8.1 Hz. IH). 3.6(i (s„ 1iq). 5.54 (d, J=53 Hz, IH), without I'urther purilicaiion: ESI-MS nt/z cdlc. 252 07 step 5.41 (s. 2H). 4.47 (d, J=l(i.0 Hz. I H). 4.12 (dd, 1=13.5. 4.8 found 253.12 (M+I) Rcicntion tune. O.S5 muiutcs. Hz. IH), 3.89 (dd, J=8.5. 3.6 Hz, IH), 3.73 (ddd, J=15.2, 12.9, 7.7 Hz, 2H). 3.61-3.52 (m. I H), 2.02 (s, 3H), 1.83-1.74 Fomiation of (+/-)-3-chloro-4-(1,4-oxazepan-3-yl) (m, 2H), ESI-MS m/z cdlc. 343.12, found 344.17 (M+I) . benzonitrile (178) Retention time 0 58 minutes 1-97 [0795] To a soluuou of 3-cltloro-4-(2,5,6.7-tctrahydro-f, [0799] Thc Ibllowing analogs acre prepared accorduig to 4-oxazcpui-3-yl)bcnzonitnlc, 177, (0.84 g. 3.S9 nmiol) in Synthetic Scheme 24 starung from tlm appropnatc boroiuc McOH (10 mL) wus addix! NaBHd (0.68 g, 18.00 mmol) ai acids room tempemture After I 5 hours, the inixture was heated at 50" (1 After a further 3 hours. added additional I 0 8 NaBHd at 50" C. and then stirred at room temperature isz overnight. The reaction mixture was concentrated and cxtractcd twice with dichloromethanc. The layers were HH si.pdratcil w i(11 tile ald ol a pilose sc'paldtor slid tile orgalllcs conccntrdtcd ui vucuo. Purification was cerned out on a reverse phase 100 g ISCO cig-aq column„nuining v ith 'I 0 1% liAil lsO and 0 1% 'ITA/( I is( N fhe pure fractions ivere partially concentrated m vacua. some I M NaOH added and the mixture extmcted with dichloromethane three tunes dnd concentrated in vacuo to give 294 mg of thc destrcxf product: 'H NMR (400 MHz, DMSO-d6) 6 8.00 (m, IH), 7.81 (m. IH), 4.28 (dd, J=8.7. 3.3 Hz, IH), 3.8S-3.78 (m, 211), 3.75-3.(i0 (ni. 111). 3 30-3 26 (m, 111). 3 13-3 03 (ni, (+/-)-4-[3-(2-chloro-5-fluoro-phenyl)-1,4-oxazepan- ill), 2.92-2.84 (m, 111). 1.91-1.81 (m, 211) I:SI-MS nt/z 4-yl]-(i-methyl-pyrimidin-2-amine 1-70 cafe. 236.07, found 237 I (M+I) . Retention time: 0.49 (182) minutes. [IN0()J high temperature (3(i0 K) 'll NMR (400 Mliz, DMSO-d6) o 7.47 (dd, 1=8.8. 5 2 Hz. IH), 7.11 (td. J=8.2, Iiormation (+/ — )-4-[4-(2-amino-6-methyl-pyrinu- of 3.0 Hz. IH). 7.06 (dd. 1=9.6. 3.1 Hz. IH). 5.62 IH), din-4-yl)-1.4-oxazepan-3-ylJ-3-chioxi-benvonitrile (s, 5.49-5.41 (m, 3H), 4.60-4.50 (m. IH), 4.11 (dd, J=13.5. 4.9 (179) 1-97 Hz. IH), 3.92-3.8S (m, IH). 3.76 (dd, J=13.S, 10.0 Hz, IH), [0796] A mixture of 3-chloro-4-(1,4-oxazepan-3-yi)ben- 3 73-3.64 (m, III), 3 56 (dd..i 14 4, 12 011z, 111), 2 02 (s, I 80-1 ESI-MS zoniuilc (0 19 g, 0.80 nunol) and 4-chlom-6-methyl-pyumi- 311). 74 (m, 211): m/z cele 336.12. found dm-2-amuse (0.10 g, 0.70 nunol) was heated m NMP (I 5 337 14 (M+I) Retention time: 0 62 minutes The racemic mL) at 160' I'or 3.5 h. Puniication was carried out on a mixture was submitted to chiral SFC purification to obtain individual reverse phase 50 g IS( 0 cl 8-aq colunin. nmning v ith 0 1% the enantiomers. 'I FA,'I liO and 0.1% 'll'A/( I is( N 1'he pure fractions v ere [IN01J Peak A (R)-4-[3-(2-chlom-5-fluoro-phenyl)-1.4- concentrated in vacuo, triethylamine (I mL) was added and oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (183); 99.9% concentrated in vacuo again Purification by colunm chro- ee, high temperature (360 K) 'H NMR (400 MHz, DMSO- matography (40 g colunm, 0-10% MeOH/dichloromethanc) d6) o 7 93 (d, 1=1.5 Hz. IH), 7.69 (dd, J=g.l, 1.6 Hz. IH), aflbrdcd 124 mg ol'hc dcsircd product. Iugh temperature 7.48 (d, 1=8.1 Hz, IH). 5.66 (s, IH). 5.54 (d, J=SB Hz, IH), (360 K) "H NMR (400 MHz, DMSO-d6) 8 7.96 (s, I H). 7.73 5.41 (s, 2H). 4.47 (d. J=16.0 Hz, IH), 4.12 (dd, J=13.5, 4.8 (dd..i 8 I, I 6 I lz, 111), 7 50 (d, .I 8 I I I z, 111), 6 37 (s. 21 I), I Iz. I I I), 3 89 (dd, J R5. 3 (i I lz, 111), 3.73 (ddd, .I 15 2, 5 'J(i (s. II I). 5 65 (s, 111). 4 47 (d, .I 16 3 I lz, ] I I). 4 16 (dd, 12 9, 7 711z, 211), 3 (il-3 52 (m. 111). 2 02 (8 311), 1.83-1.74 US 20 [9/032265 [] A [ Oct. 24, 2019

(m, 2H)t ESI-MS m/z cele. 343.12, found 344.17 (M+I) . ltetention tilne 0 58 tltinntes I-78 [0802] Peak B: (S)-4-[3-(2-chloro-5-fluoro-phenyl)-1.4- oxazcpan-4-yl]-6-methyl-pyrinudin-2-anunc (184), 98% ce, thu lugh tcmpcraturc (360 K) 'H NMR (400 MHz, DMSO-d6) 6 7.93 (d, J=l 5 Hz, IH), 7 69 (dd, J=g. I, 1.6 Hz, IH). 7.48 (d, J=g.l Hz, IH), 5 66 (s, IH), 5.54 (d, J=S.3 Hz, IH), 5.41 (s, 2H). 4.47 (d, J=16.0 Hz, IH). 4.12 (dd, J=13.5. 4.8 Hz, IH). 3.89 (dd, J=8.5, 3.6 Hz. IH), 3.73 (ddd, J=15.2, 12 9, 7 7 I is. 211). 3 61-3 52 (m, 111). 2.02 (s, 311), 1.83-1.74 (nt, 2i I): itSI-MS m/z cele 343 12. found 344.17 (M+I)'. 0 Retention time: 0 58 minutes 1-79

(+/ — )-I -[3-[4-(2-anuno-d-ntethyl-pyrtnudin-4-yl)-I, 4-oxazepan-3-ylj-4-chloro-phenyl]pyrrolidin-2-one (187) 1-119 Itsx [0805] hi h temperature (3(i0 K) 'H NMR (400 MHz, DMSO-d6) 6 7.76 (d. J=2.7 Hz. I H). 745 (dd, J=8.7. 2.7 Hz, IH), 7.39 (d, J=g.g Hz. IH). 5.59 (s, IH), 5.42 (s, 3H), 4.63 (d, J=15.1 Hz. IH), 4.12 (dd, J=13.4. 5.0 Hz, IH), 3.91 (dt, .I 11 5, 3.8 Ilz, lli), 3 81-3 73 (m. 211). 3 72-3 52 (m. 311), 2 47-2.40 (m, 211), 2 ON-2 01 (m, 211), 2.(X) (s, 311), 1.80 (ddt, J=10.9. 7.5. 4.2 Hz, 2H); ESI-MS nt/z cele. 401.2, found 402.0 (M+I) . Retention time: 0.65 minutes.

(+/— )-4-[3-(2-chloro-4-fluoro-phenyl)-1,4-oxazcpmt- 4-yl]-6-methyl-pyrimidin-2-amine (185) 1-63 I I.ut

[(18(13] high tentperature (360 K) 'I l NMlt (400 Ml lz„ DMSO-d6) 6 735 (dd„J=8.8. 6.4 Hz. 2H). 7.13 (d. J=6.0 Hz, I H), 5.59 (s. I H), 5.47-5.41 (m, 2H), 4.58 (s, IH), 4.08 (dd, 1=13.4. 5.1 Hz. IH)„3.87 (s, IH). 3.75-3.50 (m. 3H), 2.01 (s, 3H), 1.77 (s, 2H), ESI-MS m/z cele. 336.12, fi)und 337 14 (M+I)+ Itetention time: 0.62 mimttes. 0

(+/ — )-(2-(4-(2-ammo-6-mcthylpynmtdut-4-yl)-1,4- Hsg oxazepan-3-yl)phenyl)methanol-91

[Ifg()6] high temperature (360 K) 'l l NMR (400 Mi lz, DMSO-d6) o 7.77 (s, IH), 7.51 (dd, 1=7.7, 0.7 Hz, I H), 7.36 (td, 1=7.4. 1.8 Hz, IH), 7.29-7.21 (m, ZH). 6 12 (s, IH), 5.18 (t. J=5.5 Hz, IH), 4.41 (ti, J=5.5 Hz, 2H). 4.18 (t, J=S.9 Hz. 2H), 3 93 (t. J=G.5 Hz. 2H), 2.03-1.95 (m. 2H), ESI-MS mtz 0 cele. 233.11, found 23417 (M+I) Retention time: 0.62 nunutes.

(+/— )-4-[3-(2-fluorophenyl)-I 4-oxazcpan-4-yl]-6- methyl-pyrinttdin-2-amine (186) 1-32

[0804] high tcmpcraturc (360 K) 'H NMR (400 MHz, DMSO-d6) 6 7 32-7 23 (m, 2H), 7.14 (dd, 1=13.0, 5.0 Hz, 2H). 5.71 (s, IH), 5.55 (s, IH), 5.45 (s. 2H), 4.43 (rl, J=15 5 Ilz,. 111). 4 15 (dd, .I 13 4, 5 I Ilz. 111). 3 90 (d, I 12 0 1lz„

1 il). 3 77 (dd,.i 13 3, 10 21iz, 111),363349 (m, 211), 2 02 0 (s, 311). 1.89-1.68 (nt. 211): IISI-MS ndz cele 302 15. found 303 19 (M+I)+. Itetention tune: 0.58 minutes. US 20]9/032265[] A] Oct. 24, 2019 167

(+/-)-4-[3-(6-methoxy-2-methyl-g-pyridyl)-1,4-ox- -conlhuaxl azcpan-4-yl]-6-methyl-pyrunldul-2-arnica 1-77 1'I [t)807] high tenlperature (360 K) 'll NMR (400 Milz, l)MSO-d6) 6 7 56 (s. 111), 6.59 (d, .I 8.5 I lz. Ili). 6 04-5 62 (m, IH)„4.08-4.01 (m, IH). 3.89-3.85 (m. JH). 3.75-3.55 (m, 213). 3 33-3 27 (m, 2H). 2.52 (s, 3H), 2.15 (s. 3H), 2.01-1.75 (m, 2H): ESI-MS ndz cole. 329.19, found 330.24 (M+I) . Rctenuou time. 0 47 mimltes. 888.

HN 1 ui 0

NHi 0

(+/— )-4-[3-(2„5-ddiuorophenyl)-1.4-oxazepan-4-yl]- 1-52 6-methyl-pyrimalin-2-anunc lvl [0808] high tempcraturc (360 K) 'H NMR (400 MHz, l)MSO-d6) 8 7.23-7.15 (m, 111). 7 12-6 98 (ln, 211). 5 75 (s, I I I), 5 58 (1, 111), 5 47 (s. 211). 4 36 (d..i 15 71iv, i I I). 4 13 (a) 3-(tributylstannylmethoxy)propan-I -amine, 4 A moi 1=13.3. (dd. 5 I Hz. IH). 3.89 (d. J=11.4 Hz. IH). 3.80 (dd, slcves, CHsCia: (b) 2,6-1uudlnc, Cu(OTI)u hexafluoroiso- 1=13.3, 100 Hz, IH). 3.65-3.50 (m, 2H). 2.04 (s, 3H), propanol. CH,CI,; c) 2-amino-4-chloro-6-methylpyrimi- I.S7-1.68 2H), ESI-MS ndz cele. 320.14, Ibund 321 2 (m, dulc, Nil ip, 150'H (d) L1OH, McOH, HsO, (c) cyclopropyi (M+I) . Rctenuou time. 0 6 mulules. amine, HAI'll. I itsN, l)MII Example 25 I'ormation methyl Synthetic Schcmc 25: (+/ — )-4-[4-(2-mmno-6- of methyl-pyumldu1-4-yl)-1,4-oxazcpm1-3-yl]-3- 3-chloro-4-(1.4-oxazepau-3-yl)bcnzoatc (188) chloro-N-cyclopropyl-benzamide (] 91) i-155 [0810] To a solution of3-(tributylstannylmethoxy)propan- [t)809] I-anunc (8.0 g, 21.0 mmol) in anhydrous dlchloromethanc (60 ml,) was added methyl 3-chioro-4-formyl-benzoate (4 2 g, 21 0 nunol) Ibllov;ed by 4 A mohxular slcvcs (5 g). The reaction ives stirred at room tenlperature for 2 hours. filtered over Celite. and diluted with anhydrous dichloromethane pi (180 mi.). 'I'o a separate flask contaming hexafluomisopn)- panol (60 mL) tvas added 2,6-lutidine (2.5 mL, 21.7 mmol) followed by Cu(OTf)c (7.6 g. 21.0 nunol) lllc blue suspen- Cl sion v as stirred at roon) temperature for 2 h. and then the 0 inane solution prcparcd above was added ul one portion. 1'osCH; The rcacnon mixture was surrcd ovcmlght and was then quenched with 100 nil of 2 I nlixture of aqueous saturated NH sodium bicarbonate solution and 10% atumonium hydmx- was 15 1 aa ide. The mixture stirred for minutes and then separated. The organic Layer was v ashed v ith aqueous saturanxl sodium bicarbonate soluuou followed by bnne. Thc orgaluc layer was concenualed in vacuo mid puulicd via sihca gcl chromatography elutlng with 0-70% EIOAc in heptane Pure fractions lvere combined and concentrated in vacuo to give 2 9 8 (51%) of the desired product 'I I NMR (400 MHz. CDCIs) 6 8.01 (d„ i=i 7 Hz. IH). 7.91 (ddd, 1=8.1. 1.7. 0.5 Hz, IH). 7.68 (d„J=S.I Hz, IH). 4.49 (dd, J=8.9, 3 5 Hz, IH), 4.04-3.96 (m. 2H), 3.92 (s, 3H). 3.84 (dl, J=12.3, 6.2 Hz, I H). 3.42 (dd, J=12 4, 9.0 Hz, IH). 3.24 (dl, J=13.6, 5.0 Hz, I H). 3.07 (dt, J=13.6, 6.8 Hz, IH), 2.00 (qd, .I 6 4, 5 0 I lv, 211); I)SI-MS ngz cele 269.08, found 2700 (M+I)+ ltetention time 0 58 nlinutes US 20]9/0322658 A[ Och 24, 2019 168

Formation of (+/— )-methyl 4-(4-(2-amino-6-methyl- 5.79 (s. IH), 5.55 (s, IH), 4.64-4.50 (m. IH). 4.13 (dd, pynmidul-4-yl)-1,4-oxazcpml-3-yl)-3-chlorobenzo- J=13.6, 4.9 Hz, IH), 3.97-3.85 (m. IH), 3 85-3 67 (m. 2H), aic 189) 3.67-3.53 (m. IH), 2.83 (u, J=7.7. 3.9 Hz, IH), 2 09 (s, 3H), [0811] A mixture of methyl 3-chloro-4-(1,4-oxazcpan-3- 1.86-1.74 (m, 2H), 0.68 (iii, J=7.1, 4 6 Hz, 2H). 0.60-0.50 yl)benzoate, 188. (0.37 g. 1.35 nunol) and 4-chloro-6- (m, 2H), ESI-MS m/z founii 402.0 (M+I)'. Retention tune. methyl-pyrinildin-2-aniine (0 19 o. 1.35 minol) in NMP (4 0.62 nunuics. nil.) ives stirred for 3 hours at 150'1 1'he reaction niixture [(1814[ I he following analogs v ere prepared according to was cooled to room tmnperaturc, dilutcil wuh EtOAc. and Svnthetic Scheme 25: washed ivith water The organic layer ives concenuated to dryness and punfied via silica gel chromatography elutiag 0-15% MeOI I to 252 with m dichloromethane give mg la 2 (47%) of the dcslrcd product. 'H NMR (400 MHz, DMSO- d6) 8 7.94 (d, J=l.7 Hz. IH). 7.85 (dd. J=8.1, 1.7 Hz. IH), 74i) (4 .I 8 I I lz 111) 6 90 (s, 211) 6 Oi/(d .I 26 i) 1lz IH) 0 5 6i/ (8 111). 4 51 (d, J 15.6 Iiz, 111), 4 18 (dd..l 13 7. 4 i) Hz. IH), 3.97-3.79 (m, 6H). 3. 71-3. 56 (m, I H), 2.20 (s. 3H), 1.86 (d, J=5.3 Hz„2H); ESI-MS m/z cele. 376.13. found 377 0 (M+I) . Retention time 0 72 ininutes.

Formation of (+/-)-4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazcpan-3-yi]-3udiioro-benzoic wld- irliluoroiiccliltc sail (190)

[0812] To a solution of methyl 4-(4-(2-anmlo-6-mcihyl- (+/-)-4-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4- pynmldul-4-yl)-1,4-oxazcpml-3-yl)-3-chlorobenzoatc, 189, oxazepan-3-yl)-3-chloro-N-methyl-N-(tetmhydm- (0.23 0.61 mmol) in MeOH (4 mL) and water (4.0 mL) g. 2H-pyran-4-yl)benzamide (192) 1-153 was added I.iOI I (0 10 8, 4.18 mmol). 1'he reaction niixture was stirred ai room tempcraturc overnight, actdtliod with [(1815] 'll NMR (400 Ml lz. DMSO-d6) Oteated 3(iOK) tS IM aq. HEI, and conccntraicd to dryness. The resulting 7.48-736 (m. 2H). 7.29 (ddd. J=8.3, (i.7, 1.7 Hz, IH), 6.G5 v, reverse co(de residue as purified by phase chromatography (s, 211), 6.00 (s. II I). 5 64 (s, 111), 4 54 (d, J 14.9 I is. I I I), I'rac- eluting v ith 0-60% Me('N in w:ster with 0.1% 1 liA 4.19 (dd. J=13.G, 5.0 Hz, I H), 3.94-3.75 (m, 5H). 3.70-3.58 uons containiug the dcstrcxI product were combuicd and (m, IH), 3.43-3.11 (m. 2H), 2.79 (s, 2H), 2 18 (s, 3H), concenlratcd in vacuo io give 134 mg ofthe desired product 1.92-1.72 (m. 4H), 1.58 (ddt. J=13.5, 5.2. 2 7 Hz, 2H); 'H NMR (400 MHz. DMSO-d6) 6 7.93 (d. 1=1.7 Hz. IH), ESI-MS miz Ibund 460.0 (M+I) . Retcntlou time: O.G2 7 85 (dd. 1 8 I . I 7 I lz, I I I). 7 47 (d, .I 8.1 I lz., I I I), 7 3'7 (4, nunutes. 1 23 9 I lz,. 21 I), 6 46-5 31 (m, 21 I), 5 04-4 28 (m, 111), 4 20 (dd. J=13.7. 5.0 Hz, IH), 3.9G-3.80 (m, 3H). 3.65 (ddd, 1=12.2. 10.0„4 3 Hz„ I H). 2.28-2.19 (m, 4H), 1.91-1.85 (m, 0 211): I vgl-MS m/z cele 362 I I, tilund 363 0 (M+I)+ Reten- tlol'l tllilc' 63 nllllutCs

Iionnation of (+/-)-4-[4-(2-amino-6-methyl-pyrinudin-4-yl)-1,4-oxazepan-3-yl]-3-chloro-N-cyclopropyl-benzamide (191) 1-155

[0813] To a solution of 4-[4-(2-imuno-6-methyl-pynnudin-4-yl)-1.4-oxazepan-3-yl]-3-chloro-benzoic acid (Trif- luomacetate salt), 190, (0 050 g. 0 100 inmol) in I)lvl F (033 mL) was added HATU (0.057 g, 0.150 mmol) followed by Et.,N (0.041 mL, 0 290 mmol). Aller siimng for I S numitcs, cyciopropylamine (0.011 mL, 0.150 mmol) was added and (+i —)-(4-(4-(2-amino-6-methylpynmidui-4-yl)-1,4- the mixnire lvas stirred overnight 'I'he reaction mixture was oxazcpan-3-yl)-3-chlorophenyl)(pyrrolldin-I-yl) 1-151 dduicd with 0 2S mL water and cxtmcied with I mL EtOAc. methanone (193) Thc orgmuc layer was conccniraicd io dryness mid the [0816] 'H NMR (400 MHz, DMSO-d(i) (heated 360K) 6 product was purified via silica gel cluomatography eluting 7.54 (d, J=1. (i Hz. I H), 7.47-7.33 (m, 2H), 5 84 (s, 1H). 5.58 with 0-12% MeOI I in dlchloromethane. Pure fractions v ere (s, IH), 4.56 (d. J=15.0 Hz. IH). 4.16 (dd. J=13.5, S.O Hz, combulcd. concmitrated ln vacuo and lyophihzed to give 7 IH), 3.90 (dt, J=12.0. 4.1 Hz, IH), 3.86-3.71 (m, 2H), 3.60 oi'the 'H mg desired product. NMR (400 MHz, DMSO-d6) (di, J=12.2, 7.4 Hz, IH). 3.14-3 10 (m, 2H), 2.11 (s, 3H), (heated 360K) o 8.22 (s, I H). 7.85 (d, 1=1.7 Hz. IH). 7.70 I 85 (dq, 1 11 JJ, 3.6 I lz, 811): I:SI-MS m/z filund 41(i 0 (dd..l 8 I, 1.8 I lz, 111), 7 37 (d, .I 8 2 I is, I I I), 6 07 (s. 211), (M+I)+ Retention time 0 75 niinutes US 20[9/032265[] A[ Oct. 24, 2019 169

-conlhnlixl 194 197 01 0 C'0 Ct1, ;iQ;— N .Nns Nt I 8

(+/ — )-Methyl 3-(4-(2-anuno-6-mcthylpyrimidin-4- (R)-4-[4-(2-1untno-6-methyl-pynmtdu1-4-yl)-1,4- yl)-l,t-oxazepan-3-yl)-t-chlorobenzoate (194) oxazepan-3-yl[-3-chlom-N,N-dimethyl-benzamide 1-126 (196) 1-143 and (S)-4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-3-chloro-N,N-dtm- [0817] 'H NMR (400 MHz, DMSO-d6) (heatcxl 360K) b ethyl-benzantide (197) 1-144 7 91-7 82 (m, 211), 7 65-7 53 (m. 111). Ci.)7 (s. 21i), 5.95 (s, 111), 5 66 (9, 111). 4 53 (d, .I 15 3 I lz, 111), 4.] 4 (dd, .I 13 6, [0819] Peak A: 4-[4-(2-tunino-6-methyl-pyruntdut-4-yl)- 4 9 I lz,. 111). 3 92-3 85 (m, 211). 3.84 (s, 311), 3.82-3.75 (nt, I,4-oxazcjtan-3-yl]-3-chloro-N.N-dimcthylbcnzatnnle IH), 3.65 (dt„J=12.2, 7 I Hz, IH). 2.15 (s, 3H). 1.85 (dq, (196); 'H NMR (400 MHz. DMSO-d6) (heated 3GOK) 6 1=8.5, ESI-MS 4.2 Hz. 2H); m/z calc. 376.13, found 377 0 7 47 (d .I I 6 I lz 111) 7 379 (d J 8 0 I lz 111) 7 33 (dd . Rctenuou time. 0 7 mututes. (M+I) .I 8 0, 1.7 Ilz, 111), Ct 78 (s, 211), 6.05 (s, 111). 5 /75 (s. II I), 4.54 (d. J=14.9 Hz, IH), 4.19 (dd„J=13.7, 5.0 Hz. IH), 3.9Ci-3.75 (m. 3H), 3.64 (ddd, J=12.2, 9.2. 4.9 Hz, IH), 2.92 195 (s, 6H), 2.20 (s, 3H), 1.84 (dp. J=9.9. 3 7, 3.2 Hz, 2H). 0 N~ ESI-MS m'z cele. 389.16. Ibund 390.0 (M+I) . Rctentton ttme: 0.61 minutes. [0820] Peak B: 4-[4-(2-amino-6-methyl-pyrimidin-4-yl)- 1.4-oxazepan-3-yl]-3-chloro-N.N-dimethyl-benzamide (197) IH NMR (400 MHz. DMSO-d6) 8 7.47 (d, J=I.G Hz, IH), 7.39 (d, 1=8.0 Hz, IH), 7.33 (dd, J=8.0, 1.7 Hz, IH). 6.78 (4, 2H), 6.05 (s. I H). 5.65 (s. I H). 4 54 (d, J=14.9 Hz. N 111), 4.19 (dd, .I 13.7. 5 0 I iz. 111), 3 96-3 75 (nt. 3i I). 3.64 (ddd I 122 172 49117 111) 292 (9 611) 220 (9 311) 1.84 (dp. J=9.9. 3.7, 3.2 Hz. 2H)1 ESI-MS ntrz cele. 389. 16187, found 390.0 (M+I) . Retention time: 0 61 minutes.

(+/-)-3-(4-(2-amino-G-methylpyrimidin-4-yl)-1.4- oxazepan-3-yl)-4-chloro-N-methylbenzamide (195) 19S 1-129 1'1 0

[0818] 'l l NMIC (400 Ml lz. IJMSO-dfi) Bteated 360K) Ct 8 21 (s. 111), 7 79-7 67 (m, 2i I). 7 54 (d..t 8 2117., 111), 6 8tj e (s, 211), Ct 07 (s, 111), 5 67 (s, 111), 4 57 (s. I I I), 4 16 (dd, 1=13.7. 5.0 Hz. I H) „3.89 (qd. 1=9.5. 3. 5 Hz. 3H). 3.Ci4 (ddd, N 8 NH 1=12.3. 10.3. 4.2 Hz, IH). 2.78 (d, J=4.5 Hz. 3H). 2.21 (s, 3H), 1.85 (dt, J=17.6, 5.7 Hz, 2H), ESI-MS nt/4 cele. 375.15, found 376.0 (M+I) . Rctcuhon ume: 0.59 nunutes.

196 0 (S)-4-(4-(2-amtno-6-mcthylpynmtdin-4-yl)-1,4-oxazcpan-3-yl)-3-chloro-N-methylbcuzamtdc (198) 1-150

[0821] 'H NMR (400 MHz, DMSO-d(i) (heated 360K) 6 8.20 (9, IH), 7.85 (th J=l.8 Hz. IH), 7.70 (dd, J=8.1. 1.8 Hz, N I H), 7.37 (d, J=8.1 Hz. IH). 5.59 (s, I H), 5.55-5.38 (m, 2H), 4.59 (d, J=15.5 Hz, IH), 4.12 (dd, J=13 5, 4.9 Hz, IH). 3.90 (dt, .I 11.9, 3 '1 Hz, lil). 3 81-3 64 (m, 211). 3.64-3.51 (m, 111), 2 77 (d,.l 4 6117. 311). 2 00 (9, 311), I 78 (dt,.l 7 8. 3 9 US 20]9/032265[] A] Oct. 24, 2019 170

Hz. 2H): ESI-MS nt/z calc. 375.15, found 376.0 (M+I) . (+/-)-3-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4- Retcnuon time: 0.58 minutes. oxazcpan-3-yl)-4-citloro-N.N-dunethylbcnzamtdc cl 0 1-130

/ [11824] 'll NMR (400 Milt. DMSO-d6) Oteated 360K) tS 7.51 (d, 1=8.1 Hz. IH). 7.39-7.28 (m„ZH). 6 71 (s, 2H), 6.03 I (s, IH). 5.65 (s, IH), 4.52 (d. J=15.0 Hz, IH), 4.17 (dd, Nl I J=13.6. 4.9 Hz. IH). 3.96-3.73 (m, 3H), 3.6S (ddd, i=12.2. 9.2. 6 I Hz, IH), 2.89 (d. J=3.4 Hz, 6H), 2.19 (s, 3H), 1.8S (dt, J=7.6. 4.3 Hz, 2H). ESI-MS m/z cele. 389.16, found 390 0 (M+I ) ltetention time 0 61 minutes

(+/-)-4-(4-(Z-amino-G-methylpyrimidin-4-yi)-I.4- oxazepan-3-yl)-3-cldoro-N-(2-(dimethyiamino) ethyl)-N-mcthylbcnzamidc I-IS4 0 [0822] 'H NMR (400 MHz. DMSO-d6) (heated 3/iOK) 8 7.53 (d, J=1.6 Hz. IH). 7 42 (d. J=8.0 Hz. IH). 757 (dd, J=8.0. 1.6 Hz, IH), 6.72 (s, 2H). 6.03 (s, IH). S.67 (s. IH), Nl ls 4.53 (s, IH), 4.18 (dd, J=13.6. 4.9 Hz. IH), 3.94-3.7S (m, 311), 3 73 3 59 (m, 311). 3 55 (td, .I 10 2 9 3 5 6 I Iz I H) 3 3 4-3 25 (m, 111), 2 93 (s, 3i I), 2 73-2 65 (m. 61i), 2.19 (s, 3H), 1.92-1.83 (m, ZH); ESI-MS m/z found 447.0 (M+I) . Retention time: 0.52 minutes. CI 0

(+/-)-4-[4-(2-amino-d-methyl-pyrimidin-a-yl)-I,4- oxazepan-3-yl]-3-chioro-N-ethyl-benzamtde 1-171

[(1825[ "II NMI& (400 MI Iz, I JMSO-ddi) (heated 360K) 6 7 51 (d, .I 8 I I lz, 111). 7.39-7.28 (m, 211), 6 71 (s, 21 I), 6.03 IH). 5.65 4.52 J=15.0 Hz„ IH), 4.17 (dd, N (s, (s, IH), (d, 1=13.6. 4.9 Hz. IH), 3.96-3.73 (m. 3H). 3.65 (ddd. J=12.2, 9.2, 6 I Hz, IH), 2.89 (d. J=3.4 Hz, 6H), 2.19 (s, 3H), 1.85 (dt, J=7.6, 4.3 Hz, 2H). ESI-MS m/z cele. 389.16. found 390 0 (M+I) . Retcnuon time. 0.61 minutes.

(+/-)-4-(4-(Z-amino-(i-methylpyrimidin-4-yl)-1.4- oxazepan-3-yl)-3-chloro-N-ethyl-N-methylbenz- mntdc 1-152

[0823] 'H NMR (400 MHz, DMSO-d6) (heatcsl 360K) 6 0 7.46-757 (m, 2H), 7.34-7.2S (m, IH), 6.79 (s, 2H), 6.0S (s, 111), 5 66 (s, 111). 4 53 (d, .I 14 711z, 111), 4.19 (dd, .I 13 6, Nl li 5 0 ilz„ ill), 33)5-3.77 (m, Sli). 3 64 (ddd .I 12 2 9 3 4 9 Hz. IH). 3.11 (ib 1=7.3 Hz, 2H), 2.92-2.86 (m, 3H). 2.20 (s, 3H), 1.89-1 79 (m, 2H). 1.21 (t, 1=75 Hz, 3H): ESI-MS nt/z found 404.0 (M+ I) . Retention time: 0.64 minutes.

(+/-)-3-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4- oxazepan-3-yl)-4-cidoror¹yclopropylbenzamide 1-172

[0826] 'H NMR (400 MHz. DMSO-d6) o 8 25 (s, IH), 7.76-7.66 (m. 2H). 7.53 (d, J=8.2 Hz, I H), 6 93 (s, ZH). 6.08 N (s, IH), 4.56 (s. IH). 4.15 (dd. J=13.7, 5.0 Hz, IH), 3.89 (ddd, J=16.0, 9.1. 3.7 Hz, 3H). 3.64 (ddd, J=12 2, 10.3, 4.2 Hz. I H). 2.89 (s, IH). 2.80 (ttI. J=7 7, 4.0 Hz, I H), 2.21 (s, 311) 1.95-1.76 (m, 211), 0 69 (td..i 7 0, 4 6 I is, 2i I). 0.56i (dt, .I 6.9, 4 3 lit, 2i I): I:SI-MS nv'z found 402 (M+I) US 20 ] 9/032265 [] A[ Oct. 24, 2019 171

-colttlltllixl

neo 0 0

N t'Oet.'H,

(+/— )-3-[4-(2-annno-6-methyl-pyrinndin-4-yl)-1,4- C02CHs oxazcpan-3-yl]-4-chloro-N-ethyl-benzmmde 1-173 0 [0827] 'H NMR (400 MHz. DMSO-d6) 6 8.24 (s. IH), 7.76-7.69 (nt. 2H), 7.52 (dd, J=7.9, 0.7 Hz, IH), Ci.32 (s, 2H), VH2 5.89 (s. IH). 5 60 (0, I H). 4.59 (d. J=15.1 Hz, I H), 4.13 (dd, J=13.6. 5.0 Hz, IH), 3.96-3.78 (m. 3H), 3.67-3.55 (m, IH), 3.27 (tltd, J=S.O, 7 2, 5. 9 Hz, 2H), 2.13 (s, 3H), 1.89-1.76 (m, 2il). 1.12 (t, .I 7 2 Iiz. 311): IISI-MS nt/z Hotmd 390

lexample 26

Synthetic Scheme 26 (+/— )-3-(4-(2-atnino-6-methylpyrimidin-4-yl)-1.4-oxazepan-3-yl)-4-methoxy-N- methylbenzamide 1-313 C02H [t)828] 0

t:HO 2I)4 109 Meo H

ts x ./H2 C02CH,

199 Meo 0

CO.CH;

20f/ 0 Meo Nne

201 200 US 20]9/032265[] A[ Ock 24, 2019 172

(40 mL) and concentrated Ht:I (40 mL of 12.1 M solution, 484 0 mmol) was stirred o& cmight at 100'. Thc m&xture was concentrated to iiryncss. Thc product was taken up in MeOI I and diluted into diethyl ether, then filtered and dried to give 2 2 o (84"/s) of a white solid 'll NMR (400 Milz, DMSO-d6) 6 8.12 (d, J=2.1 Hz, IH). 7.98 (ddd, 1=8.7. 358 2.1 Hz, IH). 7.18 (d, 1=8.7 itz, IH), 4 77-4 55 (m. IH), 4.00 (dd. J=I3.5, 8.9 Hz. IH), 3.93 (d, J=1.9 Hz. 3H). 3.91-3.85 (m, 2H), 3.49-3.41 (m. 2H). 3.26 (ddd. J=13 4, 9.4, 3.4 Hz. IH), 2.83 (ddt, J=47.7, 12.7. 7 3 Hz, 0 5H), 2.31-2.05 (m. 111), 2 05-1 75 (m, 0 511): i&SI-MS m/z cafe 251.12, found 252 0 (M+I ) ltetention time 0 5 minutes U& 1&ormation of (+/— )-methyl 4-methoxy-3-(1,4-oxazepm&-3-yl)benzoate (202j (a) methyl 3-fora&yl-4-nðoxybenzoate. Pdffls(dppf), DMF, NaHCO,. H&O, 80" C., microwave irradiation: (b) H&, [0832] To a soluuon of 4-methoxy-3-(1,4-oxazcpm&-3-yl) Pd/C, MeOH-EtOAct (c) HCI, MeOH. 100'u (d) diaz- bcnzo&c acid hydroc&loriiic, 201, (0.53 g, 1.6S mmol) in omcthyl(trnncthyl)s&lane, toluene. MeOH, (c) 2-&unu&o-4- toluene (22 &nl,) and MeOII (2.5 n&I.) was added diazom- chloro-6-mcthylpynmul&ne, NMP, 150'., (I) L&OH, ethyl(tnnðyl)silane (0.84 ml of 2 M solution, 1.69 m&nol) MeOI I. I I,O: ( ) MeNI I,. I LAI'll. Et,N„ i&MIE (h) SIT: in hexanes. The mixture was st&rred for 15 minutes then chiral chromatography concentrated to dryness to afford 487 mg of a colorless oik ESI-MS nffz cafe. 265.13. found 266.0 (M+I) Rctcnt&on Fomtation of methyl 3-(4-formyl-4,5.6.7-&etra- t&mc. 0.57 minutes. hydro-l.4-oxazepin-3-yl)-4-methoxybenzoate (199) Fonna&ion ol (+/ — )-methyl 3-(4-(2-am&no-6-mcthyl- [0829] A mixture of J-chioro-6,7-dihydro-5H-I,4-ox- pynmuhn-4-yl)-1.4-oxazepan-3-yl)-4-mcthoxybcn- azepine-4-carbaldehyde, 109. (2.0, 12.4 nmtol), zoate (203) (2-methoxy-5-mcthoxycarbonyi-phenyl)boronic ac&il (2.6 g, 124 mmol). and PdCI (dppl) (1.0, 1.3 mmol) u& DMF (37 [0833] A mixture of methyl 4-methoxy-3-(1,4-oxazepan- mL);md a&fucous saturated sodium b&carbonate (12 mL) was 3-yl)bcnzoatc. 202, (0.44 g. 1.6S mmol) and 4-chloro-6- heated in microwave reactor at 80" (2 ti&r 30 minutes 'I he methyl-pyrinudin-2-imunc (0.26 g, I 82 mmol) in NMP (S.5 reaction mixture was d&luted w:ith water, washed with water, m[,) was stirred for 4 hours at 150" C in a sealed tube. The and then the organic phase was concentrated to dryness. The nuxture v ss diluted with &vater and extracted with i&tOAc resulting residue was purified via silica gel chro&uatography The organic layer was concentrated to dryness and the clu&u&g w &th 40-100'/s EtOAc u& hc70&u&cs li&llov ed by a 10/o resultu&g residue was purified via silica el chromatogmuphy McOH u& d&chloromcthaue llush. Fract&ons contaming the elut&n with 0-12'/v MeOH in dichlommethane. Pure fmsc- des&rcd product werc combu&cd and conccnuatcxl u& vacuo to t&ons were combined m&d concm&tratcd u& vacuo to give 89 afford 2 4 g (63"/s) of the desired product as a colorless o&1 mg (14/s) of thc dcs&re&i product: H NMR (400 MHz. ' &5 8 2 2 l NM I& (400 M I fr, ('I&CI,) ib 8 04 (dd..l 8 6, 2 2 I Iz. 111), DMSO-d6) fi&usted 360K) 7.89 (dd..l 6, i is, II I), 7.95 (s, 114). 7.92 (d, J=2.2 Hz, IH), 6.90 (d. J=8.6 Hz. I H), 7 70 (d, 1 2 2 I Iz, 11 I). 7 I f& (d..l 8 7 I Iz. 111), 6 f&0 (s, 21 I ), 6.19 (s, HJ). 4.24 (dd. J=6.3, 5.3 Hz. 2H), 4.06 (t. 1=6.6 Hz, 5 89 (s, 111), 5 57 (s, 111),4 f&0 (d..l 14 711z 111) 4 19 (dd 2H), 3.92 (s. 3H), 3.87 (s. 3H). 2.18-2.09 (m, 2H). ESI-MS 1=13.4. 5.2 Hz. I H). 3.95 (s„3H), 3.90 (dt. J=12.0, 3.8 Hz, n&/z cele. 291 11, found 290.0 (M+ I) . Retcnt&on tm&c: 0 9 IH). 3 79 (s. 3H), 3.77-3.68 (m. IH). 3.63-3.54 (m, IH), nunc&ca. 2.14 (s, 3H), 1.80 (dt. J=7.7. 4.2 Hz, 2H). ESI-MS nfiz cafe. 372 18, found 373.0 (M+I) . Rctm&tion t&mc. 0.66 mu&uies. Forn&ation of (+/— )-methyl 3-(4-formyl-1.4-oxazepau-3-yl)-4-mcthoxybm&zoate (200) l&om&ation of (+/— )-3-(4-(2-amino-6-nðylpyrimi- din/ byl)-1,4-oxazepan-3-yl)-4-methoxybenzoic acid [0830] A nuxturc of methyl 3-(4-fern&y1-4.5,6,7-&etra- trifhioroacetate salt (204) hydro-f.4-oxazep&n-3-yl)-4-&uethoxybcnzoatc. 199, (2.4 g, [I)834J To a solution 3-(4-(2-anuno-6-uðyl- 8 2 mmol) and Pd/C (I 5 8, 0 7 mmol) in ethyl acetate (25 of methyl pyrun&din-4-yl)-1,4-oxazepan-3-yl)-4-methoxybenzoate, n&I.) and MeOI I (25 mf,) was shaken overnight under 55 ps& hydrogen. The reaction mixture was filtered over Celite and 203. (0.090 g, 0.230 num&l) in MeOH (I mL) and water (I the resultin filtmuted was concentmuted to dryness. The mL) w as added L&OH (0.025 g, 1.044 nunol). Thc react&on m&xturc was st&rrcd at Ibr 3 hours, ac&di- rcsultu&g rcs&due was punlicd vui s&1&ca gel cluomatography room temperature clutu&g with 40-100/o EtOAc in heptancs. Scvcral m&xed fied &vith I M HCI m&d thc mixture was punfiixi by rcvcrsc 10-90"/ Me('N fractions conte&n&ng the desired product v,cre carried onto phase chmmatography eluting with in water 'I'I'A the next step as is IISI-MS m/z calc 293 13, ti&und 294 0 vith 01"/ Pure fractions were con&bined, concentrated. and iyophilized to give 50 (58'/s) of the desired (M+I) . Retention time 077 minutes mg product: 'H NMR (400 MHz, DMSO-d/I) (heated 360K) 6 7.92 J=8.6, 2.1 Hz. 7.72 (s. 7.41 2H). 7.17 Format&on of (+/— )-4-methoxy-3-(1.4-oxazip&m-3- (dd, IH). IH), (s, J=S.G Hz, 4.24 (s. 3.99-3.90 3.80 yl)bcnzo&c ac&d hydrochlundc (201) (d, IH), IH), (m, 4H). (I, J=7.1 Hz, 2H). 3.64 (dt, J=12.2. 7.4 Hz, IH), 2.33-1.65 (m, [(1831J A solution of methyl 3-(4-formyl-),4-oxazepan-3- 611); ESI-MS m/z cele 358 16, found 359.0 (M+I) Reten- yi)-4-methoxybenzoate, 200, (2 4 o. 8 2 &nnx&l) in MeOI I tion time 0 6 minutes US 20 ] 9/032265 [] A[ Oct. 24, 2019 ]73

Fomtation of (R)-3-(4-(2-amino-G-methylpyrimidin- IH). 7.23 (d. J=7.9 Hz, IH), 7.02 (s. 2H). 6.05 (s, IH). 5.GI 4-yl)-1.4-oxazepan-3-yl)-4-methoxy-N-methylbcnz- (s, 111), 4 62 (s, 111), 4 24 (dd..i 13 4, 5 2 Iiz, HI), 3 95 (s, mnitie and (S)-3-(4-(2-anuno-6-mcthylpyrtnudin-4- 4H). 3.81 (dt. J=13.4. 7.9 Hz„2H). 3.60 (ddd, J=12.1, 9ch yl)-1.4-oxazepan-3-yl)-4-methoxy-N- 5.1 Hz, IH), 2.82 (d, J=4.5 Hz. 3H), 2.22 (s, 3H), 1.91-1.74 methylbeazamide (205) (m, ZH); ESI-MS nt/z cole. 371 20, found 372.0 (M+I) . [0835] To a solution of 3-[4-(2-amino-6-methyl-pyrimi- Rctcntton time. 0.55 nnnutcs. din-4-yl)-1.4-oxazepan-3-yl]-4-chloro-benzoic acid (Trif- [0840] The following azepanes were made according to luoroacctatc salt), 204, (0 085 g. 0.180 nunoi) ut DMF (I Synthetic Scheme 12. Anudc preparation according to Syn- mL) was added HATU (0.102 0.268 mmol) followed by g, thetic Scheme 26 lit,N (0.125 ml., 0 897 mntol) After stirring for 10 minutes, ntethylamine (0.7(X) mi, of 2 M, 1.40 tnmol) in 'I'Iiii was added and the reaction was stirred overnight. The reaction mixture ivas diluted with water and extracted w:ith EtOAc. los The organic layer was concentrated to dryness and purified isa silica gcl cluomatography elutm with 0-10/o MeOH tn dtchloromethanc. Pure I'racuons werc combined. concen- cost:Hi trated in vacuo and subjected to SIX'urification to aflbrd the racemic ntixture, 205, which was then submitted to SliO clfiral separation. [0836] Peak A: (R)-3-(4-(2-amino-6-methylpyrimidin-4- yl)-1.4-oxazepan-3-yl)-4-methoxy-N-methylbenzamide (206): 'H NMR (400 MHz, DMSO-d6) (hotted 360K) 6 7.90 (s. IH), 7.68 (dd, J=8.5, 2.3 Hz, IH), 7.50 (d, J=2.2 Hz, 1 il). 7 04 (d..i 8 6 Iiz, 111), 5 71 (d, .I 27 7 Ilz., 311). 5 25 (s, 111), 4 43 (s, I I I) 3 92 (s 311) 3 45 (dd„.l 14 5, i 1.2 I lz„ 1 il). 2 74 (d, .I 4 6 I lz, 311). 2 34 (dt, .I 14 0. 6 9 llz. 111), 2.03 (s. 3H). I 97-1 6/2 (m. 2H), 1.52 (q, 1=12.5 Hz. IH), (+/— )-Methyl 3-(I-(2-amino-6-methylpyrimidm-4- 1.43-1.21 (m„2H), ESI-MS nFz calc. 369.22. Iiiund 370 0 yl)azepan-2-yl)-4-methoxybenzoate (209) 1-111 (M+I) . Retcnuou time. 0.68 minutes. 1-314. [0837] Peak B. (S)-3-(4-(2-anunu-6-mcthylpyrimtdin-4- [IR841[ 'll NMR (400 Ml lz. DMSO-d6) flteated 36iOK) ib yl)-1.4-oxazepan-3-yl)-4-methoxy-N-tnethylbenzamide 7 82 (dd, .I 8 6, 2 2 I Iz, 111). 7 59 (d, .I 2 2 I lz, 111), 7 11 (d, (207); 'I I NMR (400 Mliz, DMSO-d6) (heated 360K) 6 .I 8 6 Ilz, 111), 5 55 (d..i 45.8 Iiz, 311). 5 25 (s. 111), 4.3/i 7 90 (s. 111), 7.68 (dd,.l 8 5, 2 311z, 111), 7 50 (d,.l 2.211z, (d,.i 44.71lz, III) 3 96 (s 311), 3 77 (s, 311), 3.3i)-3.28 (m, I H), 7.04 (d. J=8 Gi Hz, I H), 5.71 (d, 1=27.7 Hz. 3H). 5.25 (s, lit). 4.43 (s, IH), 3 92 (s, 3H). 3.45 (dd. J=14.5, 11.2 Hz, IH). 2.39 (dt. 1=14.1, 6.9 Hz. IH)„2.00 (s, 3H), 1.95-1.71 I H). 2.74 (d, J=4 6 Hz, 3H), 2.34 (dt, J=14.0. 6.9 Hz. IH), (m, 3H). 1.71-1.44 (m. Ziq). 1.45-1.16 (m„ZH): ESI-MS nt/z

2.03 (s. 3H). 1.97-1.62 (m. 2H). 1.52 (q, J=12.5 Hz. IH), cele. 370.20, found 371.0 (M+I) . Retention tnne: 0.78 I 43-1.21 (m, 211), ESI-MS nVz cele 36i9 22. found 370 0 llllllutes. (M+I) . Itetentton time 0 68 mimttes 1-315. [0838[ 'I he following analogs were prepared according to Synthetic Scheme 26: 2/u

zos

xtt

N (+/ — )-3-(I-(2-annno-6-mcthylpyrnntdtn-4-yl)azcpmt- Z-yi)-4-methoxy-N,N-dimethylbenzamtde (210) 1-115

(+/— )-4-(4-(2-amino-6-methylpyrinutlin-4-yl)-1,4- [0842] 'H NMR (400 MHz. DMSO-dG) (heated 360K) 6 oxazcpan-3-yl)-3-methoxy-N-methylbcnz unide 731 (dd, J=84, 2.1 Hz, IH), 7.15-6.93 (m, 4H), 6.02 (s. I H), (208) 1-316 3.91 (s. 3H). 3.54 (s. IH), 2.90 (s, 6H). 2.20 (s. 3H), [0839[ 'I I NMIt (400 Ml lz. IJMSO-dfii) fiteated 360K) (t 2.01-1.68 (m, 4H), 1.63-1.20 (m. 3H), ESI-MS nt/z calc. 8 12 (s. 111), 7 49 (d,.l 1.611z, 111), 7 40 (dd„.l 7 '), 1.611z„ 383 23, found 384 0 (M+I)+ Itetention time 0.7 mimttes. US 20]9/032265[] A[ Oct. 24, 2019 174

(dt, J=14.0. 6.9 Hz. IH), 2.03 (s. 3H). I 97-1 62 (m. 2H), 211 1.52 (q, 1=12.5 Hz, IH). 1.43-1.21 (m„ZH): ESI-MS nt/z cele. 369 21646. found 370.0 (M+I)+ Itetention time 0.68 nunutes. 1-149 [0845] (R)-3-[I-(2-amino-6-methyl-pyumtdut-4-yl)azepan-2-yl]-4-methoxy-N-methylbmtzamtdc (213), 'H NMR (400 MHz. DMSO-d6) (heated 360K) 6 7.90 (s, IH), 7.68 (dd. 1=8.5. 2.3 Hz, IH), 7.30 (d„J=2.2 Hz, IH). 7.04 (d, .I 8 6 Ilz, ill), 5 71 (d..i 27.7 Iiz, 311). 5 25 (s. 111), 4.43 (s, 111),392 (s, 311), 3 45 (dd..i 14 5, 11 2112. 111), 2 74 (d, J=4.6 Hz, 3H), 2.34 (dt, J=14.0. 6.9 Hz, IH), 2 03 (s, 3H), 1.97-1.62 (m, 2H), 1.52 (q, J=12 5 Hz, IH). 1.43-1.21 (m. 2H). ESI-MS ndz cele. 369.22, Ibund 370.0 (M+I ) . Reten- tion tinte 0 68 mimttes 1-148

(+/ — )-3-(I-(2-amino-6-methyipyrimidin-4-yl)azepan- 214 2-yl)-4-methoxy-N-methylbenmmide (211) 1-114

'H NMR MHz. DMSO-d6) (heatml 360K) 6 [0843] (400 — 7.90 (s. IH), 7.68 (dd, J=8.5, 2.3 Hz, IH), 7.50 (d, J=2.2 Hz, 8 S I il). 7 04 (d..i 8 6 Iiz, 111), 5 71 (d, .I 27 7 Ilz., 311). 5 25 0 (s, I I I), 4 43 (s, I I I) 3 92 (s 311) 3 45 (dd„.i 14 5, i 1.2 I lz„ I il). 2 74 (d, .I 4 6 I lz, 311). 2 34 (dt, .I 14 0. 6 9 llz. Hi), 0 2.03 (s. 3H). I 97-1 ti2 (m. 2H), 1.52 (q, 1=12.5 Hz. IH), 1.43-1.21 (m„2H), ESI-MS n6z calc. 369.22. iitund 370 0 (M+I) . Retcnuou ttmc. 0.68 minutes. NH

(+/— )-4-[3-[2-cldoro-4-(l.l-dioxo-1.2-thiazolidin-2- yl)phenyl]-1,4-oxazepm1-4-yl]-6-methyl-pynnudut- 2-anunc (214) 1-193 [0846] heated (360K) 'H NMR (400 MHz, DMSO-d6) 6 730 (d, J=8.6 Hz, IH). 7.26 (d„J=2.4 Hz. IH), 7.13 (dd, J=8.6, 2.4 Hz, IH), 5.59 (s. IH), 5.47 (s, 2H), 4.60 (d, J=15.1 212 Hz, I H), 4.09 (dd, J=13.4, 5.0 Hz, IH), 3.93-3.84 (m, I H). 3 77-3.71 (m, 311), 3.70-3.50 (m. 211), 3 46 (t, .I 7 4 I is, 411), 2 44-2 35 (nt, 2i I). 2 Ol (s. 311), I 78 (tt, .I 82E 4 3 I is, 2H): ESI-MS m'z cele. 437.1, fitund 438.0 (M+I )'. Reten- tion time; 0.67 minutes. Example 27

Synthetic Scheme 27 (+1 — )-4-(3-(2-chlont-4- ((methylsulfonyl)methyl)phenyl)-1.4-oxazepan-4- yl)-ti-methylpyrimidin-2-amtne (219) 1-208 [I)847]

212

(S)-3-(I-(2-anuuo-6-mcthylpyrnuulin-4-yl)azcpmt-2- yl)-4-methoxy-N-mcthylbcnzanudc (212) 1-149: (R)-3-(I-(2-amtno-6-mcthylpyrinudin-4-yl)azcpmt- 0 2-yl)-4-ntethoxy-N-ntetbylbenzamide (213) 1-148 5 [0844] (S)-3-[I-(2-amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-N-mcthylbcnzamidc (212). IH NMR (400 MHz. DMSO-d6) 6 7.90 (s, IH), 7.68 (dd. J=8.5, 2 3 Hz. I H). 7.50 (d, J=2.2 Hz. I H), 7.04 (0, J=8.6 Hz, I H), 5.71 (d, 1 27 7 llz, 311), 5 25 (s, 111), 4 43 (s, 111). 3 92 (s, 311), 21 3 45 (dd. 1 14.5. 11 2112, III). 2 74 (d,.l 4 62 IIz, 311), 2 34 US 20 1 9/032265 JJ AJ Oct. 24, 2019 175

-continued Formation of (4-bromo-3-chlorobcnzyl)(methyl)sulfane (21S)

J(1848J 11&e I-bromo48(iron&onðyl)-2-chloro-benzene (120 g, 422 mmol) was dissolved in MeOH (I L) in a 2 L round-bottomed fiask equipped with an overhead stirrer, 0 o& tcmperaturc probe, and a 500 mL add&tion funnel. Thc

2&6 solution was cooled to O'. in a bru&c bath. 11&c NaSMc (235 of 15%v v,/w, 503 mn&ol) solution wac added dn&pwise g (' 0 at a rate to keep the ten&perature below 10" white solid II s— precipitated The solution was stirred over the weekend 'the reaction was poured into IN NaOH and extmcted three / times &v&th dichloromethane. The extmcts were combined, duad (MSSOc). Iiltcred and evaporated in vacuo to alii&rd I-bromo-2-chloro-4-(methylsulfanylmcthyl)benzcnc (105 ' g, 99%) as a clear, slightly purple o&l. NMR showed Ihc oil to be pure product and consistent &vith previous batches 'll NMR (300 Mllz. CD( I&) 7 54 (d,.l 8 211z, 111), 7 40 (s, IH)„7.07 (dd„1=8.2, 1.(i Hz. IH). 3.59 (s„ IH). 1.99 (s, 2H) ppn&.

Formation of 2-chloro-4-((methyl&bio)methyl)bcnzaldehyde (216)

J(1849J '[1&e I -b&omo-2-chloro-4-(methylculfanylmethyl) benzene, 215, (2.9 8, 11.4 num&1) was dissolved m THF (75 mL) in a flame-dried 250 mL round-bottomed flack equipped with a magnetic stirbar. The yellow solut&on was cooled to — 78' u& a dry icc/acetone bath Thc nBuL& (6.6 mL of 1.9 M solution, 12.S nunol) was added dropw&sc v&a synngc at N a rate to keep the ten&pemture below — 60" (1 The reaction in&t&ally turned a reddish-orange color dunng the nliul i addition but changed to a brown color after st&rrmg for 15 mu&utes. The DblF (1.2 mL„15.5 mmol) was added via syringe at a rate to keep the tempemture below —60" ('. The reaction was stirred for 30 minutes ai — 78'. m&d then removed from thc cooling bath and allowed io w arm to room temperature 1'he reaction mixture was poured into I N I I( I and extracted &vith M'(III! 'I'he extract wac duad (MgSOc), filtered and evapomted in vacuo to atford 2 2 g of the crude y+N&t& product as a yeliow oil. The product was purified via silica gel chromatography using a 120 g ISCO silica gel cartridge N using an &socrai&c grad&m&t oi 50% dichloromcihanc/heptane. Thc fract&ons cont&unu&g the largest peak werc combu&cd and evaporated in vacuo to afiiord 2-chlom-4-(methylculfanylmethyl)benzaldehyde (I 95 g, 85%) ac a slightly yellov: oil 'H NMR was consistent with the product 'll NMR (3(30 MHz. CDCI,) 10.45 (s, I H). 7. 89 (d. 1=8 0 Hz. I H), 7.43 (d, 1=1.3 Hz, I H). 7.39-7.30 (m. IH). 3.68 (s. 2H), 2.02 (s. 3H) ppm.

Fonna&ion of Nit. 2-cldoro-4-((mcthylsulibnyl)methyl)bcnzaldchyde (217) (08501 Thc 2-chloro-4-(methylsulfanylmcthyl)benzaklc- hyde 2-chloro-4-(mcthylsulfanylmcthyl) bcnzaldchydc. 216, (8 75 g, 43.60 mmol) &vas dissolved in dichk&romethane (400 ml,) in a I I, round bottomed flask equipped with a magnetic stir bar. The n&CPBA (22 2 g, 89.97 mmol) was (a) NaSMe. MeOH, O' to RT; (b) nBuLi. THF. — 78" C., added completely dissolving. After 15 minutes, a white colid then DMF: (c) mCPBA, CHcCI„(d) i) 4 A mol s&aves, prcc&p&is&cd. After st&rrmg Ibr I hour, the rcacuon m&xiurc 3-((tubuiylst;utnyl)methoxy)propan-I-annnc. CH&CI„ i&) was poured into saturated aqueous NaHCO, solut&on and 2,6-luiidu&e, Cu(OTI)„hexafiuom&sopropanol, CHcCI&; (c) extracted with dicldoromcthane. Thc orgaruc phase was 2-an&ino-4-chloro-6-methylpyumidine, nl3uOI I. 135" (': (f) dried (MSSOc) and filtered overs plug of silica gel 'I'he plug Sl&('himl chromatography was eluted v,ith 25% 1itOAc&d&chloronðane and the fil- US 20[9/032265[] A[ Oct. 24, 2019 176

trate was evapomted in vacuo to afiord 2-chloro-4-(methyl- 1=1.2 Hz. IH), 7.33 (d. J=1.0 Hz. 2H). 5.59 (s, I H). 5.46 (s, sulfonylmethyl)bmizaldehyde (9.1 g, 90/v) as a wlute solid. 3H), 4 59 (d. J=14.9 Hz. IH), 4.43 (s, 2H), 4.13 (dd, 1=13.5, 'H NMR was cons&stmi& w&th thc producu 'H NMR (300 5.0 Hz, IH), 3.94-3.S5 (m. IH), 3.74 (dd, J=13.6, 10.3 Hz, Ml is. (:I)( I,) 10 48 (s, 111), 7 97 (d..t 8 01iz. I li), 7 56 (s, 111), 3 70-3 6&2 (m, III), 3.55 (ddd,.I 12 0, 9 8, 4./i I lz, II I), I i I). 7.50-7.40 (m. 211), 4 28 (s, 211), 2 86 (s, 411) ppni. 2 88 (s, 31 I), 2.00 (s. 311), I 82-1 72 (m. 211); I IS I-MS m/z cele. 410.1. found 411.0 (M+I) . Retention time: 0.62 Fomiation of 3-(2-chloro-4-((methylsulfonyl) muiutes. 1-223. methyl)phenyl)-1.4-oxazepane (218) [0855] Peak B: (S)-4-[3-[2-chloro-4-(methylsultiinylm- c&hyl)phenyl]-I 4-oxazepan-4-yl]-6-&ucthyl-pyrimidux-2- [0851] /8 mixture of 3-(tributylstannylmethoxy)propan-I- anune (221), 'H NMR (400 MHz, DMSO-d6) 6 7.50 (d. an&inc (3.4 g. 8.9 nunol). 2-chloro-4-(methylsulfonylmethyl) .I 1.2 Ilz, 111), 7.33 (d,.I I I Iiz. 211). 5 60 (s, 111). 5 46 (s, bcnzaldehydc, 217. (2.0 g, 8.6 nunol) mid 4 angstrom 311) 4 59 (d..t 1-1 8 Hz 111) 4 43 (s 211) 4 14 (dd .I 13 5 molecular sieves in dichloromethanc (40 mL) w as surrcd for 5.0 Hz, IH). 3.95-3.85 (m, IH). 3.74 (dd„1=13.5. 10.2 Hz, 20 hours. The mixture was filtered. In a separate flask I H). 3 70-3. 62 (m, I H). 3.55 (ddd. J=12.0. 9.9, 4.6 Hz, I H), containing hexafluoroisopropanol (10 0 mi,) v as added 2.6- 2.88 (s. 3H). 2.01 (s, 3H), 1.84-1.73 (m. 2H); ESI-MS m/z lutidine (I I ml . 9.5 mmol) followed by ('u(01 f)s (3 3 g, cele. 410.1. I'ound 411.0 (M+I) . Rctenuon time: 0.64 9.1 nunol) and dichloromethane (10 mL). The mixture was nunu&cs; Optical rotauon. +47.7'3.1 mg in I mL MiqJH). stirred for 3 hours at room tempemture. The filtered &mine 1-224. solution was add&xi in oue pornon to &hc second flask all a& once. The resuluug rcacnon nuxturc was st&rred ovemi h&, Extunple 28 filtered and then treated with 100 mi, of 2 I mixture of aqueous satumted Nail('Os solution and 10% ammoniuni Synthetic Scheme 28: (S)-I-(4-(4-(2-amino-6-meth- hydroxide 'I'he organic phase was separated and washed ylpyrimidin-4-yi)-I.4-oxazepan-3-yl)-3-chlorophe- tvith aqueous saturated NaHCO, solution, dried with sodium nyl)-4-methylpipcndui-4-ol (222) 1-242 sulfate. filtered and concentrated in vacuo. The resulting rcsuluc was punlicd by silma gcl cluomatography using 80 [0856] gram ISCO column elutuig w&th 0-15/'I me&hanoi/dichloromethane to afliird I I grams of desired pmduct as a yellov oil 5 second purification by silica gel chromatography using 40 gmm IS(:0 column eluting with 0/8% methanol/dichloromethane was required to afiord 690 mg of pure desired product as a yellow oil 'H NMR MHz. 6 7.64 (400 CDCI,) Nit. (d, J=S.O Hz. IH), 7.43 (d, J=I.S Hz. IH), 733 (dd, J=8 0, 1.9 Hz. IH). 4.46 (dd, J=9.0, 3.5 Hz, IH), 4.20 (s, 2H), 4.07-3.92 (m, 2H), 3 85 (d&, J=12.3, 6.2 Hz, IH). 349 (s, 2il). 3 44 (dd, .I 12 4, 'I I Ilz, 311), 3 24 (dt,.t 13 6. 5 0 llz„ 1 il). 3 06 (dt, J 13 7. /i 8 Iiz. 111), 2 81 (d, .I 0 8 Ilz. 311), 2.00 (qd. J=6.4, 4.9 Hz, 2H). 1.81 (s, 2H): ESI-MS nt/z cole. 303.8, found 304.0 (M+I) Retention time: 048 mimues.

Iiormation of 4-(3-(2-chloro-4-((methylsultioayl) methyl)phenyl)-1.4-oxazepan-4-yl)-6-&nethylpyrimi- din-2-amine (219) Nit [0852] /8 solution of 3-[2-chloro-4-(methylsulfonylm- cthyl)phenyl]-1,4-oxazepane, 218, (1.02 g. 3.37 nmiol) and 4-chloro-6-methyl-pynmidui-2-anune (0.58 g, 4.05 nmiol) in n-BuOH (15 mL) was stirred ovemigh& m a sealed tube at 'I'he 135" ('hen concentrated to dryness residue was 7 dissolved in IitOgc and washed with aqueous saturated sodiuin bicarbonate solution. The organic layer was concentrated to dryness and purified via silica gel chromatography (a) 4-mcthylpiperidui-4-ol. NaOtBu, 2,6-luuduic, &BuXPhos clutuig with 0-10/o McOH ui dichionuncdiane. Pure frac- palladacycle (I3 uons werc combuied and conccntra&ed &o give 830 mg of dcs&rixl product: ESI-MS m/z cele. 410.1. found 411 0 Fonna&ion of I-[4-[(3S)-4-(2-amino-6-methyl-py- I -3-eh (M+I) . Retention time 0 63 minutes rimidin-4-yl)- 4-ox a repen-3-yl] lorn-phenyl]- [t)853] I he mcemic mixture was submitted for SI&(: puri- I-niethyl-piperidin-4-ol (222) fication: /kD-IT 20x250 nun column using 40% MeOH (5 [(1857J 5 solution of (S)-4-[(3 S)-3-(4-bm&uo-2-chloro- mM anunonia) 60'/v CO, isocratic method. Pure fractions phenyl)-I 4-oxazepan-4-yI]-G-nðyl-pyrimidin-2-an&ine. were concentmted to dryness and run tluou h plug of silica 33. (3.1 g, 7.8 mmol), 4-methylpiperidin-4-ol (3.5 g. 304 clu&uig wi&h 0-10% McOH ui d&chloromethaim. Fractions nunol) and NaOtBu (3.0 g, 31.2 nmiol) in 2,6-1u&iduic (40 w i:le ciilicclltratcil allil lvoplllllzed. mL) was degassed vuth mtrogcn Ihr 5 minutes. &BuXPhos [0854] Peak zu (R)-4-[3-[2-chloro-4-(mcthylsulfiinylm- palladacyclc G3 (0.9 g. 1.2 nuuol) was added mid &he ethyl)phenylJ-1.4-oxazepan-4-ylJ-6-methyl-pyrimi din-2- reaction mixture ives stirred at room temperature fiir 2 hours amine (220) 'll NMR (400 Mlis, IJMSO-d6) &3 7 50 (d, 1'he nnxture was diluted with ivater and extracted 3 times US 20[9/032265[] A[ Oct. 24, 2019 177

with EtOAc. The combined organic phases were dried over 4-[(3S)-3-[2-chloro-4-(2-oxa-6-szaspiro[3 3]heptan- magnesium sulfate. filtered and concentrated in vacuo. 'I he 6-yl)phenyl]-1,4-oxazcpan-4-yl]-6-methyl-pynmt- resulting residue was punfied via silica gel chromatography din-2-;munc (224) 1-259 clutuig with 0-15% McOH ui dichloromethaim. Fractions [(1860J heated (360K) ( I I NM(t (400 Ml lz, l&MSO-d6) 8 containing the desired product were combined and concen- 7 ON (d, .I 84 I lz I I I), 6 43 (d, J 2 4 I lz. 111), 6 33 (dd, trated to e a light brown oil. A second punlicauon using go 1=8.5. 2.4 Hz. IH), 5.59 (d„J=11.6 Hz. 4H), 5.26 (s, IH), reverse silica 275 C(8-aqueous phase gel chromatography 8 4.68 (s. 4H), 4.02 (dd, 1=13.5. 5.0 Hz. IH), 3.91-3.83 (m, S-60% colunui eluting with MeCN in water with 0 1% TFA. IH), 3.67 (dd„ i=13.4, 10.1 Hz. IH)„3.63-3.50 (m, 2H). 2.01 Pure fractions were combined, neutralized with saturated (d, J=2.4 Hz, 3H), 1.74 (dd, J=8.4, 4 3 Hz, 3H), 1.25 (s, 3H), aqueous sodium bicarbooate solution and extracted twice ESI-MS miz cele. 415.2, found 416.0 (M+I) . Rctcntion 'I'he with I itOAc. combined organic phases v ere dried over time 0 7 minutes magnesium sulfate. filtered. concentrated in vacuo and lyophilized to atfiird 850 mg of product heated (360K) 'I I NMR (400 MHz. DMSO-d6) 6 7.07 (d, J=N.(i Hz. IH), 6.86 (d, J=2.6 Hz. IH). 6.79 (dd, J=8.8, 2.6 Hz. IH), 5.70 (s. 2H), 5 60 (s. 111). 5 28 (s, 111), 4 63 (d, .I 14 Gi I lz. 111), 4 11-3 ')5 (m, 211). 3 320-3.81 (ni. 111). 3 Gi7 (dd..( 13.4. 10 0 I lz. 111), 3.63-3.47 (m, 2H). 3.31-3.08 (m. 4H), 2.01 (s. 3H). 1.75 (dp, 1=12.3. 4.5 iqz, 2H), I 57-1 45 (m, 4H). 1.13 (s, 3H), ESI-MS m/z calc 431.2. foiuid 432.0 (M+I) . Retention NH umc. 0.58 nunutcs. XP V [0858] The Ibllowing aualogs werc prepared according to Synthetic Scheme 28 223 ('I 4-[(3S 1-3-[2-c(tloro-4-[(3-mcthyloxetau-3-yl)amino] phenyl]-(,4-oxazcpan-4-yl]-6-methyl-pyrtnudin-2- amine (225) 1-266

[0861] 'H NMR (400 MHz. MeOD) 8 7.00 (d, 1=8.5 Hz, xt(i IH). 6 47 (d, 1=2.4 Hz. IH)„6.32 (dd„ 1=8.5. 2.4 Hz, IH), Xy 5.S6 (br s, IH), 5.27-4.97 (bra. 2H), 4.73 (dd, J=S 9, 2.3 Hz. 2H), 4.53 (dd. 1=5.9. 1.8 Hz. 2H). 4.19 (dd, J=13.6. S. I Hz. 111), 4 (IO (d,.( 8 3112. III). 3 68 (dd, I 13 6. 10.5112, i(I),

3 60 (dd, .I 16 6. 7 8 I is,. 211). 2.0N (s, 311), I 98-1 82 (m, IH). 1.82-1.73 (m, IH), 1.61 (s, 3H). ESI-MS nFz cole. 403 1775. found 404.25 (M+I) . Retention time: O.G min- (S)-1-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4- utes. oxazepan-3-yl)-3-chlorophenyl)-3-methyhszetidin-3- lza ol (223) 1-261 Ci

[(1859J heated (360K) 'll NMR (400 Ml lz, DMSO-d6) 8 7 07 (d, .I N.5 I lz. 111). 6 41 (d, .I 2.3 I (z., I( I), 6 32 (dd, R5. 2 4 I is, 11 1), 5 68 (s, 21 I), 5 60 (s, 111), 524 (d..( 22 4 Hz, 2H), 4 (i6 (d. J=14.8 Hz, IH). 4.09-3.99 (m. IH), 3.87 (dt, 1=11.6. 3.G Hz, IH), 3.72 (d. J=7.3 Hz, 2H). 3.63 (t, J=7.5 Hz. 2H). 3.55 (ddd, J=12.4, 9.6. S.O Hz, 2H), 2 02 (s, 3H), 1.76 (u. J=8.3, 3.6 Hz, 2H), 1.43 (s, 3H); ESI-MS nt/z cele. 403.2, found 404 0 (M+I ) . Retention time: 0.7 minutes. 224 Ci 4-[(3S)-3-[2-chloro-4-[(3-methyloxetan-3-yl)methyl- mnino]phenyl]-1.4-oxazepan-4-yl]-6-methyl-pyrinu- V 0 din-2-annnc (226) 1-240

[(1862J 'll NM(t (400 MI(z. MeOD) ib 6 99 (d, J N.5 Ilz, IH). 6.70 (d, J=2.4 Hz. IH), 6.57 (dd, J=8.6. 2.4 Hz. IH), 5.75-4.80 (m. 3H), 4.33 (d. J=5.9 Hz„2H), 4.38 (d. J=5.9 Hz, 2H), 4.19 (dd, J=13.6. 5.1 Hz. IH), 4.00 (d, J=7.2 Hz. IH), 3.69 (dd. J=13.6, 10.5 Hz, IH), 3.60 (dd, J=13 7, 10.7 Hz, 2H), 3 26 (s, 2H), 2.07 (s, 3H), 1.96-1.71 (m. 2H), 1.36 (s, 311); ESI-MS m/2 cele. 417 2, found 418 3 (M+I) Reten- tion time 0 63 niinutes US 20]9/0322658 A] Oct. 24, 2019 178

5.57 (br s. IH). 5.35-4.80 (br s. ZH). 4 19 (dd. J=I3.6, 5.1 I lz, 111), 4 01 (d, .I 8 0 I lz„ I I I). 3 65 (ddd..l 24 2, 17 3, 11.3 Hz. 4H). 2.36-2.28 (m. IH), 2.07 (s. 3H), I 95-1.72 (m, 3H), 0.73-0.65 (m, 2H). 0.42 (td, J=6.6, 4.4 Hz, 2H), ESI-MS nt/z caic. 373.2, found 374.2 (M+I) . Retention ttme: 0.65 minutes.

230

l-[4-[(3S)-4-(2-amtno-6-methyl-pyrimidin-4-yl)-1.4- oxazepan-3-yl]-3-chloro-anilino]-2-methyl-propnn- 2-ol (227) 1-247 [0863] 'H NMR (400 MHz, MeOD) 6Ci.97 (d, 1=8 5 Hz, XP NH IH). 6.70 (d, 1=2 4 Hz. IH). 6.57 (dd. J=8.6. 2.4 Hz. IH), 5 57 (br s. 111), 5 14 (br s, 21 I), 4 19 (dd„.l 13 6. 5 I I lz, I i I). 4 00 (d, 1 8 2 I lz, 111), 3 75-3 52 (m, 311), 3 03 (s. 21 I), 2.07 (s. 3H), 2.00-1.70 (m, 2H), 1.23 (s, 6H). ESI-MS nVz cele. 405.2. I'ound 406.2 (M+I) . Retcntton tmtc: 0.6 nunutes. 22S 4-[(3S)-3-[2-chloro-4-[(I-methylazetidtn-3-yl) Ct mnino]phenyl]-1.4-oxazepan-4-yl]-6-methyl-pyrinudin-2-mnine (230) 1-246

[0866] 'H NMR (400 MHz. MeOD) 6 7.00 (d, 1=8.S Hz, IH), 6.57 (d, J=2 4 Hz. IH), 6 45 (dd, J=8.S. 2.4 Hr, IH), 5.53 (br s, IH), 5.09 (br s. 2H). 4.18 (dd, J=13.6. S.l Hz, 111), 4.05-3.95 (m, 211). 3 82-3 74 (m, 211). 3 68 (dd, .I 13 6, 10 5 I lz, Ill), 3.5'2 (t. 1 12 I I lz. 211). 3.02-2.94 (m, 211), 2 39 (s, 31 I), 2 06 (s. 311), I 96-1 73 (m. 211); ESI MS m/z cele 402.2, found 4033 (M+I ) ltetention time: 0.53 nunutes. 1-[[4-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-1, 4-oxazepan-3-ylJ-3-chloro-anilino J methylJ-cyclobu- 1-263 tanol (228) 233 [0864J 'll NMIt (400 Mllz, MeOI)) 6 698 (d,.i 85 llz„ I I I), fx72 (d, .I 2 4 I iz. 111), 6 58 (dd, .I 8 6. 2 4 ilz. 111), 5.56 (br s, IH), 5.07 (br s, 2H). 4.19 (dd, J=13.6. 5.1 Hz, IH), 4.00 (d. J=8.7 Hz. IH), 3.73-3.SS (m. IH). 3.59 (t, 1=12.3 Hz, 213). 3.17 (s. 2H), 2.16-1.98 (m. 6H). 1.96-1.70 (m, SH). 1.64-1.5/I (m, I H), ES1-MS nnz calc. 417.2. found 418 I (M+I) . Retention time 2 72 minutes. 229

(+/— )-[4-[4-[4-(2-amino-6-methyl-pyrimtdin-4-yl)-1, XP NHr 4-oxazcpan-3-yl]-3-cldoro-phenyl]piperszut-I -yl]- cyclopropyl-methanone (231) 1-273

[0867] 'H NMR (400 MHz. CDCI,) 8 7.13 (d, 1=8.6 Hz, IH), 6.92 (d, J=2.S Hz. IH), 6.76 (dd, J=8.7. 2.6 Hr, IH), J=13 4-[(3S)-3-[2-chloro-4-(cyclopropylamino)phenyl]-1. 5.58 (s, I H), 4.60 (3, 2H), 4.31 (dd, 5, 5.0 Hz, I H). 4.08 4-oxazepan-4-ylJ-6-ntethyl-pyritnidin-2-amine (229) (d, 1 12 2 I lz, ll I). 4.01-3.05 (m, 1111). 2 15 (s, 311), 1-248 I 92-1.62 (m, 311), 1.14-0338 (m, 211), 0 91-0.65 (m, 211); [0865J 'll NMIt (400 Mllz, MeOI)) 6 698 (d,.i 86 llz, ESI-MS m/z cele 4702, found 471 2 (M+I) Retention I i I). 6 80 (d, .I 2 3 I Iz. II I), 6 64 (dd, .I 8 5, 2 3 I lz, 111), time 2 72 minutes. US 20 ] 9/032265 [] A] Oct. 24, 2019 ]79

4-[(3S)-3-[2-chloro-4-(3-ntethoxyazetidin-I-yl)phe- 737 nvl]-1,4-17xazcpan-4-91]-6-ntcthyl-pyrnunhn-2- mninc (234) 1-217 [0870] heated (360K) 'H NMR (400 MHz, DMSO-d6) 6 b-- 7.08 (d, J=8.5 Hz, IH). 6.43 (d„J=2.4 Hz. IH), 6.33 (dd, Q J=S.S, 2.4 Hz, IH), 5.55 (d. J=7.9 Hz, IH), 5.47 (s, 2H), 5.29 (d, J=33.3 Hz, IH), 4.67 (d. J=14.8 Hz, I H), 4.29 (tt. J=6.2. 4 2 I is, ll I). 4.06-3.9'3 (m, 311). 3 87 (dt..l 12 0, 4.0 Ilz, 111), 371-348 (m, 511). 3 24 (3, 31 I), I 99 (d, J 2 8 I lz. 311), I 81-1.67 (m, 21 I); ESI-MS mtz cele. 403 2. found 404 0 (M+I )'etention time: 0.74 minutes

4-[(3S)-3-(2-chloro-4-morpholino-phenyl)-1,4-oxazepan-4-ylJ-6-methyl-pyrimidin-2-amine (232) Cl 1-216 [0868] heated (3GOK) 'H NMR (400 MHz. DMSO-d6) 8 7.14 (d, J=8.7 Hz. IH). G 92 (d. J=2.G Hz. IH). 6.83 (dd, 1=8.7. 2.6 Hz„ IH), 5.60 (s, 3H). 531 (s, IH). 4.65 (d. J=14 9 / Hz. IH), 4.06 (dd, J=13.4, S.l Hz, IH). 3.93-3.83 (m. IH), 3.74-3.67 (m. SH). 3.65-3.50 (m. 2H). 3.14-3.08 (m. 4H), 2 01 (d, .I 1.8 I Iz. 311). I 76 (dt, .I 8 3, 4. I I I z., 21 I): 11S I -M) V m,'z cele 403 2. found 404.0 (M+I ) ltetention time 0 7 minutes. 773

4-[(3S)-3-[2-chloro-4-( I -oxa-6-szaspiro[3 3]heptan- 6-yl)phenyl]-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-;munc (23S) 1-260

[lf87IJ heated (360K) 'l l NMlt (400 Mlis, l)M)O-d6) 6 7.08 (d. 3=8 4 Hz, IH). 6.44 (t, J=2 I Hz, IH). 6.34 (dt, J=8.5. 2.0 Hz, IH), 5.70 (s, 2H)„5.60 (s. IH). 5 28 (s. IH), 4.6S (d, 1=14.G Hz. IH). 443 (td, J=7.S. 1.5 Hz, 2H). 4.12-4.00 (m, 3H), 3.93-3.83 (m. 3H). 3.74-3.65 (m. IH). 3.6S-3.50 (m. 2H), 2.83 (td. J=7 5, I 6 Hz. 2H), 2.02 (d. .I 1.4 I is, 311), I 76 (h..i 5 I, 4 4 I lz, 211); 11SI-MS m/z cele. 4152, found 4160 Retention tmte: 0.74 4-[(3S)-3-[2-chloro-4-(2-oxa-7-azaspiro[4 4Jnonan- (M+I) nunutes. 7-yl)phenyl]-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amtne (233) 1-219

[0869] heated (360K) 'H NMR (400 MHz, DMSO-d6) 1) 7 07 (d, .I 8 6 I lz. 111). 6 52 (d, .I 2 6 I lz., 111), 6 45 (dd, R7. 2.5 Iiz, 111), 5 56 (s, 111). 5 49 (s 211) 5 24 (s 111) 4 613 (d..i 14 7 llz, I II). 4 03 (dd,.i 13 4, 5 01lz, ill), 3 87 (dt, J=12.0, 3 9 Hz, IH), 3.80 (t. J=7.0 Hz, 2H). 3.67 (dd, 1=13.4. 10.1 Hz. IH). 3 59-3.49 (m, 3H), 3.29 (dddd, J=9 6, 7en 4.9. 2.4 Hz, 2H), 3.20 (ch 1=3.0, 2.3 Hz. 2H). 1.99 (s, 3H), 1.98-1.80 (m, 4H), 1.76 (tt. J=8.3. 4.4 Hz, 2H)i ESI-MS m,'z cele. 443 2, found 444 0 (M+I) . Retention time 0 74 n11nutes

v 0 4-[(3S)-3-[2-chloro-4-(3-methoxypyrrohdin-I-yl) phenyl] - I,4-oxazepan-4-yl] -(nmethyl-pyruni din-2- anunc (236) 1-218 (mixture of 2 dtastcrcomcrs) [0872] heated (360K) '13 NMR (400 MHz. DMSO-dG) 7.07 (d, J=8.6 Hz, IH). 6.53 (d, J=2.S Hz. IH), 6.46 (dd, J=8.6, 2. S Hz, I H), 5.55 (s. I H), 5 48 (s, 2H), 5.27 (d. i=3 S.5 Hz. IH), 4.70 (d, J=15.4 Hz. IH). 4.10-3.99 (m, 2H), 3.87 (d, 1 12 2 I lz, 111), 3 67 (dd, J 13 4. 10 I I lz. 111), 3 55 (qd, .I 12.0, 10 9. 3 8 I lz, 211), 3.39 (ddd, .I 10 7, 5.3. 2.5 I is, US 20[9/0322658 A[ Oct. 24, 2019 180

IH), 3.28-3.16 (m„6H), 2 09-2.02 (m, IH). 2.00 (d..1=3 9 Hz. 3H), 1.81-1.69 (m, 2H), ESI-MS nfiz cele. 417.2. filund 418.0 (M+I)'. Rctenuon time. 0.78 minutes.

&37 0 D+si k p~P

tert-butyl 3-[4-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-1„4-oxazepan-3-yl]-3-chloro-lnilino]azeti- d&ne-I-carboxylate (237) I-25(i

[0873] 'H NMR (400 MHz, MeOD) 8 7.02 (d. J=8.5 Hz, p~P IH). 6.58 (d, J=24 Hz. IH), 6.46 (dd, J=8.5. 2.4 Hz, IH), QQNI I 5.54 (br s, IH), 5.28-4.90 (m. 3H), 4.30-4.14 (m, 4H), 4 02-33/6 (m. 111). 3 72-3 58 (m. 511). 2 07 (s. 311), 1.94-1. 73 (m, 211), 1.43 (s. 911); li)I-MS m/r cele. 488 2, found 489.3 (M+I) . Retention time: 0.69 minutes.

Example 29

[08'74] Synthct&c Sclmmc 29. (+7 — )-4-[3-[2-cldoro-4- [nn:lhyi(oxctan-3-)'1)tunnlo]phenyl]-1,4-oxBLcpan-4-1'I]-6- ',~P methyl-pyrinudin-2-an&ine 1-186 D

(a) oxctan-3-onc, Na(OAC)&BH. AcOH, CH&CIC, (b) NBH. methyl iodide. DMF. (c) TFA. CH&CIC, (d) 2-anuno-4- clfioro-6-nðylpyrimidiac. nBuOI I, 130'': (e) SI C chi all SCP'lfBI&nfl

l&onnation of tert-bmyl 3-(2-chloro-4-(oxetan-3- ylamino)phenyl)-1,4-oxazepane-4-carboxylate (239) [0875] To a solu&ion of tert-butyl 3-(4-Bnuno-2-cldorophcnyl)-1,4-oxazcpane-4-carboxylate, 238, (0.67 g. 2.04 mmoi) in dichloromethane (20 ml ) was added oxetan-3-one (0 22 o, 3 05 mn&ol) then AcOI I (0.15 n&I, 265 mmol) After 3 m&m&tes. sodium triacetoxyborohydnde (0.65 8, 3.05 mmol) was added to the reaction mixture. Afier 4 hours, aqueous saturated sodnun bicarbonate solution was addcxt and lhc organic phase was passed &luough a phase scpara&or Bnd Ihc lcsuhnlg Ill&rate wt&s conccn&ra&cd nl vacuo. Thc 746 resultmg residue was purified by silica gel chromatography (12 g iS('0 column; 20-100"/u I &tOAc &n heptane) followed US 20[9/0322658 A[ Oct. 24, 2019 181

by a second purification by column cluomatogrnphy (CI 8 3H). 2.86 (s, 3H). 1.97 (s, 3H)„1.72 (s. 2H): ESI-MS m/z AQ 40 g colunm, 0.1% TFA-waieri0.1%v TFA-McCN). The cele. 4032, found 40-'14 (M+I)'etention tmie: 0.57 fractions contau»ng dcsircd product were concentrated in iiiiiiutes. vacuo and then diluted with MeOI I and filtered off 300 mg [I)879J I he racemic mixnire was submitted fiir Sii('hinsl (39%) of desired product as a ivhite solid 'l I NMR (400 AD-H 20x250 MHz. d6-DMSO) o 7 00 (s, IH). 6.60 (s, I H). 6.45 (d. J=2 0 separation: tmn column usia 40% MeOH (5 Hz, 2H). 5.18-5.14 (m„ I H). 4.82 (t. 1=6.5 Hz. 2H). 4.51 (dd, mM iunmorua) 60% CO isocratic method. 1=12.8. 6.4 Hz. I H). 4 36 (t, J=6.0 Hz, 2H), 4.25 (d. J=14 0 [0880] Peak A: (R)-4-[3-[2-chloro-4-[methyl(oxetan-3-yl) Hz. IH), 3 89 (d, J=11.7 Hz, 2H), 3.44 (m, 4H), 1.75-1.65 anuno]phenyl]-1.4-oxazcpan-4-yl]-6-methyl-pyrinudin-2- 2H). 1.17 9H), ESI-MS m/z cele. 382.2, I'ounrl 383 3 (m, (s, amine (243); 99+% ee: 'id NMR (400 MHz. d6-DMSO) 6 (M+I) . Retention time 0 81 minutes 7.06 (d, J=84 Hz. I H). 6.71 (s, I H), 6.58 (d, J=8.S Hz, IH). 5 5 45-5 5 05-4 NN I'ormation of tert-butyl 3-[2-chlom-4-[methyl(ox- 85 (br s, 211), 26 (br s, 111), (br s, 111), 4.78-4.70 J=5.0 4.10-3.95 etan-3-yi)aminoJphenylJ-1. 4-oxazepane-4-carboxy- (m. 3H), 4.57 (d, Hz. 2H), (m, 3 90-382 1 3.70-3.46 2 late (240) 111), (m, i I). (ni. 311), 86 (s, 311), 1.97 (s, 3H), 1.72 (s, 2H); ESI-MS m/z cele. 403.2. found [08'76] To a soluuou of tert-butyl 3-[2-chloro-4-(oxctan- 404 2 (M+I) Retention time 0 58 minutes 1-189 3-ylanuno)phmiyl]-1,4-oxazcpanc-4-carboxylate, 239, (0 117, 0306 mmol) m DMI (2 ml,) under an atmosphere [0881] Peak B: (S)-4-[3-[2-chloro-4-[methyl(oxetan-3-yl) 4-oxazepan-4-ylJ-(i-niethyl-pyrimidin-2- of nitro en ives added Nal I (0 021 8, of 60% v /w. 0 525 aminojphenylJ-I, nunol). Afier 20 minutes, methyl iodide (0.070 mL. 1.124 aiiiiiie (244): 99.4% ee; 'H NMR (400 MHz. d6-DMSO) 6 nunol) was added to the reaction mixture that wns then 7.06 (d, J=84 Hz. I H). 6.71 (s, I H), 6.58 (d, J=8.S Hz, IH). surrcd at room tcmpcraturc. Afier 60 muiutes. arldiiioiial 5.85 (br s. 2H). 5.45-5.26 (br s, IH), 5 05-4 88 (br s, IH), NaH (0.060 g) und methyl iodide (0.100 mL) was added to 4.78-4.70 (m. 3H), 4.57 (d, J=5.0 Hz. 2H), 4.10-3.95 (m, thc mixiure. Added water and then extractcxl iwwc with 111), 3 90-3 N2 (m, 1 i I). 3.70-3.46 (ni. 311), 2 86 (s, 311), 'I dichlommethane be organic phases were passed through a 1.97 (s, 3H), 1.72 (s, 2H): ESI-MS nt/z cele. 403.2. found phase separator and concentnsted in vacuo Purification by 404 3 (M+I) Retention time 0 58 minutes 1-190 silica gel chromato raphy (40 g ISCO colunuu 20-100% EtOAc/heptanes gradient) tn afford 101 mg of the desired [0882] Thc Ibllowing analogs were prepared accorduig to product as a colorless oil. ESI-MS m/z cele. 396.2, fiiund Synthetic Schenie 29: 397.34 (M+I) . Rcimition time: 0.87 nunuies.

Formauon of N-[3-chioro-4-(1.4-oxazeyan-3-yl) piu:nyl]-N-methyl-oxettm-3-amuse (241) [0877] To a solution of tert-butyl 3-[2-chloro-4-[methyl (oxetan-3-yl)amino]phenyl]-I g-oxazepane-4-carboxylate. in '~p 240. (0.10 g, 0.25 nunol) dichloromethanc (2 mL) was aiidcii irifiuoroacctic acid (1.0 mL, 12.9 mmol). The reaction mixture ives stirred for 20 minutes and concentrated in g vacuo 'I'he resulting residue was diluted with methanol and Xggui then passed through a SPII bicarlxmate cartridge (5 8/60 8 mL) and concentmted to give 71 mg of a colorless oil which was used isithout further purificatioiu ESI-MS nt/z cole.

296.1, found 2973 (M+I) . Retcniion tune. 0.52 nnnuics.

Iionnatinn of (+/ — )-4-[3-[2-chloro-4-[methyl(oxetan-3-yl)aminoJphenylJ-i,f-oxavepan-s-ylJ-6- 4-[(3S)-3-[2-chlom-4-(oxetan-3-ylaniino)phenylJ-I, niethyl-pyriniidin-2-amine (242) 1-186 4-oxazcpan-4-yl]-6-methyl-pyrimidin-2-mninc (24S) 1-21 5 [0878J A mixture of N-[3-chloro-4-(1,4-oxazepan-3-yl) phenylJ-N-methyl-oxetan-3-smine. 241. (0.07 g, 0 24 [0883] 'H NMR (300 MHz. CDCI,) 6 6.91 (d, J=8.4 Hz. nmiol) and 4-chloro-6-methyl-pyrimidin-2-amine (0.03 g, 111), 6.38 (d. J 2/4 I lz. 111), 6 25 (dd, 1 8 5. 2 5 I lz, 111), 0.22 mmol) in nBuOH wns heated nt 130" C. (2 mL) 5.46 (s, IH), 5.16 (s, IH), 4.88 (td, J=6.3, 2.3 Hz, 2H), 4.65 ovcrmghi. The reaction nuxiurc was cooled io room tmn- (s, 21 I), 4.55-4.33 (m, 311). 4 26-4 11 (m, 211). 4 03 (q..l 7 I pcraiure followed by purification by silica gci cluomatog- Hz. 2H). 3.58-3.26 (m, 3H). 2.04 (s. 3H), 1.83 (s. I H). 1.73 raphy (C18 AQ 50 column: 0.1% TFA-water/0.1% TFA- g (s, 111); IISI-MS niiz cele 389.2, found 390.2 (M+I) Me(:N). I'he pure fractions were concentrated in vacuo and Retention time: 0.6 minutes: Optical rotation: +324 then dissnlved in MeOI I and passed through a SPI: bicarbonate cartridge (Agilent Stratospheres 500 nig/6 mL) and (McOH). concentrated in vacuo. Added ether and concentrated a ain to gee 42 mg of product as a wiute solicit 'H NMR (400 Exiunple 30 MHz. d6-DMSO) o 7.06 (d, J=8.4 Hz. IH), 6.71 (s. IH), 6.58 (d. J=N 5 Hz. IH), S.85 (br s, 2H), 5.45-S.26 (br s, IH), [0884] Synthcuc Scheme 30: (S)-I-(3-((4-(4-(2-anuno-6- 5 05-4.8N (br s, 111), 4 78-4 70 (m, 311), 4 57 (d, .I 5 0 Ilz„ methylpyrimidin-l-yl)-1.4-oxazepan-3-yl)-3-chkimphenyl) 2il). 4 10 3 95 (ni. 111). 3 90 3 N2 (m, 111), 3 703 46 (ni, amino)avetidin-I-yl)ethan-I-one (247) 1-262 US 20[9/0322658 A] Oct. 24, 2019 182

Hz. IH), 4.00 (d. 1=6.8 Hz. IH), 3 88 (t, J=7.8 Hz, 2H), 3.74-3.45 (m. SH), 2.06 (s. 3H), 1.94-1.68 (m, 2H), ESI-MS nt24 cele. 388.2, I'ound 389.3 (M+I) . Retcnuou tune. 0.53 nunutes.

Iiommtion of I -[3-[4-[(3S)-4-(2-aniino-6-methyl- pyrimidin-4-yl)-1. 4-oxazepan-3-ylJ-3-chloro-an- ilinojazetidin-I-yljethanone (247) [0886] To a suspension of 4-[(3S)-3-[4-(azctidui-3- ylamuio)-2-chloro-phenyl]-1.4-oxazcpan-4-yl]-6-mcthyl- pynnndin-2-aniine, 246. (0 040, 0 ONN mmol) in dichloroniethane (4 ml,) and Tl lli (I ml ) was added triethylamioe (0.025 mL. 0.17(i nunol) folloii ed by acetyl chloride (0.007 mL 0.097 mmoi). The reaction mixture was stirred at room tcmperaturc. After I hour, additional acetyl chlondc (0.002 mL) v as addcdI and stirnng continued at room tcmperaturc ovcmight. Thc resulting precipitate was Iiltcrcd and wasltcxi ,S v ith nnnimal dichlommethane. 1 he white solid was dried to atford 25 mg of desired product 'll NMR (400 Mliz, MeOD) 6 7.03 (d. J=N.J iqz, Hq). 6.60 (dd. J=4.0, 2.4 Hz, IH). 6 51-6.44 (m, IH). 5.55 (br 6, IH). 4.93 (br s, 2H), ++Nit 4.57-4.49 (m, IH), 435-4.15 (m, 3H), 4 04-3 90 (m, 2H), 3.79-3.53 (m, 4H), 2.07 (s. 3H), 1.87 (6, 3H), 1.95-1.70 (m,

2H); ESI-MS ngz cnlc. 430.2, found 431.3 (M+I) . Reten- tion time 0 57 niinutes 246 0 I:xample 31 [0887] Synthetic Scheme 31: 4-[(3S)-3-[4-(1,3,3a,4,6,6a- hcxahydrofuro[3.4-c]pyrro1-5-yl)-2-chloro-phenyl]-1,4-oxazcpau-4-yl]-6-methyl-pyrunidui-2-mnuic (248) 1-220 Ci

NII

247

(a) 'I I'4, Elis('lz; (6) 2-amino-4-chloro-6-methylpyrimi- 130" dine, nBuOH. C. Ci Formation of 4-[(3S)-3-[4-(azetulin-3-ylannno)-2- Hiloro-phenyl]-1,4-oxazcpmi-4-yl]-6-methyl-pynmi- N 0 din-2-anime (2467) 1-257 [0885] To a soluuon ol'ert-butyl 3-[4-[(3S)-4-(2-amino- 6-methyl-pyrimidin-t-yl)-1,4-oxazepan-3-yl]-3-chloro-an- Ntri ilinoJazetidine-I-carlxixylate. 237. (0 118 8, 0 239 nunol) in dichloroniethane (2 mL) v as added triiluoroacetic acid (I 0 mL). The reaction mixture v as stirred at room rempermue for 30 minutes aud then partmlly conccntratcd in vacuo IM HCI (2 mL) was added and thc mixture washed twice with 246 illcliliiroillctlitlllc. Thc tlqUcoUs laser was basilied with 2M 'I NaOI I (5 ml and then extracted with dichloromethane. he ) (a) Cul. (3aS,6aR)-3,3a.4,3„6,tia-hexahydro-l H-furo[3,4-c] ivere separated with the aid of a separator 'I he layers phase pyrrolc, KsCO, N,N-ihmcthylglycinc aqueous layer v,as re-extmscted with dichloromethane and the layers were sepamsted throu/7 a phase sepamtor 7 ain Formation ol'-[(3S)-3-[4-(1,3,3a,4,6,6a-hexahydro- and the combuied organic phases were concentrated in furo[3,4-cjpyrrol-5-yl)-2-chloro-phenylJ-1,4-oxaze- i acUU tii dllord 51 illg ol tile dcsllixl plixlUct as s wllltc solid pan-4-ylJ-6-methyl-pyrimidin-2-mmne (24N) 'H NMR (400 MHz. McOD) 6 7.00 (d, J=8.5 Hz, IH), 6.56 (d, .I 2 4 I lz. 111). 6 45 (dd..l 8 5, 2.4 llz, 111), 5 53 (br s, [t)888] 4 Schlenck tube v as char ed ivith 4-[(38)-3-(4- I i I). 5 ON (br s. 211). 4 35-4 26 (m. I I I), 4 18 (dd..l 13 6. 5 I bmmo-2-chloro-phenyl)-1,4-oxazepan-4-ylJ-6-methyl-py- US 20[9/0322658 A[ Oct. 24, 2019 183

rimidin-2-amine. 33, (0 30 g, 0.75 nmioi), (3aS.tiaR)-3,3a, (S)-4-[3-[2-chloro-4-(4-methylpipemzin-I-yl)phe- 4,5.6,6a-hexahydro-lH-furo[3,4-c]pyrmic (036 g. 3 19 11VI]-1,4-iixazcpill1-4-VI]-6-llicillvl-pvrlllllilill-2- mmol). N.N-dimethylglycuie (0.05 g, 0.4364 nunoi), Cui mninc (249) 1-275 10 0 50 /73 4 53 and l)MSO (0 g. mmol), K,(:07 (0 g, nunol) 'H (4 ml,) in that order and vacuum/nitrogen cycles five times. [0890] NMR (400 MHz, Chloroform-d) 8 6.92 (d, The flask ives heated to 90" C. After 24 hours. 10'!7 MeOH J=8.7 Hz. IH), 6.74 (d. J=2.5 Hz„ IH), 6.57 (dd. J=8.7. 2.6 in EtOAc was added and the mixture was filtere tiuou h Hz. IH), 5.40 (s. IH), 4.46 (s. 2H). 4.13 (dd„J=13.5, 5.0 Hz, ('lite and concentrated (DMSO still present). purificatio IH), 3.90 (d, J=12.0 Hz, IH), 3.51-3.25 (m, 2H), 3.13-2.97 2.43-2.33 (m. 4H), 2.18 (s. 3H), 1.91-1.80 I by silica gcl cluomatogcaphy (80 g GOLD ISCO colunui, (m, 4H), (m, H). 0-10'.4 MeOH/dichloromethanc gradient) and lbactions con- I 68-1.45 (in. III); ESI-MS miz cele. 416 21, fiiund 4170 taining product were concentrated in vacua 'I'be pmduct (M+I)+ Retention time 0 51 minutes was subjected to a second purification by silica gel chmma- [0891] The following analogs it ere prepared accordin to to raphy (C18 aqueous 80 g ISCO column eluting with Synthetic Schcmc 31 with exception thai N-mcthylglycuic 0.1;7 TFA-water/0,1'!8 TFA-MeCN): 'H NMR (400 MHz, was used instead of N.N-duncthylglycinc. MeOD) 6 7.06 (d. 1=8.6 Hz. IH), 6.67 (d, J=2.5 Hz, IH), 250 6.56 (dd. J=g 6, 2.5 Hz, I H), 5. 70-4. 70 (br m, 3H). 4.20 (dd, J=13.6. 5.1 Hz, IH), 4.06-3.89 (m. 3H), 3.75-7.53 (m, 5H), 3 38 (dd..l 8 8, 7 I I lz, 211), 3.23-3.15 (rn, 211), 3 10-3 (8) (m, 21 I). 2.0/7 (9, 311), I 95-1 75 (m, 211): IISI-MS ndz cele. 429 2, found 430 3 (M+ I)+ ltetention time: 0 63 minutes. ' The following analo s were prepared according to Synthetic Scheme 31.

249 Ci

4-[(3S)-3-[2-chlom-5-(oxetan-3-ylaniino)phenylJ-I, 4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (250) 1-258

[0892] "H NMR (400 MHz. Mctlranol-d4) b 7.16 (dd. .I 25.4, 8.6 I lz, I I I), 6.53-6.35 (ni. 211), /7 05 (dd, .I 7/ 5, 5 I I lz, OH), 5 67 (s, ll I), 5 26 (dd..l 102 4 8 Ilz 111) 5 li) (d. 1=14.4 Hz. IH), 4.91 (dt, J=12.7, 6.3 Hz. 2H), 4.50 (ddt, 1=21.1. 11.9. 4.5 Hz. 2H). 4.40-4.13 (m. I H). 4.11-3.56 (m, 4H). 2.44-2.15 (m, 3H), 1.92 (s„3H); ESI-MS ndz cole. (+7 — )-4-[3-[2-chloro-4-(4-methylpiperazin-I-yl)phe- 389 16187, liiund 390.13 (M+I) . Rctcntion time. O.G mui- nylJ-1,4-oxazepan-4-ylJ-6-methyl-pyrimidin-2- uies, [&x]a=+GO.6" (c=l. McOH).

amine (249) 1-225 29 i HiN [0889] heated (3GOK) 'H NMR (400 MHz. DMSO-d6) 6 7.11 (d, 1=8 7 Hz. IH), 6 90 (d. 1=2.5 Hz. IH). 6.82 (dd, 1=8.8. 2.6 Hz. IH), 5.56 (d, J=I2.9 Hz, 3H), 5.28 (s, IH), 4.66 (d, J=14.9 Hz, IH), 4.11-4.00 (m. IH), 3.87 (dt7 J=12 I, 3.9 Hz, IH). 3.68 (dd. J=13.4, 10.1 Hz, IH), 3.64-3.49 (m, 211), 3.20-3.09 (m, 411), 2.46-2.41 (m, 411)„2 22 (s, 3H), 200 (s. 311). I 76 (tt, .I 7 9, 3 911z, 211). 17SI-MS m/z cele. 41(x2, found 4170 (M+I)'etention time: 0.5ti minutes. 0 Ci 77 7 Hi8 US 20[9/0322658 A] Oct. 24, 2019 184

2-[3-[(3R)-4-(2-amino-G-methyl-pyrimidin-4-yl)-l. 4-oxazepan-3-yl]-4-chloro-anilino]ethanol 251) 1-252 and 2-[3-[(3S)-4-(2-amino-G-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-cldoro-atulux3]ctiut- nol (252) 1-253

' [t)893] (racemic mixture): I NMit (300 Mi lz, Methanol- d4) 6 7.21 (dd„J=8.5, 4.9 Hz. I H). 6.79-6.51 (m. 2H). 6.06 (dd. J=9.8. 5 I Hz, 0.5H). 5.76-5.58 (m, IH), 5.32-5.09 (m, 1.5H). 4.46-4 15 (m. 2H). 4.12-3.87 (m. 2H), 3.8ti-3.54 (m, 5H), 3.20 (dt, J=17.0, 5.7 Hz. 2H), 2.21 (d. 1=0.8 Hz. 3H), 0 205-1.81 (m. 211): I:SI-MS nv'2 cele 3772. found 3782 Cl (M+I) . Rctenuon time. 0 57 mimttes. 1-237. SI'(: ('olmnn [0894] condttions Al)-II, 20x250 ntm, (3S)-l-[3-[4-(2-tmuno-6-methyl-pynnudu3-4-yl)-1,4- Mobtle phase. 40% McOH (S mM Atnmonia), 60% CO2, oxazepan-3-yl]-4-chloro-phenyl]pyrrolidut-3-ol I'low ('oncentrations: -50 80 ml./min; mgtmi (MeOI I) (254) 1-234 — 190.45" (c/ [0895] Peak A: ee: 99.2%: [u]o= 0 5, [l)898] 'l I NMI& (300 Ml is, Metltanol-d4) 6 7 33-7 11 (m, McOH), 2-[3-[(3R)-4-(2-amino-G-methyl-pyrinurlin-4-yl)- 211), 6 5')-6 25 (m, 311). 5 68 (s, 111). 5 36-5 11 (m, 211), 1,4-oxazcpan-3-yl]-4-chloro-atuhno]edtanol (251): 'H 4.57-4.17 (m. 2H). 4.13-3.58 (m, 5H). 3.51-2.97 (m. 3H), NMR (300 MHz, Methanol-d4) b 7.14 (d, J=8.6 Hz. IH), 2.20 (s. 3H). 2.13-1.79 (m, 4H): ESI-MS nt/z cele. 403.2, found 404.21 . Retention ttmc. 0.62 nunutcs. 6.63-6.46 (m. 2H), 5.54 (brs, IH), 5.17 (brs, IH), 4.28 (dd, (M+I) J=13.7. 5.0 Hz, I H), 4.03 (d, J=12.1 Hz, IH). 3.82-3.53 (m, 4il). 3.14 (t. J 5 7 I lz, 211), 2 13 (s. 311). 1.90 (br. 2il), Hrx l!SI-MS mtz cele 3772. found 3782 (M+I) . Itetention time 0.57 mtnutes 1-252

[t)896] Peak l3 ee 99%: +172580 (c 05 MeOII), [u]rr Bi 2-[3-[(3S)-4-(2-mnuto-6-methyl-pynmnlu3-4-yl)-1,4-oxazepan-3-yl]-4-chloro-anilmo]ethanol (252): 'l I NMR (300 MHz, Methanol-d4) 6 7.12 (d. i=84 Hz. IH), 6.68-6.46 (m, 211), 5 48 (brg 111), 5 13 (brs, 111), 4 27 (dd..l 13 6, 5 0112, I H). 4.03 (dd. 1=12 1„4 7 Hz, I H). 3.77-3.52 (m. 4H). 3.13 0 Ct (t. J=5.7 Hz, 2H), 2.06 (6, 3H), 1.97-1.71 (m, 2H): ESI-MS m/z cole. 377.2, found 378.2 (M+I)'. Retention time 0 57 mtnutcs. 1-253. It 8 263 Q

CI 266 0 (a) tBuXPhos Pd CJ3. morpholine. dioxane. tert-BuOH, Csaco, 75'. Fomtation of 4-(3-(5-bronte-2-cltlorophenyl)-1,4- (+/-)-3-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1, oxazepan-4-yl)-6-methylpyrimtdtn-2-amine (255) 4-oxazcpan-3-yl]-4-chloro-tmilino]propmt-I -ol (253) [0899] Intermediate. 235, was prepared according to Syn- 1-249 thettc Scheme 2, usin intemtedkate tert-butyl 3-(5-bromo- 2-chlorophenyl)-1,4-oxazcp;mc-4-carboxylate, 157. [t)897] 'I I NMlt (300 Mlis, Methanol-d4) 8 7.i 8 (d..l 8 7 Hz, lit). 6.59 (t, 1=7.8 Hz. I H), 6.48 (c. I H). 6.05 (dd. J=9 8, Formation of (+/ — )-4-[3-(2-chloro-5-morphohno- 5.2 Hz. 0.5H). 5.68 (6, IH), 5.31-5.12 (m, I.SH), 4.32 (ddd, phenyl)-1,4-oxazcpan-4-yl]-6-methyl-pyrunt din-2- 1=27.7, 13.8. 5 I Hz. 2H), 4.09-3.52 (m. 7H), 2.35 (s. 1.5H), aminc (256) 1-195 2.21 (s. 1.5H). 2 04-1 65 (m. 4H), ESI-MS m'2 cele. 391 2, [l)9()0] A 250 ml, flask was charged with 4-[3-(5-bntmo- found 392.2 (M+ I)+ Itetention time: 0.56 mimttes. 2-chloro-phenyl)-1.4-oxazepan-4-yl]-6-ntethyl-pyrimidin- US 20]9/0322658 A] Oct. 24, 2019 185

2-3mine„253, (0.30 g. 0.75 mmol). morpholine (0.20 mL, 0.120 nunol), pyrrolidine (0.015mL, 0.180 mmol) and 2.29 mmol)„dioxane (7 mL) and tert-BuOH (8 mL). The 1.4-dinzabicyclo[2,2.2]octane (DABCO) (0.025 g. 0.223 reaction mixture was stirred to give a clear solution 'the mmnl) m dimethylacetamide (2 ml.) was bubbled ivith a solution was then degassed with a stream nf nitrogen for 10 stream of nitrogen. 'I'o the reaction vial was added Ir(dp n&im&tes [2-(2-aniinophenyl)phenylJ-methylsulfnnvlnxy- (CF,)ppy)s(dtbpy)PFr (03 mg) in dune&hylacc&amide (0.1 palladium;ditert-butyl-[2-(2.4,6-triisopropylphenyl)phenyl] mL) and dibromo&ucl el. I-methoxy-2-(2-mcthoxycthoxy) phosphane (0.03 g. 0.04 mmol) (tBuXPhos Pd O3) was ethane (2.2 mg. 0.006 nunol) in dunethylacetamide (0.1 dildcil then nitrogen bubbluig was conunued for 5 mimitcs. mL). The reaction ivas carried out in a Vapourtec flow reactnr, with 0 2 ml Jn&in at 30" resulting mixture was CscCO& (0.59 . 1.81 nunol) was Place&1 under a &utrogen ('he dunosphcrc and then hcatcd to 75" C. After 90 nunutes, thc diluted v ith I itOAc, ivashed with I I&O, dried over Na&SOw reaction mixture was partitioned between I:tOAc and water. filtered and concentrated in vacuo Purified by 4 g silica gel 'I'he organic phase was washed with water and brine, dried cartndge elutin ivith 0-10%7 MeOH/dichloromethane to afibrd 2 desired product; 'H NMR (MSSOd) filtered and concentmnted in 3 acuo. The resulting mg of (400 MHz, CDCI&) b J=7.5 J=2.5 residue was purified v&a silica gel chromatography using 40 7.04 (t, Hz, IH), 6.56 (d. Hz. IH), 640 (dd, gram ISCO colunu& slut&ng wuh 0-100% EtOAc/heptancs J=8.6, 2.5 Hz, IH), 5.60 (s, IH), 4.60 (s, 2H). 430 (dd, linear grad&mit to ailbrd 17 mg oi'desirix! product: 'H NMR J=13.5, 5.1 Hz, IH), 3.34-3.16 (m, 4H), 2 14 (s, 3H), (300 MHz, Methanol-d4) o 7.29 (dd, J=18.3, 8.8 Hz, 2H), 2 ON-1.92 (m, 411), I 80 (d. 1 14 5 I lz, 111): IISI-MS m/z cele 387.2, found 388 I Retention time: 3.13 6 i) I (ddd. 1 16 6. 8 &3, 2 9 I Iz,. 111). 6 78 (dd, .I 26 7, 3 0 I I z„ (M+I) i&i&i&utes. 0 511). 6 48 (3, 111), 6 10 (dd .I &3 5 5 I I is 0 511) 5 68 (s IH). 5.39-5.10 (m. 2H). 4 42-4.17 (m, IH). 4.09-3.59 (m, lixan&pie 33 I IH). 3.09 (t, 1=4.9 Hz, GH), 2 28 (dd, J=40.8, 0.8 Hz, 5H), Synthetic Scheme 33 (+7 — )-I -(4-(4-(2-amino-6- 2.09-1.84 (m, 4H), ESI-MS n&/z cafe. 403.2. fi&un&1 404 2 methylpyrimidin-4-yl)-1„4-oxazepan-3-yl)-3-chloro- (M+I) . Retcnuou t&mc. 0.62 minutes. phenoxy)propan-2-ol (2GI ) 1-232 Examplc32 [0903J Synthetic Scheme 32: (+/— )-4-[3-(2-chloro-4-pyrro- llilll&-I -Yl-pili:lly'1)-1,4-oxazepai&-4-YI]-6-1&le&hvl- pynm&du&-2-aminc (257) 1-227 B& [0901]

3& 7SS

0 d

Yi 8 C.

77 OH

(a) Ir(dF(CF,)ppy)7(d&bpy)PFr, dibromoiurkcl: I-mcthoxy- 2-(2-niethoxyethoxy)ethane, pyrrolidine, IJAi3CO, dunethylacetamide. flow reactor, 30" (2

Porn&ation of (+/— )-4-[3-(2-chloro-4-pyrrofidin-I-yl- phenyl)-1,4-oxazepan-4-ylJ-6-methyl-pyrimidin-2- am&ne (257) 1-227 C. [0902J A snlut&on of 4-[3-(4-bren&o-2-chloro-phenyl)-1.4- 7(ri oxazepan-4-ylJ-6-niethyl-pyrimidin-2-amine. 31, (0050 g, US 20[9/0322658 A[ Oct. 24, 2019 186

-continued 7.50 (d, 1=2.0 Hz, IH). 7.47 (d, 1=8.4 Hz. IH), 7.38 (dd, J=8.5, 2 0 Hz, IH), 4.39 (dd, J=9.0, 3.4 Hz, IH), 4.01-3.92 (m, 2H), 3.82 (dt, J=12.3. 6.2 Hz. I H), 3.38 (dd, i=12.4. 9.0 I lz. 111), 3.20 (dt, I 13 5. 5 0112,. 111), 3 04 (dt..i 13 (2, (i 8 Yif I lz. II I), I 98 (qd..t (2 4, 5 0 I is, 211): ESI-MS m/z cele 289 0, found 290.0 (M+I)'. Retention time 0.6 minutes. [0905] To a soluuon ol'3-(4-bromo-2-chloro-phenyl)-1.4- oxazepanc (1.97 g, 6.78 mmol) and tncthylamuic (1.04 mL, 'I'I 7 46 mmol) in IF (40 ml ) was added 13oc anhydride (1.(27 C. 8, 7 65 minol) 'I'he reaction mixture was stirred at room temperature overni ht, then diluted v, ith EtOAc and washed z si with I M HCI. was concentmsted to itixf N The organic Layer i)it dryness and purified via silica gel cluomatography eluting Yi with 0-40% EtOAc in heptane. Frucuons contauun thc desired product werc combuicd and concentrated io give 2 2N g of desired pmduct, 25N, as a colorless oil that sohdiiied upon standing,'I l NMI( (400 Ml lz,. 1)M)O-d6) () 7.63 (dt. J=6.8. 2.0 Hz. Iiqj. 7.56-7 48 (m. IH), 7.26 (d, 1=8.3 Hz. IH), 5.29 (dd, J=10.4, 4.9 Hz. IH). 4.26-4.12 (m, IH). 4.00-3.84 (m. 2H), 3.(/3-3.44 (m. 3H). 1.83-1.64 (m, C.) 'si 2H), 1.25 (s, 7H), ESI-MS m'z cele. 389 0, found 390.0 (M+I) . Rctcntion time. 0.69 minutes

Fomiation of tert-butyl 3-(2-chloro-4-((R)-2-hydroxypropoxy)phenyl)-I 4-oxazepane-4-carboxylate (259) [0906] (crt-Butyl 3-(4-bromo-2-chloro-phniyl)-1.4-ux- azcpauc-4-carboxylate. 258, (1.13 g, 2.89 nunoi) and CssCOs (1.40 g. 430 mmol) werc placed in a micmwave vial under nitmgen Toluene (3 0 nil.) and (2R)-propane-l, C. 2-diol (1.10 ml,. 14 9N mmol) ivere added. I'he mixture was stirred for 5 minutes. Di-tert-butyl-[6-methoxy-3-methyl-2- (2.4. 6-trii so propylphenyl I-phenyl]phosphane;methanesul- fouatc palladium(2+).2-phenylaniluie (di-icrtBu-Xphos I (a) 3-(tributylstannyl)methoxy)propan-I -amine 4 A mol (0.12 g, 0.14 nuuol) was aildixl. Thc reaction mixture was sieves. CiqaCI,: then 2,6-lutidine. Cu(OTt),. hexafllliilolso- heated lor I hour at 100'. Thc mixture was diluted with propmiol, CHaCI,, (b) BocsO. Ei,N. THF, (c) di-tert-bu- v ster and dichloromethane I'he plmses were separated on a tylXPhos, Cs,CO,, (2R)-propane-1,2 thol, 100'G (d) phase separator and the organic phase concentrated in vacuo 'I'I'A. ('I la('I; (e) 2-amino-4-chloro-6-methylpyriniiduie, The resulting residue was purified by silica el chromato- ni3uOI I. 120" ('2 (fj SI'('hiral separation raphy (Ethyl acetate/Heptanesj to aifiird 820 m of desired product. ESI-MS ndz cele. 385.2, found 386.2 (M+I) . Formation of (+/— )-tert-Butyl 3-(4-bromo-2-chloro- Rctcntion time. 0.85 muiuies. phenyl)-1,4-oxazepane-4-carboxylate (258) Fomiation ol'2R)-I-(3-cltloro-4-(1,4-oxazepan-3- [0904] A mixture of 4-bromo-2-chloro-benzaldebyde yl jphcnoxyjpropan-2-ol (260) (10.0 45.6 mmol), 3-(tnbutylstannylmethoxy)-propan-I- g. [0907] tert-Butyl 3-[2-chloro-4-[(2R)-2-hydroxypropoxy] ammc (17.2 g, 4S.6 mmol), tmd 4 angstrom molecular sicvcs phenyl]-1.4-oxazepane-4-carboxylate, 259, (0.82 g. 2.13 in dichloromcthanc was stirred ai room (5.2 g) (180 mL) nunol) was dissolvn! in ilichloromcthanc (20 mL) and temperature for 2 hours. filtered and diluted with additional tnfluoroacetic acid (10 mL) was addixl. Thc volatilcs were dichlommethane (540 'I'o a separate flask containing nil.) removed on a rotory evaporator Satumsted aqueous sodium hexafluoroisopropanol was added 2.6-lutidine 3 (180 mL) (5 bicarbonate and dichloromethane were added I'he phases mL. 45.6 nmiol) followed (16.5 45.7 nmiol). by Cu(OTf), g. were separated on a phase separator 'I'he organic phase was Thc reaction mixture was surrnl for 2 hours and then thc concentrated in vacuo. The resulting residue was purified via iminc solution prepared above was addixi in one portion. silica el chromatography (Eluent: Ethyl acetate/Heptanes) Thc reaction mixture was stitrixl ovcmight and thni treated to aflbrd 330 mg ol'esired product. ESI-MS ngz cele. with a 2 I mixture of aqueous saturated sodium bicarbonate 285 I, found 286.2 (M+1) . Reinition tnue. O.S minutes. solution and 10% animonium hydroxide 'I'he organic layer was separated and washed with aqueous saturated sodium Fomiation ol'2R)-I-(4-(4-(2-tunuio-6-mcihylpy- bicarbonate solution, filtered tjtiough a phase separator and nmidut-4-yl)-1,4-oxazcpan-3-yl)-3-chlorophenoxy) conccniratcd to dryness. The resulting rcsiduc was puriiicd propan-2-ol (261) sia sihca gcl cluomaiography cluiuig sstth 0-75% EtOAc/ heptane. Pure fractions were combined and concentrated in [0908] 4-Chloro-6-methyl-pyrimidin-2-aminc (0.12 g, vacuo to atford 6 2 g of 3-(4-bromo-2-chlorophenyl)-1.4- 0 83 nimol) and (2R)-1-[3-chloro-4-(1,4-oxazepan-)-yl) oxazepane as a yellow oil 'll NMR (100 Mlim CI)('ii) (f phenoxy]pmpan-2-ol, 260. (0.33 g, 0 83 mmolj w:ere dis- US 20[9/0322658 A] Och 24, 2019 [87

solved in I-butanol (2.4 mL). The reaction mixture was heated for 16 hours at 130" ( The volatiles lvere removed on a rotory evapomtor. The co)de residue was puriT)ed via silica gel cluomatography (Eluent. methanol/dmhlorometh- ane). A second purihcation was carried out using an ISCO Yif anuno-silica gel colunm (Eluent. Ethyl acetate/Heptancs) to atford 270 mg of desired product as mixture of 2 diaste- rmmcrs: 'H NMR (400 MHz, McOD) 6 7.24-7.10 (m, IH), 7 01 (t..i 6.4 I iz. I I I). 6.91-6.78 (m, I I I), 4 22 (dd..i 13 6, 5.1 Hz, IH), 4.12-3.96 (m, 2H), 3.90-3.77 (m. 2H), 3.7S-3. C, 54 (nl. 311). 2 06 (s. 311), I 89 (dddd..i 35 0„32 2, 11 8, 9 7 Hz. 2H), 1.24 (dd„J=6.4. 2.5 Hz, 3H); ESI-MS nt/z cole. 3')2 2, found 393 2 (M+I) Retention time: 0 5') minutes. SF('idral AD-H, 20x250 separatton: Column: nun; Mob)le (+/ — )-4-[3-[2-chloro-4-(oxetan-3-yloxy)phenylJ- I, 4- phase. 40% McOH (S mM Atumonra). 60% CO7: Flow 80 oxazepml-4-yl]-6-methyl-pynmldul-2-lunule (265) mL/nlin: Concentrattons: -50 mg/mL (MeOH) 1-231 [0909] Peak A. (R)-I-(4-((R)-4-(2-anuno-6-methylpyrimidin-4-yl)-1.4-oxazepan-3-yl)-3-chlorophenoxy)-pro- [l)913] 'll NMIe (400 Mllz. MeOD) tS 720 (d, .I 86117, 111), 6.86 J 2.6 I lz. 111), 6 70 (dd, 1 8 8. 2 6 I lz, I I p;m-2-ol (262) optical rotation S.O mg ul 0.5 mL MeOH=— (d. I), 532-5.167 (m. IH). 5.04-4.90 (m, 2H). 4.71-4.50 (m. 2H), 17 20": 'I I NMlt (400 Miis. MeOD) 6 7 ]9 (d, .I 8 7 Ilz„ 4.22 (dd, 1=13.6. 5.1 Hz. IH)„4.01 (d. J=ll.9 Hz. IH), IH). 7.03 (d, J=2.5 Hz. IH), G.88 (dd, J=8.6. 2.4 Hz, IH), 3.73-3.53 (m, 3H), 2.07 (6, 3H). 1.86 (d, J=34.4 Hz, 2H). 4 22 (dd .I 13.7 5 01lz 111) 4.15-3.95 211), 3 85 (ddd, (rn, ESI-MS nt/z cele. 390.1, Iilund 391.2 (M+I)'. Rctentlon 1=16.2. 9.7, 5 4 Hz, 2H), 3.77-3.53 (m. 3H). 2.07 (s, 3H), time: 0.61 minutes. I 867 (d .I 29.4 Ilz 211) 1.24 (d .I 64 llz 31i): itSI-MS m/z cole. 392.2, found 393.2 (M+I) . Retention time 0 58 mtnutcs. 1-264. [0910] Peak B: (R)-I-(4-((S)-4-(2-amino-ti-methyipyrinudin-4-yl)-1.4-oxazepan-3-yl)-3-chlorophenoxy)-propan-2- ol (263). opttcal rot alton 4 8 mg ul 05 mL McOH= — 2276', Yif 'H NMR (400 MHz. McOD) 6 7.19 (d, J=8.7 Hz, IH), 7.03 (d, 1 2.4117, 111), 6 87 (d, .I 8 7117, 111)„4 22 (dd. I 13 6, OH 6 I I iz 111) 4 13-3 94 (m, 211). 3 85 (ddd, .I 16 2, 9 6. 5 4 I lz,. 21 I). 3 76 3 52 (nl. 211). 2 07 (s, 21 I), I Qi (d, .I 33 I I lz„ 2H): ESI-MS nt/z cele. 392.2. found 393.2 (M+I)'. Reten- tion time: 0.57 minutes. 1-2G5. C. [0911] Thc following analogs were preparwl wcording to Synthetic Schcmc 33. (+/ — )-4-[4-[4-(2-an%inc-d-a)ethyl-pyrtnudin-s-yl)-I, 4-oxazepan-3-ylJ-3-chloro-phenoxyJ-2-methyl-hu- tan-2-ol (26(i) 1-230

[0914] 'H NMR (400 MHz. MeOD) 6 7.19 (d, 1=8.7 Hz, Yif 0 OH I H), 6.99 (d, 1=2.7 Hz, IH), 6.85 (dd, J=8.9, 2.6 Hz, IH). g 4.22 (dd, J=13.6, 5.0 Hz, IH). 4.10 (t. J=6.9 Hz, 2H). 4 06-3.90 (tn. 111), 3 677 (ddd .I 45 9 13 8 10.6 Iiz 311) 2 09 (8 311), 2.()0-1.71 (m. 311), I 26 (s. 6118 IISI-MS m/z cele. 420.2. found 421.3 (M+I) . Retention ttme: O.G3 C. nllnutes.

267

(+/— )-[I-[[4-[4-(2-amino-6-methyl-pynnudm-4-yl)- 1,4-oxazepan-3-ylJ-3-chloro-phenoxyJtnethylJ-cy- clopropylJmethanol (264) 1-233 Yif

[0912] 'H NMR (400 MHz, MeOD) 6 7.20 (d. J=8.6 Hz, IH). 7.03 (d, J=2.6 Hz. IH), G.88 (dd, J=8.6. 2.S Hz, IH), 4.23 (dti, J=13.6, 5.0 Hz, IH), 4.05-3.45 (m, 8H), 2.17 (s, 3H). 1.89 (d, J=13 2 Hz, 2H), 0.58 (dt, J=S.2, 1.9 Hz, 4H), I/SI-MS mtz cele 4182. found 4193 (M+I) . Itetention time 0.62 minutes US 20]9/0322658 A] Och 24, 2019 188

(+/-)-4-[3-[2-chlom-4-[(3-methyltetmlhydrofuran-3- -conthliuxl yl)methoxyJphenylJ-1.4-oxazepan-q-ylJ-C&-methyl- pyrimidin-2-amine (267) 1-229

[0915J 'll NMR (400 Mllz, MeOD) 6 71') (d,.l 87 llz„ IH), 7.02 (d„J=2.6 Hz. IH), 6.87 (dd, J=8.7, 2.(i Hz. IH), 4 22 (dd, 1 13.6. 5 0 I lz, 111), 4.01 (d, .I li 3 llz. IH), 3.93-3.54 (nl. 8H). 3 53-3 38 (m. 2H). 2.08 (s. 3H). 2.03-1. )Ii, 66 (m, 4H), 1.23 (s, 3H), ESI-MS ndz calc. 432.2, fhund 433.3 (M+I) . Retention time: 0.67 minutes. Y Example 34

[t)916] Synthetic Scheme 34 (+/ — )-6-(4-(2-anuno-6- methylpyrimidin-4-yl)-1.4-oxazepan-3-yl)-7-chloro-2H- benzo[b][1.4]duaz&n-3(4H)-one (273) 1-268 mul (+/ — )-4-(3- (7-chloro-3.4-ddlydro-2H-benzo[b][1,4]thiazin-C&-yl)-1.4- oxazcpan-4-yl)-6-methylpyrinudin-2-anunc (274) 1-274 Vii 3X.— Y

26&l ~Hz

214

0 (a) 3-(tributylstannyl)methoxy)propan-l-an&me, 4 A mol sieves, Cl 11CI&: then 2.(&-lutidine ('u(O'I't)z. hexafluoroiso- pmpmiol, (.'I lz(.'I,; 8) l)oczO, Cl le(qz, c) methyl 2-sulfanylacetate, K&CO, DMR 50" C.t d) TFA. CH,CI,; e) 2-amino- 4-chloro-6-methylpyrimidine, nBuOH, 120'; I) iron, scene acid, 60" Cu g) L&AIH4. THF, 60'. 269 Formation of 3-(2-chlom-4-fluoro-5-nitro-phenyl)- 1,4-oxazepane (268)

[0917] To a soluuon of 2-chloro-4-fluoro-5-&utro-benzaldehyde (2.0 g, 9 8 mmol) in dichloromethane (50 ml ) was added 3-(tributylstmlnylmethoxy)pmpan-I-amlne (3 8 g. 9 9 mmoi) and 4 angstmm molecular sieves (I 5 8) 'I'he reaction mixture v:as stirred at room tenlpemture for two hours and filtered through a short layer of Celite and rinsed with d&cldoromcihanc. Thc Iiliraic was concenlraicd &n vacuo io ailhrd ihc crude unine. [l)918J lo a separate sohition of 2,(&-lutidine (1.4 m1„12 I mmoi) in hexafluoroisopropanoi (50 mL) was added Cu(OTI), (4.3 g. 11.9 nunol) (1.20 eq.. preheated at 110'. for I h unde& high vi&coun&) 4&xl stirred at roon& ion&pc&aisle fhr I hour. A soluuon oi'thc unius &n ihchloromcihanc (160 mL) u as added ln onc portion and thc resulung nuxiure was stirred at rooin tempenlture for 12 hours. 'I'he reaction was quenched at room temperature w&th a mixture of aqueous US 20]9/0322658 A] Och 24, 2019 189

saturated NaHCOs solution (40 mI ) and 10% aqueous v ere obtained. n-BuOH was removed to give cnide product anunonium hydroxide (20 mL) and stirred vigorously for 15 as yellow solid and used directly without further purilica- nnnutcs. Thc layers were separated and the aqueous layer tlon. was extracted with dichloroniethane (3x50 inl.). The conl- Fomiation of Ci-[4-(2-amino-Ci-methyl-pyrimidin-4- bined organic layers were washed lvith water (Jx5 mi and ) yl)-1,4-oxazepan-3-yl]-7-chloro-4H-1.4-benzothi- brine (10 nlL), dried over NasSOw filtered. and concentrated azui-3-onc (273) 1-268 in vacuo. Purification by silica gel chromatography (0-6% MeOH/dichloromethane gradient) afl'orded 420 mg of the [0923J tert-l3utyl 3-[2-chloro-4-(2-nlethoxy-2-oxo-ethyl) dcsirixi product 'H NMR (300 MHz, CDCJ,) 6 8.21-8.04 selfanyi-5-nitro-phenyl] -1.4-oxazep one-4-carboxylate, 272, (m, IH), 7.36-7.0S (m, IH), 4.03 (ddd. J=15.7, 7.3, 4.1 Hz, (0 05 8, 0.11 mmol) and iron (006, I 07 nimol) in a vial 111), 3.95-3.72 (ni. 211). 3 72-3 47 (m, 211). 3 50-3 30 (nl, was added acetic acid (2 mL). The mixture was heated to 60" 211), 2 13-1 51 (m 211); JISI-MS m/v cele. 274 I, found C. and stirred for I hour. Acetic acid v as removed and the 275.2 (M+I). Retention time. 0.84 mimites. crude mixture was pulIIJcd by slice gcl cluomatogmphy (12 g ISCO colunui. cluting with 0-10% McOH/dichloromcth- I'ormation of tert-butyl 3-(2-chloro-4-fluoro-5-nitm- ane gradient) to provide 24 mg of the desired product as phenyl)-1,4-oxazepane-4-carixlxylate (269) v hite solid: 'I I NMR (300 Mlis. ('D('ll) 6 10.01 (g II I), 7 29 (3, I I I). 6.93 (d..i 52.9 I lz. 211), 5 87 (d, .I 52 3 I is, [0919] 3-(2-Chlom-4-fluoro-5-nitro-phenyl)-1,4-ox- IH). 5.50-4.71 (m, 2H), 4.2(i (dd. J=13.7. 5.0 Hz. IH), azepane, 2Cig, (0.42 g, I 53 nunol) in dichloromethane (5 4.12-3.92 (m. IH), 3.72-3.37 (m, 3H). 3.31 (d, 1=1.8 Hz, mL) lvas added Boc,O (0.50 g, 2.29 mmol). The reaction 2H), 2.01 (d, 1=17.2 Hz, 4H), 1.81 (s, 2H), ESI-MS nffz calc. Illlxtule was stlrrixl ovcllllgllt at roonl tclnpixiinllc. Thc 40S I, found 406.1 (M+ I) . Retmltion time. 0.61 nunutes. mixture was conccntratixl ul vacuo tmd puriliixl by silica gcl chromato raphy (12 8 IS('0 column. eluting v ith 10-100% Formation of 4-[3-(7-chlom-3.4-dihydro-2H-1,4- I:tOAc,'I leptanes) to afford 350 mg of the desired product as benzotluazin-(i-yl)-1,4-oxazepan-4-yl]-(i-methyl- yellolv crystalline solid: 'H NMR (300 MHz. CDCJ,) 6 7.97 pyrimidin-2-amine (274) 1-274 1=6.1 1=10.1 (t, Hz. IH). 734 (d. Hz. IH). 5.50 (ddd, [0924] At room tempemsture, 6-[4-(2-amino-6-methyl-py- 1=33.9, 10.1, 4.4 Hz, I H). 4.55-3.94 (m, 3H). 3.(i8-3.23 (m, umidin-4-yl)-I 4-oxazepan-3-yl]-7-chioro-4H-I,4-bcnzo- 2.17-1.72 1.34 J=S9.9 Hz. ESI-MS 3H). (m, 2H), (d, 9H). thiazin-3-one, 273, (0.02 g. 0.05 nmiol) ul THE (2.0 mL) m'z cele. 374 I, found 37S.2. Retention Junc. 0.93 mmutes. v as added a solution of I iAJI Is (0.05 ml of 2 M solution in 'll IF, 0.10 ininol) The cloudy solution was stirred overnight Formation of tert-butyl 3-[2-chloro-4-(2-methoxy-2- Additional LIAJHs solution (0.10 mL) v as added and the oxo-ethyl)sulfanyl-S-Intro-phenyl]-1,4-oxazepianc-4- mixture ives heated to 60'. overrught. Ice-water (0.25 mL) carboxylate (270) v as added and the nlixture was stirred for 10 minutes. [t)920] tert-I)utyl 3-(2-chloro-4-fluoro-5-nitro-phenyl)-1, Dichloromethanc (10 mL) was added. Thc resulung wluic 4-oxazepane-4-carboxylate. 269. (0.31 g, 0/83 mmol) and sohd ives Iiltered and washcxl with dichloromcthanc. The K,COs (0.24 g, 1.77 nunol) was dissolved in DMF (2 mL) cmnbmed organic phases were concentrated In vacuo. The in a small vial. Methyl 2-sulfanylacetate (0.09 mL. 0 95 crude residue v,as pnrihed by silica gel chronlatography (4 nunol) was added to the mixture. The mixture was heated to g ISCO column. elutin with 0-10%v MeOH/dichlorometh- 50'. for 6 hours. Aller removal ul DMF in vacuo. the ane gradient) to afford 7.5 mg ofthe desired pmduct as white crude was diluted with EtOAc (5 mL). Thc orgaiuc layer was sohd: 'H NMR (300 Mlqz, C:DCJ.,) 6 6.92 (s. IH), 6.27 (s, filtered and the solvent was removed in vacuo to aflbrd 380 IH), S.49 (s. 3H), 5.06 (s. 2H), 4.23 (dd, J=13 6, 5.0 Hz. nlg of the desired product as a yellow solid EM-MS ni/z 2H), 3 98 (s. 2H), 3.61-335 (m, 6H), 3 00-2 85 (m, 2H). calc. 4(i0.1. found 461 10. Retention time: 0.92 minutes. 2 11 (s, 411), I 7-) (d, .I 13.7 Iiz, 211): I:SI-MS m/z calc 391 I, found 392.1 (M+I)+. Retention tinie 0.67 minutes. I'ormation of niethyl 2-((5-chklro-2-nitro-4-(1,4- Extunple 35 oxazepan-3-yl)phenyl)thin)acetate (271) (+,' )-4-[3-[2-chlom-4-(ox- [0921] tert-Butyl 3-[2-chloro-4-(2-methoxy-2-oxo-ethyl) Synthetic Scheme 35: sulfanyl-5-nitm-phenyl]-1,4-oxazepane-4-carixlxylate. 270, etan-3-yl)phenyl]-1.4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine 1-255 (50 mg, 0.108S nunol) in dichloromethanc (1.5 mL) was (275) added trifluoroacctic acid (0.2S mL, 3.25 nunol) and surrcd [0925J for I hour at room tempcraturc. LCMS uidicated no more starting material present. Solve n I was removed in vacuo and the cnlde pmduct ('IJIA salt) was used directly v ithout further purification. Iiormation of nlethyl 2-((4-(4-(2-amino-6-methylpy- ~i rimidin-4-yl)-1.4-oxazepan-3-yl)-5-chlom-2-nitrophenyl)thio)acetate (272) In a micmwave viaL methyl 2-[5-chloro-2-nitro-4- Yi [0922] 8 (1,4-oxazcpan-3-yl)phmlyl]sulfanylaccuite (Tnfluoro mctate salt). 271. (0.05 g) and 4-chloro-6-methyl-pyrimidin-2- ammc (0.03 g. 0.17 nunol) ul n-BuOH (2 mL) was lmatcd at 120" ( overnight I CMS indicated disappearance of the 31 starting material I)oth Methyl ester and n-Bu ester products US 20 ] 9/032265 [] A[ Och 24, 2019 190

-continued 1=11.6 Hz. IH). 3.70-3.47 (m, IH), 2.97 (d. J=7.5 Hz. 3H), 2.17 (d, J=13.1 Hz, 7H), ESI-MS m/z cele. 403.2. found 404 0 (M+I) . Retcnuon time. 2.55 minutes.

277 RH&

27.

[0926] s& Pyrex tube was charged with 3-bromooxetane

(0 025 g. 0.180 mmol), Ni('I, glyme (0 003 8,„0.014 mntol), CI 1.10-phcnantluohne (0.005 g, 0.028 mmol). NaBFs (0.007 g, 0.065 nunol), mangancsc (0.013 g. 0.240 nunol). Thc tube tv as bubbled w ith nitmgen for 5 minutes. To the mixture was added MeOI I (0.5 ntl.). 4-ethylpyridine (0007 g. 0060 mmol) and 4-[3-(4-bromo-2-chloro-phenyl)-1,4-oxazcpan- (+/ —)-4-(3-(2-chloro-4-(tetrahydmfuran-2-yl)phe- 4-yl]-6-methyl-pyrimuhn-2-anunc, 31, (0.050 g, 0.120 nyl)-1,4-oxazcptm-4-yl)-6-methylpyrimuhn-2-anunc 1-235 nunol). The reaction mixture v as stirred overnight at 60" C. (277) 'I'he reaction mixture was diluted with I'.tOhc and tiltered [0928] 'H NMR (400 MHz. CDCJ,) o 7.40 J=1.8 Hz, though a layer of ('lite 'I'he filtrate was concentrated in (t, I H), 7 24-7.10 (m, 2H), 5.56 (1, I H), 4.8S (t, J=7.2 Hz, I H), 1 acuo;md tlu: rcs&duc was puu(ied by silica gcl cluomatog- 4 60 (s, 211), 435 (ddd,.l 13.6, 5.1, 2 I Jlz, 111). 4 10 (dtd, raphy using a 4 g ISCO column eluting with 0-10% MeOH. 'I'he product recovered has niinor debromination intpunty. .I 8 7, 6 8. 2 2 I lz, 2il). 4 01-3 89 (m. 111). 3 70-3 46 (m, 'I'he product was punfied again by reverse phase IIPI.C 311), 2.39-2.28 (m, ll I). 2 14 (s, 311). 2.02 (ttd, .I 8 I, 6 7, cluomstography to allbrd 9.0 mg of desired product: 'H 6 2, 5 3 I is. 211), I 90-1 74 (m, 211) I 2&2 (d I (7 0 Jiz 111)1 NMR (400 MHz, CDCJ&) 6 7 44 (d. 1=1.5 Hz. IH). 7.28- ESI-MS m/7 cele 388 2, found 389 0 (M+I) Retention 7 22 (m, 211). 5.71 (s, 111), 5 58 (s, 111), 5 07 (ddd, I 83, time: 3.09 minutes. 6 1. 09 I lz, 211), 474 (ddd, .I 68. 61. 09 I lz, 211). 463 (s, 2H). 4.35 (dd, J=13.6, S.O Hz. IH), 4.26-4.02 (m, 2H). 2.15 (s, 3H), 2.10-1.95 (m, IH), 1.90-1.79 (m. IH): ESI-MS nt/2 cele. 374.2. found 375 0 (M+I)+. Retention time 2 63 27S ntimttes

276 H .1

(+/— )-5-(4-(4-(2-annno-6-methylpyrimuhn-4-yl)-I 4-

oxazep an-3-yl)-3-chio re Phenyl- - -m methyl pyrrc1 id i- 2-one (278) 1-239

— )-N-(4-(4-(2-am&no-6-methylpyrimidu1-4-yl)-l, (+/ [0929] 'I l NMR (400 Ml lz, ('D(11) &5 7 30 (s, I I I), 4-oxazepan-3-yl)-3-chlorobenzyl)-N-&nethylacet- 7 28-7.22 (m, 111), 7 18-7.03 (m. 111), 5.(78 (s. 5i I), 4 60-4 antide (276) 1-254 26 (m. 2H), 4.21-4.02 (m, IH), 3.65 (dd, J=26 2, 13.5 Hz, [0927] 'H NMR (400 MHn CDCJ.,) 6 7.28-7.17 (nl, 2H), 4H), 3.32 (0 J=7.1 Hz, IH), 2.71 (d, J=2.2 Hz. 2H). 7.13-6.99 (m, I H). 5.57 (s. 2H), 4.79-4.56 (m. 3H), 4.56-4. 2.64-234 (m, 2H). 2.33-1.76 (m. (IH); ESI-MS m/z cole. 43 (m. 211). 4 34 (ddd, J 13.6. 5 0, 3.6 Iiz, 111), 4.10 (d, 415 2, found 416.27 (M+I) . Retention time 0.6(i minutes US 20]9/032265[] A[ Och 24, 2019 191

Example 36 Example 37

Synthetic Schenle 37 (+I — )-4-(3-(2-chloro-4-(pyrro- Synthetic Scheme 36. — )-4-(3-(2-chioro-4-(tc&ra- (+I lidin-2-yl)phenyl)-1,4-oxazepan-4-yl)pyrimldin-2- hydmfuran-3-yl)phenyl)-1.4-oxarepan-4-yl)-CI-meth- amine (280) 1-267 ylpyrimidln-2-amine (279) 1-238 [0932] [0930J

H 8

tt 8

8 cl zso 0 CI [0933] APyrcx vial was chsrged w&th NIC116H 0 (0029 219 g, 0 121 mmol) and 4.7-&limcthoxy-l,lfi-pheuanduolulc (0.125 mL of 0.1 M. 0.013 nunol) in DMSO (I mL). Thc tube was sonicated for 5 mim&tes until materials &vere [0931] A pyrex tube was char ed with 3-bromotetrahy- dissolved In a reaction vial charged with 4-[3-(4-bmmo-2- chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2- drofuran (0.027 g, 0.179 mmol) dichloronickeh 1.2-dime- amine. 31. (0.050 0.121 nmlol), Ir(dF(CF,)ppy)l(dtbpy) thoxyethane (0.003 g„0.014 mmol). 1,10-phenantiuoline g, PFs (0 0013 g. 0.0012 mmol). tert-butyl pyrrohdine-I- (0.005 0.028 mmol). BF4 (So&bum sall) (0.007 0.064 g. g. carboxylate (O.OSO mL. 0.285 nmlol), quinucli&hn-3-yl nuuol), mangancsc (0.013 g, 0.237 mmol). The reaction acctatc (0.270 mL of 0.5 M solut&ou. 0.13S mmol) in DlvISO m&x&ure was bubbled w&th nitrogen Ihr S mim&tes. To thc (0 40 ml.) and 4,7-dimethoxy-l.lfi-phenanthroline (0.125 m&x&ure was added McOH (4 mL). 4-ethylpyndtnc (0.007 g, m[, of 0.1 M solution in l)MSO, 0.013 nlmol). 'I'he tube was 0.061 mmol) aud followed with 4-[3-(4-bromo-2-chloro- bubbled with nitrogen for 5 minutes. To the mixture was was phcny'I)-1. I-oxt&zepan-4-yl]-6-nlethvl-pv&lnudtn-2-anunc. added H10 (0.090 mL, 4.996 nunol). The reaction tube exposed to a blue LED light and stirred ovcmight. Thc 31. (0 050 g. 0 121 mnlol) I'he mixture was stirred at 55" CL nuxulrc w&ls dtlutcxl with E&OAr., washixl wnh H,O ani! 'I'he overnight. reaction nlixture was diluted v ith litOAc, bone Thc orgatuc phase was dried over Na&SOw Iiltcrcd filtered though a layer of celite and concentrated in vacuo. and concentrated in vacuo. 'I'he resulting residue was puri- Thc resulting rcsiduc was purilied by s&hca gel cluomatog- fied by silica gel chromatoaraphy using a 4 8 IS('0 column raphy using a 4 g ISCO slhca gel cartridge elutulg with elutulg with 0-109I& MeOIJ/dichloromethane to afiord 0-1091& MeOH. The product recovered was repurified by mostly pure desired product that was used in next step reverse phase chromatography 'in afiilrd 6.7 mg of desired without further puniicauon. product: 'H NMR (400 MHz, CDCI,) b 7.30 (d, J=l.7 Hz, [t)934J io a solution of the above pmduct dissolved in dichloromethane ml,) ives added tritluonlacetic acid I H). 7.24 (d. J=3.2 Hz, I H), 7.18 (d. 1=8.0 Hz. IH), 7.11 (d, (I (0.500 mL. 6.490 mmoi). The reaction mixture was stirred 1=8.1 iqz, IH), 5 58 (s„ I H). 4.90 (s, 2H), 4.51-4.2C& (m. I H), at room temperature for 20 minutes. The react&on mixture 18-4 3 I I I .I 4 05 (nl. 211), 92 (q..l 7 8 lz, l)„3 73 (ddd, 8 7, was subnuttcd dlrcctly to reverse phase HPLC purilicatlon J=7.6 7.0. 1.8 Hz, I H). 3.69-3.49 (m. 3H), 3.37 (p, Hz, IH), to aiihrd 16 mg of des&rex) product as a TFA salt Thc product 2.45-2.27 (m, IH), 2 17 (s, 3H). 2.08-1.9S (m, 2H), ESI-MS was converted to free base by passing tluough a PL-HCO, m/z cele. 388.2, found 389.0 (M+I) . Retention time 3 06 MPS Pl i cartridge mid the filtrate was concentrated In vacuo nlimltes to afford 5.6 mg of desired product 'll NMR (400 Miis, US 20 1 9/032265 [J A[ Och 24, 2019 192

CDCli) 8 7.43 (d„J=8.5 Hz. IH), 7.24-7.15 (m, 2H). 4 59 (s, -conti»uxl 311), 4.35 (ddd, .I 13 6, 5 0, I 7 IIX, 111), 4 10 (d, .I 8 0 llz, 01 3H). 3.69-3.49 (m, 4H), 3.27-3.14 (m. IH), 3.04 (d, J=S 6 Hz. IH), 2.64 (s. 6H), 2.30-2.09 (m, 4H): ESI-MS m'z cele. 387.2, found 388.2 (M+I)'. Retention time: 0.5 minutes.

Example 38

Synthetic Scheme 38: (+/-)-4-(3-(2-chloro-4- (mcthoxymcthyl)plmnyl)-I g-oxazcpml-4-yl)-6- methylpyrimidin-2-amine (286) 1-205

[093 5J

(a) BocsO, EI,N, THF; (b) NaBHO EIOH, (c) NBS. Ph,P, CHsCI, (il) NiaOMc. MCSJH. 70'., (c) HCI, dloxane, (I') 2-annno-4-chloro-6-methyipyrin»dine. nl3uOI I. 120';

Formation ol'+/— )-tert-butyl 3-(2-cldoro-4- (mcthoxycarbonyl)phenyl)-1,4-oxazcpanc-4-carboxylate (281) [0936J Io a solution of methyl 3-chloro-t-(1,4-oxazepan- 3-yl)benzoate, 188. (5 619 g, 21.10 mnlol) and triethylamine (3.25 mL. 23.32 num&l) in THF (80 mL) was added Boc anhydnde (5.07 g, 23.23 nunol). The reaction mixture was stirred at room tcmpcrature for 3 days, ihluted with I M HCI and cxtractcd twice with EIOAc. The combuled organics werc conccntldtixl to dry»cue and pullilcd via slice gcl chromatography eluting lvith 0-50% I:tOAc in heptane. Pure fractions were combined and concentrated in vacuo to give 6.27 g of the desired product as a light yellov oih 'H NMR (400 MHz, CDCli) 6 8.03 (d. J=l.7 Hz„ IH), 7.90 (dd. J=8.1, 1.7 Hz, IH), 7.34 (d. J=8.2 Hz, IH), 5.56 (dd, J=I0.6. 4.6 Hz, IH), 4.56 (dd, J=15.0, 5.5 Hz, IH), 4.31-4.06 (m, 2H). 3.94 (s, 3H), 3.58-333 (m, 3H). 2.07-1.91 (m, IH). 1.85 (d. .I 15.9 I IX, 111), I 22 (s, 1011).

Formation ol (+/ — )-tert-butyl 3-[2-cldoro-4-(hy- dmxymethyl)phenyl)-1,4-oxazcpane-4-carboxylate (282) [0937J To a solution of terr-butyl 3-(2-chlom-4-methoxy- carbonyl-phenyl)-t,s-oxazepane-s-carboxylate. 281, (Gi.25 g, I fii,05 nunol) in EtOH (80 mL) was added NaBHX (6.07 g. 1604 mmol). The reaction was stirred overnight at room tcmperaturc and then carefully tlucnchcd with ail»cons IM HCI to pH — 1. Thc product was cxtractcd tluec times with EIOAc laid thc co»lb»»xi olganlcs werc conccntrauxl to dryness and purified via silica gei chromatography eluting, v ith 0-65% EtOAc in heptane. Pure fractions were combined md concentrated in vacuo to give 4.94 g of product: 'H NMR (400 MHz, CDCIs) 6 7.37 (s. IH), 7.23 (s, 2H), 5.52 (dd, J=10.8. 4.7 Hz, IH), 4.68 (d. J=3 3 Hz, 2H), 4.54 (dd. J=15.1, 5.3 Hz. IH). 4.12 (ddd, J=28.6, 13.6. 4.6 Hz, 2H), 3.57-3.2S (m, 3H). 2.08-1.90 (m, 2H). 1.90-1.75 (m, 111), 1.24 (1, 911); IISI-MS ngz cele. 341 2, found 342 0 (M+I)+ ltetention time 0 961 nlinutes US 20[9/032265[] A[ Oct. 24, 2019 193

Formation of (+/-)-tert-butyl 3-[4-(bromomethyl)-2- dichloromethane. Pure fmctions v,ere combined, concen- chloro-phmtyl]-1,4-oxazcpanc-4-carboxylate (283) trated, and lyophiliztxi io ailiard 18 mg of desired produci. 'H NMR (400 lVIHz. DMSO-d6) 6 7.36 (d, J=1.6 Hz, IH), [0938] To a solution of tert-butyl 3-[2-chloro-4-(hy- 7 28 (d,.i 8 0 liz, 111), 7 21 (dd..i 8 1. I 7117. 111), 5 57 (s, droxymethyl)plmnyl]-1,4-oxaacpmtc-4-carboxylate, 282, 111), 5 4(7 (s. 211),4 63 (d..i 14 9117. 111), 4 38 (s, 2i I). 4 11 (4.94 g. 13.73 nunol) and tnphcnylphosphine (4.35 g. 16.58 (dd. 1=13.5. 5.0 Hz, IH). 3.93-3 86 (m„ IH), 3.76-3.60 (m, ntmol) in dichloromethane (50 ml,) was added N-bromo- 2H). 3.60-3.48 (m. I H). 3.30 (d, 1=0.7 Hz, 3H), 1.99 (c. 3H), succinimide (3 75 21.07 mmol) The reaction mixture was g, 1.77 (p. J=4.1 Hz. 2H); ESI-MS m/z cele. 362.2. found 363.0 stirred for 20 minutes at morn temperature and then diluted (M+I) Re(cation time. 0.7 muiutcs. vvith water. The organic layer was concentrated to dryness and purified via silica gel chromatography eluting v.ith Exiunple 39 0-40% EIOAc in hcptanc Pure fmcuons werc combined and concenuatcd to give S 0 g of dcsircd product as a colorless Synthetic Scheme 39. (+/— )-2-(4-(4-(2-iunuto-6- oil 'll NMI( (400 Mllz, ('D('I,) tS 743-736 (nt, IH), methyipyrimidin-4-yl)-1,4-oxazepan-i-yl)-3-chloro- 7 32-7 18 (m, 211), 5 51 (dd, .I 1078, 4 7117., 111), 4 60-4 48 phenyl)propane-l,l-dial (288) 1-236 44 35-3 98 3 48 (dddd..i 17 (m, ill),4 (s, 211),4 (m. 211). I, [0942] 14.3, 11.4„3.1 Hz. 3H). 2.09-1.90 (m, IH), 1.90-1.71 (m, IH), 1.31-1.18 (m. 9H): ESI-MS nt/z calc. 403.1, found 404.0 (M+I) . Rcteuuon time. 0.63 minutes.

I'orntation of (+/— )-tert-butyl 3-[2-chloro-4- (ntethoxymethyl)phenyl]-1.4-oxazepane-4-carboxy late (284)

[0939J A suspension of (+/ — )-tert-butyl 3-[4-(bronioni- ethyl)-2-chloro-phenylJ-1,4-oxazepane-4-carboxylate. 283, (0.37 g. 0.88 mmol) was stirred in sodium methoxide (3 mL of25% w/v solution in MeOH. 14 mmol) at 70" C, overnight in a sealed tube. Thc mixture was diluiixi with water and Ci cxiractcii with EtOAc. Thc orgaiuc layer was concentrated io dryness and puniicd via sihca gcl clu orna( ography clu ting with 0-50% I:tOAc in heptane. I'ractions containing the desired product were combined and concentrated to give 161 m colorless oil 'H NMR (400 MHz, CDCls) 6 7.39-7.30 (m, IH). 7.30-7.17 (m. 2H), 5.52 (dd. J=I0.9. 4.7 Hz. IH), 4.62-4.49 (m, IH), 4.42 (s, 2H). 3.55-3.43 (m, 2H), 3.40 (s, 3H). 1.98 (ttdd, J=l1 2, 5.8. 2.2 Hz IH), 1.87-1.72 (m, IH), 1.47-1.24 (m. 9H): ESI-MS nga calc. 35S.2. fi&und 356 0 (M+I) . I(etentton time 0 55 mimites 0 Formation of (+/— )-3-[2-cition»4-(methoxymcthyl) phenyl]-1,4-oxazepane (28S)

[0940] A solution of (+/-)-ien-butyl 3-[2-cldoro-4- (methoxymethyl)phenylJ-1,4-oxazepane-4-carboxylate. 0 c 284. (0.1(7 u. 0 45 mntol) in I I('I (3 0 ml, of 4 M. 12 00 nunol) was stirred for I hour at room temperature. The reaction mixture was then concentrated to dryness to alford Ci 132 mg of the desired product as an HCI salt and used in the ti7 next step without I'urthcr purification: ESI-MS nVz cele. I I xt 255.1, found 256.0 (M+I) . Retcniion tune. 0.56 nnnuics. —, Fomtation of (+/-)-4-[3-[2-chloro-4-(methoxym- )~/ cihyl)phenyl]-1.4-oxazcpmi-4-yl]-6-methvl-pyrnnidin-2-anuuc (286) 1-205 OH [0941] A mixture of (+/— )-3-[2-chloro-4-(mcthoxymcthyl) phenylJ-1.4-oxazepane-l I('1. 285. (0.13 8, 0.45 mniol), Oii 4-chlom-6-methyl-pyrimidin-2-amine (0.10 g. 0.70 mniol), (7 and triethylanune (0.19 mL, 1.36 mmol) in n-I3»OH (2 mL) was heated in a sealed tube at 120" C. overnight. The reaction mixture was conccuiratcd to dryness then dissolved in EIOAc and washed with ail»ex»ts saiuraiml sodnim bwar- bouaic solutiou. Thc orgaiuc phase was isolatml and con- (a) Ir(dF(CF,)ppy)z(dibpy)PFw NiCI, glymc, TTMIvIS, centrated to dryness 'lite resulting residue v, as puritied via Nas('Os, DME, I,I ID blue light, (6) Il'A, ('Iiz('1„(c) silica gel chmmatography eluting with 0-10'!v MeOII in 2-annno-4-chloro-6-methylpyrin»dine. nliuOI I. 130' US 20[9/032265[] A[ Och 24, 2019 194

Formation of (+/-)-tert-butyl 3-(2-chloro-4-(oxetan- 3-yl)phenyl)-1,4-oxazepane-4-carboxylate (286)

[0943] To a react&on vtal was add&xi N&CI& glymc (0 003 g, 0.014 mmol), 4-&crt-butyl-2-(4-tert-butyl-2-pyridyl)pyndinc (0.004 g. 0.015 mmol) and DME (I mL). The nuxturc was bubbled with nitrogm& Ibr 5 nunutcs until thc solul dtssolved in DME (I mL). In m&other vtal was added tert-butyl 3-(4-bromo-2-chloro-phenyl)-1,4-oxazepanc-4-&arboxylatc, 258. (0 200 g, 0.510 nunol), 3-bromooxetane (O. I if g. 0 800 mmol), Ir[di'(Hi&3)PPy]s(dtbby)PI s (0.003 g„0 0034 mntol), 'Ii1FMSS (0.170 ml . 0 550 mmol) and Na&CO, (0062 g, (+/-)-4-(2-(2-bromophenyl)azepan-l-yl)-6,7-di- 'I'o 0 590 mmol) and DMI: (2 ml.) the mixture was added hydm-5H-cyclopcnta[d]pyrimtdu&-2-aminc 1-7 NiCls lyn&e solution and stirred for 18 h in front of blue LED lamp. The mtxture v as diluted with H,O, extracted [0946] 'H NMR (400 MHz, MeOD) o 7 58 (c, IH), 7.29 with dicltioromethane and the organic phase was concen- (d. J=65.1 Hz, 3H), 5.61 (d. 1=166 6 Hz, 2H). 4.54 (s. IH), 3.82 IH), 3.48 (s. IH). 3.27-3.21 (m, IH), 3.20-1.31 (m, trated in vacuo. The residue was purified by silica gel (s, 12H), ESI-MS nv'z cole. 272.16, Ibund 272.92 (M+I) . clm&matography using a 12 ISCO colunu& eiutit&g with g Rater&tlon trit&e' 58 &111&1<es 0-50'%tOAc/heptane to afiord 80 mg of desired product 'H NMR (400 MH&, CDCI,) 6 7.22 (s. IH). 7.11 (s, 2H), 5.47-5.27 (m. IH), 4.92 (t, J=7.2 Hz, 2H), 4.57 (d, J=6.4 Hz, IH). 4.16-3.76 (m, 3H), 3.49-3.12 (m. 4H). 1.74 (d. J=46 8 Hz. IH). 1.41 (s, 3H), I 08 (s, 9H).

Formation of 3-(2-chloro-4-(oxetan-3-yl)phenyl)-1, 4-oxazepanc (287)

[0944] To a solutton of tert-butyl 3-[2-chloro-4-(oxetmt- 3-yl)phenyl]-1.4-oxazepane-4-carboxyh&te. 286, (0 080 g, 0.220 num&1) in dichloromethane (5 mL) was added trifiuo- roacetic acid (0.20 mL. 2.60 nunol). The reaction mixnue (+/— )-4-(2-(2-bromophcnyl)azepan-i-yl)-5.6-dtmcth- was surrcd for I hour at room tcmperaturc. The mtxture was ylpyunudtn-2-am&ac 1-8 concenuatcd in vacuo. Thecrudc TFA salt was converted to parent form passing though a VI.-IICO3 MP SPI& car- by [0947] 'H NMR (400 MHz. MeOD) 6 7.60 (d, J=8.0 Hz, tridge with MeOI I as solvent I'he filtrate was concentrated IH). 733 (&b 1=7.7 Hz, 2H), 7.15 (dd, J=l I 3, 5.2 Hz. IH), in vacuo 'I'he cmde product was carried to next step without 5.51 (s. IH), 4.49 (s. IH), 3.90-3.51 (m, IH). 2.62 (s. IH), further purificatton; ESI-MS m/z cele. 26&7.1 found 268 2 2.27 (s, 3H). 2.08 (s. 3H). 1.84 (dd, J=33.6, 27.8 Hz, 5H), (M+I) . Retention time: 0 66 minutes. I 59-1.37 (m, 211): Iigi-MS m/z cele 375 0. found 375 I (M+I)+ ltetention time 2 95 n&inutes Formation of (+/ — )-2-(4-(4-(2-amino-6-nðylpy- rimidin-4-yl)-1.4-oxazepan-3-yl)-3-chlorophenyl) propane-I 3-dioi (288) 1-236 H&N

[0945] A nuxturc of 3-[2-&hloro-4-(oxctan-3-yi)phenyl]- 1,4-oxazcpanc, 287, (0.050 g, 0.190 nm&ol) an&1 4-cltioro-6- methyl-pyrimidin-2-amtne (0.035, 0.240 nunol) in n-liuOH (5 ml.) was heated overnight at 130" C. I C-MS showed oxctm&c ru&g openu&g product. Thc nuxturc was concenuatcd u& vacuo. Thc re&alta&g rcsiduc v,as put&lied by silica gel chromatogvraphy ucmg a 4 g ISCO colmnn eluting 0 with 0-10'%eOI I/d&chloromethane to atford 11 4 mg of dcstr&xi product. 'H NMR (400 MHz, CDCI,) 6 7.30 (s. IH), 7.23-7.10 (m. 2H), 5.58 (s, IH), 4.89 (s. 2H), 4.35 (dd, 4-methyl-6-(2-(2-(mcthylsulfonyl)plmnyl)azcpm&-I- J=I3.6. 5.1 Hz, IH). 4 10 (dd. J=I2.3, 4.8 Hz. IH). 4.02-3. yl)pyrmudtn-2-anunc 1-38 84 (m. 4H). 3.67-3 53 (m, 211). 3 13-2 89 (m. II I), 2 14 (s, 3H). 2.08-1.95 (m, IH), 1.83 (d. 1=14.4 Hz, IH). 1.38-1.14 [0948] high tcmpcrature (360 K) 'H NMR (400 MHz, (m, IH). ESI-MS n&/z cele. 392.2, found 393.0 (M+I) . DMSO-d6) 8 7.93 (dd. J=8.0, I 4 Hz, IH), 7.61 (td, J=7.6, Retention time: 2.82 minutes. The foliowin analogs were I 511z, 111), 7 47 (td,.i 7 6. I 311z. 111), 7 38 (dd..i 7 9 I 3 accorditm to Synthetic Scheme 3. I lz. 111), 6.05-5.80 (m. 111), 5 65 (d, .I I I.G I I&, 111), US 20 ] 9/032265 [] A[ Oct. 24, 2019 195

5.56-5.29 (m, 2H). 4.14-3.80 (m. I H), 3.60 (s. 3H), 2.66-2. 5.41-553 (m. 3H). 4.10 (d, 1=12 0 Hz. IH). 3.52 (dd, 54 (m, IH). 2.05 (s, 3H). 1.97-1.76 (m, 2H), 1.81-1.54 (m, .I 15.0, 11.0 I lz, 2H). 2 62 (s. 311). 2 25-2 14 (m, 111). 2.04 2H). 1.56-1.11 (m, 4H). (s, 3H), 1.93 (s. IH), 1.87-1.72 (m. 2H). 1.56-1.28 (m. 4H);

ESI-MS m'z calc. 29S.19, found 299.19 (M+I) . Rctcntton time: 0.53 minutes.

%if 0

4-[2-(2,6-dnuethoxy-3-pyudyl)uzepmt-l -yl]-6- methyl-pynnudin-2-tenure, 1-73 [t)949] 'll NMlt (300 Miiz. J&MSO-d6) 6 737 (br, IH), 7 11 (s. 2H). 6 31 (g 111), 5 66 (br, 111), 4 73 (br. IH), 4.02-3.72 (m„6H). 3.68-3.01 (m, 2H). 2.17 (brs. 3H), 1.98-0.93 (m, SH): ESI-MS nu'z cole. 343.20, found 344.35 (M+I) . Rctenuou time. 0 72 mimttes. 3-(I-(2-amino-6-methylpyrimtdin-4-yl)azepan-2-yl)- 2-Ihtoro-N-methylbenzamtde 1-54

[0952] "H NMR (400 MHz. DMSO-d6) o 7.87 (s, IH). 7.43 (td, J=7.2, 1.9 Hz, IH), 7 22 (td, J=7.5. 1.9 Hz, IH). Yif 7 .I 7 5 4 12 (t, 6 llz, ll I). 72 (s, 111), 5.40 (s, 211), 20 (d, .I 14.4 Ilz, ll I). 342-3 29 (nt. 111), 2 97 (s, HI), 2.80 (d, 1=4.7 Hz. 3H). 243-2.29 (m. IH). 2.03 (s. 3H). 1.97-1.71 (m, 4H). 1.67-1.23 (m. 3H). ESI-MS nt/z calc. 357.1965, fitund 358.0 (M+ I) . Rctenuon time. 0.66 minutes.

Example 40

4-(3-(5-iluoro-2-methoxyphenyl)-2-azabicyclo [ 3.2. — 2]nonan-2-yl)-6-methylpyrimidin-2-amine 1-76 Synthetic Scheme 40 (+t )-4-(3-(2-chlorophenyl)- 6-methylene-1,4-oxazepan-4-yl)-6-methylpyrimidin- [0950] high tempcraturc (360 K) 'H NMR (400 MHz, 2-amine 1-75 DMSO-d6) 8 6.99 (dd, J=9.0, 4.6 Hz, IH), 6.95-6.81 (m, 211), 5.65 (s. 111), 5 53-5 33 (m, 211), 5 26-5 11 (m, IH), [0953] 3 88 (s. 311). 2.45-2 31 (m, 111), 2.23-2.11 (rn, 111), 2.10-1. 96 (nt. 213). 1.91 (s. 3H). 1.88-1.74 (m, IH). 1.73-142 (m, 7H); ESI-MS nt/z cole. 356.20. found 357.25 (M+I) . Retcnuon time: 0.68 mtnutcs. Sec~~S

IIO

(+t — )-4-ntethyl-6-[2-(4-methylpyrimidin-5-yl)azepan-I-yl]pyrimidin-2-amine 1-42

[0951] high tentperature (360 K) 'l l NMlt (400 Mila„ l)MSO-d6) 6 8 Sl (s, 111), 858 (s. 111)„5 74 (s. 111), US 20 ] 9/032265 [] A] Och 24, 2019 196

-continued through a phase separator. The organic phase concentrated in vacuo to afford 575 mg of orange solid: heated 'H NMR

HN (360K) (400 MHz, DMSO-d6) I) 7 (i9-7 52 (ni. II I), 7.50- 7 36 (m, 111), 7 36-7 20 (m, 211), 5 76 (s, 111), 5 73 (d..l 2 2 I lz. 111), 5.52 (s. 211). 5.05 (d..l 51 9 I lz, 2i I), 4 72 (d, 1=16.0 Hz. IH). 4.29-4.09 (m, 2H), 4.08-3.97 (m, 2H). 3.92

(d. 1=16.0 Hz, Example 41 Synthetic Scheme 41: (+/ —)-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophe- 70'. nyl)(imino)(niethyl)-).'-sulfanone (1-156) (a) 3-chloro-2-(chloromethyl)prop-I-ene. Lil. NaH. DMF, [0957] rt. Ihmi 50'., (b) TFA, CHaCI,: (c) NHsOH, CHsCN,

Formation of (+/— )-tert-butyl 3-(2-cldorophcnyl)-6- HiN methylene-l,l-oxazepane-4-carboxylate [0954] To a solution of tert-butyl N-[I-(2-cltiorophenyl)- 2-hydroxy-ethyl] carbiunatc (5.00 g, 18.40 nmiol), 3-chloro- 2-(Hiloromcthyl)prop-I-cnc (2.60 g, 20.80 nmiol) and litlmun iodide (0.11 g. 0.84 mmol) in DMF (200 mL) was added one equivalent of Nai I in portions (0 75 8, 18 62 mmol). 1 he mixture was stirred at rooin teinperature for 15 hours. Then added the 2nd equivalent ofNaH (0.75 g, 18.62 nunol). After 24 hours„heated reaction mixture to 50'. for Hix 3 days. The reaction nuxture was diluted into aqueous satumttxt NHsCI solution and extracied twwc with EtOAc. Thc combuicd organic phases were washed twwc v lth bone, dried (MgSOi). filtered and concentrated in vacuo 1he resulting residue was puufied via silica gel chromatography ivith 80 g ISCO colunul using 0-30% (EtOAc/hepmnes) 'H NMR (400 MHz, DMSO-d6) 6 7.50-7.25 (m. 4H). 5.50-5.19 (m, IH). 5.00 (s, 2H), 4.72-4.23 (m, IH). 4.16 (s, 2H), 4.09-3.74 (m, 3H), 1.54-1.02 (m. 9H). oil . fix Fonna/ion of (+/ — )-3-(2-chiorophenyl)-6-methylcnc- 1,4-oxazepane [0955] To a solution of tel(-butyl 3-(2-chlorophenyl)-6- methylene-1,4-oxazepane-4-carboxylate (0.76 g. 2 23 nuuol) in dichloromcthane (8 mL) was addixl tufluoroacetic acid (6 mL). Stirred reacuon mixture at room lemperaturc fiir I hour and concentrated in vacuo 'I'he residue was diluted ivith dichloroniethane and neutralized with aqueous saturated Nal ICOi solution 'lite or anic phase was passed through a phase sepamtor and the resulting filtrate was concentrated in vacuo to afford 485 mg of product as yellov

Fonna/ion ol (+/— )-4-(3-(2-cldorophcnyl)-6-mcthyl- ene-1,4-oxazcpan-4-yl)-6-mcthylpyrimidui-2-anunc 1-75

[0956] To a solution of 3-(2-chlomphenyl)-6-methylmm- 1.4-oxazepanc in (0.49 g, 2.17 nuuol) ui NMP (6 mL) was added 4-chlom-6-methyl-pyrimidin-2-amine (0.38 g. 2 61 mmol). I'he reaction nuxture w:as heated to 150' for 16 hours. The mixture was cooled to room temperature and loaded directly onto 100 ISCO ci8-aq colunui and the ciiidc was piirllicil by reverse phase chitulg wllh 0.1% TFA/H 0 and 0.1% TFA/CHsCN audient. The lyse/tons contailung dcsircd product were concentrated in vacuo, diluted v ith dichloromethane. neutralized with aqueous saturated Nell('Os solution and the mixture ives passed US 20[9/032265[] A[ Oct. 24, 2019 197

-continued Example 42

Synthetic Scheme 42; (+/-)-2-[4-(2-amino-6- methyl-pyrinndin-4-yl)-1,4-oxazcpan-3-yl]bcnzoni- Irilc, (+1 —)-4-[3-[2-(anunomcthyl)phenyl]-1,4-oxazepan-4-ylJ-6-methyl-pyrimidin-2-anune. and (+/— )- N-[[2-[4-(2-amino-6-methyl-pyrimidin-4-)l)-1,4- oxazepan-3-ylJphenylJmethylJ acetanude [0963]

(a) Vhl(OAc)1, (NI 14),('06 MeOI I; (b) SFC chiral separa- I I N tion

Fonna(ion of (+/ — )-(3-(4-(2-tunulo-6-mcthylpynml- dln-4-)'1)-1. I-oxazcpan-3-vl)-4-chk&lophcnvi)(tnltno) (methyl)-).'-sulfanonc 1-156

[0958J 4-[3-(2-chloro-5-methylsulfinyl-phenyl)-1,4-ox- H azepan-4-ylJ-6-methyl-pyrimidin-2-mnine (0 25 g. 0 59 nlmol). ammonium carbamate 18 2.34 mnx&l) and (0 8, II&N (diacetoxyiodo)benzene (0.57 g. 1.78 mmol) &vere combined in a round bottom flask follov ed by the addition of MeOH (4 mL) and stirnug continued fi&r 75 mimi(ca. The reaction mixture was diluted into EtOAc and washed with aquimus saturated Nal I('0, solution 'I he aqueous phase was extracted with IitOAc. 'I he combined organic phases v ere dried (MgSO4). tiltered and concentrated in vacuo 'the crude residue was purified by reverse phase silica gel clm&matography with 50 g ISCO clg-aq column nuu»ng wilh 0.1% TFA/H&O aud 0.1% TFA&CH&CN. The pure fractions werc concentrated in vscuo and resulue was diluted with dich)oromcthanc mid ueutrahzed with aqueous saturated Nal I('0& solution 'lhe mixture was passed through a phase separator and the filtrate was concentrated in vacuo to afii&rd 27 mg of desired racemic product as a li ht yellow solid: heated NMR (360K) 'H NMR (400 MHz, DMSO-d6) 6 7.90-7.70 (m, 2H), 7.63 (dd, 1=14.2, 8.3 Hz, IH), 635- 532 (m, 4H), 4.91-4.41 (m. IH), 4.18-3.50 (m, 5H). 3.06- 3.00 (m, 3H), 2.12-1.99 (m. 3H), 1.87-1.64 (m, 2H).

The Racemic Mixture v as Submitted for SFC Chiral Separation

[0959] Peak A, 2.9 mg (89.8% cc). 4-[3-[2-CI&ioro-5- (meth)'isa1fonlnudovl)phon)'1]-1,4-oxazcpan-4-vl]-6- methyl-pyrimidln-2-aminc (2.9 m, 5%). ESI-MS ntfz cele. 395 12, found 396.0 (M+I) . Retention tilne: 0 52 minutes. 1-1 64. [0960J Peak H, 4 3 nlg (97-Igf ee) 4-[3-[2-chloro-5- (a) Mn01. MgSO4.;munonia. THF, (b) L&AIH4, THF, (c) (methylsulfonimidoyl)phenyl]-1.4-oxazepan-4-yl]-6- Ac,O, Nift,, D('M. methyl-pvrimidin-2-amlne (4.3 mg. 7%4): ESI-MS n&/z calc. 395.12. found 396.0 (M+ I) . Rctenuon umc: 0.52 numitcs. I&urn&ation of (+' )-2-[4-(2-amino-6-nlethyl-pyrimi- 1-165. din-4-yl)-1,4-oxazepan-3-yl]benzonitrile 1-89 [0961J Peak C, 3 2 nlg (98% ee) 4-[3-[2-chloro-5-(meth- [0964J I o a solution of [2-[4-(2-amino-6-nlethyl-pyriini- yisulfonimidoyl)phenylJ-1,4-oxazepan-t-ylJ-G-methyl-py- din-4-)I)-1.4-oxazepan-3-)I]phenyl]methano) (0.16 g, 0.52 rinlidin-2-&mine (3.2 5%): ESI-MS m/z cole. 395.12, mg. mmoi) in THF (3 mL) was added anmlonia (2 mL of 2 M found 39(xfi . Retention time: 0.52 minutes. 1-166. (M+ I) solution, 4.00 nuuol) thml anhydrous MSSO4 (1.07 g, 8.89 [0962] Peak D. 4.7 mg (98% ec). 4-[3-[2-chloro-5-(meth- nunol) and Iinally MnO, (135 VL, 7.78 nunol). Thc next ylsulibnimidoyl)phenyl]-1,4-oxazcpm&-4-yl]-6-methyl-py- morning I g more MgSO4. Ig more MnO, and tunmolua (4 rimidin-2-amine (47 mg, 8%) 1&SI-MS m/z calc 395 12, ml, of 2 M, 8.(X)0 mmoi) were added and the mixture heated found 396.0 (M+I)+ Retention time: 0.52 mimltes. 1-167 at 45''fter I h, the reaction mixture was filtered through US 20[9/0322658 A] Ock 24, 2019 198

Celite with the aid of 10% MeOH in EtOAc and concen- Example 43 trated in vacuo I.ther was added and 160 ma of the desired [l)967] Synthetic Schenie 43 (+/— )-3-[4-(2-amino-(&- product filtered off': high temperature (360 K) 'H NMR (400 methyl-pyrimidin-4-yl)-1.4-oxazepan-3-yl]-4-chlom-ben- MHz. DMSO-d6) 8 7.76 J=7.7 Hz. IH). 7.63 (t, J=7 6 (d, zonitrile. I-(i5 Hz. IH), 7.49 (d„J=7.5 Hz. IH), 7.43 (t, J=7.(i Hz. IH). 5.75 (s, I H). 5.55 (dd, J=10.6, S.2 Hz, IH), 5.39 (s, 2H), 4.38 (d, 14 8 llz, 111),4.11 (dd..i 13 6, 5.1 Ilz, 111), 3 95-3 83 (ni, 2H). 3.74 (dd, J=15zk 12.7 Hz, IH), 3.58 (dil, 1=14.6, 12 I I iz. 111). 2.04 (s. 311), I 83-1 75 (m. 211): I)SI-MS nt/z calc. 309.16. found 310 22 (M+I) Rctcntion time. O.SS mimitcs.

Formation of (+/ — )-4-[3-[2-(amuiomcdiyl)phenyl]-1, 0 4-oxazepan-4-yl]-6-ntethyl-pyrimidin-2-amine 1-94 C'i

[0965] To a solution of 2-[4-(2-tmuno-6-methyl-pynnudin-4-yl)-1.4-oxazepan-3-ylJbenzonitrile (0 055 8„0 177 nmiol) in THF (3 mL) with ice bath cooiiitg was added I iAII Is (0034 g, 0.873 mmol) under nitrogen and the C'N mixture was stirred overnight at room temperature. Care- fully dropivise addition of water and then added dichlo- 0 romethane. Fdtered the reaction mixture dtrough Celite v.ith C'i thc md of aqueous saturated sodium bicarbonate solution. The Layers were separated and the aqueous Layer was re- cxiracttxi with dichloromcthanc and concmitratcd ui vacuo. 'I'he residue was loaded directly onto a 30 g IS(:0 c1 8-aq colunui mid punlied by rcvcrsc phase runnuig v,ith 0.1% C.'N Ci 'IX%,'I lsO and 0.1% 'll'A/( I is( N The pure fractions v ere 0 concentrated in vacuo and then dissolved in MeOH and passed thmugh a SPI: bicarbonate cartridge (Agilent Stmto- spheres 500 mg/6 mL) and concentrated in vacuo to give a pmk oil. Ether was added and the mixuirc soiucated and 43 mg of the desired product was filtered oif: hi/~i tempermue CN (360 K) 'H NMR (400 MHz. DlviSO-d6) b 7.37 (d, J=7 I I iz. 111), 7 25 (d, .I 7 5 I Iz. 111), 7 17 (tt..i 7 4. 5 9 I iz. 2H), 5.82 (s, IH), 5 54 (d, J=4.6 Hz, IH), S.37 (s, 2H). 4.47 (d, 14 I llz, 111), 4 08 (dd,.i 13 5, 4 911z, 111),4 003 80(ni, 3H), 3.75 (dd. 1=13.5. 9.7 Hz. I H), 3.59 (ddd, J=16.7. 14 I, 7 3 I is. 211), 2 00 (s, 311). 1.76 (s, 411): I'SI-MS m,'z calc. 313.19, found 314 23 (M+I ) Retention time: 0.48 minutes.

Iiormation of (+/ — )-N-[[2-[4-(2-amino-ti-methyl- pyrimidin-4-yl)-1.4-oxazepan-z-yl]phenyl]methyl] acetamide 1-95 (a) IJMI', POCli; (b) 2-chloro-5-cyanophenyl bonmic acid, [0966] To a solution of 4-[3-[2-(amuiomediyl)phenyl]-1, PdCI (PPh ), Et N, DMF, 70'., (c) nBuLi, 2-McTHF, 4-oxazcpan-4-yl]-6-methyl-pyrunidui-2-mnine (0.015 g, — 78'G (d) NaBHu 2-McTHF, MeOH: (e) 4-cldoro-G- 0 049 mniol) in dichloroniethane (2 ml,) was added trieth- methyl-pyrimidin-2-aniine, NMP. 160'. yiamine (0.035 ml . 0 251 mmol) then acetic ainhydride (0.006 mL. O.OG4 nunol) at room temperature. After 20 lionnation of 3-chloro-6,7-dihydm-1,4-oxazepine-4 minutes. aqueous satumted sodium bicarbonate solution and (51 I)-carbaldehyde dichloromethanc werc added mxl thc layers separated Thc 3-neck 2 I roiuid bottom flask with an aqueous layer was rc-extracted with dichloromcthane Thc [l)968J A equipped ovcrhcad stirrer, temperature probe, addition funnel. nitro- layers werc scparatcd with thc aid ol a phase separator and gen inlet and reliux coniimiser was charged with DMF (ISO the organics were concentmted in vacuo to give 2.8 mg of mL. 1.94 mol) in dichloromethane (300 mL). The mixture the desired temperature 'I I NMI( product high (360 K) (400 was stirred for 5 minutes and then cooled to 0" C. POCI, (90 MHz, DMSO-d6) 6 8.07 (br s. IH). 7.28-7.13 (m. 4H), 5.75 ml., 0.97 mol) in dichlommethane (100 nil.) was added over (s, IH), 5.53 (s. 2H)„5,48-544 (m. IH), 4.76 (dd, J=15 2, 30 minutes v,bile niaintaining the internal teniperature 5.8 Hz. IH), 4.42-4.22 (m, 2H), 3.98 (dd, J=13.6. 4.9 Hz, below 6" C. Thc rcacuon nuxturc was wanncd to 40'. and IH). 3.87 (d, J=11.8 Hz, IH). 3.78-3.G4 (m, 2H), 3.61-3.52 stirred at tlus tcmpcraiure lor 45 minutes. 1,4-oxazcpan-3- (m, IH), 2.02 (s. 3H). I 92 (s, 3H), 1.76 (dd. J=8.2. 4.2 Hz, one (50 . 0.43 mol) in dichioromethane (300 mL) was 2i I): iiSI-MS m/z calc 355 20. found 356.28 (M+I)'. added oser 40 minutes, observed exotherm. maintained Retention time: 0 53 minutes internal temperature -40" ( 'I he resulting reaction mixture US 20 ] 9/032265 [] A[ Oct. 24, 2019 199

was stirred at this temperature for 90 minutes at which time overnight. Water and excess solid K&CO, v ere added and TLC (10 !8 methanol &n dichloromethane) and LCMS-analy- the mixture partially concentrated Dichloromethane was sis revealed consun&ption of the starting material. major added and siirnng continutxl o&cmight. Thc layers werc peak RT 0 51 nunutes (M+I I)+ 189/)91 that corresponds to separated with the aid of a phase sepamstor. The aqueous ihe anudine intcnneduiie. Reaction nuxiurc was cooled io layer &vas re-extracted &vith dichloromethane and the layers amb&cni temperature, poured into crushix! &cc (1.2 L), and v ere separated through a phase separator agam and the then allowed to v arm to ambient temperature over I hour cmnbmed organics concentrated u& vacuo 1'he co&de residue and stirred further for I hour. Sepamsted the aqueous layer, was puniicd v&a sihca gcl cluomatography w&ih a 40 g &sec basified ivith solid Ks('Os until pl i '), allowed to an&bient colunm using 0-100% E&OAc/heptane grad&cni fi&llowed by ten&pemture. stirred at this ten&perature for 12 lx&urs. Reac- 0-30% MeOH/dichloromethane to afford 283 mg of the uon nuxiurc was d&lu&cx) with d&chloromethane (300 mL) des&red product as a pale yellow oik 'H NMR (400 MHz, and ihe organic layer was separated. Aqueous layer was DMSO-d6) &5 8 01 (d,.l 2 I Ilz, III), 7.75 (dt..l 6 2, 3.1 1lz, extracted &vith dichloromethane (2x 100 mL). The comb&ned 111), 7 64 (d, .I N.3 I is„ ill). 4 26 (d, .I 5 8 I lz, 1l I), organic extracts v ere dried over Na&SOw filtered and con- 3.84-3.78 (m, 2H), 3.71 (m, IH), 3.33 (m, IH), 3.08 (m. IH), centrated under reduced pressure 'I'he residue was puritied 2.92-2.83 (m, IH) 1.86 (m, 2H), ESI-MS m/z cele. 236.07. by silica ael chromatography (330 8 isco column linear found 237.14 (M+I) . Retention time: 0.52 minutes. grad&eni, 20 C&/, 0% 50% ethyl ace&a&e/hcpranc-which [0972] A side pn&duct, 3-(1.4-oxazepan-g-yl)benzonitrile contained 1% Ei&N), io aff'ord 3-chloro-6,7-d&hydro-SH-J, v as also isolated after re-purification of son&e of the frac- 4-oxazepine-4-carbaldehyde (40 g. 57%) as a clear colorless tions: 100 o IS('0 clg-aq reverse phase column numing oil which contained traces of DMF. wi1h 0.1% TFA/H 0 and 0.1% TFA/CH CN and 1he pure fracuons were concenua&cd in vacuo. The rcs&duc was Fonuation ol'-chloro-3-(4-1i&rmy1-4,5.6,7-tctra- dissolved in MeOH and passed tlrrough a SPE bicarbonate hydro-1,4-oxazcpu&-3-yl)bcnzoniirilc cartndge (Agilent Stratospheres 500 mg/6 mL) and concentrated to give 64 mg of the desired product as a colorless oil [0969] ('barged a 20 ml. vial &vith pressure relief cap 'H NMR (400 MI Iz, DMSO dfi) &5 7 81 (d, .I I 7 Ilz, 1l I), under nitro en with (2-chloro-5-cyano-phenyl)boronic acid 7.72-7.67 (m. 2H), 7.51 (t. J=7.7 Hz, IH). 3.93 (dd, J=9.0, (2.98 g, 16.43 mmol), 3-chioro-6,7-d&hydro-SH-J,4-ox- 3.4 Hz, IH). 3.85-3.79 (m, 2H), 3 69 (dd, J=12.4, 6.1 Hz. azcpine-4-carbaldchydc (2.00 g. 11.76 mmol), PdCJ&(PPh.,)a IH). 3.35 (dd. J=12.2, 9.1 Hz. IH)„3.08-3.01 (m. IH), (0.40 0.58 nunol). DMF and triethyksmine 0 g, (9 mL) (5 2.87-2.79 (m, IH), 1.85 (n&. 2H): ESI-MS m/z calc 202.11, mL, 35.9 mmol). The mixture was heated at 70'. over- found 203.14 (M+I) . Retention tin&e 0 5 minutes night Added water, brine and )itOAc and then separated layers lhe aqueous layer was re-extracted ivith I'.tOAc and Format&on of (+/— )-3-[4-(2-anuno-6-methyl-pyrinu- thc combined or mucs werc washed with water (x3), dried du&-4-yl)-1,4-oxazcpan-3-yl]-4-clfioro-bm&zorutnlc (MNSOs). Iiltcrcd and concentrates) u& vacuo. Purification by 1-65 silica gel chromatography (120 g ISCO colunm; 0-100% [0973] A nuxuirc of 4-cJ&loro-3-(1,4-oxazcpau-3-yl)bcn- EtOAc in heptane) to afford desired product as a pule green zonitrile (0.078 g. 0.333 nunol) and 4-chloro-6-methyl- solid (1.5 8, 49%)'I I NMR (400 Ml lz. A('N) &5 7 85 (s, pyrun&din-2-amine (0.047 v. 0.330 nunol) in NMP (0.60 I i I). 7 77 (d, .I 2 0 I lz. 111), 7 68 (dd, .I 8 3, 2 I I Jz, 111), ml.) was heated at 160''n a sc&ntillation vial on a heating, 7.60-7.57 (m, I H), 6.19 (s, I H), 4.28-4.24 (m, 2H), 4.00 (t, block 1'he mixture was cooled to room ten&perature and J=6.6 Hz. 2H), 2.11-2 05 (m, 2H), ESI-MS m/z cele. 262.05, loaded d&rccily onto a 50 g ISCO c18-aq column and punliod found 2(i3.08 (M+I) . Retention time: 0.74 minutes. by revcrsc phase ruiuung w&th 0.1% TFA/H&O and 0.1% TFA/CH.,CN. The pure fractions w ere partially concentrated Formation of 4-chloro-3-(2.5,6.7-&ctrahydro-l.4- in vacuo. IM NaOH &vas added and the m&xture extmscted oxazep&n-3-yl)benronitrile with dichlommethane twice I'he layers were separated &vith the aid a phase separator and the orgamcs concentrated in [0970] To a solution of 4-chloro-3-(4-fonnyl-(i.7-dihydro- of vacuo Tnturai&on v,&ih cshcr gave 64 of the dcs&rcxl 5H-1.4-oxazepin-3-yl)benzon&trile (1.5 g. 5.7 nunol) in mg proililcl ds awhiie solid. Iugh temperature (360 K) 'H NMR 2-Me'I'I II'23 ml.) at — 7N" ( was added nl)ul,i (4 7 n&I. of (400 MHz, DMSO-d6) 6 7.72-7 (il (m. 3H). 5.69 (s. IH), I 6 M. 7 5 mmol) under nitmgen atmosphere over 2 min- 5.55 J=9.9. 4.9 Hz. 5.41 (s. 4.46 J=I5.8 utes. Added water and then rcn&ovcxl cold bath. Extracted (dd. IH), 2H). (d, I lz, II 4.08 (dd..l 13.5, 4 9 1lz, 111), 3.&)2-3.85 (m. ) I I), with d&chloromethanc, separated thc layers w&d& the aid of a I), 84-3.72 61-3.53 I 2 03 I N3-I phase separator The aqueous layer was re-exrracted v.ith 3 (m, 211), 3 (m, II), (s. 311), 75 ESJ-MS m/z cele. 343.12, fi&uud 344.17 . dichloromethane and the layers were separated tl&rou h a (m, 2H), (M+I) Rctcnt&on time. 0.59 mu&utes. phase separator again aud the co&nbined orgai&ics concentrated to afford desired product (I 34 8, 100!v)'&SI-MS nt/z Example 44 cole. 234.06, fi&uud 235.11 . Reicnt&on (M+I) tune. 0.74 [l)974[ Synthetic Scheme 44: (+/ —)-4-[2-(2-methoxy-3- nuncios. pyrnlyl)-5.5 wiimcthyl-azepan-I -yl]-6-methyl-pyrimidu&-2- anune 1-64 Formation of (+/-)-4-chloro-g-(1,4-oxazepan-3-yl) benzonitrile and (+/— )-3-(1,4-oxazepan-3-yl)benzo- n&tule CHO CHO [0971] 1o a solut&on of 4-chloro-3-(2,5.6,7-tetrahydm-l, 0 4-oxazepin-3-yl)benxunitrile (I 34 g, 5 71 nunol) in 2-MeTHF (15 mL) was added Ni&BHs (2. 16 g, 57.10 nuuol) at room tcmperaturc ovcrmghi. The reac1&on nux1urc was cooled in an ice bath and MeOH (5 ml ) &vas added. After 10 minutes. the cold bath v as removed and stirrin continued at mom ten&perature The reaction was heated at 50" C. US 20]9/032265]] A] Ock 24, 2019 200

-continued MHz. DMSO-d6) 6 8.53-8.04 (m. IH), 5.92-5.77 (m. IH), 3.56-3.38 (m, 2H), 2.05-1.82 (m, 2H), I 63-1 39 (m, 2H), 0.97-0.83 (m. 6H).

Formation of (+/-)-7-(2-methoxy-3-pyrtdyl)-4.4- dimethyl-3.5-dihydro-2H-»zcpute-l-carbaldchydc ]0976] A nuxturc of (2-methoxy-3-pyndyl)boronic acid (086 g, 561 mntol). 7-chloro-4,4-dimethyl-3.5-dihydro- 211-azepine-I-carbaldehyde (0.74 8, 3.74 mntol). Pd( lz (PPhs)z (128 mg, 0.182 mmol)„DMF (8 mL), NEts (2 mL, 14.4 nunol) was heated in a 20 mL vial v ith pressure relief cap under nitrogen at 70" C, for 2 h. Water and EtOAc were added and thc layers separated. Thc aqueous layer was rc-extracted with EtOAc and tlu: combtncdi orgatucs were washed with v,ster then brine. dned (sodium sulfate), filtered and concentrated in vacuo Purification by silica gel cluomatography (40 tiOLD colunuu 0-75'/» EtOAc in heptane) gave 750 m of the desired product as a brown oik 'H NMR (400 MHz, CD»CN) 6 8.14 (dd, J=5 0. 1.9 Hz, I H), 7.88 (s, IH), 7.61 (dd, J=7.4. 1.9 Hz, IH), 6.97 (dd, J=7.3. 5.0 Hz, IH), 5.92 (t. J=7.1 Hz. IH), 3.74-3.68 (m, 2H), 2.17 (m, 211), 1.67-1.63 (m. 211). I 01 (s, 6111) I ISI-MS nkz calc 260 15, found 261 18 (M+I)+. Itetention time 0 85 minutes

Fonna/ton of 7-(2-methoxy-3-pyndyl)-4,4-dimethyl-2,3.5,6-tetrahydroazepine ]0977J To a solution of 7-(2-methoxy-3-pyridyl)-4,4-dimethyl-3.5-dihydro-2H-azepine-l-carbaldehyde (0.75 g, 2.88 mmol) In THF (5 mL) at —78'. was added under nitrogen n-BuLI (2.3 mL of 1.6 M solution. 3.68 nunol) Afier 15 minutes, added an addtuonal I mL n-BuLI. Aflcr 5 minutes. thc reaction was qucnctcd with water mtd warmed to room temperature llrine was added and the mixture extnzcted ivith dichloromethane ( oncentration in vacuo atforded 6619 mg, of the desired product as a brown oik ESI-MS m/z calc. (a) POCI„CHICI„(b) (2-methoxy-3-Pyridyl)boromc acid, 232 16. found 233.17 (M+I) . Retention time: 0.57 minutes. PdCII(PPh,)„EI,N. DMF, (c) n-BuLI, THF, -78'.. (d) I il311». Tl 2-amino-4-chloro-6-methylpyrintidute, ilk (e) lionnation of NMR 150" (2 2-(2-methoxy-3-pyridyl)-5,5-dimethyl-azepane Formation of (+/ — )-7-cldom-4.4-dimethyl-2,3,4.5- ]09781 To a solution of 7-(2-methoxy-3-pyridyl)-4,4-dim- tetrahydro-111-azepine-I -carbaldehyde ethyl-2,3,5,6-tetrahydroazcpinc (300 mg, 1.29 nunol) in THF was aiklcd LIBH» (250 11.5 at RT Jt)975] A 250 ml round-bottomed flask with magnetic (3 mL) mg, mmol) stirrer under nitrogen atmosphere was charged with DMF and thc nuxturc snrrcd oi ernight I M HCI (I mL) was added and the mixture extracted with D('M twice The layers were (8.2 mL. 106 nmtol) in dichloromethane (13 mL) and cooled separated v;ith the aid of a phase separator and the oi anics to O'. in an Icc bath. POCI, (5 mL. 53.6 nunol) In concentrated to give 72 of the desired product ac a pale dtchloromcthane (10 mL) was added over 5 nnnutcs. Reac- mg yellow oik 'H NMR MHz. DMSO) 6 7.99 J=4.9, uon nnxturc was wamtcd to 40'. and stirred at tlus (400 (dd. 1.9 Hz. I H), 7.82-7.77 (m, I H). 6.93 (dd, J=7.3, 4.9 Hz, I H), temperature for 30 ntinutes 5.5-dimethylazepan-2-one (2 5 4.00 (dd, J=8.1, 3.5 Hz, IH), 3.86 (s, 3H), 2.85-2.78 (m. I H), , 17 7 mntol) in dichlorontethane (20 ml,) was added over 2.75-2.65 1.74 J=104, 7.8, 3.9 10 minutes The resulting reaction mixture was stirred at tlus (m. IH), (ddd, Hz, IH), I 52-1 38 511), 0 ')2 (s. 311), 0 91 (s, 311) I SI MS m/z temperature for 4 hours. The reaction mixture was cooled to (m, cele 234.17, found 235 2 tune: 0.57 »mbicnt temperature, poured into crushed Ice (200 mL), and (M»I)+ ltetention nunntcs. then allo%cd wtllnl to anlblcnt tcnlpctiiturc over I h and surreal for a further I h. Thc aqueous v;as bastficxI with layer Formation of 4-12-(2-methoxy-3-pyridyl)-5,5-dim- solid until I 9-10 and stirred at room temperature Kz( Os pl ethyl-azepan-I -ylJ-6-methyl-pyrinudin-2-entice over the iveekend 1 he reaction mixture was diluted v ith dichloromethane (200 mL) and the organic layer separated. ]0979] A mixture of 2-(2-methoxy-3-pyridyl)-5,5-dim- The aqueous layer w as extracted with dichloromethane. The ethyl-azepane (0.21 . 0.88 nunol) and 4-chloro-6-methyl- combutcd orgatuc extracts werc washcxl v;Ith bone. sepa- pynmulin-2-anunc (0.11 g, 0.77 mmol) In NMP (1.3 mL) ratixl tiuough a phase separator and concentraIcd ut vacuo. was heated In microwat c»t 175'. for 30 nuuutcs. Puri- Thc residue was punlied by silica gel cluomatography using licatton was carried out on a reverse phase 50 g ISCO c1 8-aq a 80 g isco coluntn (0-40'/ litOAc/CIIC(:lz gradient) to coluntn, nutning ivith 0 I'/» I IIA/1lzO and 0 I»/ 'I'I'A/ afford I 56 grams of the desired product: 'I I NMIt (400 ('I IICN. 'I'he pure fractions »vere partially concentnzted, US 20 ] 9/032265 [] A[ Oct. 24, 2019 201

some IM NaOH added and extracted with dlcitioromethane Formation of (+/-)-2-(2-methyl-3-pyridyl)azepane- twice. Thc layers werc scpardtcd with thc md of a phase I-carbaldchydc si pdrator Slid tile orgaillcs collccllildtixl 111 vdctlo to Bllord 18 [0981] A nuxiurc of 7-(2-methyl-3-pyrtdyl)-2.3.4,5-tctm- nig of the desired product as a yellow solid 'l I NMIJ (400 Pd/('10% hydroazepine-I-carbaidehyde (I 60 8, 7 40 mniol), Miis. 1)MSO) 6 8 00 (dd,.l 4 9, 1.8 IIV. 111), 7 38-7 32 (ni, Degussa ivet type, 400 mg). MeOJ I (10 mi.), iitOAc IH), (i.86 (dd, 1=7ob 4.9 Hz, IH). 5.58 (s. IH). 588 (s. 2H), (10 mL) and AcOH (2 mL) vvas stirred under an atmosphere 5.12 (s, IH), 4.1(i (s, IH). 3.96 (s, 3H). 3.43-332 (m. I H), of hydrogen gas. After 2 hours„ the reaction mixture was 2.22-2.12 (m. I H)„1.99 (s, 3H). 1. 80 (m, I H). 1.54-1.23 (m, liltered tluough Cclitc with tiu: aid of McOH and then 4H), 0.96 (s, 3H), 0 90 (s. 3H): ESI-MS m'z cele. 341.22, concentrated in vacuo to goe 1.61 g of thc desired product found 342.23 (M+I) . Rctcntion tune. 0.67 nnnutcs. as a pale yellow oil. 'H NMR (400 MHz, DMSO-d6) 6 8.27 Example 45 (dd..t 4.8, I 7 Hz, III). 8.15 (s, 111). 7 95 (s, I i I), 7.15 (dd, .I 7 8, 4.7 I Iz, 111), 5 01 (dd, I 12 8. 4 7 I Iz. 111). 3.87 (dd, Synthetic Sclleilie 45 (+/ — )-[3-[ I-(2-anlitto-6- 1=15.0. 4.9 Hz, IH), 3.59 (dd, 1=14.8, 10 2 Hz. IH), 2.89 (s, methyl-pyrimidin-4-yl)azepan-2-ylJ-2-pyridylJ 3H). 2.12-2.02 (m. IH). 2.00-1.92 (m. IH). I 82-1.61 (m, methanol 1-57 2H), I 37-1.28 (m, 4H). ESI-MS m/z cele. 218.14, found [0980] 219 17 (M+I) . Rctenuon time: 0.49 minutes. Formation of (+/-)-2-(2-methyl-3-pyridyl)azepane- I -carbaldehyde [0982] To a solution of 2-(2-methyl-3-pyndyi)azepane-I- carbaldchydc (I.GI g. 7.38 nunol) in dicldorometlmnc (20 mi,) was added m('PBA (2 54 g, 14 80 mmol) and the nuxture stirred overnight at room temperature 1 he white sohd was filtered ofl'ashing vvith some dichloromethane. To the filtrate tvas added sat. aq sodium bicarbonate carefully The organics werc washed a second Junc with sat. aq. sodium bicarbonate. The layers werc scparatcd with the aid of a phase separator and the orgmncs concentrated in vacuo to give GS00 mg of the desired product as a yellow oih 'll NMlt (400 Ml iz, DMSO-d6) 6 8 18 (s. 111), 8 15 (d..t 6 0 Hz. IH). 7.22-7.17 (m. IH), 7.08 (d, 1=7 9 Hz. IH). 5.04- 4.95 (m. IH), 3.89 (dd, 1=15.1. 5.3 Hz, IH). 3 61-3.51 (m, IH), 2.45 (s. 3H), 2.11-1.83 (m. 2H), 1.82-1.59 (m, 2H), 132 (d, J=S.8 Hz, 4H). ESI-MS nt/z cole. 234.14. found 23S 16 (M+I) . Retention time: 0.53 minutes.

Fomtation of (+/ —)-2-[2-(hydroxymethyl)-3-pyridyl] azepmie-I-carbaldchvdc

[0983J I o a solution of 2-(2-methyl-I-oxido-pyridin-I- ium-3-yl)azepane-I-carbaldehyde (0 60 g, 2.5/i mmol) in dichloromethane (15 ml ) was added '11SAA (0 36 ml „2.59 mmol) at room temperature. After 7 hours„sat aq. NBSCOs v as added carefully and stirrin continued overnight. Water was added and ihchloromcihdnc. lite luycrs werc scparatcxf with thc anl of a phase separator. The aqueous layer was rc-cxtractcd wi ill diclilorolllcilidlic alii tile Iavcrsw etc scpa- mated tllrough a pllase separator again aild tile coinbined organics concentrated in vacuo qhe crude residue was punfied via silica gel clu omatogmphy with 12 g isco I)OLD colunut usin 0-12.5i'o MeOH/dichloromethane to alford 324 mg of thc dcsircd product as a brown solnl. 'H NMR (400 MHz, DIVISO) 6 836 (dd, 1=4.7, 1.6 Hz, IH), 8.11 (s. IH), 7 Gg (dd, J=7.8, 1.6 Hz, IH). 7.27 (dd, J=7.8. 4.7 Hz. 111), 5.16 (dd, .I 7.0. 4.0 Hz. 111). 4 91 (dd. I 12.4, 7 0 IIV, 111), 4 64 (dd..t 12 4, 3.9 Hz,. 111), 3.84 (dd,.l 14 9, 4 5 IIV, IH). 3.66 (dd, J=15.0, 10.2 Hz, IH). 2.21-2.11 (m, IH), 1.97-1.70 (m, 3H). 1.38-1.22 (m. 4H): ESI-MS m/z cole. 234 14, found 235.2 (M+I) . Rctmition time. 0.48 muiuies.

liormation of (+,' )-[3-(azepan-2-yl)-2-pyridyl] Hs. 10'Ao Pd/C, MCOH, EIOAO, AcOH; mCPBA, (a) (b) methanol DCM. (c) TFAA, DCM then aq. NBSCO,, (d) conc. HCI, 100" Cd (e) 2-amino-t-chloro-6-methylpyrimidine, NMP, [l)984] A mixture of 2-[2-(hydroxymethyl)-3-pyridyl] 150" (2 azepane-I-carbaldehyde (0.28 8„1 20 mmol) and I I( I (I 5 US 2019/032265[[ A[ Och 24, 2019 202

mL of 38% w/v, 15.6 nunol) was heated at 100'. over- -colttlltllixl tught. Purr]ication was carried out on a reverse phase SO g Bv;Ss 0 RHz ISCO c18-aq colunm, runtung wtth 0.1% TFA/HzO and 'ITAR 0 1% I I,CN 1 he pure fractions were cnncentrated in g vacuo and then dissolved tn MeOI I and passed through a SPE bicarbonate cartridge (Agilent Stratospheres 5 g/60 mL) and concentrated to give 150 mg of the desired product as an orange oih 'H NMR (400 MHz, DMSO) 8 8.35 (dd, J=4.7. 1.7 Hz, IH), 7.83 (dd, J=7.8. I.G Hz, IH), 7.27 (dd, J=7.8. 4.7 Hz. I H). 4.62 (dd, J=28.7, 12.7 Hz, 2H). 4.00 (dd, 1 9.4. 3.5 I lz, 111). 23]5 (dd. J 11 6, 6 6]lz. 11]), 2 77-2 69 (m, 111), 1.87 (ddd, .I 13 9, 6.6. 3 2 I lz, I] I), 1.80-1.72 (nt, IH), 1.72-1 43 (m. 6H), ESI-MS nffz cele. 206.14, found 207.19 (M+ I) . Retention time: 0.25 minutes.

Fonna]ion of (+/ — )-[3-[I-(2-tunuto-6-methyl-pyrunt- din/ gyl)azepan-2-y]1-2-pyridy]Jmethanol

[09851 A mixture of [3-(azepan-2-y])-2-pyridyl)methanol (0 15 g. 0.72 ntntol) and 4-eh]ore-6-tuethyl-pyrimidin-2- amine (009 g. 0 66 ntmolj was stirred in NMP (I mi,) at (a) trityl chlondc, EI,N. CHzC]z, (b) NaH, DMF, tnbutyl 170" C, in a scintillation vial for 3 h. Purification was carried (iodomethyl)statumnc. (c) 2,2.2-tnfluorocthanol, AcOH, out on a reverse phase 50 g ISCO c1 8-aq column, nuuung CHzC]z, (0) 2-fluorobmtzaldehyde: 4 A mol stcvcs, CH,C]„ with 0.1% TFA/HzO aud 0.1% TFA/CHzCN. Thc pure (e) 2,6-]utidine, Cu(O'I'f)z. hexatluoroisopropanol. CI]zff]z, fractions were concentrated ut vacuo anti flten HC] (2 mL of (f) 2-amino-4-eh]em-6-methylpyrimidine, NMP, ]50" ( 2 M, 400 mmol) and Me('N (5 m] ) tvere added and concentrated in vacuo again to give I] 9 mg nf the destred Fonna]ion of pmduct as an off white solid: 'I I NMit (400 Ml lz., DzO) 8 2,2-dtmcthy]-3-(uitylamino)propan-l-oi 8.55 (d, 1=5.8 Hz, IH). 833 (d, J=8.1 Hz, IH). 7.86-7.79 (m, [t)987[ I o a solution of j-antino-2,2-dimethyl-propan-l-ol IH), 6.35 (s. IH)„5 46-5 36 (m, 2H). 5.14-5.07 (m. IH), I 4t).2 mntol) and triethylamine (13.5 96.9 mmol) 4.08 (tld. J=I5.5. 4.5 Hz, IH). 3.83 (dd, J=]5.7, 10.8 Hz, (5 g, ntl., in CHzCI, (50 mL) at 0" C. was added dropw ise a solution IH). 2.25 (s, 3H), 2 22-2 12 (m. IH), 2.05-1.77 (m, 4H), of trityi c]t]oride (13.6 48.8 mmol) in CHzCIz (50 mI ). I 60-1.25 (m. 311): I/.SI-MS m/z cele 313.] 9, found 314 23 g, The rcactton nuxturc was sutrcx] for 48 hours wtth gradual (M+I) . Itetentton time 0 49 mimttes warming to room temperature. Thc reactton mtxturc was washed with 50 mL water and the organtc layer was Example 46 extracted with 50 m]. ('I iz('lz 'I'he combined organic phases were concentrated to dryness and purihed via silica gel [t)9861 Synthetic Scheme 46 (+/— )-4-(3-(2-fluorophenyl)- cluomatography eluting with 0-25% EtOAc/heptanes. Pure 6.6-dimethy]-1.4-oxazepan-4-yl)-6-methylpyrimidin-2- fracttons were combined and concentmted in vacuo to ive ]-49 amine 14.4 g (85%) of thc dcstrcd product as a colorless oih H NMR (400 MHz, CDC]s) 6 7.47-7.42 (m, 6H), 7.36-7.29 (m. 6H), 7 27-7.21 (m, 3H), 3.63 (s. 2H), 2.17 (s, 2H), 0.89 (s. HO 8Hz 611); I ISI-MS m/z cele 345.21, fnund 346 0 (M+I ) Iteten- Q tion tints 0 82 mimttes Fomtation ol',2-dune]by]-3-((tributylstannyl) met]toxy)-¹ntylpropan-I-auunc

[t)9881 Sodium hydride (I 0 g, 26.0 mmol. 60'%n mineral oil) was washed with heptane under nitrogen then suspended HO in anhydrous DMF (85 mL) and cooled to 0" C. A solution of 2.2-dimethy]-3-(trityhsmino)pmpan-l-ol (6.0 g, 17.4 nuuolj ut DMF (85 mL) was added dropwtsc over 15 mtnutes and then thc rene]ton was wunucd to room tcmpcraturc and sttrrcd for I hour. Thc mtxture was coo]cd again to 0" C and then tributyi(iodontethyl)stannane (8 2 8, ] 9 0 mmnij was added droptvise. The reaction was stirred at 0" C. wtth gradual v:arming to roont temperature over 4 hours. The reaction was quenched at O'. by slow addttton of 85 .. Sa~O mL aqueous saturated tumnonium chlondc soluuon. The layers were separated. anti thc orgunic layer was washes] wtth water. The organic layer was concentrated, dtssolvcd in 500 ml. M'I'Hl i and washed 3x150 ml. water 'I'he organic layer was concentrated to dryness, dry loaded onto Celite, US 20]9/032265]] A] Och 24, 2019 203

and purified v&a silica gel chromatography eluting with (d. J=13.7 Hz, IH), 2.77 (d, 1=13.7 Hz„ IH). 0.98 (s. GH). 0-35'!c EtOAc in hcptanc. Pure fract&ons werc combined and ESI-MS nflz cele. 223.14. found 224.0 (M+I) Rctcnt&on conccntratcd to give 4.55 g (40%) of product as a iigh& t&mc. 0.56 minutes. yellow oik 'I I NMR (400 Miit, CD( I,) ib 7 58-7 54 (n&, 7i I). 7 32 (dd, J 8 4. 6 9 lit. 711), 7 25 7 18 (m, 311), 3 71 Fom&ation of (+/-)-4-(3-(2-fluomphenyl)-6,6-dim- (s, 2H). 3.17 (s. 2H), 2.04 (d, 1=7.8 Hz. 2H), 1.85 (t. J=g 0 e&hyl-1,4-oxazcpm&-4-yl)-6-methylpyrun&d&n-2- Hz, IH), 1.58-1.49 (m. 5H). I 38-1.30 (m. 10H). 0.98-0.93 anunc I-')9 ESI-MS n&/z cele. G49.34, found ti49.0 . (m, 18H): (M+I) ]l)991] A mixture of 3-(2-fluorophenyl)-6,6-dimethyl-l.4- Rctenuon tinux 0 95 m&mites. oxazepane (009 g, 0 38 n&mol) and 4-chlom-6-methylpyrun&din-2-amine (0.06 g. 0.38 num&l) &n NMP (1.2 mL) I&ormation of 2,2-dimethyl-3-((tributylstannvl) v as heated at 150" C. for 150 minutes in a sealed tube. The methoxy)propan-I-amine reaction mixture was purified via reverse phase chromato- raphy clutn&g with 5-50% McCN in water with 0 1% TFA. ]t)989] 2,2-dimethyl-3-((tributylstannyl)methoxy)-¹ri- Pure fractions were combu&cd. neutral&zud using sodium tylpropan-I-a&nine (4.55 g. 7 02 mmol) was dissolved in bicarbonate solution. and extracted with I:tOAc. 'I'he organic dichloromethane (150 mL). 2.2,2-trifluoroethanoi (43 mL), layer was dried over magnesium sulfate, filtered, concen- and acetic acnl (22 mL) imd surred ovcmight at ruom trated in & acuo, and lyophilized to tnve 12 mg (9'!c) of the tcmpcraturc Thc react&on was ncutrahzcd by port&on-w&se des&red product: 'H NMR (400 MHz. DMSO-d6) (heated addition of saturated aqueous sodium bicarbonate solution 360K) 6 7.30-7.18 (m. 2H), 7.18-7.07 (m. 2H). 5.73 (s. I H), over 90 minutes 'I'he organic layer was removed and the 5.61 (s, 2H). 5.47-535 (m, IH). 4.57 (d, J=14.9 Hz. IH). aqueous layer was ex&meted three tiines with dichlorometh- 4.13-4.03 (m, I H), 3.71 (dd, J=13.4, 11 0 Hz, I H), 3.53-3.38 ane. The combined or anic phases were dried over magne- (m, 211), 3 31-3 21 (m. 111), 200 (s. 311), 0 89 (d, .I 8 I I it, sium sulfate, filtered. and concentrated in vacuo to give 4 7 611); I ISI-MS m/z cele 330.18, found 331 0 (M+I)+ iteten- g of a hght yellow oil contaiiung a wlute pp&. The crude tion time: 0.74 minutes. product was puniicd v&a s&lice gel cluomatography clu&ing with 0-5% MeOI I/dichlommethane containing 0.1% trieth- I:xample 47 ylamine Pure fractions were combined and concentrated to ]l)992] Synthetic Schen&e 47 (+/— )-3-(4-(2-amino-6- I 21 of pn&duct as a colorless oih 'I I NMR give g (42%&) methylpyrimidin-4-yl)-1.4-oxazepan-3-yl)-4-methoxy-N- (400 MHz, CDCI„) o 3 (ig (s, 2H). 3.08 (s, 2H), 2.52 (s. 2H), methylbenzamide 1-82 1.60-1.45 (m. (iH), 1.3(i-1.28 (m. GH), 0.95-0.87 (m. 15H), 0.86 (s. 6H), ESI-MS m/z cele. 407.22. found 408.0 (M+I) . Retcnuon time: 0.76 m&nutcs.

I&ormation of (+/ — )-3-(2-fluorophenyl)-6,6-dimethyl-I.4-oxazepane Mco

]0990] To a solution of 2.2-dimethyl-3-((tributyismnnyl) B/0&t&, metiu&xy)propan-I-amine (1.21 g, 2.979 mmol) in anhy- M&0 drous dichloromcthanc (8 mL) was added 2-fluorobenzal- 0 dchydc (0.33 mL, 2.25 riunol) followed by 4 A molecular sic&cs (0.32 g) Thc hazy colorless nuxturc was snrrcd a& room ten&perature for 2 hours then filtered over Celite. 'I he filter pad &vas rinsed with 55 ml. dichloromethane and the i-.flri i'0 t.'H& filtrate was stored under nitrogen. In a separate 250 mL M&0 round bottom flask containmg hexafluoroisopropanol (15 0 mL) under n&trogen was added anhydrous 2,6-1utidu&e (0.35 mme 19 2. 99 nunc mL. 3.02 I) follow ed by Cu(OTI) & (0. g, 1). Thc mixture was st&rrcd at room temperature Ibr I hour. &hen the imine colut&on prepared above was added. 'I he reaction n&ixture was stirred overnight at n&om temperature and CO&t'H; quenched with 75 mL of a 2: I mixture of aqueous saturated sodiu&n bicarbonate solution and 10% ammonium hydrox- 0 ide. The mixture was st&rrcd for 15 mmutes imd then separated. The aqueous layer was cxtractcd 2x75 mL ilichloromcthanc. 11&c comb nuxl organics werc washed w &th bnnc, dried over magnes&um sulfate, filtered and concentrated in CO H '11&e vacuo cnide matenal was purified via silica gel chro- M&0 matography eiuting with 0-8%& MeOH in dichloromethane. 0 Pure fractions &vere combined and concentrated to give 90 mg (13%) ol'hc dcs&rcd product. 'H NMR (400 MHz, CDCI,) 6 7.51 (td. J=7.5, 1.8 Hz, IH), 7.30-7.20 (m, IH), 7.14 (id, J=7 5, 1.3 Hz, IH), 7.02 (ddd, i=10.5. 8.1, 1.3 Hz, i'0 t.'H& H I). 4 31 (dd, .I 9. &J. 4 4 I Iz, 111). 4 05 (ddd, .I 12 0. 4 4. 0 7 I lt,. 111). 3 6&2 (d. J 12.1 I lz, I I I). 3.50-3AI (m, 211), 2 86 US 20]9/032265[] A[ Oct. 24, 2019 204

-continued Fomiation of (+/-)-methyl 3-(4-formy1-1,4-oxazepan-3-yl)-4-methoxybenzoatc A mixture methyl 3-(4-formyl-4.5,6.7-tetra- cost H [0994] of 0 hydro-l,4-oxazcpin-3-yl)-4-mcthoxybmizoatc (2 4 g. 8.2 nunol) and Pd/C (1.5 g. 0.7 mmol) ui ethyl acctatc (25 mL) and MeOII (25 mi.) was shaken overnight under 55 psi hydrogen. 'I'he reaction niixture ivas filtered over ('lite and the resulting filtrated was concentrated to dryness The resultuig residue was purified via silica el chromatogmphy elutin with 40-100'/o EtOAc in heptanes Several mixed fractions containuig thc dcsircd product werc cerned onto thc next step as is. ESI-MS m/z cele. 293.13, I'musd 294.0 (M+I ) Retention time 0 77 minutes CO. I I linnnation of (+,' )-4-methoxy-3-(l,t-oxazepan-i- yl)benzoic acid hydmchloride [0995] A solution of niethyl 3-(4-fiirniy1-1,4-oxazepan-3- yl)-4-methoxybenzoate (2.4 g. 8.2 nmiol) in MeOH (40 mL) and concentrated HCI (40 mL of 12.1 M solution, 484.0 nunol) was stirred ovcnught at 100'. The mixture was concentrated to dryness. Thc product w as taken up ui MeOH and dilutixl into diethyl ether. then filtered nnd drwd to give 2 2 g (84%) of a v,hite solid: 'l l NMR (400 Mi lz, I JMSO- d6) (1 8.12 (d, .I 2 I i lz. 111), 7.98 (ddd, .I 8 7, 3 3, 2.1 I lz, IH). 7.18 (d. J=8.7 Hz, Hi). 4.77-4.55 (m. IH), 4.00 (dd, J=13.5. 8.9 Hz. IH), 3.93 (d, I=1.9 Hz„3H), 3.91-3.85 (m, 2H), 3 49-3.41 (m, 2H). 3.26 (ddd. J=13.4, 9 4, 3.4 Hz, I H). 2.83 (ddt, 7/47.7, 12.7. 7.3 Hz, 0.5H), 2.31-2.0S (m, IH). 2.0S-1.7S (m. 0.5H). ESI-MS m'z cele. 2S1.12, I'ound 252.0 (M+I ) Retention time 0 5 mimites.

Formation of (+/— )-methyl 4-methoxy-i-(1,4-oxazepan-3-yl)benzoatc (a) 3-chloro-6,7 thhydm-5H-I,4-oxazepine-4-carbaldc- [0996] To a soluuon ol'-methoxy-3-(1,4-oxazcpmi-3-yl) hyde). Pd('I (dppf), DMI( Nell('0,, JiiO, 80' . micro- benzmc acid hydrochloride (0.53 g, 1.(i5 nimol) in toluene wave irradiation; (b) I la. Pd/C, MeOII-I'.tOAc: (c) IK'I, (22 ml,) and MeOI I (2.5 mi,) was added diazomethyl MeOH. 100'z (d) diazomethyl(trimethyl)silane, toluene, (tnmethyl)silane (0.84 mL of 2 M solution. 1.69 mmol) in MeOH; (e) 2-amino-4-chloro-6-methylpyrimidine. NMP, hexanes. The mixture ives stirred for 15 minutes then 150''.I (f) LiOH. MeOH, H,O; MeNHi. HATI J. Et,.N, (g) conccntratcd to dryness to alford 487 mg of a colorless oil. DMF. ESI-MS m'z cele. 265.13. Ibund 266.0 (M+I) . Retention time: 0.57 minutes. Formation of methyl 3-(4-fomiy1-4.5,6,7-tctrahydro-1.4-oxazepin-3-yl)-4-methoxybenvoate Fomiation of (+/-)-methyl 3-(4-(2-amino-6-methyf- pynmulin-4-yl)-1.4-oxazepan-3-yl)-4-mcthoxybcn- [0993] A nuxturc of 3-cltloro-6,7-dthydro-5H-J,4-ox- zoati: azcpine-4-carbaldchydc (2 0 g, 12.4 nmiol), (2-methoxy-5- mcthoxycarbonyl-phmiyl)boronic acid (2.6 g, 12.4 nunol), [0997] A mixture of methyl 4-nu:thoxy-3-(1,4-oxazepan- and Pd('ls(dppf) (I 0 g, 1.3 mmol) in l)Mli (37 mi,) and 3-yl)benxoiate (0.44 8, I 65 mniol) and 4-chlom-6-methyl- aqueous saturated sodiuni bicarbonate (12 mf,) v as heated pynnndin-2-aniine (0.26 g, 1.82 mmol) in NMP (5 5 mi,) in microivave reactor at 80" C. for 30 minutes. The reaction was stirred for 4 hours at 150" C, in a sealed tube. The mixture was diluted w ith v ater. washed with water, and then mixture was diluted ivith water and extmcted v ith EtOAc. the organic phase w as conccntra lcd to dryness. The resu1! ing Thc organic layer was conccntmtcd to dryness and thc rcsnluc was punfied via sihca gcl cluumatography cluting resulting residue was punlicd via silica gcl chromatography with 40-100vgv EIOAc in hcptancs liillowed by a 10% McOH cluttng with 0-12% MeOH ui dichloromcthanc. Pure frac- in dichloromethane tlush. Jiractions containing, the desired tions were coinbined mid concentrated in vacua to give 89 pmduct were conibined and concentrated in vacuo to aflbrd mg (14%) nf the desired pmduct: 'I I NMR (400 Mliz, 2.4 g (63%v) of the desired product as a colorless oil 'H DMSO-d6) (heated 360K) 6 7.89 (dd. J=8.G, 2 2 Hz, IH), NMR (400 MHz. CDCls) 6 8.04 (dd, J=8.6. 2.2 Hz. IH), 7.70 (d. J=2.2 Hz. IH). 7.1(i (d, 1=8.7 Hz. IH), 6 60 (s, 2H), 7.95 (s, IH), 7.92 (d, J=2.2 Hz, IH). 6.90 (d, J=8.6 Hz, IH), 5.89 (s, IH), 5.S7 (s, IH). 4.60 (d. J=14.7 Hz, I H), 4.19 (dd, 6.19 (s, IH), 4.24 (dd, J=6 3, 5.3 Hz. 2H). 4.06 (t. J=6.6 Hz, J=13.4, S.2 Hz, IH). 3.95 (s, 3H). 3.90 (dt, J=12.0. 3.8 Hz, 2H). 3.92 (s, 3H). 3.87 (s, 3H), 2.18-2.09 (m, 2H). ESI-MS JH), 3 79 (s. 3H), 3.77-3.68 (m. JH), 3.63-3.54 (m, IH), nflz cafe. 291 11, found 290 0 (M+I) . Retention time: 0 9 2 14 (s, 311), 1.80 (dt..l 7.7. 4 2 Hz, 211) I ISI-MS m/z cafe niimites 372 18, found 373.0 (M+I) . Retention time 0.6(i minutes US 20]9/032265[] A] Oct. 24, 2019 205

Formation of (+/-)-3-(4-(2-amino-6-methyipyrimt- (+/-)-4-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4- din-4-yl)-1.4-oxazepan-3-yl)-4-methoxybenvoic acid oxazipan-3-yl)-3-methoxy-N-methylbmtzamide 1-83 trifiuoroacetate salt [1001] 'H NMR (400 MHz, DMSO-d(i) (heated 360K) 6 8.12 (s, IH), 7.49 (ib J=1.6 Hz. IH), 7.40 (dd, J=7 9. 1.6 Hz, [0998J 'lo a solution of methyl 3-(4-(2-amino-6-ntethyl- I H), 7.23 (d, J=7.9 Hz. I H). 7.02 (s, 2H), 6.05 (s, JH), 5.61 pyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-methoxybenzoate (s, I II), 4 62 (s, 111), 4 24 (dd,.l 13 4 5 2 Ilz 111) 3 95 (s (0 090 a. 0 230 mntol) in MeOI I (I inl,) and water (I ml,) 411), 3.81 (dt, .I 13.4 7.9 I iz, 211). 3.60 (ddd, .I 12 I, 9 4, was added LiOH (0.025 c. 1.044 mmol). The reaction 5 I I Iz, I I I), 2 82 (6, .I 4 5 I lz. 311), 2 22 (s, 311). 1.91-1.74 nuxturc vvas surrcd at room tcmpcrature lor 3 hours. acidi- (m, 2H); ESI-MS m/z cele. 371.20. found 372 0 (M+I) . fied with I M HCJ and the mixture was purified by reverse Retention time: 0.55 minutes. phase chromatography cluting with 10-90% MeCN ut water with 01'%liA Pure fractions ivere combined. concen- Example 48 trated, and lyophtfizcxI to give 50 mg (58%) ol'hc dcsircd pmduct: 'll NMR (400 Ml iz. DMSO-d6) (heated 360K) 8 Synthetic Scheme 48 (+i — )-4-(4-(2-amino-6-meth- 7.92 (dd. )=8.6. 2.1 Hz. IH), 7 72 (s, I H). 7.41 (s. 2H), 7.17 ylpyriinidin-4-yl)-1.4-oxazepan-3-yl)indolin-2-one (d, .I 8 6 I lz. 111), 4 24 (g I I I), 3 99-3 90 (m„411). 3.80 (t, 1-105 1=7.1 Hz. 2H). 3.64 (dt. J=12.2, 7.4 Hz. IH). 2.33-1.65 (m, [1002J 6H). ESJ-MS nt/z cele. 358.16, found 359.0 (M+I) . Reten- tion time; 0,6 minutes

Formation of (+/-)-3-(4-(2-amino-6-methylpyrimidin-4-yl)-1.4-oxazepan-g-yl)-4-methoxy-N-methyl- s. 6 bcnzamidc 1-82 H [t)999] qo a solution of 3-[4-(2-amino-6-ntethyl-pyrimi- C. din-4-yl)-1.4-oxazepan-3-ylJ-4-chloro-benzoic acid ('I'rif- luomacetate salt) (0 085 8, 0 180 minol) in DM Ji (I ml,) was added HATH (0.102, 0.268 mmol) followed by Et.,N C (0.125 n)L, 0 897 mmol). After stirring for 10 minutes, H methylamine (0.700 mL oi' M, 1.40 nunol) m THF was addCd arid tllC ritICtlotl Wtls stllTCd ovi'Illlgltt. Tile nxIC)loll ntixture was diluted ivith water and extracted v ith I ttOAc. 0 'I'he organic layer was concentrated to dryness and purified via silica gel chrontatography eluting with 0-1(7% MeOI I in uix dichlorontethane. Pure fractions were combined. concentrated in vacuo to afford the desired product: 'H NMR (400 MHz. DMSO-d6) (heated 360K) 6 7.90 (s, JH), 7.68 (dd, J=8.5. 2.3 Hz, IH), 7.50 (d, J=2.2 Hz. IH), 7.04 (d, J=8 6 I lz. 111). 5 71 (d. 1 27 7 I lz, 311). 525 (s, 111), 4 43 (s, I I I), 8)t 3 92 (s. 311). 3 45 (dd..l 14 5, 11 2 I lz, 111)„2 74 (d..) 4 6 Ilz311) 234 (dt .I 140 69 Iiz 111), 203 (s, 311), 1.97-1.62 (m, 2H). 1.52 (q. J=12.5 Hz. IH). 1.43-1.21 (m,

2H); ESJ-MS m/z calc. 369.22. found 370.0 (M+I) . Reten- tion lime. 0 68 minutes. (a) NJ)S, t-l)uOII, Cl Is('I: (b) aq II('1(4M), dioxane. 110" [1000] The Ibllowtng analogs were prepared according to ('; (c) 2-amino-4-chloro-fi-methylpyrimidtne, NMP, 150" Synthetic Scheme 47: ('

Formation of (+/-)-4-(1.4-oxazepan-g-yl)indolin-2- 0 11C

[1003] To a suspension of 3-(JH-indo1-4-yl)-l,q-oxazepanc-4-carbaldchydc (0.22 g, 0.91 nmtol) ut tBuOH (5 mL) was added NBS (0.18 g, 1.00 nunol) at room tcmpcm- turc. After 2 hours, dichloromethane (5 mL) was addixi to aid solubility After I hour. additional Nlig (008 8) was added Afier another I hour, aqueous saturated sodium bicarbonate solution was added and the mixture extmcted v ith tvvtce with dichloromethane. The combined organics werc ssashcd st tth water and then the layers werc separated with the aid of a phase separator and the organics concentrated. Thc brossn residue was dissolved ut dioxanc (4 mL) and aq IK'I (4 n)I,. 4M) ives added and the mixture was heated in microivave reactor for 10 min at 1(X)" ( and then US 20[9/032265[] A] Och 24, 2019 206

an additional 50 min at 110" C. The reaction w:as partially -conthlllixl conccntratcd and then punlicd by column cluomalography (C 1 8 AQ 50 g co 1unm, 0. 1% TFA-water/0. 1% TFA-MoON). 'I'he pure fractions were concentrated and then dissolved in Me()I I and passed through a SPII bicarbonate cartudge (Agilent Stratospheres 5 g/60 mL) and concentrated to give 72 mg of the desired product. 'H NMR (400 MHz. DMSO) 6 10.32 (s. IH), 7.12 (t, J=7.7 Hz. IH). 6.96 (d. J=7.7 Hz, 0 I H), 6.69 (d. J=7.6 Hz, I H), 3.89-3.6 S (m, 4H), 3.51 (s. 2H), 335 (m. 2H), 3.08 (dt, J=13 3, 5.0 Hz. IH), 2.80 (dt, J=13 9, 7 I I lz, ill). 1.91-1 78 (m, 2i I); Ilgi-MS m/z calc 232 12, found 233.26 (M+1)+ Retention time 0/46 minutes

Fonna(ion of (+/ — )-4-[4-(2-lunule-6-methyl-pyuml- din-4-yl)-1,4-oxazepan-3-yljindolin-2-one 1-105 4-(1.4-oxarepan-3-yl)indolin-2-one [1004] A mixture of 0 (0.07 g. 030 mmol) and 4-chloro-6-methyl-pyrimidin-2- anline (0.04 „0.28 mmol) was heated in NMP (1.5 mL) at 150" C, overnight in a reaction vial equipped with a pressure rcl ref cap. lite mixture was cooled to room tmnperaturc and loaded ilirectly onto a 50 g ISCO c I 8-aq column anil purified by reverse phase nuuung with 0 1% 1'IlAllilO and 0 1% 'IJRA,'( I ls('N 'I'he pure fractions were concentrated in vacuo 0 Hlg and then dissolved in MeOH and passed tluough a SPE 0 bicarbonate cartndge (Agilent Stmltospheres 300 mg/6 mL) N and concentrated to ive 74 I m of the desired product lugh tcmpcraturc (360 K) 'H NMR (400 MHz, DMSO-d6) 6 9.97 (s, IH). 7.03 (t, J=7.7 Hz, IH), 6.77 (d. J=8.0 Hz, IH), 6 62 (d, .I 7 7 I is. 111), 5 62 (s. 111), 5 57 (s, 111). 5 3') (s, 2i I). 5 30 (s, 111), 4 28 (s. I I I) 3 98 (dd .I 13 4, 5 I I lz„ Yif I H). 3.74 (dd. J=13.5. 9.6 Hz. 2H). 3.45 (t. 1=15.5 Hz, 3H), 3.24 (d, 1=22.5 Hz„ I H). 1.95 (s, 3H), 1.66 (m, 2H): ESI-MS nt/z cele. 339 17„ found 340.25 (M+I) . Retention time 0.51 nulmtcs.

Example 49

Synthetic Scheme 49. (+,' )-4-(9-(2-fluorophenyl)- 1.4-dioxa-8-azasplro [4.6] undiuan-8-yl)-6-medlylpy- rimidin-2-amine and (+/— )-I-(2-amino-6-methylpyrimidin-4-ylj-7-(2-fluorophenyi)azepan-4-one Yif [it)05] 4 (a) PdCI (dppl'), aq NaHCO,, DME, 80'., (b) ozone, CH,Cll, — 78'., then PhsP, (c) NHsOH HCI, NaCNIJHu MeOI h (d) I ll, Pd/(1 MeOI E (e) EtOI I, 180" (', (f) I I('I, acetone, 50" (1

Fomlatlon ol'-(2-fluorophmlyl)-1,4-dloxasplro[4.5] ilcc-7-ene

[1006] To a solution of I-bromo-2-fluoro-benzene (0.98 g, 5.64 mmol) and 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-4.4.5, 5-tetramcthyl-I ch2-dloxaborolanc (I.SO g, S.64 nunol) in DME (20 mL) was aiklixl NaHCO, (9.4 mL of 1.2 M aq solution, 11.27 mmol). and PdClc(dppij (0.43 g, 0.52 nunol) under a nitrogen atnlosphere 1'he mixture was heated at YO" ('or 20 hours lite reaction mixture was hltered through a US 20[9/032265[] A[ Och 24, 2019 207

pad of celite and concentmsted in vacuo. The resulting plate and heated at 180" C. without cover for 2 hours. The residue was punlicd by silica gel cluomalography (40 g crude solid v, as purified by silica gel cltromatography (40 8, ISCO column) eluting with heplancsiElOAc (0% lo 40% ISCO column) eluting vvith DCM. 20% MeOH/DCM. The 'I radient) to afford I 0 8 (76%) of the desired product I dcsirixl fractions werc collcctcxl and cvaporatcd to afliird N MR (300 M I lz, CI )('I ) () 7A4-7.1 6 (in, 211), 7.1 4-6.90 (ni, 260 0 nlg (72%) ofthe desired product: 'H NMR (300 MHz, 2H). 5.87 (qd. 1=2.2. 0.7 Hz, IH). 4.05 (s. 4H). 2.6(i (tdd, DMSO-d6) 6 7.39-7.10 (m. 4H). 6 90 (s, 2H), 5 80 (m, IH). 1=3.5. 55-2.43 1.99-1.86 2.6, 1.3 Hz. 2H). 2 (m, 2H). (m, 4 74-4.38 (m, 111), 3.8'7 (m, 411). 3 35 (m, 211), 2.33-1.51 2H). (m, 9H), ESI-MS m/z cele. 358.18, found 359.21 (M+I) . Retention time 66 niimites I'ormation of 2-(2-(3-(2-fluorophenyl)-3-oxopni- 0 pyl)-1.3-dioxolan-2-yl)acetaldehyde liormation of (+/—)-I-(2-amino-6-methyl-pyrimidin- To a solution of 8-(2-fluorophenyl)-1,4-dioxaspiro [1007] 4-yl)-7-(2-fluorophenyl)azcpan-4-onc 1-56 [4.5]dcc-7-cne (1.00 g. 4 27 nunol) ui dicltioromctltanc (30 mL) was bubbled ozone at — 78'. until lhc solution I 'I'o a solution 4-[8-(2-fluorophenyl)-1.4-dioxa- remained blue. 'Itic ozone generator was turned otf and air [III I] of was bubbled tltrough the niixtme for 30 minutes I'riphenyl- 9-azaspiro[4.6]undiman-9-yl]-6-methyl-pynmxlin-2-tmune (0 22 0 5') inmol) in acetone (10 ml,) was added I I( I phosphine (1.12 g. 4 27 mmol) was then added and the g, aq mixture vvas warmed up to room temperature and stirred for (10 mL of 6 M. 5947 nunol) at room temperature. The 50" 'I'he 12 hours. The cnide product was purified by silica gel nuxture was heated at (L tbr 3 hours. solvent was cluomatography (40 g ISCO column) clutmg v,ifli EIOAc/ evaporated and the residue vvas purified by silica chroma- hcptanes. Thc desired fractions were collcrlcil and evapo- tography (40 g IS( 0 column) eluting with D('M. 109ls rated to afliord the desired product 'll NMR (300 Milz, MeOH/DCM. The desired fmsctions were collected and ( D('I,) 6 9.77 (t, 1 2 9 I lz. I I I), 7 8/i (td, .I 7.6. I 9 I lz, evaporated lo afl'ord 57 mg (28%) ol'lm dcsircd product. 'H I H), 7.53 (dddd. J=8.3. 7.1. 5.0. 1.9 Hz. IH). 7.32-7.21 (m, NMR (300 MHz. DMSO-d6) 8 7.31 (m. I H), 7.26-7.06 (m, IH), 7.15 (ddd, J=ll.3, 8.3, 1.1 Hz, IH), 4.03 (d. JW.8 Hz, 3H), 5.93 (s, 2H). 5.77 (br. I H). 4.43 (br. I H), 3 74 (t, J=13.3 3H), 3.10 (ddd„J=7.6. (Cg, 2 9 Hz. 2H), 2.74 (d, J=2.9 Hz, I lz. 111), 3 35 (d, .I 24.5 Hz. 2H). 2 83-2 68 (m, 111), 2.54 2H). 2.23 (ddd, J=8.1, 6 9, 0 9 Hz. 2H). (m, 2H), 2.36-2.21 (m. 2H). 2.04 (s, 3H), ESI-MS m,'z calc. 314 15, found 315 26 (M+I)+. Retention time 0 61 minutes Formation of 9-(2-fluorophenyl)-l.q-dioxa-g- azaspiro [4.6]iuidecan-g-ol I:xample 50 [1008] To a solution ol'-[2-[3-(2-fluorophcnyl)-3-oxo- propyl]-1,3-dioxolan-2-yl]aceuildchydc (1.00 g, 3. 76 nunol) Synthetic Scheme 50 (+1 — )-4-(3-(1 I l-indol-4-yl)-i. in MCOI I (20 ml ) was added hydroxylamine hydrochloride 4-oxazepan-4-yl)-6-mcthylpynmidin-2-tmune (0 26 g, 3.76 mmol) and Nal I('Os. 'I'he mixture was stirred at room temperature for 30 minutes before sodium cyano- borohydride (1.18 . 18.78 mmol) was added. The reaction [ll)12J was stirred at room temperature over night. The mixture was quenched by adduig of cthylcnc diaminc. Thc solvent was cvtiporalixl aiiil lllc I'csliluc was pintlicil bv sihcii gcl chro- niatocraphy (40 8 I)('0 column) eluting with I:tOAc/ hepimies The desired fractions were collected and evaporated. The desired product was used without further s purification. H

Iioniiation of (+/ —)-9-(2-fluorophenyl)-] „4-dioxa-8- azmspiro[4.6Jundecane [1009] To a solution of 9-(2-fluorophenyl)-1.4-dioxa-g- azaspiro[4.6]undiman-g-ol (0.20 g. 0.75 mmol) m MeOH (15 mL) was addcxt 10% Pd/C under nitrogen aunosphcre. Thc flasl was charged with a hydro cn balloon and Ihishcd with vacuum and hydrogen three times 1he reaction was stirred at room teniperature under an atmosphere of nitrogen 0 over night. The mixture was Iiltered through celite and the filtrate vvas concentrated in vacua. The desired product was used without further purification.

HH Iioniiation of (+/ — )-4-[8-(2-fluomphenyl)-1,4-dioxa- 9-azaspim[4 (i]undecan-9-yl]-6-methyl-pyrimidin-2- amine 1-53 0 [1010] To a nuxturc ol'ohds 4-chloro-6-methyl-pynnudin-2-annnc (0.14 g, 0.95 nmiol) and 8-(2-fluorophcnyl)-1, 4-dioxa-9-azaspiro[4 6Jundecane (0.24 g, 0 95 nunol) in a vial was added I tOI I (2 ml ) The vial was placed on the hot US 20]9/0322658 A[ Och 24, 2019 208

continued dichloromethane. The combined organic phases were separated through a phase sepamtor and concentmted in vacua to atford 90 mg (')5%v) of the desired product as a pale yellow Yif firam "H NMR (400 MHz. DMSO-d6) 8 11.06 (s. IH), 732-7.29 (m. IH). 7.29-7.24 (m, IH). 7.05-6.99 (m. 2H), 6.55 (ddd. J=3.0. 2.0, 0.9 Hz. IH). 4.19 (dd, J=9.7, 3.3 Hz, 111), 3 96 3 81 (m, 211), 3 75 (dt, I 120. 6 7 llz, 111), 343 (dd, J=ll.9, 9.7 Hz. IH), 3.16 (dt, J=13.3, 5.0 Hz, IH). 0 2.93-2.81 (m, IH), 1.89 (td. J=11.8, 6 4 Hz, 2H): ESI-MS m/z cele. 216.13, found 217.19 (M+I) . Retention time: 0 49 minutes. (a) ill-indol-4-ylboronic acid, Vd(phsp)s(:ls. EtsN. DMI', 70" (2: (b) 112. Vd/(2 MeOI I; (c) nl Jul,i. Tl llq (d) 2-antino- 4-chloro-6-methylpynmidute, NMP, 140'. Founatton of (+/ — )-4-(3-(IH-indo1-4-yl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-atuine 1-142

lionnation of 3-(1 I l-mdol-4-yl)-6,7-dihydro-I.4- oxazepine-4(511)-carbaldehyde [1016] A mixture of 3-(1 H-indol-4-yl)-1,4-oxazcpane (0.09 . 0.42 mmol) and 4-chloro-6-methyl-pyrimidin-2- a vial with [1013] Charged 40 mL pressure relief cap amine (0.06 g. 0 40 ntmol) was heated in NMV (I 5 ml,) at under nitro en with 3-chloro-6,7-dihydro-511-1,4-ox- 140" (2 in a vial equipped ivith a pressure relief cap azcpinc-4-carbaldehyde (3.4 g, 20.0 nunol). IH-indol-4- ovcmight. Thc crude rcacuon was loaded directly onto a ylborotuc acid (3.2 g, 20.0 nunol). PGCls(pph.,)s (0.55 g, Ci8 AQ 50 ISCO coiunm and purihed by reverse phase 0.78 nunol) and triethylamine (11 mI . 79 mmol) in DMF chromatography elutin ivith 0.1% 'I liA/MeCN and 0.1% (16 ml ) and bubbled nitrogen through the mixture for 10 'll'A/v ster 'I'he pure fractions v ere partially cimcentrated, nunutcs. Thc reaction mixture was heated at 70'. over- some I M NaOH added and extracted w ith dmhloromcthane night. Thc mixture was dtlutcx) into water and EtOAc and twice and concentrated in vacuo. Added ether and concen- filtered off the darl solids. Added brine to the filtrate and trated in vacuo to afford 79 mu (54%) of the desired pmduct then separated the layers The aqueous layer was re-ex- as a white solid (heated 360K) 'll NMIJ (400 Milz, con- uacttxl with EIOAc mtd the combined orgamcs were DMSO-d6) 8 10.86 (br s. IH), 7.34-7.24 (m, 2H), 7.0G-6.97 ccntratcd tn vacuo. Puulication silica cinematogra- by gel (m, IH), fx90 (d. 1=7.2 Iqz, IH), (/.52 (s, IH), 5.G9 (s. IH), (120 column: 20-100% EtOAc in heptane) gave the phy g 5 64 (8 I I I), 5 45 (s, 211). 4 53 (s. 111), 4 23 (dd, .I I 3 3, 5 2 mostly pure desired product that was used without further I lz, III), 3.94-3.80 (m, 211). 3.57 (ddd I 2i) 7 18 i) 8 211z punlication 2H), I 94 (s, 2H), 1.87 (s, IH). 1.73 (d, J=15.0 Hz, IH), ESI-MS m'z cele. 323.17, found 324.27 (M+I) Retention Iionnation of (+/— )-3-(Ill-indoi-s-yl)-),4-ox- time: 0.56 minutes. azepane-4-carbaldehyde [1017] The folloiving analo s were prepared: [1014] A mixture of 3-(l H-indol-4-y))-6,7-dihydro-5H-I, 4-oxazepine-4-carbaldehyde (4.8 g, 19.8 nmtol) and Pd/C (10 ivt % Degussa, I 6 8) in MeOI I (30 ml ) was shaken under an atmosphcrc of hydrogen gas ovcmight ut thc Parr hydrogenator at 55 psi Hs. Filtered the reaction mixture through Fiorisil with the aid of MeOH and then on concentration. a v hite sohd precipitated 1.05 g. Iyiscarded tiltrate. Isolated solid ailhrdcd 1.05 g (22% 2 steps) of thc desired product: 'H NMR (400 MHz, DMSO-d6) 6 (rotameric gi/ SH RT) 11.13 (s, IH), 8.26 (s, IH), 7.35-733 (m. IH). 7.29 (d, I Rl I lz. 111), 7 05-6 99 (m, 111). 6 85 (d, .I 7 3 Ilz. III), 6.54-6.47 (m. IH), 5.62 (dd, 1=10.5. 5.1 Hz, IH), 4.32 (dd, J=13.4. 5.7 Hz, IH), 4 00-3 91 (m, 2H), 3.72 (m, 2H), 3.57-3.49 (m„ IH). 1.78-1.67 (m, 2H). ESI-MS m/z cole. (+t —)-4-(3-(IH-indazo1-4-yl)-1,4-oxazepan-4-yl)-G- 244 found 245.2 (M+ I)+. Retention tiine: 0 62 minutes. 12, methylpynmidut-2-amtnc 1-112

Formation of (+/— )-3-(IH-indol-4-yl)-l.q-oxazepane [1018] lugh tcmperaturc (360 K) 'H NMR (400 MHz. [1015] To a solution oi'3-(IH-tndo1-4-yl)-1.4-oxazcitanc- DMSO-d6) 6 12.83 (s. IH). 8.07 (s, IH), 7 41 (d, J=84 Hz, 4-carbaldehyde (0.11, 0.44 mmol) in THF (10 mL) was IH). 7.30-7.24 (m. I H). 7.01 (d, 1=7.1 Hz, IH), 5.91 (s. I H), added nliul,i (0 82 ml. of I 6 M solution. I 30 ltlltlol). Illa 5 72 (s, 111), 5 47 (s, 211), 4 34 (8 111), 4 27 (dd,.l 13 2, 5 3 reaction was done at room tcmperaturc because oi'tsolu- Hz. IH), 3.96 (dd, J=13.2. 8.8 Hz, IH), 3.84 (m. IH), bdtty issues at colder tempcraturcs. Aficr 30 mimites. thc 3.67-3.58 (m. IH), 3.55-3.45 (m, I H), 1.99 (s, 3H), 1.91 (m. mixture was diluted into water and extracted with dicblo- I H). 1.75 (m. IH): ESI-MS nv'z calc 324.17. fotutd 325.2G romethane The aqueous phase was extracted again v ith (M+I)+ ltetention time 0 52 ntinutes US 20[9/032265[] A[ Oct. 24, 2019 209

-colttlltlaxl

8 (+/-)-4-[2-(1.5-dimethylpyrazol-q-yl)azepan-l -yl]-6- methyl-pyrimidin-2-amine 1-48

[1019] high temperature (360 K) 'H NMR (400 MHz, DMSO-d6) 6 7.36 (s„ I H). 6.22 (s, IH), 6.13 (d, J=15 9 Hz, tt 8 I H). 5.81 (dt. J=15.9. 6.8 Hz, IH), 5.59 (s, I H). 5.33 (s. 2H), Ct t 3.66 (s. 3H), 3.20 (dd, J=l1.5, S.8 Hz, 2H), 2.19 (s. 3H), 2.18-2.10 (m. 2H). 2.00 (s, 3H), I.S4 (dt, 1=13.7, 6.9 Hz, 211), I 49-1 40 (m, 211), I!SI-M) m/z cele 300 21, found n 301 26 (M+I) Reteiltion time: 0.55 ntinutes.

H.t Rtt (a) 3-(tributylstannylmethoxy)pmpan-I-amine. Cu(OTf)„ 2,6-lutidtnc, CHzClz. (b) nBuOH, pw 170'.. 45 nuns: C. HCJ, MeOH. rctlux

Formation of N-[4-chioro-2-fluoro-5-(1.4-oxazepan- 3-)'l)pltclly'I] ilcctalllldc [1022] To a solution ol'-(4-chloro-2-fluoro-5-lbnnyl- (+/-)-4-[2-(13-dimethylpyrazol-4-yl)azepan-I -yl]-6- phenyl)acetamide (0.66 3 06 mmol) in ('I lz('I, (20 mf,) 1-39 g, methyl-pyumidut-2-anune was added the antino tributylstannane SnAP reagent 3-(tributyl propan-I-amine (1.20 3.17 [1020] high tempcraturc (360 K) 'H NMR (400 MHz, stannylmethoxy) g. mmol) (1.00 equiv) and MolecuLar sieves (0.9 The DMSO-d6) o 7.50 (s, IH). 6.22 (s, IH), 6.13 (d, J=16 0 Hz, g). reaction mixture vvas stirred at room temperature for 2 h and 111), 5 81-5 73 (m, 111), 5 59 (s, 111), 5 33 (s, 21 I), 3 68 (s, filtcrcd through a short layer of Cclttc (CHzClz nnsc). Thc 311), 3.23-3.16 (m, 211), 2.26-2.12 (m, 311)„2 00 (s, 311), filtrate was used directly 1.79-1.14 (m, 8H): ESI-MS nVz cole. 300.21, found 301.26 [1023] Separately. to a solution of 2.(i-lutidine (440 PL, (M+I) . Retention time: 0 54 minutes. 3.798 mmol) in HFIP (13mL) (4 mL/mmoL dried over allllydrous MgSO ) was added Cu(OTJ)z (1.35 g, 3.73 Jixample 51 nuuol) (1.20 cxlutv, preheated at 110'. I'or I h under lugh vacuum)) and stirred at room tempcraturc lbr I h, dunng Synthetic Scheme 51; 4-(3-(5-maine-2-cltloro-4- v hich a homogeneous suspension was fornted with soine lluorophcnyl)-1,4-oxazcpmt-4-yl)-6-mcthylpyruni- v hite solid still existin dtn-2-amuse [1024] 4 solution ofthc unuse ut CH,Clz (40 mL) (160 ml. 16 mLinuuol total) was added in oue portion and thc [1021] resulting nuxuire was surrcd at room tcmpersturc for 12 h and became clear homogenous solution 1 he reaction was quenched at room temperature with a mixture of aqueous saturated NaHCO, solution (40 mL) and 10'/v aq NHsOH (20 mL). and stirred vigorously for 15 min. The layers were sctzaratcd and theaquixius layer was extracted with CHzClz (3x50 mL). Thc combuttxi orgamc layers were washed wist HzO (3x5 mL) and brute (10 mL), dned over NazSOz, filtered, and concentrated in vacuo Purification by silica gel chromatography on 'I'eledyne IS('0 (MeOI I/Cl lzClz 0-8'8 US 20 ] 9/032265 [] A] Och 24, 2019 210

in 20 mins) aiforded 435 mg of desired product as a yellov -colitllillixl liquid, then tunicd solnl under vacuum (50%): 'H NMR r'I (300 MHz. CDCI,) 8 839 (d. J=8.G Hz, IH), 7.67 (s, IH), 706i (d, .I 104 Ilz, 111), 434 (dd, .I 9.3, 3.4 Iiz, 111), 402 3 87 (m. 211), 3 79 (ddd,.l 12 3, 6 7, 5 91iv, 111), 3 40 (dd, 1=12.4. 9.3 Hz„JH). 3.21 (dt, J=13.7, 5.0 Hz. IH), 3.01 (ddd, J=13.6, 8.2. 5.4 Hz. IH). 2.51 (s, 2H), 2.18 (s, 3H), 2.07-1.82 (ni. ZH): ESI-MS m'z calc. 286.09. found 287.09 (M+I) . Retcnuon time. 0.53 minutes. Fomtation of N-[5-[4-(2-amino-6-methyl-pyrimidin- 4-yl)-1,4-oxazcpmi-3-yl]-4-chloro-2-fluoro-phenyl] acctamidc 1-85 t.'I i'I [1025] 4-('hloro-6-methyl-pyrimidin-2-amine (0 11 g, 0 77 mmol) and N-[4-chloro-2-fluoro-5-(1,4-oxazepan-3-yl) phenyl]acetamide (0.20, 0.70 mmol) in nBuOH (5 mL) ivere irradiated in micro~ave at 170'. for 45 minutes. nBuOH was removixl under vacuiun anil the crude residue was purilied by silica gcl cluonmiography: 12 g ISCO cohunn, eluting with 0-10% MeOI I in ( I isCIz to atford 186 mg of desired product as yelloiv solid NMR showwI tv o rotamers (67%) 'll NMlt (300 Mlis, CD('I,) ij 8.36 (d, SH 1=8.2 Hz, IH)„7.51 (s, IH), 7.18 (dd. J=19.2. 103 Hz. IH), 6.02-5.77 (m, I H). 5.28-5.09 (m, IH), 4.28 (dt. 1=13.7. 5 I Hz. IH). 4 20-3 95 2H). 3.84-3.49 4H). 2.42-2.27 (m, (m, (a) 3-(tributylstannylniethoxy)propan-I -amine, ( u(O I'f)s, (m, 3H). 2.22 (d, J=0.9 Hz, 3H), 2.03-1.82 (m. 2H); ESI-MS 2.6-lutidine, CH,CI„HFIP; (b) nBuOH, pui 170" C., 45 ngz calc 393 14, found 394 09 (M+I) . I&etention time nuns; (c) chiral IIVI C separation 0 59 niimites

Formation of 4-[3-(5-amuio-2-chloro-4-fluoro-phe- lioniiation of nyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2- 3-(2-chlorothiophen-g-yl)-1,4-oxazepane amine 1-269 [1026] To a solution of N-[5-[4-(2-amino-6-methyl-py- [lt)28] To a solution of3-(tributylstannylmethoxyjpnipan- rinnilin-4-yl)-1,4-oxazcpan-3-yl]-4-chloro-2-fluoro-phenyl] I -mnine (SnAP reagent) (13.0 g. 34 4 mmol) in CH,CIz (170 acctamiilc (0 065 g, 0.162 mmol) in metlianol (0.25 mL) was ml.) at rooin tempemture was added 2-chlorothiophene-3- added HCI (I mL of 2 M, 2.000 mmol). 11tc soluuon was carbaldehyde (5 0 g. 34 I mmol) and Molecular sieves (5 0 100" heated to ('ntil IT MS indicated no more startiag g). The reaction mixture was stirred at room temperature for amine (2 h) Majority of solvent was removed under vacuuni 2 hours and filtered through a short layer of Celite (CHsClc and rentaining solution was neutralized with aqueous satu- rinse). The hltrate was concentrated under reduced pressure rated NaHCOs solution. The aqueous phase was then to alfiird the imine (contaui 10'!o aldchydc SM, b, 9.96). 'H cxtractcil with CHsCls (3x5 mL). Thc combined orgtuuc NMR (300 MHz, CDCI,) 8 8.26 (s, IH), 731 (t, 1=6.7 Hz, i3 layers were dncd (MgSOo), liltcred and concentrated in 111), 7 ON-6 i)2 (ni, I I I), Gi5 (s, 211). 3 58 (t, .I 6.9 I lz, 211), i acuo to aiihrd 42 mg of desired product as a yellow solid 3 31 1 6 2 I lz, 2i I). 1.85 1 6 5 I is, 211), I 44 'l (t, (p, (qd, (73'i) l NMIJ (300 Ml lz, CIJClsj 8 7 06 (d, .I 10.4 I lz, J=9.0. 8.0, 6.1 Hz. GH). 1.23 (h. 1=7 I Hz. 8H). 0.82 (td, ill), 6 65 (d, .I ') 011z, 111), 5 53 (s, 411), 4 30 (dd..i 13 7, J=8.0„7.3. 3.7 Hz, 15H). 5.0 Hz, IH), 4.17-4.01 (m. IH). 3.82 (d. 1=14.4 Hz. 2H), to a solunon 2,6-lutnline mL, 3.71-3.51 (m„3H)„3.50 (s, I H), 2.21 (s. 3H), 2.04-1.75 (m, [1029] Scparatcly, of (4.8 41.4 nunol) in hcxafluoroisopropanol (150 mL) was addcxI 2H). ESI-MS m/z cele. 351.13, liiuntl 352.15 (M+I) . Retcnuon time: 0.61 minutes. Cu(OTI)s (bis(tnfluoromcthylsulfonyloxy)copper) (15.0 g, 41 5 mniolj mid stirred at mom temperature for I hour, Example 52 dunng which a niostly homogeneous suspension was formed ivith some white solid stdi existing. A solution ofthe Synthetic Schmnc 52: (+/— )-4-(3-(2-chlorotluophen- 3-yl)-1,4-oxazepan-4-yl)-G-methyipyrinudin-2- imine in CHsCli (500 mL) was added in one portion and the amine 1-163 resulting nuxturc was siirrcd at room tcmperaturc lor 12 hours Thc reaction was quenched at room tcmpcrature with [it)27] a mixture ol'aqueous saturated NaHCOi (60 mL) and 10% 'I aq NI IoOI I (40 mi ), and stirred vigorously for 15 min. he layers v ere separated mid the aqueous layer was extracted v ith CHsCi, (3x50 mL). The combined organic layers were v ashed with HsO (3x5 mL) and brine (10 mL), dried over NaiSOo, Iiltcred, and conccntratcd in vacuo Purilication by sihca gcl column cluomatography (McOH/CHzClz 0-10% gradient) aflhrdcd 2.4 grams of thc dcsircd product as hght bmwn liquid (32!oj; I ISI-MS m/z cele 217 03, found 215.13 (M+I)+ ltetention time 036i niinutes US 20[9/032265[] A[ Oct. 24, 2019 211

Fomlation of 4-[3-(2-chloro-3-tlfienyl)-1,4-oxaze- conthulixl pan-4-yl]-6-methyl-pyumidul-2-aminc

[1(130J A mixture of 4-chloro-6-methyl-pyrimidin-2- amine (0 21 g. I 46 mnlol) and 3-(2-chloro-3-thienyl)-1.4- oxazepane (0.32 g. 1.41 mmol) in n-butanol (3 mL) was irradiated in a micmwave for I hour in a sealed tube at 170" ('. The mixture was concentmted to dryness and purified via sihca gel cluumatography elutulg with 0-10% McOH/ CHcCll. Pure fractions werc combined tmd concentrated to give 455 mg of desired product as a light yellow solid xil (i/9'i) 'I I NMR (300 Ml lz, ( blonlfouu-d) iS 7 16 (d..t 5 6 Hz. IH)„6.83 (s. IH). G.33 (c, 2H). 5.75 (s, IH), 4.34-4.17 (m, IH), 4.06 (s. IH). 3.77 (s, 2H), 3.74-3.42 (m. 2H). 2.36 [1034] SFC separation of E29862-1390. 4-[3-(3-cldoro-2- (s, 313). 2.18-1.80 (m. 2H): ESI-MS m/z cele. 324.08. found thlenyl)-1,4-oxazipan-4-yl]-6-methyl-pynmnhn-2-amine 325.05 (M+I) Rctmltlon time. 0.67 mimltes, ESI-MS m/z (295 mg, 0.9082 nuuol) Column. Cellulose-2, 20x250 nun cole. 324.0811S. Ibuud 325.0S (M+I) . Retention tmlc: 0.67 Mobile phase 40% MeOI I (5 mM Ammonia). 60% ('0, nlimltes lite title compound was submitted for chiral I I PI,C tsoct'atlc separation of enantiomers Peak A 1-210 Peak A. 1-211 [1035] 4-[3-(3-chloro-2-thienyl)-1.4-oxazepan-4-yl]-G- methyl-pyrimidin-2-amine (122 mu. 82%) IH NMR (300 [it)31] 4-[3-(2-chloro-3-thienyl)-1.4-oxazepan-4-yl]-6- MHz. Cldoroibnn-d) 6 7.19 (d, J=5.3 Hz, I H), 6.91 (d. J=S.3 methyl-pyrimldin-2-amine (128 mg): 'H NMR (300 MHz, Hz, IH), 5.7S (s. IH). 4.78 (s, 2H), 4.33 (dd, J=13.S, 5.S Hz. CDCls) 6 6.98 (d, 1=5 8 Hz, IH), 6.72 (d, J=5.8 Hz, IH), IH), 4.08 (dd, J=12.6, 5.1 Hz, IH). 3.74 (dd. J=13.5, 10.1 I 3.68-347 2 21 5.58 (s, I H), 5 25 (s, I H). 4.89 (s. 2H). 4.12 (dd. 1=13.5. 5 4 lz, IH), (m, 211). (s, 311), 2.00 (dddd, Hz. IH). 4 05-3 84 (m, IH). 3.75-3.57 (m, IH). 3.57-3.25 .I 14 0, 11/k 5 4, 2 7 I 1 su 111). I 81 (dd..l 14 3, 2 5 I lz. I I I) (m, 2H). 2.09 (s, 3H), 2.01-1.52 (m, 2H): ESI-MS m'z cele. ESI-MS m/z cele. 324.08115. found 325.1 (M+I)'. Reten- 324 08, found 325 15 (M+I )'etention time: 0 62 minutes tion time; O.G3 minutes. clural HPLC &98% Method. 20% cbiral I I PI,('98'/u ee. Acq Method 20% MeOI 1-30% [1036] ee, Acq. EtOH-50iu ITEX in 20 Mtns on C:hiralPAK IC colunul MEOH-30% ETOH-50 /v HEX ln 20 Mins on ChiralPAK IC colunm Optical rotation: T=24.2'u 5 mg in I mL of Optical rotation: T=20,(P Cu 5 m in I mL of CHCI.„C=I, ('ll('13, C I, [u] 6 8"

[u]W.92'eak Peak B 1-209 B: 1-212 [1037J 4-[3-(3-chlom-2-thienyl)-t,q-oxazepan-4-yi]-6- methyl-pyrimidin-2-anline (121 m . 82'iu) IH NMR (300 [1032] 4-[3-(2-chloro-3-(hicnyi)-1,4-oxazcpan-4-yl]-6- MHz. Cldorofoml-d) 6 7.19 (d, 1=3.3 Hz, I H). 6.91 (d, J=5 3 methyl-pyumalin-2-amlne (142 m ). 'H NMR (300 MHz, Hz. IH), 5.75 (s. IH), 4.78 (s, 2H). 4.33 (dd, 1=13.5, 5.5 Hz, J=13.S. ( D('ll) 6 6 98 (6, .I 5 8 I lz, 111), Cl 72 (d, .I 5 8 I lz, III), IH), 4.08 (dd, J=12.6. 5.1 Hz, IH), 3.74 (dd, 10.1 (sl, Hz. 3.68-3.47 2.21 2.00 5 58 I I I), 5 25 (s, 111). 4.8i) (s. 211), 4 12 (dd..t 13.5. 54 IH), (m, 2H), (s, 3H), (dddd, .I 11 uk 5 I iz. I 81 14 2 5 I lz. I I I is. 111). 4 05-3 84 (nl. 111). 3 75-3 57 (m„] II). 3 57-3 25 140, 4, 27 111). (dd..l 3, I) (m, 2H). 2.09 (s. 3H), 2.01-1.52 (m, 2H): ESI-MS m/z cole. ESI-MS nv'z cele 324.08115. found 325 I (M+I)+. Reten- tion time: 0.(i2 minutes. chirai HPLC: &98% ee, 324.08. found 325.15 (M+I) . Retention time: 0.62 minutes, Acq. Retcnuon time. 0.62 minutes cluml HPLC: &98% ec. Acq. Method 20%v MEOH-30% ETOH-50% HEX in 20 Mins on method. 20!u McOH, 30% EIOH, SO/u HEX ul 20 nulw on ChlralPAK IC column Optical rotation: T=24.3" C . 5 mg in — ChlralPAK IC column Optical rotation. T=23.2'C.. 5 m ln I mL of CHCI3, C=l. [u]= 0" 7.4':xample I ml of ('ll('ll, ('. [uJ 2 53 s were [1033] The following analo prepared accordin to Synthetic Scheme 53: 4-[4-(2-mnlno-6-methyl-py- Svnthetic Scheme 52: 1-209 and 1-210: rimldul-4-yl)-1,4-oxazcpan-3-yl]-S-chloro-N,N-dun- ethyl-thiophene-2-carboxamide 1-244

[ l()38J

SHl US 20[9/032265[] A[ Oct. 24, 2019 212

continued Formation of 4-(4-tert-butoxycarbonyl-l.4-oxazepan-3-yl)-5-chloro-thiophcnc-2-carboxyhc actd

[1040] To a cold (— 70" C.) solution of tert-butyl 3-(5- bromo-2-chloro-3-thicnyl)-1.4-oxazepanc-4-carboxylate (0.186 g, 0.46S nunol) tn THF (4 mL) was added dropwtse n-l3ul,i (0 220 nil, of 2 5 M. 0 550 mmol). 1 he color of the solution tumed front li ht yellotv to dark brown right asvay After 15 mitnttes, dry ice COs (0.5 8, 10 mnlol) was added and the reaction was stirred for 30 minutes and then allowed to wamt up to room temperature followed by workup with aqueous waturatcd NHoCI soluuon and EtOAc. The orgatuc plrase was dried (MgSOo). Iillcred and conccntmled in vacuo to afford 160 mn of cntde pmduct, (93%): 'I I NMR (300 Mllz. ('DCls) 6 7 41 (s. III) 5.11) (d .I 40 5 Iiz 111) 4 16 (s 111). 3 95 (d .I 37.3 Ilz 211) 3 68-2 1)8 (m 311) 1.93-1.51 (m, 2H). 1.20 (qd, J=G 9„G 2, 2 7 Hz. 9H); ESI-MS m'z calc. 361.08, found 362.1 (M+I ) Retention tome. 0.87 minutes.

Formation of tert-butyl 3-[2-chloro-5-(dimethylcar- banloyl)-3-thienyl]-I 4-oxazepane-4-carboxylate [1041] To a solutton ol'-(4-(crt-butoxycarbony1-1.4-oxazepan-3-yl)-5-chloro-thiophene-2-carboxyhc acid (0.150 8, 0 415 nunoi) in EtOAc (2 mi,) was added sequentially dimethylamine (1.0 mL of 2 M, 2 0 tmnol), diisopropylethyl amine (0.150 mL, 0.8(il mmol) and T3P (0.50 mL of 50% w/w, 0.84 mmol) ut EtOAc. Thc reacuon was stirred ovcrntght LCMS utdtcalcd only product. Aqueous washes wtth aqueous saturauxl NHoCI soluuon and bone. Thc orgatuc phase was dried over MgSOo. filtered and concentnsted in vacuo to afford 157 mg of cntde pmduct as yellow solid (97!): 'H NMR (300 Mifz, CDCls) o 7 09 (d. J=37.5 Hz, I H). 5.26 (d, 1/ 49,8 Hz, I H), 4.43-3.78 (m, 4H), 3.GG-3.38 (m, 2H), 3.09 (s, GH), 1.94-1.54 (m, 2H). 1.45-1.21 (m, 9H),

ESI-MS m'z cole. 38S.12, found 389.27 (M+I) . Rctcnbon tome. 0.85 minutes.

Fomlation of 5-chloro-N,N-dimethyl-4-(1.4-oxazepan-3-yl)llnophcnc-2-carboxamtdc

a 3-[2-cltioro-5-(dimcth- SH1 [1042] To soluuon of tert-butyl ylcarbamoyl)-3-(lncnyl]-1,4-oxazcpanc-4-carboxylate (0.16 8, Oiqi nunoi) in 1.4-dioxane (3 nil.) was added II('I (I 0 ml. of 4 M, 40 mmol) After sttrnng for I hour at room (a) NBS, CHsCN: (b) nBuLi, COa, THF. —78" C: (c) temperature the vohstiles were removed to afi'ord 120 of Me,NH. iPr,NEt. T3P. EtOAc: (d) HCI, MeOH. Reflux: (e) mg des(red product as a TFA salt„which v as used without nBuOH. Ht 1, 170'o 45 mons Iitrlhcr punficatiotu ESI-MS m/z cele. 288.07, I'mtnd 289.16

(M+I) . Rctcnlton lime. 0.53 minutes I'ormation of tert-butyl 3-(5-bromo-2-chloro-3-tlue- nyl)-1.4-oxazepane-4-carboxylate Fomlation of 4-[4-(2-anlino-(i-methyl-pyrimidin-4- yl)-1.4-oxazepan-3-yl]-5-chloro-N.N-dimethyl-thio- [1039] To a solution of tert-butyl 3-(2-chloro-3-thienyl)- phcne-2-carboxamidc 1-244 1.4-oxazepanc-4-carboxylate (0.42 g. 1.30 mmol) tn CHsCN (5 n1L) was achlcxl NBS (0 25 g, 140 nunol) at rt1tun [1043] A solution of 5-chloro-N,N-dunclhy1-4-(1,4-ox- lempcralurc. Thc rcacbon was shrred at room lempcralurc azepan-3-yl)tluophene-2-carboxamulc-TFA sall (0.120 g) for I hour 'the solution was evaporated and puritied by and 4-chiom-6-nlethyl-pyrimidin-2-anlme (0075 8, 0.522 silica nel chromatography using 40 8, ISCO column eluting mmol) in n-liuOII (3 ml,) tvas trradiated m microwave with EtOAc/ifexane (0-30%) to afford 495 mg of product as reactor at 170" C. for 45 minutes, nBuOH was removed a clear yellow oil (95'!o): 'H NMR (300 MHz. CDCI o) 6 6 73 under reduced pressure and the cntde residue was purified (s, IH). 5.45-5.00 (m, IH), 4.39-3.78 (m. 3H). 3.35 (dl, by stlica gcl chromatography using 12 g ISCO colunut, J=60.4. 12.8 Hz, 3H), 1.86 (dtdd. J=13.7, 10.9, 5.0. 2.7 Hz, eluung w ith 0-10% McOH ut CHsCls to alford 40 mg of IH). 1.77-1.68 (m, IH), 1.51-1.22 (m, 9H) Rotamers, rauo dcstrcxI product as v'hite sohd (25%o). ' NMR (300 MHz, I 2.5: I(SI-MS nv'z cele. 395 00, found 395.75 (M+I)'. ('IX'I ) 8 7 15 (s, I i I). 5 70 (s, 111), 5 24 (s, 211), 4 42 (s, Retention time: I 07 minutes 211), 4 I') (dd..l 13 5. 5.211z, 111). 4 00 (d,.l 11.711z, II I), US 20 ] 9/032265 [] A[ Oct. 24, 20]9 213

3.76 (dd. J=13.4. 9.5 Hz, IH). 3.64 (d, i=103 Hz. IH), 3.50 -colttlltllixl (t. J=13.1 Hz. I H), 3.15 (s, 6H). 2.25 (s, 3H), 2.04 (s. I H), I 83 (d..l 14 4 I lz, 111): li)I-MS m/z cele 3')5 I i, found 396 16 (M+I)+. Retention tune: 0.59 minutes. [1044] The Ibllowtng analogs were prepared accorrling to %if Svnthctic Schcmc 53. 4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-5-chlom-N-ntethylthiophene-2-carboxant- ide 1-182 [1045] 0 Yif 0

Y Yif 0

[1046] 'H NMR (300 MHz, Methanol-d4) 6 7.53 (d, 15 5 I iz. H I), 6 46 5 88 (s. 111). 6 02-5 ] 9 (dd .I s) 3 5 4 I lz,. 111), 4 29-3 60 (m, 611). 2 84 (d, .I 2.4 I lz, 311). 2.30 (d, 1=24.3 Hz, 3H), I 56-1 34 (m, 3H). Itxample 54 [1047] Synthcttc Scheme 54. (+/ — )-4-[3-(2-chloro-4-rhm- (a) methylphosphonylmethane. KsPOs. Pd(OAc)s. Xant- ethylphosphoryl-phenyl)-1.4-oxazepan-t-yl]-6-methyl-py- phos, DIVIF, (b) TFA. CHcCI„(c) 2-amtno-4-cldoro-6- rimidin-2-anttne 1-202 methylpyrimidine, nliuOI I. 120" ('4 (d) chiral IIPI,('epa- ration

Formation of (+/— )-tert-butyl 3-(2-cldoro-4-dimeth- ylphosphoryl-phenyl)-1,4-oxazepane-4-carboxylate

[1048] A Schlock tube was chargtxl wtth (crt-butyl 3-(4- bromo-2-chloro-phenyl)-1,4-oxazcpanc-4-carboxylate (223 mg, 0.542 mmol), Xantphos (37 mg, 0.065 nunol), Pd(OAc)s (12 2 mg„0.054 mmol), methylphosphonoyl- methmte (70 mg, 0 897 mmol). Ks POs (230 mg. I 08 mmol), sstl DMI'3 ml,) and vacuunv'nitrogen cycled three times, then inunersed in a hot bath set to 120" ('. overntght D('M and water were added to the reactton mixture and the layers separated with the aid of a phase sepamtor. The aqueous layer was re-extracted with DCM. separated with the aid of N a phase separator and the combined organics crmcentrated The rcsulttng restduc was puniicd vta stltca gcl chromatography cluting with 30-100% EtOAc/heptane then 0-10% MeOH/DCM. Pure fractions vvere combined and concen- 0 trated in vacuo to afford 63 ntg of tert-butyl 3-(2-chloro-4- duucthylphosphoryl-phenyl)-1.4-oxazcpanc-4-carboxylate as a straw colored otl. 'H NMR (400 MHz, McOH-ds) b 7.84 (d. 1=11.7 Hz, IH), 7.78-7.68 (m. I H). 7.52 (dd. J=7.9, 3 0 I lz, 111). 5 52 (dd, .I 10 7, 4.2 I iz. 111). 4 42 (d, .I 15 7 Hz. I H), 4.29 (s, I H). 4.08-4.00 (m, IH), 3.71-3.52 (m, 3H), 1.86 (s. 2H), 1.83 (s, 3H), 1.79 (s, 3H), 1.24 (s. 6H), ESI-IvIS m/z cele. 387.1, found 388.3 (M+I) . Retention time 0.67 nunutes. US 20]9/032265[] A[ Oct. 24, 2019 214

Founatlon of (+/-)-3-(2-chioro-4-dimethylphospho- Example 55 ryl-phenyl)-1,4-oxazepane Synthct&c Scheme 55. 4-(3-(6-chloro&m&daze[1,2-a] [1049] tert-Butyl 3-(2-chloro-4-duncthyiplx&sphoryi-phe- pyridin-7-yl)-1,4-oxazepan-4-yl)-6-methylpynmi- nyl)-1.4-oxazepane-4-carboxylate (Ci3 mg, 0.162 mmol) was din-2-amlne dissolved in dichloromethane (I ml ) and trifluoroacetic acid (05 ml.) &vas added After 15 min, the volatiles vere [1054J renlovcd on a rotory evaporator. The reaction mixture was conccntrstcd and then d&ssoiv&xl ul McOH and passed through a SPE bicarbonate cartridge (Agilent Stratospheres 500 mg/6 mL) and concentus&cxI to afli&rd 38 mg of thc desired product as a straw colored oil 'I I NM R (400 Ml lz„ McOH-de) 6 7 87-7 82 (m, IH). 7.80-7.71 (m, 2H)e 4.49 (dd, 1 92 3 5 Ilz 111) 402 3 l)4 (m, 211) 3 90-3 82 (n& IH) 3.49 (dd. 1=12.5. 9.2 Hz, I H), 3.25 (dt. J=13.9. 5.0 Hz. I H), CO Me 3 05-23)C& (m. 111), 2.08-1.99 (m. 211), 1.82 (d, .I 2.9 I lz„ ('0 M 3i I). 1.7'3 (6, 1 2 9 I lz, 311) I IS I-MS m/z calc 287 1. funnel 288.3 (M+I) . Retention time: 0.46 minutes.

I'om&at&on of (+/— )-4-[3-(2-chloro-4-dinðylphos- pho&yl-phenyl)-1,4-oxazepan-s-yl]-C»-uethyl-pyri&ui- din-2-amine C&

[1050] A mixture of 4-chloro-6-methyl-pyrimidin-2- ammc (18.4 mg. 0.128 nmloi) and 3-(2-chloro-4-&lime&hyl- phosphoryl-phenyl)-1.4-oxazcpt&nc (38 mg, 0.132 nunoi) &n ni3uOI I (1.3 ml ) was heated at 125" (2 overnight. The reaction mixture was concentrated and the resulting res&due purified via silica gel cluomatography elutiltg with 0-30% C'& MeOH/DCM to afl'ord 14 m of a white solid. 'H NMR (400 MHz. MeOH-de) 0 7.89 (d. J=ll.5 Hz. IH). 7.75-7.Ci7 (m, I H), 7.51 (dd, J=8.0, 3.0 Hz, IH), 7.00-4.90 (br s, 3H), 4.35 (dd. J=13.7. S.O Hz, IH), 4.06 (d, J=11.8 Hz, IH). 3.83 (dd, 1 13 7 10 311z 211) 3 68 (dd .I 18.9 8 211z 111) 2 22 (s 311), 2 00-1 82 (m, 211), I 82 (s. 311). I 79 (s. 311) I &SI-M) m/z cole. 394.1, found 395.4 (M+I)'. Retention time 0 51 minutes. [1051] Chiral HPLC set&ace&ion: Colunul. AD-H, 20x250 nuu. Mob&le phase. 70% Hexane). 30% E&OH/MeOH (0.2% V C Dicthylannnc); Flow: 20 mL/nun, Concentrat&ons. — 15 mg&ml (MeOI I). Absolute stereochemistry of each peak unassigned. NII& [1052] PeakA 4-[3-(2-chloro-4-dimethylphosphoryi-phe- 0 nyl)-1,4-oxazepan-4-yl]-Ci-methyl-pyrimidin-2-amine; 99+%& om H NMR (400 MH'z, DMSO-de) 6 7.77 (dd, J=11.3, 1.3 Hz, IH), 7.67-7.60 (m, IH). 7.43 (dd, J=7.9, 2 9 I iz. 111). 5 C&4 (s. 111). 5 54 (s, 111), 5 44 (s, 211). 4 55 (s, 111), 4 14 (dd, 1 13.4. 5 0 I lz, 111), 3.90 (d, .I I i 7 I lz, IH), 3.78-3.66 (m, 2H). 3.56 (dd, J=14.6, 12.2 Hz. I H). 2 02 (s, C& 3H), 1.81-1.75 (m, 2H), 1.65 (s. 3H). 1.62 (s. 3H). ESI-MS m/z calc. 394.1. found 395.2 (M+I) . Retention time: 0 5 nnnutcs. 1-213 StI [1053] Peak B 4-[3-(2-chloro-4-duncthyiplx&sphoryi-phe- 0 nyl)-1.4-oxazepan-4-ylJ-6-methyl-pyrimidin-2-amine; 9'3+% ee: 'll NMR (400 Mi lz, l)MSO-de) 6 7 77 (dd, 1=11.3, 1.3 Hz„ I H). 7.67-7.60 (m, iH). 7.43 (dd. 3=7 9, 2 9 'I'I I I&('M. Hz. IH). 5.(i4 (s. I H). 5 54 (s, IH), 5.44 (s, 2H). 4.55 (s, IH), (a) 2-chlomacetaldehyde. I:tOI I; (b) )113AI.-I I. Ilk 4.14 (dd, J=13.4. S 0 Hz, IH), 3.90 (d. J=11.7 Hz. IH), (c) MnO&. DCM, 2-MeTHF. acetone; (d) 3-(tributylstannyl) 3.78-3.66 (m. 2H), 3.56 (dd, J=14.6, 12.2 Hz, IH), 2 02 (s, methoxy)propan-I-amine 4 A mol s&cvcs, CH&C'I&: then 3H). 1.81-1.75 (m, 2H), 1.65 (s. 3H). 1.62 (se 3H). ESI-MS 2.6-lutidine, Cu(OTi)„hexafluoroisopropanok (e) 2-amino- nFz cele 394.1. fi&und 395.1 (M+I ) Retention time 0 5 4-chloro-6-mcthylpynmidule, NMP, 150'., (lj clurai nlimltes 1-214 I IPI (: separation US 20[9/032265[] A[ Och 24, 2019 215

Formation of methyl 6-chloroimidazo[1.2-a]pyrt- 7.56 (d. J=l.l Hz. IH), 7.40 (s, IH), 5.71 (s, IH). 5.45 (s, duie-7-carboxylate 3H), 4 51 (d. J=15.1 Hz, I H), 4.18 (dd, J=13.5, 4.8 Hz, IH), 3.90-3.80 (m. 2H), 3.73 (ddd, J=15 2, 9.5. 3.5 Hz, IH). 3.60 [1055] A mixture of methyl 2-amino-5-citior&wpyridine-4- (ddd, .I 12.1. 9.7 4 7 I lz,. 111). 2 03 (s, 311), I 83-1.7&J (m, carboxylate (7.1 5 383 nunol), 2-chloroacetaldehyde (7 3 g, 211); ESI-MS m,'z cele. 358 I, found 359 I (M+I)+ Reten- mL. 115 nunol) and EtOH (60 mL) was heatcxl at rcfiux. tion time: 045 minutes. After 3 h, a further 3 nil. chloniacetaldehyde was added and stirring continued overnight. 'I'he reaction mixture was par- Ex&unple 56 tially concentrated Water and 6 M NaOI I were added and the ntixture extracted with EtOAc twice. The combined Synthetic Scheme 5(x 4-(3-(2-chloro-4-(cyclobutyl- organics were dned filtered and concentmted (Na,SOs), sulfonyl)phenyl)-1.4-oxazepan-4-yl)-6-mcthylpy- giving 8 of methyl 6-chloroinudazu[1.2-a]pvndmc-7-car- g rimidin-2-anunc 1-222 boxylate as a greyish brown solnl. 'H NMR (400 MHz, l)MSO-d&) 6 8 96 (d..l 0 6 I lz, H I), 8 13 (d..l 4 2 I is. I H), [ lt)60] 807 (d,.l 0 &7 Iiz. 111), 7 81 (d..l I I Iiz, 111), 3 89 (s, 311). I:SI-MS m'z calc 2100. f&iund 211.1 (M+]) . Retention time: 0.48 minutes.

Formation of (6-chloroimidazo[1,2-a]pyudin-7-yl) metlianol

[1056] To a solution of methyl 6-chloronunlazo[1,2-a] pyndinc-7-carboxylate (8 g, 37.98 nunol) ui DCM (60 mL) and THF (100 mL, to aid solubihty) was add&xi at DJBAL-H (I M. 45 6 Illillol);it — 78 ( oval' il. 1 he I'cacti&111 lllixtllre was allo&ved to warm to IT I'vernight. A further 15 mi, of DIBAL-IJ with ice bath cooling was added. After 2 h at the same temperature, Rochelle'c salt (1.5 M, 200 mL) was added mid stirnng conunued for a I'urdicr 2 h. 3.7 of thc dcsir&xi product was Iiltercd oif as a white solid after w ashuig with water. 'H NMR (400 MHz, DMSO &1&) 6 8 82 (s, II I), 7 88 (s. 111), 7 58 (d, J I 2 I iz 211), 5 55 (t..l 5 6 Hz. 111), 4.57 (dd, J 5 0 I 3 1lz. 211) Iigi-MS miz cele. 182.0, found 183.0 (M+I)'. Retention time: 0.44 minutes.

Fern&ation ol'-chloroimidazo[1,2-a]pyudinc-7- carbaldchvdc [1057] To a suspension of (6-chloroimidazo[1.2-ajpyridin-7-yl)methanol (3.7 g, 203 mmol) in DCM (60 mL), 2-McTHF (50 mL) aud acctonc (50 mL) v,as added activated MnOi (10 g. 115 mniol) After three days at 50" C., the reaction niixture was hltered through ( elite with the aid of EtOAc and concentmted, EtOAc was added. the mixnne sonicated and 2 93 g of desired product filtered off as a yellow solid: 'H NMR (400 MHz, DMSO-d,) 6 10 18 (s, I H), 8.97 (d, J=O.S Hz, I H). 8.20 (s, IH), 8.14 (d. J=0.8 Hz, I H), 7.90 (d, J=l.l Hz, I H). ESI-MS nffz cele. 180.0. fiiund 181 0 (M+I) . Retention time 045 minutes.

Fomtation of 3-(6-chloroimidazo[1,2-ajpyridin-7- yl)-1„4-oxazepane and 4-(3-(6-chloroimidazo[1,2-a] pyridin-7-yl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-aminc (1-191)

[1058] Fonnauou of thc oxazcpmie nng system product) f&illo&ved by addition into 2-amino-4-chloro-6-methylpyrimidine &vas carried out in same fashion as shown in Synthetic Scheme 55 to afiord racemic 4-[3-(6-chloroimidazo[1,2-a]pyridin-7-yl)-1,4-oxazepan-4-ylj-ti-methyl-pyrimidin-2-amine 1-191. [1059] Clural HPLC scpamtion: Column. AD-H, 20x250 (a) cyclobutancthiol, EI,N. CH,CN, 60', (b) Oxonc, mm. Mobile phase. 70% Hcx&mcs, 30 /o EIOH/McOH (0.2% McOH. HsO: (c) NaOH, HsO. then HCI: (d) TMS-diaz- Dimhylamuu:); Flow. 20 mL,'nun. Conccntrauons. — 15 ometlianc, tolucnc, methmiol. (e) NaBH4, McOH, (I) Dess- 'I nigiml (MeOI I) afforded the single enantiomer (1-221) I Martin periodinane, dichloroniethane: (8) 4 A mol sieves, NMR (400 Ml lz. 1)MSO-dfii) &5 8 78 (s, I I I). 7.86 (s, HI), 3-((tributylstannyl)methoxy)preps- - -imnin. (:I IsOIz. then US 20 ] 9/032265 [J A[ Oct. 24, 2019 216

2.6-1utidine, Cu(OTf)s„hexafluoroisopropanoi. CHICI,: (h) time: 0.68 minutes. The followin analogs v ere prepared 2-anuno-4-chloro-6-methyipynmuluie. NMP. 150'G according to Synthetic Schcmc 56.

Iiorulatuul of 4-(3-(2-chloro-4-(ethyisulfonyl)phenyl)-I 4-oxaze- 2-chlom-4-(cyclobutylthio)benigmitrile pan-4-yl)-6-methylpyrimidin-2-mninc 1-183 mid 1-317 [1(161J A mixture of 2-chloro-4-fluoro-benzonitrile (I 00 , 6 43 mmol), cyclobutanethiol (I 15 8, 13 04 nunol), and [1065J triethylamine (1.79 ml . 12 84 mmol) in acetonitrile (8 mi,j Ives stirred in a sealed tube at 60" C. overnight. The mixture Ives diluted with v ater and extracted with EtOAc. The organic layer was conccntratcxI to dryness, dry loadcxI onto loose silma gcl and punlicd via silma gcl cluomatography eluting with 0-25'g IitOAc in heptane. I'ractions containiug the desired product were combined and concentrated to ',Iif-'.= afford 1.0 8, of desired pmduct as a colorless oil 'll NMR .~ (400 MHz. Chlomform-d) 6 7.49 (d. i=83 Hz, IH). 7.20 (d, 1=1.8 Hz„ IH). 7.07 (dd. J=8 3, 1.8 Hz, I H), 3.98 (dq. J=9 5, 7.1. 6.3 Hz. IH), 2.65-2.SO 2.21-2.02 4H) Yi (m, 2H), (m, 8 Iiorulatuul of 2-chloro-4-(cyclobutylsulfonyljbenzonitrile

[1062] To a solution ol'2-chioro-4-(cyclobutylthto)bcnzo- nitrile (2.S g. 11 9 mmol) in MeOI I (150 Inl.) was added a solution of Oxone (14.CI g. 23 N mmol) in water (75 ntl,). The reaction mixture was stirred for 2 days at room temperature and then concentrated to dryness. The resulting ~i w lute precipitate was partiuoncd between water and EtOAc. Thc orgmuc layer was concentrated to dryness and purified Yi I is silica gcl cluomatography elutm with 0-SO/o EIOAc in 8 heptane Pure fractions were combined and concentrated to give I 07 g of desired product as a white solid: 'I I NMR (400 Mifz. Chloroform-d) 6 8.02 (t, J=l. I Hz. I H). 7 86 (d, I=i.l ifz, 213). 3 83 (pd. J=8.2. 0.7 Hz, IH). 2.Ci6-2.50 (m, 2H). 2.28-2.17 (m. 2H), 2.12-1.96 (m, 2H). [1066] Peak A: 4-[3-(2-chloro-4-ethylsulfonyl-phenyl)-1, 4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine: 'H NMR liormation of (400 MHz. DMSO-d6) 6 7.89 (d. J=l 9 Hz. IH). 7.77 (dd, 2-chloro-4-(cyclobutylsulfonyl)benzoic acid J=S.I, 1.9 Hz, IH), 7.57 (d. J=8.2 Hz, IH), 5.66 (1, IH), 5.SS (dd, J=10.2, 4.8 Hz, IH). 5.45 (s. 2H), 4.50 (d. J=15.3 Hz. [1063] A solution of 2-clfloro-4-(cyclobutylsulfonyi)ben- 111),4 15 (dd, J 13 5, 4.911z, 111). 3 90 (dt..l 123 3 9 Hz zoniuilc . 4.46 and NaOH 10.00 (1.14 mmol) (0.40 g, 111), 3 83-3 6') (m, 2i I). 3 62-3 52 (m, 111), 330 (q, .I 7 4 nunol) pellets in wuter (30 mL) was rcfluxcd ihr 4 hours, Hz. 2H). 2.02 (s. 3H). 1.80 (dq, J=11.0, G.7, 5.4 Hz. 2H), cooled to room tmnpcraturc, mid actddicx! to pH — 3 using 1.12 (d. J=7.4 Hz, 3H); ESJ-MS m/z calc. 410.12. fiiund HC'I (10 ml of Ci M, 60 mniol) The resulting white pre- 411.0 (M+I) . Retention time: 0.64 minutes. cipitate was filtered, washed with ivater, and dried under [1067] Peak B: 4-[3-(2-chloro-4-cthylsulfonyl-phenyl)-1. vacuum overnight to afford 1.21 g of desired product as a 4-oxazepan-4-ylJ-Ci-niethyl-pynmidin-2-aniine 'l I NMR white powder 'H NMR (400 MHz. Chloroform-d) 6 7.93 (400 MI Iz, DMSO-dti) 6 7 NN (d..t I 8 Iiz. 111), 7 77 (dd, (d, J=S.I Hz. IH), 7.81 (d, J=1.7 Hz. IH), 7.65 (dd, J=8 2, 1=8.2. 1.9 Hz, IH), 7.37 (d. J=8.2 Hz„ IH), 5.66 1H). 5.58 1.7 Hz, IH), 3.71-3.S9 (m, IH). 2.47-2.33 (m. 2H), 2.09-1. (s, (dd. J=10.0. 4.8 Hz. IH), 3.44 (s. 2H). 4 50 (d. J=15.3 Hz, 97 (m. 2H). 1.91-1.77 (m, 2H). IH). 4.15 (dd. 1=13.5, 4.9 Hz, IH)„3.90 (dt, 1=11.9, 3.9 Hz, 3.75 J=18.4. 144, 8.0 3.57 J=12.1, Formation of 4-(3-(2-chloro-4-(cyclobutylsulfonyl) IH), (ddd, Hz, 2H), (dt, J=7.3 phenyl)-1,4-oxazcpan-4-yl)-6-mcthylpyruntdut-2- 7.2 Hz, I H), 3.30 (q. Hz, 2H), 2.02 (1, 3H), 1.80 (dq, .I 7 4.2 I I 12 1 '1 I I!SI-M) anunc 2, lz, 211), (dd. 7.4, 0 lz, 311): nv'z cele 410.12, found 411 0 (M+I ) ltetentiou time: O.C14 [1064] Conversionof2-chioro-4-(cyclobutylsullhnyi)ben- uunutcs. zoic acid to the title compound was prepared according to the procedure hsted in )ynthetic Scheme 8 'I I NMlt (400 I:xampie 57 MHz, DMSO-dG) o 7.83 (d. J=1.9 Hz. IH). 7.76-7.68 (m, I H), 7.56 (d. 1=8.2 Hz„ IH), 5.69-5.51 (m. 2H). 5.4Ci (s. 2H), [1068] 'H NMR was recorded on a Bniker 400 MHz 4.48 (d. J=I S.3 Hz, IH), 4.12 (dq. J=12.3, 7.8, 6.8 Hz, 2H), spcctrometcr, usuig residual signal of dcutcratcd solvent as 3.95-3.S4 (m, IH), 3.84-3.64 (m, 2H). 3.S7 (q, J=10.1, 8 6 hitcrual rcihiencc. Chcuucal shifts (6) ai'e repelled ui ppnl Hz. I H). 2.34 (p, J=9.6, 9.0 Hz, 2H). 2.22-2.07 (m, 2H). 2.02 relative to the residual sob cnt signal (6=2.49 ppm Rir IH (d, .I 3.7 I II. 311), I 93-1 N7 (m, 211), 1.84-1.74 (m. 2il), NMR m DMSO-dti). II I NMlt data are reported as follows l!SI-MS miz cele 4361. found 4370 (M+I) . Itetention cheniical shift (nuiltiplicity. coupling constants. and munber US 20 ] 9/032265 [] A[ Oct. 24, 2019 217

of hydrogens). Multiplicity is abbreviated as Ii!Ilov.s: s (singlet). d (doublet), I (tnplct), q (quanet). m (multiplet). br (broad j. [1069] LCMS-Armlysi ~ was perfonmxl under the following conditionm [1070] Method: A; 0.1% TFA in HSO. B: 0.1% TFA in ACN. [1071] Runtime: 6.5 min [IU72] lilow Rate I 0 nil ymin [1073] Grmhenh 5-95% B ui 4.5 min. wavelength 254 and 215 nM [1074] Column. Waters Sunlirc C18, 3.0x50 nun, 3 5 um, positive niode I&eagents: 4 A mol sieves. [1075] Muss Scan. 100-900 Da [I U76J a) i) 3-((tnbutylstannylj methoxy)propan-l-amine, CHSCISI ii) 2„6-lutidine. Cu(OTf) ,. hexafluoroisopropanol. CHSCI,I b) Di-tert-butyl decar- bonatc, TEA, DCM. — j-2-chloropropan-I-oL KOH, Scheme i Syoihes e of('poemd t.'i! cj (r)-( DMF; dj TFA, DCM, ej 2-amino-4-chloro-6-mcthylpyrimi- dine, nl3uOII, 135'

Fomiation of S-Chloro-4-[1.4]oxazepan-3-yl-phenol (I) [I U77J A mixture of 3-(tributylstannylniethoxy)propan-I- amine (2 42 o, 6 4 mmol), 2-chloro-4-hydroxybenzajdehyde (1.0 g. GS4 mmol) and 4 angstrom molecular sieves in Ou dichloromethane (10 mL) vvas stirred for 20 hours. The mixture was hltered. In a separate flask containing hexafluoroisopropanol (20.0 mL) was added 2,6-jut!dine (0.9 mL, 7.6 mmol) followed by Cu(OTI)h (2.78 g, 7.6 nunolj and dichloromethane (3 nil.j '11!e mixture was stirred for 3 hours at le!oil! temperature I'he filtered imine solution was added in one portion to the second flask all at once 'lite resulting vvas i reaction mixture stirred overnight. filtered and then treated with 100 mL of 2;I niixture of aqueous saturated NaHCOe solution mid 10% anunoiuum hydroxide. Thc orgalllc pili!so was scpat'at!xi i!lid wtisllcd wltll aqucoils saturated Nal ICOs solution, dried with sodiuni sulfate, filtered and concentrated in vacuo. '11!e crude mixture was punfied using l3iotaue systeni. 100 g column ususo 2-159tr MeOH.DCM to aiford 1000 mg (55%o yield) of product as a colorless oil. LC-MS (M+Hj: 228. lionnation of 3-(2-('hlom-4-hydroxy-phenyl)-[1,4J oxazepane-4-carboxylic acid tert-butyl ester (2) [1078] To a stirred solution of3-Chlom-4-[1.4]oxazepan-

3yl phenol (1.6 g, 703 nunol; 100 txj 1 in DCM (1500 ml. 234 01 nunol, 33.30 cq.) was add!xi Di-teit-butyl dicarbon- ate (I 68 8: 7 73 mmok I 10 eq ) and Tl:A (2 94 mh 21.08 'I'he 'I mmoh 3 00 eq ) reaction was stirred at it for I h he solvent was evaporated and the crude mixture was dried to afli!rd the title compound (2.3 g: Yield: 100%) as a ofl'white sohd. LC-MS (M-Boc): 228.

Formation of 3-[2-1 'hloro-4-((R)-2-hydroxy-I- methyl-ethoxy]-phenyl]-[1.4]oxazcjtauc-4-carboxylic acid tert-butyl cater (3) [1079] To a stirred solution of 3-(2-Chloro-4-hydroxy- 0 phenyj)-[I.4]oxazepane-4-carboxylic acid tert-butyl ester (50 00 mg, 0.15 nunol, 1.00 cq. j in DMF (1.50 ml, 1945 nuno1; 12754 ui a microw a! c vial was added potassium o ixh j hydroxide (34.23 mg, 0.61 nunol; 4.00 cq.) and. Thc reaction mixture ives stirred at 1()0 ( overnight 1 he reaction was quenched using water and extracted with DCM 1'he US 20[9/0322658 A[ Oct. 24, 2019 218

'H organic layer was concentrated under vacuum and the crude (M+H) . 409. NMR (400 MHz. DMSO-d6) 6 7.18 (d, nnxturc was punlicd us&ng Btotage system, 10 column J=8.7 Hz, IH), 7.04 (d. J=2.5 Hz, IH), 6.89 (dd, J=8.7, 2.6 using 5-50% AcOEt.PS to alTord 5S mg (93% y&cld) of title Hz. I H), 5.91 (s, 3H). 4.92 (dd, J=5.1, I 6 Hz, I H), 4.63 (dd, compound I (:-MS (M-Iioc): 286 .I 6 4, 4.9 lip, 111), 4 11-3.96 (n&. 211). 35)4-3.82 (m, 211), 3 79-3.58 (tn. 311). 3.58-3.48 (m. 111), 3 42 (t, .I 5 7 I is, Fonuation ol'R)-2-(3-Chloro-4-[1,4]oxazc7&an-3-yi- 2H). 1.99 (s. 3H), 1.73 (s. 2H). phcuoxy)-propan-I-ol (4) [lt)8U] 1o a stirred solution of 3-[2-( hlon&-4-((R)-2-hy- dmxy-I -methyl-ethoxy)-phenylJ-[1,4Joxavepane-4-carbox- C mpvssd('t ylic acid tert-butyl ester (55.00 mg: 0.14 nunok 1.00 eq ) in D('M (2.00 mk 31.20 nunol, 218.91 eq.) at rt wns added TFA (0.50 ml; 6.53 nunok 45.81 eq.). The reaction contin- ucxl lbr 30 min. Thc solvent was evaporated and d&e crude nnxturc was dncd to alTord the title compound (40 mg Yield: 100%) as a off white solid. I,( -MS (M-l3ocff 286

Fonnauon of (R)-2-&4-[4-(2-Amu&o-6-methyl-pyrinudin-4-yl)-[1.4] oxazcptm-3-yl]-3-chloro-phenoxy)-propan-I-ol (5) ('ompound ('-60 [lt)81] 1o a stirred solutton of (R)-2-(3-('hlon&-4-[I.4] oxazepan-3-yl-phenoxy)-propan-I-ol (15.00 mg: 0.05 nunol; 1.00 eq.) in I-butanol (1.50 ml), 2-amino-4-chloro- OH 6-mcthylpyrnmdtne (15.07 mg, 0.10 nunoi; 2.00 cq.) and TEA (0.02 mk 0.16 mmol, 3.00 cq.) acre addcxI. The react&on was hcatcxI at 13S C ovem& lu. Next day LCMS Formation of (R)-3-14-[4-(2-Amino-6-methyl-py- was recorded to confirm the completion of the reaction 1 he nmidin-4-yl)-[1.4]oxazepan-3-yl]-3-chloro-phc- reaction nuxture was loaded as is on the Intershim prep noxy)-propane-1,2-tltol (7) Compound C-61 system using Basic conditions, 10-90% Acetonitrile;H20 to (R)-3-[1-[4-(2-Amino-6-methyl-pyrin&&din-4-yl)- afft&rd 3.7 ntg (18% yield) of title product. I C-MS (M+H) [IU84J J-3-ch -propane-1,2-di el 393. 'H NMR (400 MHz, DMSO-d6) 6 834 (s. I H). 7.18 (d, [1,4 J ox a repen-3-yl lorn-phenoxy) v as afforded as white solid 11% I.('-MS J=8.7 Hz. IH), 7.03 (d, J=2.5 Hz, IH). 6.88 (dd, J=8.7. 2 6 (6 mg, yield) 'H DMSO-d6) Hz. IH), 5.86 (s. 3H), 4.0S (dd, 1=13.6. 5.0 Hz, IH), 3.91 (M+H)'. 409. NMR (400 MHz. 6 7.18 (d, 1=8.7 Hz. IH), 7.03 (d. J=2.5 Hz, IH). 6.89 1=8.7. 2.G (dt, .I 11 6, 5.6 I iz. 211). 3 80 (dd..l 6 0, 3 0 I iv, I I I), 3 6N (dd, Hz. IH), 5.84 3H), 4.93 (d, J=5.1 Hz, I H), 4.63 J=6.0 (dd. 1 13 4. 10.6 I lz, 211), 3.55-3.49 (m, 211). 3 37 (s. 511, (s, (d, 4.11-3.9G 3.95-3.82 3.79-3.58 overlaps with H20 peak), 1.98 (s, 3H). 1.73 (s. 2H). Hz. IH), (m, 2H). (m, 2H), (m, 311), 3 57-3 4N (m, ill), 3.41 (t..i 5 I Iiz, 211), I 9N (s, ( ompounds Prepared Similar to ('ompound ('-60: 311), 1.74 (d. J 9 5) I lz, 211) [1082J Oompnuad 0 . 't

Fom&at&on of (S)-3-[4-[4-(2-Anuno-6-methyl-py- I&ormation of 2-[4-[4-(2-Amino-6-nðyl-pyrimi- rtmidin-4-yl)-[1,4] oxazepan-3-yl]-3-chloro-phc- din-q-yl)-[1.4]oxazepan-g-yl]-3-chloro-phenoxy)- noxy)-propane-1,2-dial (6) ('otnpound ('-42 acetamide (8) Compound C-53 [1083J (S)-3-[1-[4-(2-An&mo-6-methyl-pyrimidin-4-yl)- [1085] 2-&4-[4-(2- sunino-6-methyl-pyrun&dtn-4-yl)-[1,4] [1.4]oxazepan-3-yl]-3-chlore-phenoxy)-propane-1.2-diol oxazepan-3-ylJ-3-chloro-phenoxy)-acetamide was affi&rded vvas afforded as &3 hite solid (51 mg. 63% yield). L('-MS as a white solid (2.8 mg. 4.8% yield) I (:-MS (M+I I)+ 392 US 20[9/032265[] A] Och 24, 2019 219

'H NMR (400 MHz„Methanol-ds) 6 8.49 (s. I H). 7.28 (d, 3.82-3.54 (m, 3H), 3.04 (s. 3lj). 2.09 (s, 3H), 1.98-1.87 (m, J=8.7 Hz. IH), 7.14 (d. J=2 6 Hz, IH), 6.97 (dd, J=8.7. 2 6 IH), 1.82 (d, J=14.9 Hz. IH). Chtral SFC purilicatton to Hz. IH), 6.22-5.19 (br s, 3H), 4.52 (s. 2H), 4.26 (dd, J=13 7, obtatn thc indtvtdunl mrdntiomcrs: Compounds C-64 and 5 I I lz. 111), 4 02 (d, .I 12 0 I is, 111). 3 82 (dd, .I i 3 7, 10 I C-65 I lz,. 211), 3.67 (t..l 11 I I lz, 111), 2 67 (s, 111)„2.20 (s, 311), 1.9(i-1.90 (m„2H)

(usx «do ttt.

I'orntation of 4-[3-(2-(1tloro-4-methylsujfanyl- methoxy-phenyl)-[1.4]oxazepan-4-yl]-ti-methyl- pyrnnidin-2-ylamtne (9) Compound C-105 [1086] 4-[3-(2-Chloro-4-methylsulfanylmethoxy-phenyl)- [1.4]oxazepan-4-yl]-6-ntethyl-pyrimidin-2-ylamine was ajlbrdcd ds ojl'lute sohd (25 mg, 6.1% ytcld). LC-MS (M+H); 393. 'H NMR (400 MHz, Methanol-ds) 6 7 22 (d, 1=8.7 ljz. IH), 7.08 (d. J=2 5 Hz, iH). 6.92 (dd. 1=8.7. 2 G I lz,. 111). tx02-5 32 (m, 311), 5.22 (s. 211), 4 26 (dd, I 13 6, 5.1 Hz, IH). 4.03 (dd. J=12.3, 4.7 Hz, IH), 3.74 (tld, J=13 6, 10.5 Hz„ IH), 3 63 (td. J=I2 2, 3.7 Hz, 2H). 2.22 (s, 3H), 2.09 (s, 3H). 1.93 (ddd. J=11.2. 5.2, 2.5 Hz. IH). 1.88-1.75 (m, 111)

OnaecusdC-tza

(S)-3-[4-[(S)-4-(2-Anuno-6-methyl-pyrimidin-d-yj)- [1,4]oxazepan-3-yl]-3-chloro-phenoxy)-propane-l. 2-diol (11) Compound C-64

I was Fomtation of 4-[3-(2-Chloro-4-methanesulfonyl- [1088[ he racemic mixntre (6) subntttted for SI'('urtfication: methoxy-phenyl)-[1.4]oxazepan-4-yl]-ti-methyl- Al j-I I 10x250 mm column using 5-60% MeOI I pyrimtdin-2-ylamine (10) Compound C-120 (0 5% IJMI bsr) gradient method over 5 min I.('-MS 'I [1087] 4-[3-(2-Chloro-4-methaneculfonylmethoxy-phe- (M+I I)+ 409. I NMI& (4(j0 Ml lz, l)MSO-d6) 6 7.18 (d, nyl)-[1.4]oxazepan-4-yl]-6-ntethyl-pyrimidin-2-ylamine .I 8.7 Ilz, HI). 7 03 (d, .I 2 5 llz, 111), 6.89 (dd, .I 8.7. 2 6 was ajlbrded as ojf whtte sohd (20 mg, 13% ytcld). LC-MS Hz. IH). 5.83 (s, 3H). 4.93 (d, J=5.1 Hz„ IH), 4 64 (t, J=G.G

(M+H) . 427 'H NMR (400 MHz, Mctlrdnol-d4) 6 7.29-7. Hz. IH). 4.09-3.95 (m. 2H), 3.93-3.82 (m, 2H). 3.81-3.GI 27 (m, 2H), 7.08 (d„ 1=8.9 Hz. IH). 6.00-5.29 (m. 3H), 5.21 (m, 3H), 3.57-3.48 (nt. IH). 3.41 (t. J=G.G Hz, 2H), 1.98 (s, (s, 21 I), 4 25 (dd, .I 13 6, 5 I I lz, 111), 4 12-3 95 (nt, 111), 311). 1.73 (s. 211). Retention time: 3 58 minutes US 20 ] 9/032265 [] A] Och 24, 2019 220

(S)-3-[4-[(R)-4-(2-Ammo-6-methyl-pyrimidin-4- 4-[(R)-3-(2-Chloro-4-ntethylsulfanylmethoxy-phe-

yl))-[I.4]oxazepan-3-yl]-3-citloro-phcnoxy}-pro- nyl)-[1,4]oxazcpan-4-yl]-6-methyl-pyrnntdin-2-

pane-1,2 thol (12) Compound C-65 ylammc (14) Compound C-122 [lt)89] 1he racenttc nttxture (6) was submitted for Sl'C [1091] I he racemic mixntre (9) was subntttted for SI'('uufication: purification AD-I I 10x250 mm colutnn using 5-titp/v MeOI I IA I I 4 Gxl00 mnt coluntn usmg 5-50% MeOI I (0.5% DMEA) gt'adtent tnethod over 5 ruin, LC-MS (0.5% DMEA) gradient ntethod for 5 mtn followed by 50% (M+H): 409. 'H NMR (400 MHz. DMSO-d6) 8 7.18 (d, MeOH (0.5% DluIEA) isocmtic method for 3 min. LC-MS J=8.7 Hz. IH), 7.03 (d. J=2 5 Hz, IH), 6.89 (dd, J=8.7. 2 6 (M+H) 395. 'H NMR (400 MHz, Mctiranol-ds) 8 7.21 (d, Hz. IH), 5.84 (s, 3H), 4.97 (s, IH). 4.G9 (s. IH), 4.05 (dd, J=8.6 Hz, IH). 7.07 (d, J=2.4 Hz. IH), 7.00-6.84 (m, IH), J=13.5. 5.0 Hz. I H), 3.99 (dt, J=10.0, 4.1 Hz, I H), 3.94-3.82 6.09-5.22 (m, 3H), 5.21 (s, 2H). 4.25 (dd, J=13.6, S.l Hz, (m, 211), 3.80-3 58 (nt, 311), 3 57-3 48 (m„ ill), 342 (d, 111) 4.03 (dd .I 12 s) 44 Ilz 111) 3 78-3 69 (m, III), 5.7 I la,. 211), I 98 (s, 311), 1.73 (s, 211). Retention time 3 70-3.57 (m, 211), 2 22 (d..l I 6 I lz, 311), 2 09 (s, 311), 1.93 4.1(i minutes. (dd. J=12.3. 4.1 Hz, IH). 1.87-1.74 (m. IH). Retention time: 334 munttes.

ts ot 0 zy iX 0 0

t ~a.- Da.- Al& 0 0 4-[(S)-3-(2-Cltioro-4-methylsulfanylmethoxy-phenyl)-[1,4]oxazcpmt-4-yl]-6-methyl-pynmtdut-2- ylamtnc (13) Compound C-121 The racemtc mtxturc was submittcxl lbr SFC [1090] (9) 4-[(S)-3-(2-Chloro-4-mctlranesullbnylmethoxy-phe- puniicauon. IA-H 4.6x100 nun column 5-50% McOH usutg nyl)-[1,4]oxazepan-4-yl]-6-methyl-pyrtnudin-2- (0 5% DMEA) gradient ntethod for 5 min followed by 50% ylamine (15) Contpound C-153 MeOI I (0.5% DMI:A) isocratic method for 3 min I C-MS (M+H)': 395. 'H NMR (400 MHz, Methanol-ds) 6 7 22 (d, [1092] The racemic mixture (10) was submttted for SFC 1=8.6 Hz. IH), 7.07 (d, J=2.1 Hz, IH). 6.92 (d. 1=8 4 Hz, punfication: IA-H 4.(ix250 nun colunm ustng 5-G0% MeOH I H). 6.07-543 (m, 3H), 5 21 (s, 2H). 4.25 (dd. J=13.6, 5 I (0.5% DMEA) gradtcnt method for 5 mtn Ibllow cxI by 50% Hz. IH), 4.12-3.98 (m, IH), 3.80-3.G9 (m. IH). 3.63 (dd, McOH (0.5% DMEA) tsocrauc method for 3 mut LC-MS J=13.9. 10.5 Hz, 2H), 2.22 (s, 3H). 2.09 (s. 3H), 2.02-1.87 (M+H) 427. 'H NMR (400 MHz. DMSO-ds) 6 7.32 (s, (m, ill), 1.82 (d, .I 130 Ilz. 111) Retention time 320 111),7 24 (d, J 8 8 iiz, 111). 7 09 (d,.i 8 711z, II I). 5 83 (br ntimttes s, 31 I), 5 34 (s, 21 I), 4 07 (d, 1 12 6 I is, II I), 3 s) I (d .I 13 3 US 20 ] 9/032265 [] A[ Oct. 24, 2019 221

Hz. IH), 3.77-3.60 (m, 2H). 3.52 (d. 1=14.3 Hz. IH), 3.05 [1094] Reagents: (a) NaSMe, MeOH. 0" C. to RT: (b) (s, 3H). 1.99 (s, 3H). 1.74 (br s, 2H). Rcienuon time 4 72 nBuLi, THF, —78'.. thmi DMF: (c) mCPBA, CH1('11: (d) Initio(i:s. i) 4 A mol swvcs. 2-Methyl-3-tributylstannanylmcthoxy- PiOPylamin. (81 ii) 2,6-1utidine, ('u(O'lfln. hexaflu- 4-[(R)-3-(2-Chlom-4-methanesulfonylmethoxy-phe- Cln: oioisOPrOPanO, ('lln( I,; (e) 2-nmino-4-chloro-6-methylPy- nyl)-[1„4]oxazepan-4-yl]-6-methyl-pyrimidin-2- rimidine. nBuOH, 135" (( ylaminc (16) Compound C-154 [1093] The racemic mixture (10) was submiued for SFC lionnation of purification IA-H 4.6x250 mm colunut usin 5-60% MeOH (4-broino-3-chlorobenzyl)(ntethyl)sulfane (17) (0.5% DMEA) gradient method I'or 5 nun followixl by 50% [1095] The I-bronto-4-(bromomethyl)-2-chloro-benzene McOH (0.5/c DMEA) wocratic method Ibr 3 min. LC-MS 'H (3.5 g, 12.3 mmol) tvas dissolved in MeOH (40 mfl in a 250 (M+H) . 427 NMR (400 MHz, DMSO-d&) 6 7.32 (s, ml round-bottomed flask equipped with an overhead stirrer, lil). 7 24 (d..l 8 6 I lz, ill, 7 17-703 (in, 110, 6 06-5 64 tcmpcrnture probe, mtd a 25 mL addition funnel. Thc solu- (m, 31 fl. 5 34 (s. 211), 4 07 (d..l 11 8 I Iz., 110, 3 ') I (6, tion was coo)cd io O'. in a brine bath. Thc NaSMe (2.1 1=12.7 Hz, IH), 3.77-3.43 (m. 3H), 3.05 (s. 3H). I 99 (s, g, 29 5 ntmol in 5 ntl MeOI solution was added dropwise at 3H). 1.74 (br s, 2H). Retention time: 5.38 minutes. 0 a mate to keep the temperature below 10" (2 A white solid ache&ac Synthcsn n(Cnnxpnnna C-63 precipitated. The solution tv as run for 24 h at rt. The reaction was poured into IN NaOH and extracted three times with dich)orometlnsne. The extracts v, ere combined, dried (MgSOn), Iiltcrcd mtd ci aporated in vacuo io afliird I-bromo-2-eh)ore-4-(mcthylsulfanylmethyl)bmtzcne (2.8 g. 86% yield) as a clear oil ' l NMR (300 Ml lz, CD('I,) 7.54 C (d,.l 82117, 110, 740 (s. 110, 707 (dd,.l 82. I 6117. 110, 3.59 (s, IH). 1.99 (s, 2H) 8 ppm lionttation of m 2-('hloroi hntethylsnlfanylmethyl-benzaldehyde (18) Ci To a stirred solution I-Bromo-2-chloro-4-meth- 37 [1096] of ylsulfanylmethyl-benzene (4800.00 mg; 19 08 mmol; 1.00 cq ) in THF (130.00 ml) nt — 78 C was added n-butyllitluum (8.40 ml; 20.99 numil, 1.10 cx).). lite reaction was stirred Ibr 30 min followed by addition of DMI'2.00 ml). Stirring, continued for addition 15 nein at —78 ('iillowed by stirring, 0 i.'I at rt for 3 h. The reaction mixture was poured into IN HCI is and extracted v, ith MTBE. The extmct was dried (M SOs), filtered and evaporated in vacuo to afliird crude product as a yellow oil. The product was purified using Bio(age system, 100 g column using 10-50'!c dichloromcthane/hcxtmc. Obtained 3000 ntg (76% yield) of desired compound I D- MS (M+I I)'01 0 Fonna(ion of 2-(.'hlom-4-methanesul fonylntethyl-benzaldehyde (19) [1097] To a stirred solution of 2-Clt)oro-4-methy)sulfany)- methyl-benzaldehyde (2000.00 mg: 9.97 nmtoh 1.00 eq.) in DCM (80.00 mfl v as added 3-chloropcroxybenimiic acid (3783.47 mg: 21.92 nunol, 2.20 eq.) at rt. After 15 mui s white solid prccipitnicd. After stirruig for I hour, thc reaction mixture tvas poured into saturated aqueous Nail('0, solution and extracted tvith dichloromethane I'he crude mixture was purified using Biotage system, 100 g column using 5-40%v AcOEt;DCM. Obtained 2000 mg (78% yield) of product. LC-MS (M+H): 233. Iiormation of 3-(2-( hlom-4-methanesulfonylmethyl-phenyfl-6-methyl-[1,4]oxazepane (20) 8 [1098] Tlus is a 2 step reaction. Stcpl. A mixture of 2-Chloro-4-mcihimcsulfonylmcthyl-benznldchydc (75 mg, 21 032 nunc), 1.00 cq.), 2-Methyl-3-tnbutylstaiuianyl- methoxy-propylamine (126 mg: 0.32 mmol; I 00 eq ) and 4 angstmm inolecular sieves in DCM (I ml) was stirred for 20 US 20]9/032265[] A] Oct. 24, 2019 222

hours. The mixture w as filtered and carried forward for next ylamine was agorded as a white solid (30 m, 30%n yield). reaction. Step 2. To a surrcd solut&on of copper(ii) trilluo- LC-MS (131+H): 437. 'H NMR (400 MHz, DMSO-dG) 6 romctluincsulfonatc (139.50 mg. 0.39 nunol, 1.50 cq ) in 7.52 (d, J=8.2 Hz, IH). 7.38 (d, J=2.2 Hz. IH), 7.32 (dd, 1,1.1,3,3.3-hexafluoro-2-pmpanol (4 ml) at rt was added .I 8 2, 2 I I lz. 111). 5.81 (s, 211). 5.33 (3, 211). 4.5C&-4.38 (m, 2,6-dimethylpyridine (0 04 nih 0 39 nunoh I 50 eq ). 1 he 311), 4 10 (dd..t 13 7. 4.6117„111), 4 01 (d, J 15.0117, 111), reaction mixture was stirred for 1.5 hours follow:ed by 3.85 (dd, J=13.4. 10.3 Hz. 2H). 3.09 (d, J=12.1 Hz. I H). 2.78 addition of [I-(2-Chloro-4-methanesulfonylmethyl-phenyl)- (s, 3H), 1.94 (s, 3H), 0.89 (d. J=22.3 Hz, IH), 0.57 (dt, meth-(E)-ylidene]-(3-tributylstannanylmethoxy-propyl)- J=9.3. 4.7 Hz, IH). 0.39 (ddt. 1=33.0. 9.5. 4.8 Hz, 2H). dnunc (195 mg, 0.32 nunol, 1.00 cq.). Thc resultmg reaction mixture was stirrixl at rt ovcrrught. Thc reaction m&xture is diluted ivith C'112('12. treated with a solution of 12% aq C mnnuud r'3 NI 1401 I and brine (I I), and stirred vigorously for 15 min at rt. The layers are separated and the aqueous layer is extracted ivith CH2C12. The combined organic layers are washed with H20 nnd brine, dried over anhydrous Nn2SO4, Iiltcrcd.;md conccntratcd. Puulicat&on by Biotagc systmn, 330 g column us&ng 10-40% AcOEt.DCM ibllowed by 5-20%u MeOJI DC:M Isolated 75 mg (51% yield) of title compound I I:-MS (M+II)+ 318

I'orniation of 4-[3-(2-(1&lorn-4-metJ&anesulfonylm- ethyl-phenyl)-6-methyl-[1,4]oxarepen-d-yl]-6- methyl-pyrimidin-2-ylamine (21) Compound C-63 [1099] To a mixture of 3-(2-Chloro-4-methaimsulfi&nylm- ethyl-phenyl)-6-methyl-[1,4]oxazepane (75.00 nm: 0 24 Fnrmation of 4-[3-(2-('hlnro-4-methanesulfonvlm- nimoh I.N) eq.) and 2-amino-4-chloro-C&-methylpyriniidine ethyl-phenyi)-6.G-dimethyl-[1.41oxazepan-4-yl1-G- (67.76 nig: 0.47 nunoh 2.00 eq.) was added I-bumnol (2.00 methyi-pyrimidin-2-ylamine (23) Compound C-73 ml). The reaction mixture was heated at 135 C for 16 hours. [1100] Next day LCMS was rimorded to conlimi the [1103] 4-[3-(2-Chloro-4-mctluincsulfonylmcthyl-phenyl)- completion ofthe reaction 1'he reaction mixture was loaded 6,6-dimethyl-[l 4]oxazepan-4-yl]-6-methyl-pyrimidux-2- as is on the Intershim prep system using Basic conditions, ylaniine &vas afforded as a ivhite sohd (50 nig, 50% yield) I I:-MS I)': 439. 'l l NMR Ml DMSO-d6) tS 10-90%n &3&cetonttrile:H20 to afford 44 mg (44% yield) c&f (M+I (400 lz, pure product. LC-MS (M+H): 425. 'H NMR (400 MHz, 7.50 (d. J=8.6 Hz. IH), 730 (d, J=2 0 Hz. 2H). 5.85 (s. IH), DMSO-d6) 8 7 50 (d. J=8.2 Hz, IH), 7.33 (d, J=2.1 Hz. IH), 5.14 (s. 2H). 4.44 (s, 2H), 4.04 (dd. J=13. 6, 4.9 Hz. I H). 3.60 730 (dd. J=8.2, 2.1 Hz, IH), 5.79 (s, 2H), 5.43 (s, IH), S.22 (dd. )=13.5. 11.1 Hz, IH), 3.48-338 (m„ IH). 3.32-3.22 (m, 2.7S 1.93 (s, IH), 4.51-4.38 (m, 2H), 4.03 (dd, J=13.6, 4.4 Hz, IH), 4H, overlaps with H20 peak). (s, 3H), (s. 3H), 0.88 1=43 Hz GH) 3 82 (6, .I 15.0 I lz. 111). 3 72-3 51 (m. 311). 2 76 (g 311), (d 2 07 (s, 211). I 323 (s, 311). 0 87 (d, .I 7 0 I lz. 311).

I'ompounds Prepared Simihur to (21): C mnnuud r'4 [1101]

Cnux&nuud C-62

Formation of 4-[3-(2-Chloro-4-methanesulfonylm- cthyl-phenyl)-6-ethyl-[ J.4]oxazcl&an-d-yl]-6-mcthyl- pynmulin-2-ylammc (24) Compound C-74 [1104] 4-[3-(2Cltloro-4-methanesulfonylmethyJ-phenyl)- Formation of 4-[7-(2-Chloro-4-methanesulfonylm- 6-ethyl-[ I 4]oxazepan-4-yl]-6-methyl-pyrimidin-2-ylamine ethyl-phenyl)-5-oxn-8-aza-spiro[2.6]non-g-yl]-C&- was allbrdixl as white soliii (40 mg, 40%v yield). LC-MS 439. IH NMR MHz, DMSO-d6) 8 7.50 niethyl-pyrimidin-2-ylamine (22) Compound C'-62 (M+H) (400 (d, J=8.2 Hz, IH), 7.33 (d. J=2.2 Hz, JH), 730 (dd, J=8.2, 2.2 [1102] 4-[7-(2-Chloro-4-methanesulfonylmethyl-phenyl)- I Iz. 111), 5.81 (s. 21 I). 5 18 (8 I I I), 4 50-4 38 (m. 211). 4.00 3-oxa-8-aza-spiro [2.6]non-8-yl]-6-methyl-pyrimidin-2- (dd. 1 13 6, 4 4 Hz„ ll I). 3 83-3 75 (m, 211), 3.69 (dd, US 20 [9/032265 [] A [ Oct. 24, 2019 223

1=13.6, 10.0 Hz„ IH). 3.54 (dd, J=I2.1, 2.8 Hz, IH), 3.33 (d, J=2.7 Hz, 3H, overlaps with H20 pmh). 2.7S (s, 3H), 1.92 (s, 3H). 1.40 (tih J=12 7, 7.4. 6.S Hz. IH), 1.29-1.14 (m, I i I). 0.88 (t, .I 7 4 I is. 311).

Cnzzxznuud C-11 NHz

~Hz

Formation ol'-[3-(2-Fluom-4-metlmncsulfonylm- clbyl-phenyl)-[1.4] oxazcptm-4-yl]-6-melhvl-pynmidin-2-ylamine (25) Compound ('-l i [1105J 4-[3-(2-11uoro-4-methanesulfonylmethyl-phenylj- [1.4]oxazepan-d-yl]-G-methyl-pyrimidin-2-yiamine was afi'orded as ivbite solid (15 mg, 44%a yield). LC-MS (M+H) 395. 'H NMR (400 MHz, DMSO-d„) 6 731-7.18 (m. 3H), 5.97 (s, 3H), 4.49 (s, 2H), 4 25-4.14 (m. IH), 3.96-3.90 (m, I H). 3.74 (t. J=12.0 Hz, IH), 3.63 (d. J=11.9 Hz, I H), 3.52 (td, J 11 7. 3 9 I lz, 111). 3 32 (s. 211. overlaps with 1120 gyxllz 2 2 I 77-1 peak). 92 (s, 311). 04 (s, 311). 69 (m. 211). N

Cnzzxznuud C-11

0 Formation of 4-[(R)-3-(2-Fluoro-4-methancsulfonyl- niethyl-phenyl)-[I 4Joxazepan-4-ylJ-6-niethyl-py- 0 rimidin-2-ylamine (27) ('onipound ('-49 [1107] The raccmic mixture (25) was submiucd for SFC purzfication: IC 4 Gxlt)0 mni colunln usmg 5-60% MeOI I (0 5% DMIIA) gnsdient method for 5 niin followed by 5(yfiz MeOH (0.5% D81EA) isocmstic method for 3 min. LC-MS 'H (M+H) . 39S. NMR (400 MHz. DMSO-d„) 6 7.31-7.18 (m, 3H), 5.97 (s, 3H). 449 (s. 2H), 4.2S-4.14 (m, IH), 3.96-3.90 (m, IH), 3.74 (I, J=12.0 Hz, IH), 3.63 (d. J=11.9 Hz. IH), 3.52 (td, 1=11.7, 3.9 Hz. IH), 3.32 (s, 2H, overlaps Formation of 4-[3-(2-Chloro-S-methancsullhnylm- with 1120 peak). 2 92 (s, 3H). 2 04 (s, 311), I 77-1 69 (m, ethyl-phenyl)-[1.4J oxazepan-4-ylJ-6-methyl-pyrinu- 211). Retention time: 5.06 minutes dm-2-ylamine (26) ('ompouod ('-] 2 Fomiation ol'-[(S)-3-(2-Fluoro-4-mclhancsul fonyl- [1106] 4-[3-(2-Chloro-S-methancsullonylmcthyl-phenyl)-

mclhyl-phenyl)- [ I 4] oxa zap an-4-yl] -6-methyl-py-

[1.4]oxazepan-4-yl]-G-methyl-pyrinudin-2-ylaznine was rimidin-2-ylamine (27) ('ompound ('-50 afforded as v hite solid (55 mg, 54% yield) I,('-MS (M+I Ij 411 'll NMR (400 Mllz, DMSO-d6) 6 7 5] (d, .I 8.1 Ilz, [1108] The racemic mixture (25) was submitted for SI'('unfication: IH), 7.36 (d„J=2.1 Hz. IH), 7.32 (dd, J=8.2, 2.1 Hz. IH), IC 4.6xl00 nun colunm using 5-G0% MeOH 5.66 (d. J=144.9 Hz. 3H). 4.55-439 (m, 2H). 4.15 (dd, (0.5% DMEA) gradient niethod for 5 min folhiwed by 50% J=13.4. 5.0 Hz. I H), 3.92 (dt, J=12.2, 3. 8 Hz, I H), 3.72-3.48 McOH (0.5% DMEA) isocrauc method for 3 mui LC-MS (m, 3H). 3.33 (s, 2H, overlap with H20 peak). 2.83 (s, 3H), (M+H) 395. 'H NMR (400 MHz, DMSO-ds) 6 7.31-7.18 1.99 (s. 3H). 1.77 (ib J=3.7 Hz, 2H). Chiral SFC puulicalion (m, 3H), 5.97 (s, 3H). 449 (s. 2H), 4.2S-4.14 (m, IH), to obtain the individual enantiomers ('oinpounds C-49 and 3 96-3.90 (m, III), 3 74 (t, I 12 0 llz, 111), 3.63 (d, .I 11 9 ('-50 I lz. 111), 3 52 (td..f 11 7, 3 911z,. 111), 3.32 (s, 211. overlaps US 20]9/032265[] A] Oct. 24, 2019 224

with H20 peak)„2.92 (s, 3H). 2.04 (s. 3H). 1.77-1.69 (m, MeOH (0.5% DMEA) yndient method for 5 min followed 2H). Rcicntion umc 5.SO nunuies. by S0% Mcq)H (0.5%a DMEA) isocratic method for 3 min.

LC-MS (M+H) . 411. 'H NMR (400 MHz, DMSO-dG) b 7 51 (d, .I 8 I I lz, I i I). 7 36 (d, J 2 I I lz. 111), 7 32 (dd, Ci .I 8 2, 2 I I is, ll I). 5 6(i (d. J 144 i) I is. 311). 4.55-4 3i) (m, 0 2H). 4.15 (dd, i=13.4, RO Hz, IH). 3.92 (dt. J=12.2. 3.8 Hz, IH). 3 72-3.48 (m, 3H), 3.33 (s, 2H. overlap with H20 peal ). 2.83 (s. 3H), 1.99 (s. 3H)„1.77 (q, J=3.7 Hz. 2H). 0 Rctcntion time. 2.77 nunutcs. S=o I:xample 58

Colo 205 Reporter Assay

[I I I IJ the compounds of the invention described herein v ere screened using the assay procedure for [I-cateninrf(:Iu mediated reporter transcription activity described below. Ct [1112J in cells with activated WN1 signabng, we have found that induction of ER Stress by the mechanism ofthese compounds results in a rapid reduction in the activity of this reporter gene and that the activity in the assay correlates with thc activity of thcsc compounds as uiducers of ER s=o Stress and thc UPR, mtd all other mcasurcs of speciiic activity of these compounds, including calcimn release, viability, and displacentent of radiolabeled version of these compounds from their specific binding site in cells. [1113J Reporter cell lines were generated by stably trans- fecting cells of cancer cell lines (e.g . colon cancer) with a plasmid reporter construct (From SABiosciences, a QIA- 29 CIEN company) that includes TCF/LEF pmmoter driving Ci expression of the firefly lucifemase ene. TCF/LEF reporter constructs werc made ut winch TCF/LEF promoter, a promoter with optimal number ol'CF/LEF binding sites designed by SABiosceinces, was linked upstreain of the firefly luciferase gene 'I'bis constnict could also include a puromycin resistance gene as a selectable marker. Tlfis constnict could also be used to stably transfect Colo 205 cells, a colon cancer cell line having a mutated APC gene that cmiscs a consmutively active [I-ca(caus. A control cell lute was gcncratcd using another plmmid construct containing the luciferase gene tuider the control of a ('Mxy basal which is not activated i-catemn us pmmoter by $ [1114] Colo 20S Cultured cells with a stably tramli:ctcd reporter construct were plated at approxintately 10,000 cells per well into 384 well nnilti-v ell plates for twenty four 4-[(R)-3-(2-Cltloro-5-methanesulfonylmethyl-phe- hours The testing compounds were then added to the wells nyl)-[1,4]oxazcpau-4-yl]-6-methyl-pynnudut-2- in 2-fold seriai dilutions using a nventy micromolar top ylaminc Compound C-51 (29) concentration. A scncs ol'ontrol wells I'or each cell type [1109J 'I'he macemic mixture (26) was submitted for SliC reccivcd only compound solvent. Five hours aficr thc addi- purification OD-H 4 6x100 mm column using 5-60% tion of compound, rcportcr activity for lucifcrasc was MeOH (0.5% DMEA) gradient method for 5 min followed assayed, by addition ofthe Steady(ilo luntmescence reagent by 50% MeOH (0.5%v DMEA) isocratic method for 3 min. (Pi'otlleg:I) ltm reporter Iululnescellce activity was lllei- LC-MS (M+H) 411. 'H NMR (400 MHz, DMSO-d6) 6 sured using Pherastar phate reader (BMCI Labtech). Read- 7.51 (il, J=8.1 Hz, IH). 7.36 (d, J=2.1 Hz. IH), 7.32 (dd, ings were normalized to DMSO only treated cells, and R2. 2 I I lz. 111), 5 66 (d, .I 144 9 I lz, 311). 4 55 4 3') (ill, normalized activities acre thmt used in thc IC50 calcula- 2il). 4 15 (dd, .I 13 4, 5 011z, 111), 3 92 (dt,.l 12 2. 38 1lz„ tions. The Colo 205 rcportcr assay data are stunmarizcd in IH). 3.72-3 48 (m„3H). 3.33 (s, 2H. overkap with H20 Table 3. A&0.3 ItM, 0.3 uM«B&1 0 PM, 1.0 PMuuC&5.0 peak). 2.83 (s. 3H). I 99 (s, 3H). 1.77 (q, J=3.7 Hz. 2H). RM: De5 0 PM Retention time: 2 37 minutes. 4-[(R)-3-(2-('hiero-5-methanesulfonylmethyl-phe- Hepfi2 XBPI Reporter Assay nyl)-[1,4Joxazepan-4-ylJ-(i-methyl-pyrimidin-2- [1115] HcpO2 hepatoma cells werc transduced with a C-52 ylamine (30) Compound retrovirus cncodutg thc cDNA for unsphced (u) XBPI, [1110] I'he racemic mixture (26) was submitted for SliC which contains a non-processed intron, fused to the cl)NA purification OD-I I 4 6x100 nun column using 5-60% for hrefiy luciferase Upon induction of IIR stress. the US 2019/032265[[ A[ Oct. 24, 2019 225

non-processed intron of XBPI(u) is spliced out by active TABLE 3-conunucd IREI alpha cndouuclease. The rcsultm sphced (s) XBPI ls now ul franu: with luclgecasc wluch causes thc production of Col &5 Cal uuu I'lux XBPI lu active luciferase protein, resulting in binluminescence Colo205 :&asar 384« Boatou C:I Hcpo I Coutpo&utd 4 IC50 assay FLIPMS (olo F(50 BC 0 [11161 HepO2 XBPI (u)-Luc cells were pla&cd Colo 205 Cuhurn! cells with a a&ably &remit:etc&1 reporter construct I 25 127 were plated at approx&mately 30.(100 cells &veil into ')6 per I 'll well nnllti-well plates for twenty four hnurs The testing I 'I compounds &vere then added to the wells in 3-fold senal I '&6 B dilutions using 0 twenty seven micromolar top concentm- 107 B 1-40 uon. A scn ca of control wells lbr each cell received unly type 1-46 B compound solvmlt. Slx hours aller dlc addition nf cum- 1-47 B pound. reporter actlvny for luciferase was assayed, by I 'Itl n addition nf the Steady(ilo luminescence reagent (Prnmega). I 51 I A 'I'I 'I'he repnrter luminescence activity was lneasured usiag I I 59 I Pherastar plate reader (BMCi Labtech). Readings was nor- I 62 B A malized to DMSO only treated cells. and nomtalized activi- I O'I B ties were then used in the IC50 calculations. The Hepfi2 I 66 C XBPI reporter assay data are summarized m Tables 3-S I 68 B 1-69 B A&0.6 PM; 0 6 BMBB&2.0 PM. 2.0 PMBC &S.O PMI D S 0 1-70 B uM 1-71 1-7 B Calciunt Flux Assav I 74 A I 79 I 82 [1117[ ('onlpounds described herein induced I IR stress by I 84 causing intracellular calcium tiux. Calcium tlux w:as mea- 185 B sured in Colo-205 cells using the FI IPRg Calcium 5 Assay I 87 Kit according to manufacter's protocol (Molecular Devices, I 88 B 1-90 Can 4 RSIS6) ou a FLIPR3 system (Molanular Devmcs). B 1-9 A Calcium ilux is measured over 36 nunules. The Colo-205 1-93 B calcium tlux assay data ale summarized in 'i'able 3 A&0 6 1-97 B BM: 0.6 BMxii&2 0 PM, 2 0 RMxC&10.0 PM; Hei 0 0 FM. I 98 I 99 I 101 A Cell Culture Methods I It&6 I 1 07 [111gj Cells were rcmovaxl Irom Equal nilrogen storage, I 1&&8 thayved and expanded in appropriate growth media Once I 110 B expanded. cells &vere seeded in 3gt-well tissue culture IIH B At'ter 1-113 B treated pLates at 500 cells per well. 24 hours. cells were 1-114 B treated for either 0 hours or treated for 96 hours with a 1-118 B 1-1 testing compound (at the concentmstions of 100 nM and 2 1 7 B uM). Al lhc end of ellhcr 0 hours or 96 hours. cell slalus was I I it& I 119 arutlyzed using ATPLltc (Pcrkul Elmer) ln assess the bio- 12 'I'he I logical response of cells to the testing compnund. K'50 I 123 data in N('1-1192') (Multiple myelolna cells) and Dl)4475 1 124 11 6 B (breast cancer cells) are smumarized in Tables 4 and 5 A&1 1 127 PM: I RM«B&10.0 BM: 10.0 PM«C 25.0 RM: Do25.0 BM. 1-1 B 1-13 B TABI E 3 1-133 B 1-134 B I IW I 138 A ('ul 205 . y 384 B .Io &1 H p(3 I C mpomd a I&' .ya.y N IPR3 (' t&' H'I I I 39 I 140 A 1-3 A 1 141 14 B I 144 B 1-5 B 1 146 B A 1 147 16 )3 ('' I-14tl 111 A I.l B I 14 1-161 B 116 B B 1-163 B 117 B B A I 157 110 1158 I X) B B B I 159 A 1-21 B B C I 161 I 16 1-2'-'." B B B O I-16tl B US 2019/0322658 A1 OCL 24, 2019 226

TABLE 3-connnt)cd TABLE 3-cont)nucd

Coin 0( Cllcnlrn Flux XBP) lu Col (( Cal nun I'lux XBP) lu Colo u (a(ay xt!4 Bo.ton Ca Hcpol I Colo205 :la(ay 384m Bnaton C:l Hcpo I Cmnpnund 4 ICGD :laa:lc FLIPIL) Cnlo ECGD EC. 0 Colllpotuld 6 IC(t) au(ay FLIPR) Coin EC(0 EC 0

I 17tl I 26 1 171 C B I 263 117 B C I 65 1171 B B I 266 1 174 B B I 67 I-ly( A I-26tl A A 1-176 B B I- 71 B A 1-177 A 1-27 B B 1-178 A I- 73 A I 179 I 274 D 1181 A A I 27. A I 183 )3 I 277 I 184 13 A (' I 278 A A I 18 B I 79 I 186 I 28u B I 188 B I 81 B B I 100 I 282 B B 1-191 B B I- 84 B 1-192 B 1-28 B 1-193 A I- 86 B 1-19( A 1-287 B D I 197 13 A I 288 A (. I 199 )3 13 I 289 tl) 13 A I 290 I B) B B D I 91 B I 04 I 292 B I B) B I 93 B I 07 I 294 B 1-208 A I- 9 B A B 1-214 B C I 97 B A 1-21( A I 298 ( 1-216 A I 299 n 17 A A IDD(l B A B I 218 I 'lilt 19 13 A I 'lt(2 ti I lt(3 A I I ID 04 B B I B B )DO B I 4 I 'lf)6 B I B B 1-2" 6 B I lt(7 1-2', B B I lt(8 1-2" 8 B IDD9 A 1-229 B ti )3 31 A TABLE 4 A n I B C mpound 6 XBP) HC (Ol H9 9 (IC(0) DU447( HC(tlt 3 I 16 C-I A A A I-'37 A C B 13 1-2'8 A (' )3 )3 I-'39 B (un B 13 1-240 A (' l I 241 C 6 B B A 42 A C7 B B B )3 C 8 B 46 A Cn B I 47 C. I u C I 48 C-11 B A A I 40 C-I B B A I 0 C 13 13 1-2(1 A B ('4 )3 )3 I- A C I B ('-2(4 A ('6 l I- (( A C 17 D D 6 A C 18 C B B I 257 )3 C 19 B B A C 2(l A 1 259 C- A A A I 26tl C- D D 1-261 A C- 3 A A US 2019/0322658 A1 OcL 24, 2019 227

TABLE 4-contin(fcd TABLE 4-continued

Cmnp und 8 XBPI IIC(01 Hy ) HCO(t) DC4475 HC(ttl C mpound 9 XBPI )IC 501 H9 9 (IC 501 DU447( HC(tlt

('4 ('9 13 If)fl (''6 A ('fn(I ('3 C 7 B C ltt B C 28 B C lf)t C 9 A C lt)4 D C 3) B B B C 1)) Cn I A B A C-lt)6 C-32 C-lt)7 C-33 B B C-1))8 C-34 D B B C-It)9 ('' (' lt) A A C ill (' ('12 13 (' (' n C ill C 39 B C 114 D CA( A B C ll CA I A C C 116 CA2 B C 117 C-43 C-118 C-44 B C-119 A C-45 B C-I (1 A C-46 C C-l I D (O47 C I (u48 (' 13 (uny C I C 5) C 12 B C 51 C 126 B C 5 B C 127 C C 53 C 128 B C- 4 C-I 9 D C.5 B C-130 B C- 6 C C-I 31 B C.5, B C-132 (' 13( ('9 ('14C ('0 C 135 ('1 ('I 6 C 62 D C 137 C 63 D C 138 C 64 C C 139 D C 65 C 140 C-66 C-141 C-67 C-142 C-68 C 14t B c-69 ('(l ('4C 144 B ('1 (' C-146 (' C-147 C 148 C 74 C 149 (' C 75 (I I fl C 76 C-151 A A C-77 B C-78 C 15 A A C-79 D C 151 A A C-80 ('14 ('1 C-I 5 D ('2 (' ('4 C 85 A TABLE 5 C 86 D C 87 B 1 oft)pot))f6 4 XBPI f!Ctoi H929 (IC5)t) C 88 C c-89 B I& I B D C.yo A D 2 C-91 B 13 '4 B D c-92 D (' A D B B ('4 D6 B B ('5 A D7 B ('6 D-8 B D ('7 D-9 A c-98 A D-I O A US 2019/0322658 A1 OCL 24, 2019 228

TABLE 5-conllmmd TABLE &-con(toned

Comp uud4 XBPI (IC(03 B9 9 (IC(ul I utltputtt)6 5 XBPI l!C(0) H&29 (IC(o)

D 11 ( ('i I& PG D 12 H D 87 D D 13 li D I& 8,8 (' D 14 A D 89 D I D 9LI D 16 B D 91 D 17 B B D9 B D-18 B B D-93 D-19 B B D-94 C D-20 A A D-9 B D-21 A B D-96 B D 2- D -. A D D 98 D 24 D I& 99 D 25 A D D lt)0 B D 6 D IL)1 D 7 C D 102 D D 8 D IL)3 C D 9 n D 104 D-30 A A D-ID D-31 A A D-IO( D-32 B D-ID7 B D-33 C D-I OG C D 34 A D lt)9 D. ( (' D 110 D 36 A D 111 D 37 B D ll D 38 D 113 B D lo B D 114 D D 40 D 11( B D-41 A D-116 D-42 B D-117 D-43 B B D-118 B D-44 B D-119 D 45 A D 120 D 46 I& 121 D D 47 H D 12 D 48 li D 123 (' D 49 D 124 D 0 D I D I D IPG D D I 7 D-53 C D-12tl D-54 A B D-I D D-55 A A D-13u D D-56 D C D-I) I D D 57 I& I" D A D I'» D 59 D 134 D D 6) A li D I'» D D 61 B D 136 D6 C D I')7 D 63 D 138 D D-64 B D-13& B D-65 A D-140 D D-66 C D-141 D B D-67 B D-14 D A D 68 I& 143 D D D 69 H D 144 D D D 7t) ( I& 14 D D D 71 A D 146 D D D7 B D 147 D73 B D 148 D 74 D 149 D7 D I D- 6 A D-151 D-7 B D-I D D D- 8 A D-153 D D D-79 B D-I 4 D D D 8) A D I» D D D 81 I& 156 D D 82 H D 157 D D D 83 I& 158 D D D 84 li I& 159 D D D-85 B D-16u D US 20]9/032265[] A[ Oct. 24, 2019 229

TABLE 5-conttmmd conthnaxl

Comp uude xBp1 Hcso) H9 &9 HCsul

D 161 D u-Buteuoj lr 13 16 D 118', 14 D16 D D 164 D D 166 D D 166 D D 167 D D-168 D XH D-169 D D-I 9 D D-171 D D 17 D 13 17 D D 174 D 13 17 D D 176 D D 177 D D 178 D D 179 D D-Iso D D-181 D I 66 D-182 D NHI D-183 D 13 184 D D 186 D 13 186 D D 187 D I D 188 D D 189 D D 19( D D-191 D D-192 D-193 SO M

Itxample 59 NI II [1119] Synthcttc ol'+I — )-4-(3-(2-chloro-4-(mcthylsulfonyl)phenyl)-1.4-oxazepan-4-yl)-6-methylpyrimidin-2- amine (I-6(i)„and (R)-4-(3-(2-chloro-4-(methylsulfonyl) phenyl)-1.4-oxazepan-4-yl)-G-methylpyrimidin-2-qmine (1-67) and (S)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-1, 4-oxuzcpan-4-yl)-6-mcthylpynmnhn-2-annnc (1-6g)

I:O.H peek B

m IS m I, 6O', 14 8 Mos Cl Formation of methyl 2-chloro-4-mcthylsulfonyl-benzoate

THF u It:umjo is 11 [1120] A 5 L 3-neck RB flask wtth ovcrhcad surrcr, temperature probe, reflux condenser and additional funnel V«O s Cl was clmrged 2-chloro-4-methylsulfonylbenzoic acid (I(X) g„ 426 2 mmoi) in methanol (1.5 L), sttrred for 10 minutes and then cooled to 0" C. with an ice bath Thionyl chloride COIOH (40 Muo i7equvj mL, 54S.4 nunol) was added over 20 mtnutcs, allowed to ambient tcmpcrature over I h mtd thmt Banned to GO'.. c.ui'0, 46' sttrrcd at tlus tcmperaturc for 12 h (ovcrntght) at wluch iimc MeOIS ('I I.(:MS and I IVI ('-analysis revealed consuntption of the starting material. ('HO [1121] HPLC shows starting material I peak retention Sunp 1euseut 0 equ v ) I'u(0 I 0 It eqiuvj time at 1.23 minutes. desired product 2 peak retention time 41 2.37 nunolcs. 2,6-luudure tl 2 cquoj C [1122] Reaction nuxturc was cooled to ambmnt temperature, conccntratcd under reduced prcssure, thc crude nmie- rial was partitioned between ethyl acetate (I I,) and aqueous sat Nal ICOs solution (500 ml.), stirred for 20 mimttes and US 20]9/032265[] A] Oct. 24, 2019 230 then organic phase was separated. Aqueous layer was Formation of 2-chloro-methylsulfonylphenyl cxtractcd with ethyl acetate (500 mL), combined or Bnic ilxaLCpiuli: werc washed with water, (100 mL), bnnc (100 mL), phase 'I'o dried over Na,SOB filtered and concentmnted under reduced [1132] a solution of 3-(tributylstannylmethoxyjpnipan- I-amine I pressure to atTord nlethyl 2-chloro-4-methylsulfonyl-benzo- (70 g, 185 mmol) in anhydrous dichkiromethane (1.4 was added 2-cltioro-4-mcthylsulfonyl-bcnzaldchydc ate (106 g. 99'/v) as a white solid. IH-NMR conform to L) 182.9 mmol) followed 4 angstrom molecular structure. (40 g, by sieves (130 g). The mixture was stirred for 12 h at which [1123J Ill NMR (400 Ml lz, ('D( 13) 8 8.04 (d..l I 6 I lz, time IH-NMR of the aliquot revealed consumption of the IH). 8.00-7.93 (m, IH). 7.88 (dd, J=N.I. 1.8 Hz. IH), 3.98 starting materials. (s, 3H). 3.08 (s, 3H) [1133] 111 NMR (300 Ml iz. ('1)(13) 6 8 72 (d, .I 0.5 Iiz, 111), 8.23 (d, .I N.2 I lz, Ill). 7.97 (d. 1 I 6 I lz. I II). 7.83 liormation of (ddd, J=8.2, 1.8, 0.7 Hz, IH). 3.89-3.63 (m, 4H), 3.40 (k (2-chlom-4-nlethylsulfonyl-phenyl)methanol J=6.1 Hz, 2H), 3.07 (s, 3H). 1.96 (p, J=6.7 Hz, 2H), 1.70-139 (m. 8H), 1.40-1.19 (nl. 6H). 0.98-0.77 (m, 15H). 5 I, 3-neck RI3 flask with overhead stirrer, [1124J A [1134] The reaction nuxturc was Iiltcrcd tluough cchtc tenlpemture probe and reflux condenser was charged nlethyl bed, bed ives washed with dichlommethane (1.5 L). In B 2-chloro-4-methylsulfonyl-beninlatc 9 (110 g, 437. nunol) in separate flask containing hexafluoroisopropanol (700 mL) B mixture ofTHF (1.3 L) and methanol (4SO mL), stirred for v as added 2,6-1utidine (25 nil.. 215 8 mmol) fiillowed by 10 minutes and then cooled to 0" C. with an ice bath. NBBHB ('u(OTI), (70 g, I')3.5 nlmol) [('u(O'I f)B was dned under (85 2.247 mol) v as added in four portion over 30 minutes. g. rcduccd prcssure Ibr 8 h at 100'.]. The blue suspension After the addition cooling hath was removed and allowed to was stirred for I h, then thc uninc solution (product 3) ambient tentpemsture (observed exothenn„ 1'max 50" (', 50' prepared above was added in one portion. The green reaction surrixi at this temperaturc (40 to ) for 4 h at w luch time mixture was stirred at room temperature. TLC. and HPLC-analysis rcvcalcxI consumption ofthc start- overnight ing material. [1135] LCMS shows small peak corresponding to desired pmduct Rl'-IN mimites (M+II) 289 95 'I'he mixture IIPI C shows starung material I retention [1125J peak v as diluted with I 7 I, of 2 I aqueous saturated Nell('Ol time at 2.47 nlinutes. desired product 3 peak retention time solution and 10/o imunonium hydroxide. After stirnng Ior Bt 148 minutes. TLC (50/o ethyl acetate in Heptane) shows 30 nllnllti:s. thc orginllc phascw Bs si:piirati:il, washcil twice RI'=O.S startulg material mid product R1%) 4. v ith aqueous saturated NaHCO., solution (2x200 mL). brine [1126[ The reaction mixture was cooled to ambient tem- (-200 mL). dried over NalSOC filtered and concentrated perature, quenched with slov: addition of methanol (100 under reduced pressure nil.). follolved by aqueous I N I I('I solution (-I I ) until pi I [1136] The residue was diluted w ith acetonitnle (600 mL), —7 to 8. The rcacuon nuxturc was ex)meted with ethyl washed with heptane (4x 100 mi,) to remove stannane impu- acctatc (2x500 mL). The combined orgaruc phase was rities Acetonitrile phase (bottom layer) was evaporated ivashed with brine (-300 mL), dried over NB,SOC filtered under reduced prcssure to Bflbrd yellow solid wluch was and concentrated under reduced pressure to aflord (2-chloro- tnturatcd with MTBE (400 mL), Iiltcrcd through mednun 4-methylsulfionyl-phenyl)methanol (90 g, 92%) as a wlute fritted funneL rinsed with MTBE (100 mL) to afford desired solid 111-NMR confornl to stnlcture. product 4 (28 . 52"/v yield) as a yellow solid. IH-NMR and [1127] IH NMR (400 MHB, CDCI3) 6 7.92 (d, J=1.8 Hz, I.CMS confomi to stmcture. 111 NMR (400 Mliz. 1)MSO) IH). 7.85 (dd. J=8 1„1 8 Hz. IH), 7.78 (d. J=8.1 Hz. IH), ij 7 96-7.92 (m, III), 7 92-7 N3 (m. 211). 4 31 (dd..l 8 7, 3 3 4.87 (d. J=5 9 Hz, 2H). 3.06 (s. 3H). Hz, IH). 3.94-3.78 (m. 2H), 3.78-3.62 (m, IH), 3.3G-3.28 3.2G 3.18-3.04 IH), 3.00-2.82 2H), [1128J 'I'his material was taken into the next step v ithout (m, 2H), (s, 3H), (m, (m, further punlication. 1.98-1.71 (m, 2H). ESI-MS n)/z cele. 289.05396. found 290 I (M+I) . Retention time; 0.49 minutes. liormation of [1137] Filtrate was concentrated under reduced pressure to atTord bght brown oil lvhich was purihed silica 2-chloro-4-nlethylsulfonyl-benzaldehyde by gel cluomatography (330 B isco column linear gradient. 20 ( ld 0'/o 100/o ethyl acmate which contain I'/o EI,N,'CHBCIB), [1129] A 5 L 3-neck RB flask ivith overhead stirrer, tenlpemture probe and reflux condenser ives charged fractions wluch contained desired product were collcctixk concentrated under reduced pressure, followed by trituration (2-chloro-1-methylsulfonyl-phenyl)methanol (')6 8, 435 0 with MTBE (-100 mL) to afford desired product 4 (5.8 as nunol) in CHCI, (2.S L), surrcd for IS mimues and then g) a yellow solid III-NMR conform to structure added Manganese dioxide (250 g. 2.876 mol). lite resulting reaction mixture was warmed to 45" C, (exotherm Tmnx 50" C.), stirred at this tempemuture for 3 h at which tiine Fornlation of I-(i(i 'I'I.C-analysis revealed consunlption of the starting, matenal. [1138] A 2 L 3-neck RB flask with ovcrhcad surrcr, 'll.('50"/ I itOAc/heptane) shows no more starting nlatenal (RI'=0.2). tcmperaturc probe, reflux condmlser and nitrogml ullet was charged 3-(2-chloro-4-methylsulfonyl-phenyl)-1,4-ox- [1130] The reaction mixture was filtered through cehte azepane (28 g, 92.7G nunol) in n-BuOH (550 mL). stirred for bed, bed ilas washed with DCM (3x100 mL). combined 15 nlinutes and then added 4-chloro-6-methyl-pyrimidin-2- filtrates were concentrated under reduced pressure to afford amine (17 g, 118 4 mmol) 'I'he resulting reaction mixture 2-chlom-4-methylsulfonyl-benzaldehyde (82 5 8,. 86'/) as a was wamlcd to 118'., surrixi at tlus tempcraturc for 14 h wlnte solid. IH-NMR conform to structure. (ovcnught), at winch time HPLC and LCMS mlalysis [1131] I H NMR (400 MHz, CDC13) o 10.54 (d. J=0.8 Hz, revealed consumption of the starting matenal. The reaction IH), 8.13-8.09 (m, IH). 8 07 (d, J=1.7 Hz. IH). 7.95 (ddd, mixture was cooled to ambient temperature (observed pre- Rl. 1.7, 0.8 Iiz, 111). 3 I I (s, 311) cipitationj, diluted lvith Ml i3E (5(X) nil.) stirred for 30 US 20 ] 9/032265 [] A] Oct. 24, 2019 231

minutes svhite precipitate was formed which was filtered Example 60 tluough medium fritted funneL rinsed with MTBE (2x100 1311 .) Synthethis of 3-chloro-6.7-ddiydro-l,4-oxazepine-4 [1139] The precipitate (HCI salt of product 3) was parti- (5H)-carbaldehydc tioned betsveen ethyl acetate (500 mi ) and aqueous sat. [1148] Nal I('Os solution (-7(X) ml ). stirred for 30 minutes (pll —8). Iilgaiiic pllasi: was si:patri(oil. Aqueous pllBSC wits cxtractcil with ethyl acctatc (2x100 mL)e combined orgiuuc phase was washed with brine (-100 mL). dried over NB2SOo, filtered and concentrated under reduced pressure. THF H 0 0 I ) it 14 li [1140] The residue v as purified by trituration with 10% ethyl acetate in MTBE (500 mL) to aflord 4-[3-(2-chloro- 4-methylsulfimyl-phenyl)-1.4-oxazepanq-ylJ-(i-methyl-pyrimidin-2-an)inc (32 g. 86%) as a white solid. I I I-NMR and LCMS conform to structure. IH NMR (400 MHz, DMSO) 6 7.96 (d, J=1.7 Hz, IH), 7.82 (dd, J=8.2, 1.8 Hz, IH). 7.58 1=8.6 (d. J=8.2 Hz, IH). 5.69 (d, Hz, IH), 5.(il (dd. J=9 7, 6.1 ~ iOH IS equ i ) 4.6 Hz. IH). 5.46 (s. 2H), 4 52 (d. J=15.6 Hz, IH). 4.16 (dd, io Iu cue, 6()" C . 14 Ii I 13 5. 4 9 I lz. 111). 3 92 (dt, .I 12 0. 38 I le, ] I I). 385-3 69 SO('I Oi 6 equ ) (m, 211), 3 66-3 53 (m, 111). 3 23 (s, 311), 2.05 (5, 311), 1.88-1.76 (m. 2H). ESI-MS miz cele. 396.1023, found 397 I OH iiio2ii" (N14h (M+I) . Rctenuon time. 0 55 mimites.

Formation of 1-67 and 1-68 0

8 t.'Oi, t2 cqiu ) [1141] 1-66 (66 g, 166.3 nunol) was scparatixl via SFC 13 using AD-H column with 30% McOH and 0.2% anmionia. 0 methunl. 6U''. 2 h [1142] Peak B obtained by SFC is destrusi enantiomer (S-conformer) which was dissolved in (:112C12 (I I,), washed with aqueous sat Nail( solution (2x200 nil,), 0 Oi POCI. i'I equ i) + DMI (6 equ i) water (30 niL), bnne (100 mL). dried over Na2SO4. filtered ni was vvashed with — through silica-gel bed (-80 g). bed DCM HN POC1,12 I cquiv) DMF t4 cqiu ) (60 mL). Combined filtrates were concentrated under 0 CH ('Ii. 0 io 43" resluccd prcssure to alford desired product as an amorphous ma)anal — 32 g, which was dissolved ui ethyl acetate (200 nil.). concentrated under reduced pressure 1'his niatenal was triturated with M'1131: (2x200 ml 1 to atford white solid, followed by azeotropped with ethyl acetate (200 mL). and ('ieoiia

I:I mixture of ethyl acetate and heptane (2x200 mL), dried 5 in vacuum oven at 50" C. for 14 h to aflord desired product FHs,itfni 161i wluch contained residual solvent ethyl aceIate —4.6% by moles. which was further dried ui vacuum oven at 70' for 14 8 ui afilord 4-[(38)-3-(2-chion)-4-methylsulfonyl-phenyl)-1.4-oxazepan-4-ylJ-6-methyl-pyrimidin-2-amine (28 7 ' 85%) -2 6% by moles of residual ethyl acemte. IH NMR (400 MHz, DMSO) 6 7.96 (s. IH), 7.83 (dd. J=8.2. 1.4 Hz, I H), 7.58 (d. 1=8.2 Hz„ IH), 5.70 (s. I H). 5.66-5.55 (m. IH), 5.46 (6, 2H). 4 52 (6, J=14.9 Hz, IH). 4.16 (dd, J=13.5. 4 9 Hz. IH). 4 00-3 88 (m, IH). 3.85-3.70 (m, 2H). 3.65-3.52 (m, I I I). 3.23 (5. 311), 2 05 (s. 311), I 88-1 72 (m, 211) [1143] ESI-MS n)/z calc. 396.1023, found 397.15 (M+I) . Retention time: 0.55 minutes. XRPD confirms material is crystalline [1144J Fonna)ion of tert-butyl [1145] DSC shows meltin point 194'. N-(3-hydroxypmpyl)carbamate [1146J Smail niolecule X-ray crystal stnicture for the peak B confirm this is S-conformer. [1149] A 3-nix:k 2 L RB llask with magnetic stirrer. 3-aminopropan-I-ol [o]o '9.47 (c I I, MeOII) for 99 4% ee (peak l3) tcmperaturc pmbe was charged (43 g. 'I 572 5 mmol) in a mixture of I ili (450 mi,) and water (450 Peak A (R-conformer) ml.), stirred for 10 minutes and then cooled to 0" ('vith an ice-bath. tert-butoxycarbonyl tert-butyl carbonate (131 g, [1147J 4-[(JR)-3-(2-chloro-)-methylsulfonyl-phenyl)-1. 600 2 nunol) vvas added portion wise over 10 minutes and 4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (25 g. 74%) then the rcsulung rcacston mixture was slowly allowed to as an ofi'-white solid ambimit tcmpcraturc oicr 12 h (overnight) at wluch time ESI-MS m/z calc. 396.1023. found 397.1 (M+I)'. Retention TLC (50% ethyl acetate ui heptane)-anulysis rcvcalcd con- time: 0.55 minutes. sumption of the starting material Reaction mixture was [o]oos —23 33 (c I 0, MeOII) tiir 99% ee (peak A) cmicentrated to -5(pgo of the volunie (to remove 11 0') and US 20]9/032265[] A[ Oct. 24, 2019 232

then extracted with DCM (2x500 mL). Combined organic temperature for 2 h. observed desired product 2 cpot (TLC extracts werc washed with water (100 mL), brmc (100 ml), 10'/o methanol in DCM) and baseline spot could bc starluig dncd os cr Na2SO4. Iiltercxi and concentrated unilcr reduced malcrial). Reaction mixiure was cooled to ambient tempera- pressure to aflilrd tert-butyl N-(3-hydroxypropyl)carbamate ture, filtered through celite bed, bed was washed ivith (98 a. 98/o) as a clear, colorless oil III-NMI( conforni to methmiol (2x25 nil,) ('ombined hltrates were concentrated structure. IH NMR (300 MHz, ('hloroform-d) 6 4.73 (s, under reduced pressure. The residue u as partitioned IH), 3.6(i (t, J=5.7 Hz. 2H). 3.28 (t, J=6.2 Hz. 2H). 2.55 (s, between DCM (150 mL) and is ater (50 mL), organic phase IH). 1.77-1.38 (m. 2H). I 44 (c, 9H). was separated. clashed with brine (50 mL). dried over Na2SO4, filtcrmt und concentrated under reduced pressure. Formation of 2-[3-(tert-butoxycarbonyLlmino) Thc residue was purified by sihca gel chromatography (40 g propoxy]acetic Acid isco column linear gradient, 20 ('V. 0'/ 2(y/b methanol/ I)('), fractions which contained desired product were col- [1150[ A 3-neck 2 I, RI3 flask with overhead stirrer, lected. concentrated under reduced pressure to aflord lg- temperature probe and reflux condencer was charged tert- oxazepan-3-one (1.8 o. 32'/o) as a white solid. IH-NMR butvl N-(3-hydmxypropvl)carbamate (42 g. 23r).7 mmol) conform to structure. IH NMR (300 MHz, DMSO-d6) 6 and tcuabulylanunoruum (Bmmidc Jon (I)) 12 41 (4, 7.65 (s, IH), 3.99 (s. 2H). 3.83-3.61 (m, 2H), 3.25-3.06 (m, nuuol) in toluene (300 mL), stirred for 5 muiutes and then 2H), 1.87-1.62 (m, 2H). cooled to O'. with an ice bath. NaOH (200 mL of 6 M, I 200 mol) was added while maintaining internal temperature below 10" (2 and stirred further 20 minutes tert-butyl Formation of g-chloro-(i,7-dihydro-5H-1,4-oxazepine-4-carbaldehyde 2-bromoacetate (55 g, 282.0 mmol) in toluene (50 mL) was added over 5 minutes The resulting reaction mixture was [11551 A3-neck 2 L RB flask with overhead stirrer, w amied to 60' (Tmnx 6 5'.). stirrcxl al lhis temperature tcmperaturc probe, addiuonal funnel, nitrogen uriel and for 14 h. Reacuon mixture was cooled to mnbienl lempera- rctlux condeimcr was charged DMF (141.6 150.0 mL. turc anil layers werc scparalixk aqueous layer was cxlractcd g, I 937 niol) in I)('M (300 0 ml.), stirred for 5 minutes and with toluene ((i0 ml ) Aqueous phase was cooled to O'. then cooled to 0'2 ivith an ice bath PO(13 (90 nil .. 965 6 with an ice bath and acidified with 12 N I I('I until I is3. pl mmol) in I)('M (100.0 nil.) was added over 30 mimites Ethyl acetate (150 mL) was added and the layers v.ere v bile maintaining the internal temperature below 6" C. separated, aqueous layer was extmlcted with ethyl acemte (50 Reaction mixture was warn)ed to 40'. (Note, reaction mL). Combined organic layer was dried over Na2SO4, nuxlurc tumed into clear. red color soluuou and obsetvcxi Iillcred and conccntralcd under rcduccd pressure lo aflbrd exothcmi, maintained uitcrnal tcmpcrature —40'.) surred 2-[3-(tert-buloxycarbouylamino)propoxy]acetic acid (36 g, at this temperature for 45 minutes I ogoxazepan-3-one (50 61'/) as a clear. colorless oil which contained small aniounts 8, 434.3 mmol) in I)( M (3(X) ml,) ives added over 40 ofethyl acetate. I I I NMR (300 Ml lz, MeOD) 6 4 07 211), (m nunutes, observed exotherm, maintained internal tempem- 3.60-3.54 (m. 2H). 3 32-3 30 (m. 2H), 1.79-1.70 (m. 2H), ture -40'. The resulting reaction mixture was stirred at 1.47 (s, 9H) this temperature for 90 minutes at which time TLC (10'/o [1151] This malenal was taken uilo thc ncxl step without mcthmlol in DCM) and LCMS-analysis rcvcalcxI consump- further puntication tion of thc starting malarial I, major peak RT=0.51 mimites (M+I I)+ 189/191 which corresponds to the mnidine inter- I'orniation of methyl 2-(3-mninopropoxy)acetate mediate. Reaction mixture was cooled to ambient tempera- [1152] A 3-neck I L RB flask lvith magnetic stirrer, ture, poured into cmshed ice (1.2 I ). and then alloived to lempcralurc probe, was charged 2-[3-(tert-butoxycarbo- ambient temperature over I h and stirred further I h. nylanuno)propoxy]acetic acid (12, 51.44 nunol) ui mcllm- Sepamted the aqueous layer. basified with solid K2CO3 nol (120 0 mi,), stirred for 5 minutes and then cooled to 0" until pH 9, allowed to ambient temperature, stirred at tlus ( ivith an ice bath thionyl chloride (10 mf, 137 I mmol) tcmpcrature filr 12 h (ovcmight) at which tune LCMS- was added over 10 nunutes and then slov lv allowed to analysis revealed major peak at 0 (i9 minutes (M+I ) 162.04 ambient teniperature for 12 h (overnight). Reaction mixture which corresponds to desired product 2 Reaction mixture was concentmlted under reduced precsure. The residue was was diluted with I)( M (3()0 nil.). Organic layer was sepa- azcotroppixt with DCM (2x60 mL) lo aflbrd methyl 2-(3- rated. Aqueous layer ives extracted with DCM (100 mL), ammopropoxy)acetate (Hydrochlondc salt) (10 g, 95'/o), combuied or anic extracts were dried over Na2SO4. tittered -90/o purity as a clear. colorless viscous oil IH-NMI( and conccnlralcd under rmtuced prcssure. Thc rcsiduc was conform to stnicture. III NMJ( (300 Milz. 1)MSO-d6) 6 punfied by sihca gcl Huonuitography (330 g isvo colunui 8 05 (s. 311), 4 12 (c. 211). 3.66 (s, 311), 3 54 (t, .I 6 0 I lz„ linear gradient, 20 Cld 0o/o 50o/ ethyl acetate/heptane- 2H). 2.84 (t, J=7.4 Hz. 2H), 1.95-1.75 (m. 2H). v hich contained Io/o I:t3N). fractions which contained [1153] This material was taken uito lhe next step wilhoul desired product were collected. concentrated under reduced further purification pressure to aflord 3-chloro-6.7-dihydro-5H-1,4-oxazepine- 4-carbaldehyde (41 o, 58'/o) as a clear, colorlecs oil. IH I oi'inutloll of 1.4-oxazepal1-3-nile NMR (400 hfHz, DMSO-d6) b 8.32 (rotamcr, d. J=JS7.3 Hz. JH), 6.59 (d, J=4.2 Hz. IH), 4.19-3.87 (m, 2H). 3.85- [1154] A 3-necl I L RB flask with magnetic stirrer, 3.51 (m, 2H), 2.02-1.71 (m, 2H). tcmpcralurc probe mid reflux condcnscr was charged methyl IH-NMR 2-(3-anunopropoxy)ace(etc (Hydrochlondc sall) (10 g, [1156] shows mn«ure of rotamcrs. 49.01 nuuol) in methanol (100 mL), stirred fbr 5 numitcs [1157] Compounds ui Table 2A arc prepared by synthesis and then added K2('03 (I4 8, 101 3 inmol) 'I he resultiag methods siiniLlr to those as described above Analytical data reaction mixture was warmed to (i0" C., stirred at tlus of some of the compounds are listed below US 2019/0322658 A1 Oct. 24, 2019 233

HP melon LC po nt LCTM( Pure nuttroinen pouts I')

1 IH 'HMR (4!!f! M)tr, DMSO d6) 6 7 2 (s. IH), 724 (M + kl)+ It!A lint I It lf . »

(I, 1=86 M . 1H).7!19((L I = 88 llr. IH't, Sl (s, ('a 4 7 9. it)f1 * I'Sk('DH Imn )H!. (34(s H), ((!4(s. )H) 4tr6 (d J = l)9 Hz. found 427 ee = rn9" 2H!. 'I Hl (d J = I 9 Hz IH). 'I 76 'I 61 im. H) 4 fs. IH! (I( (s 3H). 199(s,3H). 174(s. Hl 2 IH HMR (400:VIHz. DMSO d6) 6 7 3 (a )H). 724 (;VI + H]+ )Au secmtd slur n samer id. I = 8 Hz IHI, 71!9 (td, I = 8 7 2.6 Hz. IHI. Cac 4 79 (SFC RDH olutnn) 83 Is 3H) 5 34 (s 2HC,. Vl is, IH) 4tr7 (d J = fouttci 4 7 2 c= 13D Hz, H). 3 91 Id. I = I 5 Hz IH),377-"».8 " (m. 2H!, ." (5 (d, I = 13 tl Hz. I H), I!5 (s SH l, I 99 (s. H), I 74 (s. 2ll!

'HMR I = It!A I .

IH (4!!f! nil(A Mel) aol Ia) 6, 9 I l. I tl (M + kl)+ lint It lf » H, I Hi, 7 77 (Id. I = 8 2, I 9 llr. IH), 7 )G ld, I = ('a 4 7 0, l(Hi 'ol rI'Sk('11 m) H. 2 I(, I I tl. 5 75 (s, H). 4 td(L I = I G. ( (t Hz, IH!.Hf!399 (m SHI. '1 86 17 tm, Hl. 364 (td J= I)8,3(Hz IHI. 57 4 (m. H),226

2161m H) 213(s. 'IH) 2trg 193 (m. 3H!. 171 I 83 fm IH)

IH ".IMR i4tal MHz. DMSO-d6) 6 72t! Itt I = 12 (M ~ H]e IOD first elututg rsontcr 6, Hz, I Hi, 7 tl6 idd. I = ll 3, 9 1 Hz. IH). 5 84 Is. Cac . 14 (SFC IC-IDA colunta) 3H). 5 3-477 Im 2H), 4 13 ts, IHI 3 97-3 81 fouttci 3 I I ce = 99'M in& 4H), 36 it. I = I I Hz,2HI R(3-34v iar, I H), '0 (s. )H), I Stl I 61 tm. i)i .IMR (4IHI MII, DMSO dd) 6 t!(St, I = 12 7. + H)+ 6 71(, 1 ill. 713 697 (m, IH). tl4 In H), (SM''OO 4 86 Irn H) 4 13 (s. I H). 3 88 (s. 4Ht I 6t) (d I = fotrtrd I( I I ee = u39" I! 1 Hz. H!. 3 (3 3 40 (m. i HI 17 1 88 (nt. !H!. I 71 (s SH) 6 IH .IMR (4($ :VIHz. DMSO d6) 6 ltr i!u ia IH) (M + H]+ 97 first elut ng somer 54 itn. JHI 737 (d .I= 8 Hz IHI, 9tl ts. Cac 4t)6 9 (SFC IC-IAV oluntn) JHI. 13(d .I=833 Hz,SH1,463(s. IH).414(d. fouttci 4t)6 I ce = '-99'r J= 136Hz IHI 393(d J=12 Hz IH) : 61 Ini 3H) 3 54 ttd. I = 11 6. 4 4 Hz. I HI. 2 41 tt, (=6 H, HL198(.ill),i 7 iti IMR latal MII, t)MSO dd) 6)t) tr! (s Ht!, (M + H)+ lot! se*rt Itfp 7 68 7 4 A, OH), 7 7 (d. I = 8 ( H, ill), W) I ', (I 406 9. (SM''OO ti), 4 %861 .)H) 46)CH,IH14ta(d, I= t'ml 406 I = -'99"6 I! 3 Hz. IH!. 3 93 (d. J = I().( Hz IH). 'I 7( I 6 im Hl,3(4(rd.J=)l( 4(Hz.)H). 4)(t.J= 6 I Hz, Hl. 198 (s. 3H) 177 (s H! IH HMR (400:VIHz. DMSO d6) 6 10.88 (s. IH!. (;VI + H]+ )Au first slur n samer ,Sets.IH) 749(d )=85Hz,lH1,729id.1=8. Cac 412 tl (SFC IC-IDA colunta) Hz. I HI. 6 3 (t .T = 53 7 Hz, I HI. 5 8's. 3HI. 5 03 fouttci 412 I c= is 2HI 416 4AS ltlt, IHI 39 Id..l = ltr 6 Hz. IHi 3,6-3 Gf1 im 2H), 3 52 td I = IS 7 Hz. IH) l.99 is, HL I 7( (n Sill

! (Stlo MH, I)nl'IO d6) 6 T( I . )Hi, 649 (s. HI!, (M + kl)+ lt7 119 (.68 is, IHL 7 (n llll, (46 is. SH), IG (s. I tll. ('a 3741. (*hual tv(K I(li 4ftl Ill, I = ic K ( I llr. Ill), 89(l, I = 124 H IH!.'t74341(m 3HI.'I l((s, H).26( (4(m. H!.2ul (s H),174(s.4H) 1 fl IH HMR (300:VIHz. DMSO d6 nused tt rh one drop (;VI + H]+ 99 9 h ral PRK IO 19fr I92 of DCI ur dcutcrnmt osrdc solutrorx ppm) tcontaurs Cac 4tr I o rotatncrs) 6 = 744 (s 04 H). 73 (s, (f (t H). t'ourrd 4tr 0 68!-68 (m. ) H). 667(s,t! 5 H) 584-581 An, A.o( H), (SG(s. u4 Ht, It!. Oe tnt.f. 4. H) 4.98494 im,oa II!,42941 I, I ( H), 393 Si I . 2 H), 1 78 71 ( . 1 H), I 6» 7 ( ), I H), 2.1f (s, I 6 II!, 2t! Is, I 3( H), I 9tt I 72 (m, 'HMR Ti I il IH (I!!f! M)tr! 7 7 71 I . till, '9 IR (M + kl)+ 1atl ( J = I 6 Hz. 2H) 5 70 5 67 (m. )H), 447 (d. 1 = I( Ca'19 I Hz. IH!.413 403 (m IHI. '1 88 164(m.dH), A7 lotuld 419 I 20ttm H) 178(d,J=(6Hz, H). O'I 1 IHRMR 1300 MHz. DMSO ppnt) 8 (s. IH) 7 Gfl (M + H]+ 999 131 (s. IHl t!9 (s, IHL 5 57 Is. IH), 546 (s SHI, 63 Cac 4t)4 is I HI 4 66 Id, I = 15 3 Hz, IH). 4 t!7 (dd, J = 13 4. touttd 4t)4 D tf Hz, IH), 39tl id. I = 113 Hz IHI, 3 78.3.43 (m. JHI. 2 34 (q .I = 7 ( Hz 2H), 14 ts, IH). 2 vv ts. H),176(H,SH),i )f10, I= 11 I)i IMR (lilt) MII, t)MSO dd) 7 r!4 rs, t)tl 6 99 (M + H)+ 0

(s, I H!, 7 ((, I I I!, ( 46 (s, H't. I ts, IH), 4 66 (I 446 I . (R I = 14 7 H . Ill!, 4 fl( iill, I = I 4. 5 2 H . HI), t'ml 446 I

.97381 im, HI), 177 4 I 3)t),298 2ttl in& 2H), 8't-2 67 im. 2H!. 2 16 (s, SHI..(!0 Is. US 2019/0322658 At Oct. 24, 2019 234

-uon(tt)IICKI

HP melon LC po nt De SMR LC;VIS Puny: enanr omen pur ty (')

Hi, 17((a,JH),! 6!10, I = 611,4H), 118 (1„ Ii)

14 (Stl(t MH . I)nit(O d6) 6 9 I . )H), 6 4 (a. HI), IM + )l)+ li!2 104 (. 6 is, IHL 47 (.. Jill, j -"- is. IH) 474 (6, I = ('a 3741. (*hue( tv(K Ioi I( Hz. IHi. 4 01 (dd. i = I'I 4. ( I Hz. IH). 3 9A for!ltd 174 it id. I = I I 9 Hz. IH). 3 74 3 4( (m 'IHt l 'li) (t; J = 8 r Hz, Hl. 8'i (t. J = 8.3 Hz. 2HI 71 Ia 3Hj. 200 ts. 3H) 176 (s H) " Ij I HBMR (30tl I IHz. DMSO, D201 6 63 (, I Ht, 6 . 4 IM + Hjt 99 Clnral ART cellulose SB 191! (s. IHI 585 (s, Hh 540 Is. IH), j i!0 (s SH1,403- Cac 363 tl : Sit In& 2H) "68 is, jHL 3 0 lr. I = 13 ( Hz. IHI. ToutlCI 363 9 (.96 ts. 3H) I 711 (s 2H! 16 iti IMR(ifltl MII, t)MSO dd) zrora, t)tl 68, jut + HI+ 10

(1, IH!, 'J (d. I = ll 2 H, H). 3 (a. IH),460 ii 417 0. (a. 1H1, 4 t17 M I I = I 3 4, r) H, )H; 3 tlS ( I t'ntt 417 tt

it 6 H, (H), 3 nt 64 (m. 1 1 tl..'»4 (l. I = 2! HZ. Hl. 2(t'! (S 3H), 1.75(S. Hi. 061 (d I = 11 Hz. 4H) 17 IH HMR(300:VIHz. DMSO d6 ppm l('I K) 6 = I;VI + HI+ i sf) 6 71 ts. I H). 6 57 Is. I H), j t! (s I Hl (.47 thr s, 2 Hl, Cac 4(tl ."4 5 20 itn. I H). 4 724 68 Im I H) 4 f12 Md. tourtd 4 1 tl 0 I = 13 1,. I Hz I Hl 390-3 t!6 (m I H) 3.76-R52 (m. 6 Hl 3 2 j-3 22 Ini, 4 HI, '!0 is, 3 HI, I 83-1 GA ( .4H!,176(b,JH) 18 ID%MR (iftil MH, DMSO, ppm) 7 r)7!a, I H), 6 73 ia. IM + )l)+ I 0 itii, 89(s,2H) 017(d I = I r) H,)H't„41))8) ('a 4 I 9. (m, 4HI. 3 7it (s, H), ! I ( . I = 11 9. 7 H . )H), '1! = it J 7 'z SHI. '12 1 84 im, (H). 172 ls. SHI 19 (ruf MHz DMSO d6) 684 (s. IH) 6 78 ts. IHj. IM + HI+ 99 I 118 9ts. IH) 547 (s H), (!I (s. IH). 466 Mt. 1 = Ca 4342 I( I Hz. IH). 4 0( (dd. i = I 'I 4. ( 0 Hz. IH). 3 91 (s totllld 434 4 IH). 3 88-3 16 Im IIH). 2 99-2 9 Im SHI, Rul ts. JHI. 176 (s 2HI 20 HTEM. KMR I "IN MHz. DMSO-d6) 9.14 is, IH). IM ~ HI+ 30 , A9 ts. IH) 6 73 Is IH!, 5 50 id, I = 5 4 Hz 3HI. Cac .4tl 9 2! t I, I = I tl, HI).472 It. I = I4 I Hr. IHL .99(dd,f=jl.j 4II,III). 8(),I= 67 ti, IH), 69 491m. ))I). 0 !1,!Il), I 98 (1, tii, I 89 I 7! I . 2)I). u'I 21 I H . IMR ( (N:VIHz. DMSO. pprn) 9 (s. I H). 6 83 IM + HI+ is IHi 674(s. IHI. ( jj (s. )H) (48 ts. JH). (B4 Ca 379 fl = rl 't = '179 (s IH) 4 67 ( t. I 14 Hz, IH). 96 fur I IG 3. for!ltd it 7 9 Hz. r H), 3 79 3 64 (m. I H) l 1st Is. 6 Hi, 'tt ts. 3H) I Su-I 72 Int 2HI, I 26 tr.! = 70

Hz. 4H I i 3VA MHz DMSO d61 747 6 93 lm, 4H1..70 is. IM + Hjt 99 6 second eluting cnatrotncr 1 02-11!4 -.' H't, .(8'I I H), ( '1. J = H . )I I), 4 4417 4!4 ( I l. (1 44 I i('h . I * Ilui 1 '.(B) I = I 4. 0 2 H', Ill), i 91 (I, I = I2 7 H, litt. 79 t'ml 44 I . )H), - 88 (1, tl I), — tt (a, H).! 76 ( . H) i)i IMR i)fit) MII, t)MSO dd) 6! (a. IHt, G 5 (s. jut + HI+ 9( !00 IH). 6ul (s I ( H). ( 67 (s. IH! (.3'I ( 31 tm. IH). Cr 379 11, 4 67 4 G6 (rn. IH) 4)') (dd l = 13 ( 1 I Hz. IHj. fotutd '179 f!

! 89 fd. J = ll I Hz, IH). 'l8( '144(rn. 3 (H). 1 G is Hi 177(s.SHI IHBMR (30tl MHz. DMSO, ppnt) 698 ts. IH) 6 tH IM + Hjt 796 115 (s. IHI 5 (8 (s, IHL 5 47 Is. 2H), 5 31 (s IHI, 4.7 (s. Crc " 4911'outlCI JHI. 463 (s IHI, 41!4 (dd, I = 134, 0 Hz, IH), 89 49( 1 I (d. I = 11 ." Hz, IH). 3 74 Is. 7H), "45-3 37 (nt. 4HI. tf1 Is 3H) I 77 (s 2H1, I (8 td, J = 5 I Hz. 2H) I 49 (s 4H)

I)i .IMR i)fit) MII, t)MSO dd) 6 ) !11, t)tl. 6 pft jut + HI+ 99 tur. I (RI «II I . SB )6 IG( (a. JH), 646 (a. Ill), 86 Ia, IHj, tj. 1)IL 5!it ('a 36 is IH) 46( is, IH) 409 394 trn. IHI "91.3 811 ToutlCI 36 (m IHI. 'I 80 3 6( (m. 2H). 'I 66 ') (I Irn I HI. 2 7'I (s H) l((s,3H1.201(s.3H) 18!id.J=74 ti IH IMR (3url MHz. DMSO-d6) 685 ts. IH), 644 IM ~ HI+ 99 clurrl ART c80!osc SB 108-110 (s. IHI 5 (3 (d, I = I 2 Hz, 3H). 5 It! (d. J = 7.9 Hz. Cac 36 I H). ( f 0 (d J = ( 3 Hz I H!, 4.7'I (d, I = I( 3 Hz for!ltd 162 I iti),4(t(t(m.J=I 4. I H, IHj, Stltl. I=119

II, llii, 74- 4) I . )II),- 2 it, I =48 )I, Ili, I 99 t t J = I 6 Hz. 6HI I 73 (d .l = 8 Hz, SH) US 2019/0322658 A1 Oct. 24, 2019 235

-von(tt)iten)

HP melba LC po nt De KIIR LC;VIS Puny: enanr omen pur ty (')

7 iH '&MR ()ttft Vlllf, DMSO d6. ppm. 1» K) 6 = (M + Il)+ ot(I liml I frtp «tto ('a 6.91 ia, I H), 64 ts, I H). & I, I H), 49 (h 3749. (*hue( p. I &Q) 2- 19 0, I Il),47&%68 (m I HL 99 (li. 1=1 -.)IH.III).39!I)86( t,1 tli, 69349 (m Hi 3 8(t,)=84Hz, H), 81(r.i=84Hz 2 Hl. 269 (s. 3 H). I 99 ts 1 Hj 17'I (bf s, 2 H) 28 IH .IMR( (D:VIHz. DMSO d6 ppnt. 'I&3 K) 6 = (M + H)+ 962 sec nd elutng anent omar 6 91 ts. I Hl. 6 43 (s. I H j 5 « (s I Ht & 49 (bi s. 'l. Ca 3749 (ch t.il pak AGi " 5 '"-. 19 (m. I H). 4 7 -4 68 Im, I H), 99 (di, (otlttti 374- " J = 13 2, & I Hz I H) 9(l-3 86 (m, I Hl. L69-3 49 in& 3 Hl 3 28 (t, 1 = tl4 Hz, Hl, 2 Bl It. J = 84 Hz. '). 2 69(s. 3 H). I 99 (s "Hl 173 (bt s. 2 H) 9 I ti IMR (&fltl Ml I, ('D)OD, pp l 6 = 6 96 ( I, (M + H)+ 84,1 H),67 (rl. 1=21.11(1,676(ll, (=84.24 (1 e 340. (*tt . I p, I, I 1) H, I II), 761hra, I II), 't Jf)492 (br. )Il 418 I'nct )34 tt (thl, 1 = I 7, & I l(r. I II). 4()3 .'8 rr, I H), 1 7 ) 4 Irn H) fl7 (s 3 Hl I.pt 17& tm. Hj IH .IMR( (D:VIHz. CD3OD. pprn) b = 696 (d. J = (M + H)+ 994 sec nd elutng anent omar 8 4. I Hi. 6 72 (d 1 = .I, I H). 6 &6 (dd. J = tl 4. 2 4 Ca'34 !1 (ch t.il pak Ai) Hz. I HL . 6 ibr s, I Hl, 7 Jrn492 ibr. 'l 41tl (otlttti )D4 0 Idd J = 13 7. 5 I Hz, I Hf, 401-1 98 im. I H) 72- : &4(nt 3 H) 2u7(s "H), 193-175 tm. Hl

".IMR "53 = ~ 31 IH !3(ul MHz. DMSO-d6 ppm, K) 8 (M H)+ 98 9 sceottd eltttlttg cltattttotncl'('hu: ('a 6.99 is, I H), 681 ts, I H). 61 I, I H), 49 (h 419 0, I I'&K &(Dl )ti 0, I H),460% 77 (m I HL 4(» (li.

I = I ». 7 I H . I H), 3 88 3 &I I t, 8 tlj, -(I (a. 2 1 74 I br &, - I I), (i ) 7 Ia, 6 I I) 2 IHKI IR ( 00 MHz. DMSO ppm) 7 4& (s. IH). 6 98 ts. IH). (;VI + H)+ 99 9 19 67 fs. !H) & 86 (s BH) & t7 is, IH). 498 ts. IH1.441(s. Ca 4779. 2HJ. 'I 94 (dd 1 = 6 6. I 4 Hz. H). 'I 73 ts. Hi. 3 I (dd fotutd 478 fl J = 18,89 Hz IH). 197(s,3H). 172 (s. Hl, I 6(s. IftHI 33 (Sttu MHz DMSOd6) 79477 Im IH), 74(l (dd. (M ~ H)+ 97 3 I ttf I-I 02 1= 6,21Hz IHl 580ls,lH1.5 6(d.J=296 Cac .964 Hz. 3H1.454(s 2H1,433-407 (tn, H). 39 - 76 (otlttri . 96 I in& 2H), 3 723 4&!m. 2Hj. 3 06 (s, SHl. 2(t&

(s,&H),19116 ( t,211) 95 9 iH '&MR ()ttft Vlllf, DMSO d6. ppm. 1» K) 6 = (M + Il)+ 94 7 7.93 ia, I H), 746 ta, I H). 66 I., I lt). 6 7 I ('a 40 (m I Hi 545 (bt s 2 H) 4 &f1 446 (m I H141 fotutd 43ft 40 Im H) 3 9(t 3 87 (m 'I Hl '1.77 'I 6 tm. 2 Hj. .6f . 2 (m, I H), t)2 (s.) H).1 79 tln ., O'I, (12(t, (=96M.& H)

36 IH VMR (3(at MHz. DMSO-d6, ppm 351 K I b = (M+ H)t 95 I tlut d clututg isontcr 66 fs. 2 H). & 9& (s. I H) & 88 (bt s. H). &66!s. I Hl. Cr 462 'J, !Cheat PAK ADHI I (m. I H). 4 67 4 6'I (rn I H) 4 I 4 fl totutd 462 I (m,)H),38918 ( . I II).377 368!, I H), 3.63-3 51 itn. 3 H). 3 02-2 98 Im I H) 2 f12 (s. 3 Hl. 174flrs, H)142(s "H),112 lt,1=96,3H) 7 IH HMR(300:VIHz. DMSO d6 ppm 1&'I K) 6 = (;VI + H)+ 98 2 tourrh elutmg s met

6.62 ia, H), 9 ts, I H). 78 tin ., H), 63 ia. I Hj. ('a 46 9. (('hu: I I'&K &Dl(l &.22719(m, I II),47()%6&! .I H).40 39 t'ml 46 2 in& 3 Hl 389-3 tl2 (m, I Hl, 3 71.365 tnt. IH) 16 3 &0(m. 'I H). '!02298 (rn I H) fl (s, 'I Hl. 174fbrs, H1142(s 3H) f198(t,1=96.&Hj iH '&MR ()ttft Vlllf, DMSO d6. ppm. 1» K) 6 = (M + Il)+ 7.19(a. I H). 689 Is. I Hj 579 (bt s. 2 Hl. 569 Is. I Hl. Cac 4(t (ciural ART cellulose-SH) .42-& 38 itn. I H). 5 09 (s 2 H) 4 63-4 tt Im. I Hl. (otlttri 4f )4 I 4 06 Idd. J = 13 «. I Hz, I Hl, 391 '169 (tn. 6 Hj. .6f ..'m, I H), tt (s. 1 H). I 79 tin ., Hi 39 it(SM!1 t)tltt MH, DMSO. pp t 1(sf)6 (a, IH). 7 68 (M + H)+ , &4 tnt 2H) 7 31 it, 1 = 79 Hz, H). 7 15-6 98 Im, SHI. Cac 4979 677 fs. IH) & 86 (s BH). & 4& is, IH). 494 is. IHI. fotutd 498 it 47 fs. 2H) 9& (dd 1=3fl9 113 Hz H). 37& (s Hl. 6 t)90, IH),197(&.&II).)7 !a,PH),1- (a.)Hl 40 IH IMR !3url MHz. DMSO-d6) f146 tt, 1 = I 9 Hz. (M ~ H)+ 96 6 ll -117 IH) 789(d 1=19Hz IHl 77ht )=209Hz Cac 4119, 2HJ. & 3& (s BH).451(s, H). 4 7!a. IH1.417!dd. fotutd 412 f)5 I=t .7 H.,lll),)utlid,I=11 H.2H).287

.78 im. )H), 1 6 (I, I = 1411(f. IH), 94 ia. &t(). '3 ts. 3H) I 7tl (s 2H) US 2019/0322658 A1 Oct. 24, 2019 236

-eon(It)IICKI

HP melba LC pn nt De KMR LC;VIS Puny: enenr omen pur ty (')

41 IH 'uMR ()ttft Mlle, DMSO d6, ppm.!» K) 6 = IM+ Il)+ 9tl 1(t(t

742 7)6 im, H), 67 (s. I H). »4-(49 (m. I t(). ('a 461 4. (*hue( p. I Ibl ei lhr(,21(),4 itis, II)44944 rr, I H), 412 sile (m, I H), 9() 7( I . 2 H).! G43 Hl. 88 (s. '! H). 201 (s 1 H) 18( 17 (nt, Hl 42 IH HMR (300:VIHz) 7 fel 698 (nt, IH). 684 (s. I;vl + HI+ 13( 138 IH). ( 6( ( (6 (rn IH), i.(0 5 46 lrn. H). ( 3G Cr 465 2, 7 Irn IH) 476 4 72 (m. H). 4 66 (d. J = li 4 Iotutd 465 tl Hz. IH). 423 416 Int 2H),40fl )99 lnt. )H) 39A fd J = I 2 Hz IHI 379-359(m,3HI. 2tl- Att tnt 3H) I 8t!-I 72 Int, Hl I 9-1 tt tm. 6H) 43 13nu MHz DMSO-d6) tl39 (d, 7 =17 Hz, IHL 767 IM ~ HI+ 99 I lift-112

= I C9 ', ('a ( Id..l l(t 8, I 8 I, I H), ( I St)i. 4() (s H), 3964. 454 te, H),4 64t)9 (m. 2II) et)6 7 .63 3 47 im, HI),! ()0 (s,! H) 204!(, Ill, I 9- I 68 I, 2H) 44 IH HMR (300:VIHz. DMSO. ppm) 699 (a IHj 6 tl2 I;vl + HI+ 97 9 (s IHj ( 57 (s, I HI. ( 47 (s. 2H) ( I ( 38 tm. IH). Ca'(l i, 47 Is. H) 46(l 466 (m IH),3 (i 4.u8(tn. 10HI. fotutd 4(1 I Al ts„ IH) I 66-1 86 Int 2HI, I 2(t.l "I tnt. SH) IHKMR I)t)0 MHz. DMSO ppml 717 (d. I = I 6 Hz IHI IM ~ HI+ 99 4 Scc tld clitlttt ctt.'tttttottlcr lu 684(s. IH) (6u ls 3HI,529 fs, (H).467 M J= I 0 Hz. I Hl, Cac 4(tl I ( lut(l pack IOI 41( fdd J = 13 K 5 0 Hz, IHI, 3 9t ld I = IRI Hz. IH), t'ourtd 417 9 .66 id(01 J = 22 6, 14 0. 9 H, H). 2 06 (s. H), I 81 f . 46 (Sti(t MH . I)91!(O d6) 7 24 I I, I = 4- t H . 2lt). IM+ Il)+ tl 2 (46 (t, I = )2 6 H, 41(), 4 69 (I, I = I 0 H, lot„ ('a 36 418 t 8) 0,2H),! 81 39 tm. Itl. 2 !e,)Hi, 201 Id. J = 9 6 Hz. '!Hl I 87 171 (nt. 2H). I (4 (s. Ht 47 IH HMR(300:VIHz. DMSO. ppm) 71((a IHj 7 A2 I;vl + HI+ 10( 107 (s IHi 6 79 (s, !HI. ( i6 (d. J = 19 2 Hz IHI, ( ( Ca'92 tt, (s. IHI 469 (s, IHL 439 Is. 2H),412-383 (a(,4HI. fotlttri 49 I , Stt-3 (tt (m. 2H) I 99 (s SHI, I 74 ts. (H). I -8 Id J = 13 9 Hz. SHI I 28 (s, ISHI 48 IH VMR (3(O MHz. DMSO-d6 ntn.cd irh oac drop IM + H)e 132-135 (1 419 »lamm() b = 7 11 ((, it H) 0 t'ml 4192 68tite,(t'tll),678te,o'tll),6 'Ie.f) H),61() (.89 im. H), 64 (s. t) H), 4 .'m. I H). 7 (m. I H). ( I'! ( I fr (rn 0 ( H) 4 Gl 4 (7 im Hi 421 380 (m,6.( Hl 169 I (8 tnt. I Hl. 30 fs. ! ( H), 18 (s. I i H), I 87 I 7iJ (tn. 2 Hj I 31 I 26 (m. 3 H) IHKMR (30tl I IHz. DMSO, ppnt) 8 48 ts. IH) 7 61 Is. IH), IM + H)e 97 15A fs !H) 56A(dd I=99.49Hz,)H).545(s,SH1.4.8 Cec 41 I is 2HI 441 td, I = 152 Hz, IHI. 412 (dd, J = 13 '. 51 t'ound 411 9

tl, I Hl, 94384 (m,SH).! tl 71 I . IH), 66 49!m. ltil, 48 (m. J = I 9 II, )lt), i)4 (e, H). I tl(t ( . H) IH 'uMR ()ttft Mlle, DMSO d6, ppm.! K) 6 = IM+ Il)+ 130 I 712(e,l H),7tt It. I=7 llf.t ltl.687(e, I H), ('a 401 8. fs. ! H). ( 49 (br s. 2 H). ( 9 i 2i (rn. I Hl. fotutd 4Att 9 4 6 4 61 (m. I H). 4 10 (dd I = 13 i. ( I Hz. IH). 3 90 3 86 (m. '! H). 'I 71 '! itt (rn I H) tl1 (s, 'I Hl. I 77 I br s. Hl (I i3t)A MHz DMSO-d6I 7 Id. 1 = fl9 Hz. IHt,700 IM + H)e 161-163 (d. J = ." It Hz IH), 6 86 id, I = f! 4 Hz, IH). 5 66- Cec 3491 " 5 18 tnt 4H) 4 7t!-4 4 Int, )HI 4 0 Is. IHI, 87 ts. fotlttri 349 3 IH). 3 70 (s 3H), 't 56 ts, )HL 248 is. 3HI I 6 ts. SH) (2 i30i I IHz DVI(O d61 7 io (s. IH) 7 33 td. J = I A I;vl + HI+ 97 9 1()8 I lfl

H, Hi, (70 (!I I . 4H),44 (s. SH't,41 ('a 4. I. 1=1 4.oil H'. Ill),iul (I, I=12 H, IH(. Stl t'ml 4 : 6)tnt 2H) 359346 Int, IHI 288 ls. SHI, 23(- 18 fm 2H) 177(s, H) I ltt trod(rn. 3Hi 'I(3 5 IH .IMR ( (D:VIHz. DMSO d6 ppnt. K) 6 = IM + HI+ 94 I 79) te, I H),747 (, I H), 67ts. I tli. »6 ( I (1 416 8. (m. I H) ( 44 ibr s 2 H), 4 0-443 (m I Hl. 4 11 t'ourtd 416 0 (dd J = 13 ). 5 I Hz, I Ht,.' -'l8 (m. 3 H) 378353(m.6H).202ls tH) 179th(a,2H)

I IIKMR t)tltt MH, DMSO. pp t 8 ti) 742 (m, I(t + H)+ 732(1,1= 77H, IH), 6 td I=Stl lt,4II14 ('a 444 I. SHI. 438(s IHI,(17 (dd, 1 = 134, 2 Hz, IH), 392(d. fotlttri 444 0 US 2019/0322658 A1 Oct. 24, 2019 237

-cont)nttcq)

HP melon LC po nt Da VIIR LC;VIS Puny: ensnr omen pur ty (') 1=1 )H,IH),3833(tlf t,!Itl.3 (ll.I=f16. 47 Hr. Ill),! Itl ta, H), 202 ts.)H). I 76 (a, JHi IH '(MR ((l)fl Vlllr, DMSO d6, ppm.! K) 6 = )M + )I)+ I ftl 19(t 7. I ia, I H), 7 34 is,2 H). Gb tw I lt). 4((b ('a 41 0, 46 4(7 (m. I H). 44( ts H) 414 tdd.J = for(std 4)tt 9 li ( I Hz. I H). 3 91 3 f17 (m. I H). 378 3 (I (m. I Hl. 89 (s. ') H). 20) ts 3 H) 178 tbt s. Hl. (G IH VMR(300:VIHz. DMSO d6 ppm 3('I K) 6 = (M+ H)+ 99 'I first elur n anent amer 118 17(l 9 84 (br s, I Hi, 7 17 Is. I HI. 7 vo fr.! = 7 0 Hz. I Hl. Cac 4t)1 tl ((R.RIWELK chrotnastl) 6 91 Is. I H). 5 56 Is. I H) 5 Gtl (bt s. 2 H). 5 2- t'ourtd 4ttl 0 5 28 tnt I H) 4 6 -4 60 (m, I H), 4 15.4 tt9 (na I H) 3.91-3t!6 itn. I H). 373-356 (m "H) ttl I "Hl

1.77 (8 .. 2 I I) 7 IH '(MR ((l)fl Vlllr, DMSO d6, ppm.! K) 6 = )M + )I)+ 9(8:( onl «lol 8 «nant«» 984(b ..I II).717(a,Ill),fttt)tt, 1=7 I H.l H). ('a 401 8. Hlf R)W) I K *tmm. ( I) 69)ta,IH),((6(w)H), (0th a,!H't I) mM 401 tt 8 Irn I H) 4 6( 4 60 tm I H! 4.1( 4 t!! tm. I Hj. ') 'I 391 386(m. I H). '!7') (6 (rn 3 H) tll ts, Hl. I 77 I br s. H) IH VMR (4(a) MHz. Met)sano)-d416 7 ti9 td I = I (M+ H)t 100 First elutina tsontcr Hz. IHI. 753 (dd 1= 85. 2 Hz, IH). 7 7 Id. 7= Crc 4 ii! (SFC whelk-vt co)tant() 3" 8 ( Hz, IHi, 588 5 im. 3H) 42ti(dt, i = 136. foci(fr) 4 t t- ce = 98 4'r .I Hz, IH),414 Is. (H),411-39fl tnt. 4H). 3 76 (ld..l = I 6, ill H, IH),! I )tl fm. 2H). 69 t)9 . )H), 244 2 I) (, l ill, (a, H). 1.99 I 88 im, HI), I 8 GL J = 14 ( llr. IH). ! (Stiv Mlt . I)91!(0 d6) 7 50 ta, IH), 41l. I = I I )M + )I)+ 99:( onl «lol 8 «nant«» Hz. JHI. ((6 ts IH), (47 (s. 'IH). 46( (d. I = 1(1 Ca 42( 3 (ch i.il pak fni Hz. IH).443 ts SH).41 (dd, I = I'.(. (.0 Hz, IHL for(std 42( I ! 01 Id J = I 0 Hz IH) 32hl 'I 67 tm. H). 3 61 0fm IH) 87(s,3H).237 2tt(rn. Hi,178 (s. 2HI I 12-0 91 (m, 3Ht 6t.t IH VMR (3(a) MHz. DMSO. ppm) 7 13-7 08 (nt. I (M+ H)t 174-176 Hl. 6 88-6 8- Vn. I H). ( 66-5 60 Im I Hl (MS Is. Cac 4t)3 tl " -'L 5 36 ld. I = 7 9 Hz. I H). 4 flu td, l = .4 Hz. t'outtd 4t)3 0 If), 4 7 4 6tl I, I I I), 4 I I 4 02 tm. I I I 1 . 92 ( l. I = I II H, I H),! 8 (R I = 9 H, I H). 77 ((L I=SIR, H), 7) i)it .2HL)4 3 Sf .I Hi, .Ita (a, H), I 84-) 76 fm. 2 Hi Gl (lof MHz DVI(od6)7 77.19(m.2H) 7167t7 (M + H)+ 96 9( 97 lm IHI, ((8 (s. iH). (46 ts 'IHI 462 (d. I = 1( I Ca'(12 I

H, IHi,4 ll Gll. I = )34. 5 I H, ltli.! 89 (I, I = t'ml 402) 117 H, IH),! 76 42 ( .(II),! f628 (m, 3H!, '7-2 (2 (m. 3H) 20u ts SHI, I 86.1 GV tnt. 4H) I 3)M(m.2H) G )H . IMR (4(D:VIHz. Metlmnol dd) 8 7 89 td. I = 2 I (M + H)+ 1(iti sec nd elutng somer . II,IH),7( (rid.J=85, II,IH),!27(d,!= (1 4. 0 9. t(M' lkpl I r rl 85 Hz IH),. 865 26 (m 3H) 42ti tdt l = 136, fotlttr) 4 tt 2 c = 9«' t) Hz, IH), 4 14 Is. IH), 4 12 3 99 Im 4HI, 3 76 idd J= 13 6. 10 ( Hz. )H) t7 3 (6 (nt. HL 261 ( ldl, I = II . 13 9. 8! H . Ill), - 44 - 28 (m, I H),

2.ti9 (a, H), I 9 ( lthl l. I = I I 4, 8 I, 0. 2 G H IHI. I 88-179 Vn IHl G )H .IMR(4(D:VIHz. Metlmnol dd) 8 72t) td I = 8 it (M + H)+ sec nd elutng somer Hz. I H). 6 49 tdd l = 8 8. 2 9 Hz, IH). 6 37 (6 J = Ca't)4'J, iSFC ODH colunutl 9 H, IID. 577537 (m,!H). 17 I', 211),449 I) mM 404 9 = 99 7') tdq J = 4 8. 2 . Hz, IHt 4 31 Idd .I = 13 ( . 0 Hz. IH) 4114 ttl Int, IH). 3 893 48 tm. 4Hl 3 46- ! 3i lm H) 332 32') tm. IH). 31( (dt.J= l(13 1.6 Hz. Ill),2)2111, I = tl,a H .)Ill. Vg (l. H, (H), 197 (dddl, I = tl, ISr),,24 Hz, !HI. I 89-1 77 Irn 2Hl G4 )H .IMR (4(D:VIHz. Metlmnol dd) 8 7 2t) td I = 8 7 (M + H)+ 8 first elutng somer Hz. I H). 6 49 tdd l = 8 8. 2 9 Hz, IH). 6 37 (6 J = Ca't)4'J, iSFC ODH colunutl — 9 H, lltl. 5 (4 (a, JH). IS IW Jtli,449 (dl,! = I) mM 404 9 49. '4 Hz, IH).4344 7 (m IH),40fl 402 (nt. IH). 3 79-3 71 Im IH), 3 7t) IR I = 67 Hz, IH). ! 67 f 57(m. 2H) 348 '!42 tm IH),34 'l.l( ( . Ill), 3 27! Jll (m, IH), 10 tdl. I = I( 4. I G

H, I HI, — I( — t)2 I . 4H), - t2 I 91 (m. 2H), I 87-1 . (rn. 2H) US 2019/0322658 A1 Oct. 24, 2019 238

-oon(tt)ties)

HP melon LC po nt De %MR LC;VIS Puny: ensnr omen pur ty (')

7 ID%MR ()f)tl MH, DMSO, ppm) ASS!a, IH), 3 ia. ) M + )I)+ 96 4 fit), 687 (s. 1H). & 6 ((, 1)I), (48 (a, Hi. 32 (l. I = ('a 4 71. Gf H, lltl.46& (I, I= I I H, IH).4464 4( .2H), 4.16 (dd, f = 1), tt lt, 1)I). 9tt (I, I = ll 9 H . IH), 376346(m. '!H) 8( ts 3H). 0) (s. 3H), 177 rd J= 6 'z. SHl, I '( (s. I H) G6 (100 MHz DVI(O d6) 7 '13 7. 0 (m. 2H) 7 14 tdd. (M + H]+ 9( 2 second slut ne saint omar )A( )t)7 J = 8 I, I 8 Hz IH) ( 59 (s, IH). ( 4( irn )Hl, 4 6'I Ca ~ 4022 (ch t.tl pack 14i id. I = le 2 Hz IH), 4 ll Idd, l = I '» 5 tt Hz. IH) touttd 4tt I 3 9A fd J = ll 8 Hz, IHt, 376-3 42 im. 3H) 31!2 (d I =12( Hz. 3H) 2682 I Ini, Ht, ~ VA is. SH), 1.83-1 60 itn. 4Hl I 53-1 34 (m, 2HI

67 ltl IMR()tal M)I, DMSOhppml 78G I I, I = I 8 (Vt + H)+ )20 )2 tl, IH),717 (s. 1H).6tlk (fh I = I I H, IH), 33 (1 444 4. (a. 1H), 3 (a. &Il),4tttt(a, )Hl, 3 80 t(L I = I 7 t'nd 444 tt tl, IH), 7I &71m. 1H). 348 3 6 r,,&H), 30 2 90 lm I H) I 98 I & I (m. 4H). I (3 is. 3H) GS (tof MHz DVI(0 d6) 7 3 (d. J = 83 Hz. H1,714 (M + H]+ 99 5 I'osr elututh enant amer )H& 12 id. J = 7 I Hz IH). ( 58 (s, )H). (44 Is. 3H1,46u Ca ~ 4022 (ch t.tl pack 14i is IHl 411(dd. I = 13 ". 51 Hz, IH), 389 td J = Jotlttr) 4t t I' Hz, IH). 3 69 idd. l = I '. If f 2 Hz, 3H). 2 98 is 3Hl 267 2 u Int,&HL 200 is. 3Hl I tt6 1 60 (m. 4H), 147 (dd. I = I 4,84 Hz,2HI

69 ()f(t MHr, 1&MSO d6) 7 N 7 ltt lr, H). 8 ( . (Vt + H)+

IH), (44(a, )H),462 (t, I = I G llr, IH't,4 G (*tm. I p..h IO! 448 im. H), 448 4 7 Gn. II), 4) I trkL I = 134. t'ml 4. 8 I

I H, I I Il. 3 89 (I, I = I 2 2 H, IH). 3 77 3 38 ( 4H). Su (d J= )lit Hz, H). 19( ld. J= (7 Hz. (Ht. I Sf ! 47 (rn 7H) 7 f1 i30t I IHz DVI(O d617 34 7 f18 (rn. 3H). ( (8!s. (;VI + H]+ 118 17(l IH). (44 (s H), 4 68 3 &(t Iut. 7H). 3 79 3 4) (m Ca'(8), 4H). '80 (d i= 114 Hz, H) 2tm&-186 lm (H), tourt d 4& tl 0 I Jo It. J = 99 Hz. 4Hl I 67-144(m, SHI I IHRMR IS(10 MHz. DMSO ppml 8 fl4 (s, IH). 694 (d 7 = (M ~ H]+ 120 4'z, IHi,67 is. IH) 549(d .l= 16 Hz,3H). I ld Cac .791 I = 8 6 H, IHL 474 (I. J = 1481)r. Ii)1 4()6 idd, 1 =174. 0 H,IHi, 96 8&l,lH),3 6it,)=49)l, Hi,368 3'J I I (I( . )H), 2 - 18 (, Sl tl, 6 (a, H). ( if(. I = 8 7, 6 4 H . )H)

7 IH .IMR ( (4:VIHz. DMSO. pprn) 7.u'I (s. IH). 6 82 (M + H]+ 99 5 I'l8 140 is IHi 5 (8 (s. IHl. (47 (s. 2H) ('ll ts. IH).4.63 Ca 43( 9 (d. J = 16 I Hz IHl. 4 4'I (s, H). 4 11 'I 91 im. 3H). fottttd 43 6 I ) 88 lm = 12 ( Hz. iH) 374 tnt = I'I 4 It) I Hz. )HI. '9 (s IHl, tt1 (s, 3HI. I 76 Is. 2Hl, I 28 (m = A Hz. 3H) 3 IH VMR (3(O MHz. DMSO-d6) 740 is, IHI. 16 (M+ H]t 99 8 lv- 12 H't. I (s, IH!, 6 ((, III), (43 (a, 44 I t. = I H, I Hi, 9 (ld. I = I 6. 0 H, itl), tlk 3 74 (m, Hl. 3 71 (a, H), 68 't& (m, 2(li, - 7 (a. tl), (t (s. )H). I 77 (d. I = (( llr. H't, I (tl ls, Ht 'I 74 IH HMR (300:VIHz. DMSO. ppm) 7 7 29 (s, I (;VI + H]+ 7 17ft itft 172 f)fr H). 7 Ou 6 9( (s. I Hl. ( 60 ( 57 (s. I H). ( (0 Ca'19'J, (46 lm H) 539 53(l (m. I H) 46ft(d I = 148 fottttd 41 8 95 " Hz. I H). 418-411 (s I H), 93-385 (s I H), 3.74 3 56 ttn. 3 H). I 84173 Im 3 Hl 127 1-". ini 2 Hl ISttv MHz DMSO-d6) 7&l ls. IH) 7 17 (4, IHI. (M ~ H]+ 98 Scc tld clitlttr ctt.'ttttlottlcr 87-90 (s. IH) 544(s 2H),.''s, IH). 469 (d. 7 = Cac 36 (clural pack (41 1(1 Hz, IH). 406 (dd. i= 134. ( I Hz. )H), 9) fotutd '162 2

(R I = II 91)r. 1H), 72 Is, IH), 368 6i ( (,2)lh . 9 . D im, H), 2 'a, )II), I 99 (a. SH't, I 8( I 73 tnt 2H) I 6( is, Hl 76 IHRMR l300 MHz. DMSO ppnt) 848 (s. IH) 7 61 (s. (M + H]+ 98 9 I'osr elututh enant amer 14tt IH). (7) (s IH), (6()(dd. 7 =98 4.7 Hz. IH). 4 ts. Ca'121, (cheat pack IGi

ID, 4 8 (a, III), 4 4I (t, I = I 4 llr, III't, 4 I ( Il. I = 13 ( & A Hz. JH). 397-3 83 un, IHl, L77 ltn J = 15 '. 104 & 6 Hz. IH). 3 68 3.2 lm, "Hl, R99(s, 6H). 204 ls. 3H) I 7& (d l = 69 Hz 2H) 77 ()f(t MHr, 1&MSO de, ppm) tl ll (a. IH't, 7 9 (s, (Vt + H)+ 9( 9 tto )0(

I tl), 7 (s. IH). & 6)t (d. I = ( 91)r. IH't, 4G ls, ('a 403 0, JH1.442 (d l = I& Hz, IH1,421-L99 ltn. IH). touttd 4tt I US 2019/0322658 A1 Oct. 24, 2019 239

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HP melba LC po nt De hMR LC;VIS Puny: ensnr omen pur ty (')

99 t 68 0, 6H), 3 58 (d. I= Ibs lt, t)tl, 04( ID, I 81 (s. 2H) 78 (Sti(t MH, I)ult(O db. ptm ) 9 I ts. I tli. 7 09 (a. I t(). (M + )lt+ 264 267 6.73 is,l H), 50IR (=8)H'Hi, - — (s.t Hl. ('a 3 0 0, (*hue( p..k K)) 47 fs. I H).419406 (m I H) )9 ts. I Hl, fottttd '149 I ) 71 I 47 (m. 3 H). 207 ts 1 H) 199 ts I Ht. 1.77 (s 2H) 'I 79 IH HMR(300:VIHz. DMSO. ppm) 764(a )H) 694 (;VI + H]+ 96 19ft )92 is IH) 564 is, IH). 53 ls. 2H) 459(tn = I fr Hz, Cac 41 9 't I H). 4 19 fnt = I 5, 5 0 Hz, I HI, L93 im = 12 I Hz. tottrtd 413 ltt IHI. 3 2 (m = )3 5, It) t) Hz, IH), 3 9 ts. 2H) 2 it6 (s. Hl 181 (s, Ht 8() ()f (1 MHr, DMSO d6) 7 21 (I, I = 8 7 H, IH). 6 )9 (ut + Ht+ 88 ttfr 90 t)0 H' (d, I = 2 6 )H), 6 86 it). I = 8 b. 2 6 H, )H). (1 49 1. i('Slit,(l 84K K)t 5. 6 is, IHL 45 (. Jll), 734 idl, I = ltt1. Jf) H . t'ml )49 I I H), 4 64 ( I. J = )5 6 H . I I I), 4 tb t I I, I = 17 4. Hz. IHi. 188 (d t= I 0 Hz IH),374 (s. 3HI. 371 )47 fm 3H) 0(t (s,3H). )75 (dd J = 82 4(t Hz. 2H) tt I I3i)A MHz DMSO.d61 tl ctl Id 1 = I 9 Hz. IHt, 7 92 (M + H]t 99 second eluting cnuttrontcr 119-121 (d. 1 = 19 Hz IH),58" is, IHI 76 la. IHl, 437 Cac 41 I clursl ps k IO is 2H) 454 is, H).43)Is. IH) 42(t(tt,J= 13 Jotlttr) 41 I " 4 Hz, IH), 4 f)94 93 (m. 2H), ft3 (dt .t = 13 l(t 7 H, IH), 57 (II, I = It -, I 01)r. IH!, 3 f)b (s, )Ht, t)6 (s, !I I), I 89 I 7 rt, Jtli

ltl IMR(4(HIM)I, M lb. I dslh 715 (I. I = 86 (ut + Ht+ tl, IH), 70 (s. )H). 691 (rh I = 8 llr. IH!, tl (1 04 04. id. J = I Hz H), 4 4 (dd. J = I) 6. I I Hz. H). fottttd St)4 ltt 410 396 (m. 2H) 378 3 60 tnt 4H). 'I 56 Is. )H). ')16 (s 3H). 08(s,3H). 194177 (rn. 3HI. I 40 fd J = I 6 Hz. SH) I 36 I 9 lm )H) 83 I H ".IMR (4(ul MHz. Metis utnl-d4 t 6 7 Vu (d, .t = tl 6 (M ~ H]4 100 Hz. IH). 666 fd t= 4 Hz, IH1,654 idd, I = 86, Cac 4179 24 Hz, IH),. 76-5 30 (m. 2H), 5 13 (s IHI,4 I Jotlttr) 41tl" idd J = 13 .. I Hz, IH). 403 (d. 1 = ll Hz. IHI 93 t 8- 0,2H), 38() 7 tm. )ltl. 373 .66

( . Ill), ) 66 3 I (m, H), f)b t I I. I = 4, I tt tl, H), 56(rl),I=I .6 H,IH),21 (d(.I= 7.8,5 tllr )H), I it I )H), rD)86( r, )Hl. I 82 (s IH), I 69 (dd. I = I) tl. 6 4 Hz I HI 84 I H HMR (400:VIHz. Metluu el d4) 6 7 14 id, I = tl 7 (;VI + H]+ Hz. IH).698 (d t= 4 Hz IH!,6.88(d. I = 88 Hz. Ca 432 tl, IH). 5 68 5 46 (m SHl. 4 24 (dd, I = I '1.6. 5.) Hz. fottttd 432 I IH1.403(d .t= ll I Hz, IH). 383-3 7 Im, SHI. 3 3rd J=1)SHz, Ht, 34(t.J=II Hz. Hl 'S ts. 3H) 19tl I 75 Int SHI, I 23 td, I = 62 Hz

1)ISMR t)tltt MH, DMSO. pp 't 8 38 (a. IH!, 7 66 7 f)l (ut + Ht+ I (to ( t, Hl 568(e,ttl) 5490) 1=7 H .IHI 5 8(s, (1 444 1. 4. f is, Hh 4 I (I. J = I(I llr. Il)1411 97 fm. I =134. t'ml 444 2 5 I Hz, IHI. 'I 89 'I 56 (rn. 3H) 'I (6 341 (m. IH). 20) ls Hl 197 (s. 'IH). I 71 (s. 2H) 86 )HRMR I 300 MHz. DMSO ppnt) 9 8) (s. IH) 7 34 (s. I Hl. (M + H]+ 98 7 (R.R) Welk f I 'lutt 687 la. IH) 5 54 td (= 143 Hz. 'IH). ('I (s, IH).465 td. Ca 427 I I = 15 4 Hz. IH) 446 4 tt3 Int, 'Hl, 3 9(r Id. J = )RA Hz Jotlttr) 42 6 9 IH). 3 78-3 't8 Im 3H), 85 ts, 3HI 2 ul ls. SH), I 78 ts. JH) IH IMR i3(!0 MHz. DMSO. ppm) 7 bl ts. IH) 6 93 (M ~ H]4 176-17ft (s. IHl 559 (s, IHL 541-53 im. )H),4 9 (nt = Cac 4 69 15 I Hz, )H). 414 (m = )3 (, 49 Hz. )H) 3 ) I 8 fotutd 427 ft ( . Ill), ) 77 348 (m, H), 19 lb. )H). 4- (s, 1)D, 1(m=76H, H),trot =4(t».lt(l. I 77(a. JH) I A6 Int = 76 Hz SH)

IH .IMR ( (D:VIHz. DMSO d6) 7.47 7 34 lm. IH). (M + H]+ 98 I Ch».il Pak )G )A7 lfr9 7t071 (m.2H) 5(6ls IH).54 (d.J= 6Hz. Ca'88'J, ID, 4 i4 ( I. J = )5 II.. 111), 4 I ) 99 (m, 3 9A rd J = ll 7 Hz, IHt, 378-34b im. 3H) 3 10- 2 79 rm SHl 221-204(tn, IHI. 199 Is. 3HI. I 85- 16 lm 4H) 159 136 (m. IH)

89 Ill IMR ()fit) M)I, t)Mso db) 74 I rrL I = I 6 Hr. (ut + Ht+ 99" ('tn. I lhd I( It)6 108 1)0,7 71)I .2H).5 7!s,lH1,54 (d,l= ('a 388 9. 234 Hz, 3H).464 Id. I = 15 I Hz IH),418-399 Jotlttr) Stltl 2 US 2019/0322658 A1 Oct. 24, 2019 240

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HP melba LC po nt De SMR LC;VIS Puny: ensnr omen pur ty (')

(m, Hl.)89(l. 1=1 f)H, Hli.)78 4 (m„ tii, (t 841,)H) 2172(t I,IH), I)m!(a, Hi, 185 162 (m. 4H), I 6142 tm. IH't

9(t I)i .IMR i)fit) M)I, t)MSO db) 4 t (a, I)tl. 7 (vt + H)+ 9 6 &'tu I Iad If 71 fm 2H) 557(s, IH). 54'I (d. J= 144 Hz. !Hl. Cs'88), 4 64 ld J = I! 2 Hz I H) 4.16 'I 9! Im. H). 3 89 (d. fotutd l8 8 I I = 12 Hz. iH) 379 3')( tn,3H). '116 77 (m. )H). 23 03 (m IHl. 199(s,3H). 188164 (m. 4HI. I 56-1 36(tn IHl 91 IH ".IMR i3tel MHz. DMSOd6) 741 ti, I = 14 Hz. (M ~ H)+ Qb Clutal Pak IG 9 -9tt IHI. '-'-'(6 .l = ' Hz 2H), '6 fs, IH). '.46 ts. Cac JH). 5 43-5 't) Im IH), 4 64 IK I = 14 tt Hz. IH) Jotlttr) Jtltl"

418399im, H)395 8 I Illl 3 93 7(m, 4H), 99 78 (m. JH), )i! (dl I, I = )2, 7 6, 4 H, IHi, 199 (e )H), I Stl I 61 tm.eH't, 15 I 6 (m,lnl 92 IH HMR(300:VIHz. DMSO. ppm) 97 (a )Hj 7 tH (;VI + H)+ 99 6 134 136 (m = 2 I Hz. iH) 7 '!7 tm = 8.5, Hz. IH). 7. I Ca'18'J, im = 8! Hz. )H) 556 (s IH),!.46 (s. H). 464 fouttd 418 tl in&= )f 0 Hz. IHl 4u8 (tn= I'» 5&! Hz. IH) tl9 " (m = 118 Hz IH), 3 76-3 51 tnt. 2H). 00 (s. JH). '7 1t. J = 64 Hz. 2Hl 2 16-2 03 (m, IHI. (Tv I» 3H). 1 76 fs 2H), 0 9" in& = 6 5 Hz bHI 't &'tu 9 itibM!f t)tltt MH, DMSO. pp 98 7 9 (m, (vt + H)+ 999 . I Ibd If 1(TO 732!(,f=77H,HI). 7)ta Illl, 4 fe,3H!,4 lis. f( 444 1. 2)i),438 (d, 1 =)53 H lit) 42) er!8 Ma l=1)L I t'ed 444 tt ti, I Hi, Ql (rl. I = )2 I )I . I Ill. 3 tte .'4 (, I = I ') lt Hz, )H). 68 (t. T= I 4 Hz )H). 3 f4 (s IHj. 99 (s Hj fl (s, 3Hl. I 77 (s. 2H) 94 IH HMR(300:VIHz. DMSO d6 ppm ls'I K) 6= (;VI + H)+ 9 68 fs. I H). 7 82 (s. I H) 7 19 M T = 8 4 Hz. I Hi. Ca'15 'J, , 23 fd J = 84 Hz.! H). 57 (s, I H), 547 (br .. 2 Hl t'ourtd 416 I "" 5 365 (m. I H) 4 69 4 63 Im, I H) 4 09 (di, " J = 13 5, 4 8 Hz I H) 92-3 87 (m, I Hl. .7s-3 5" in& 3 Hl 2 22 (d, I = 6 9 Hz, I Hl, 01 fs, 3 H) I 7, (hre, lll, I f!9 I fti I b I H), fi I fi46 (m. H). ().21 f 17 (m, H) 9 IH 'QMR ()t!ft Vtltf, DMSO d6. ppm. 3 K) 6 = )M + )I)+ H. 9.72 (a, I H), 7 N) i I, l = 2 I I Hj, i ( I I ('a 403 9. 8 7. I Hz, I Hi, 7 I (d. J = 8 7 Hz. I H). 5 (5 (s I Hl. fottttd 4A4 I ! 46 !br s. Hl. ! 3! ! 31 (m. I H). 4 67 4 6 (m I Hi 4 (!7 (dd. I = 13 5 4 8 Hz. I H) l Jl 3 87 im IHI 7 3(vlm,3H), .6(r.J=7 Hz. Hl. I 99 ts. 3 H). I 74 Ibr s. 2 Hk ! 631 56 Im. 2 H). 2 26 ft„J = 7 a Hz 3 H) 96 IH VMR (3(e) MHz. DMSO. PPm) 9.66 fs, IHI. 81 (M+ H)e 99 14u-142 (m= IH,IH),7 7(m=tl,--n.l)il.721 (( 43 0. ( = 85 H, ltik 6 (e lll),545(e. H't,464 t'ed 43 (m = I 2 H, HI),4()tl (m= )i), f! II, IH) 389 ( = 12 tt H, IH), 3 6'J ( = 13 5, 10 )I, 1ni, 3 6 (s IHj 99(s, IHl. 244 (s. IH) 218(a H). 2AA is Hj I f!2 (s. 9HL 0 90 (s. 2H) 27 IH .IMR( (D:VIHz. DMSO d6) Q72 (s. IH). 887 (M + H)+ )i( 158 ls IH) 789 (s. )Hl. 679 (s. iH) 5 5&J bi I = 138 Cr 4&16 8 Hz. 3H). 5 23 fs IH), 4 7t! IK I = 14 9 Hz. IH) 4 11 Jotlttr) 4!)6 I " (dd J = 13 ). 5 0 Hz, IH). 3 96-38&tiff!, IHl, 68 idd J = 13 5 lt!! Hz. IHj 358 (dt, I = 14 . 76 Hz. JHI. 244-227(m 2Hl, 00 is,3H). 176 ld. J= .9 Hz, JH!, I 08 Id. 3H) 98 IHSI IR ( 00 MHz. DMSO ppm) 986 (s. IH). 7 34 ts. IH). (;VI + H)+ 99 I 686 ia, IHL I (I. J = I 5 llr. 31)L Jt) M, I = 8 Hz, I ('a 441 I. Hi 4 7(t (I, I = 15 tl H', )Hi 4 43 4 2 (m. Ht, 4 I'ed 441 tt " 4 11 in&, I = 13 4 4 9 Hz. ! H), 9t! (t, l = 12 I Hz. !HI )78344(m. ')H) 84 (s JH). 28(Q. I = 75 Hz Hl. )79fs.2Hi )&13 tt T=76Hz.'IH) 99 IH 'QMR ()t!ft vtltf, DMSO d6) 7 40 (a. IH), 7 17 )M + )I)+ 99 ('h ial tb k I() 1)0 112 (s. IHl 5 66 (s, IHL 5 4&1 Id. 1 = 17D Hz SHl. -I 42 Cac 36 I (d. J = 16 2 Hz IH!, 4 003 46 itn, 7H). 2 37 (s, "Hl. Jotlttr) 36- I 20 ls. 3H) 19) )6( (m H) l(t(t i)i .IMR i)fit) MII, t)MSO db)932 ta, I)tl. 8 it (vt + H)+ )60 Io

(a. )H), 6 82 (a. I I I), 5 i I I, l = 16 H . )Ill. 5 26 ('a 4 0 9. is IHl 4 3 td, 1 = 14 Hz, IHI. 414(dd, J = 134. Jotlttr) 4 (t- US 2019/0322658 A1 Oct. 24, 2019 241

-vontfnrteu(

HP melba LC po nt De %MR LC;VIS Puny: ensnr omen pur ty (')

, I I il. 4 r)1 .'- (m, I I I). 3 7(i tdrL I = 13 4. ,IH), 6tt(l,l=94H, H),244 7( H), (t (a,)H),i 78(t, I=71)I,PH),124(a, 6)i)

lt I )H .IMR ( (D:VIHz. DMSO. pprn) 7.u8 (rn = 9 6 Hz. (M + H)+ 99 9 Cb».il Psb RG l)2 114 4H). 685 (s IH). 561(s, IH). 549 is. Hl. 5 39 Cr 4369 5 )0 fm IH) 466(m= ls Hz. IH),446 (s,2HL forutd 43 6 tr 4 04 Im = 13 4 6 0, 7 Hz tH) 'I err (rn = 12 3 Hz. I HI. 3 76 (m = 13 4, )A I Hz, )HI, '8 Is. IH). 3 . 8 (s. IHl 2()3 (s, 'tHL 1 79 (m =44 Hz, H). 131 in& = 6 9 Hz. 3H) l»2 IH IMR i3ttn MHz. DMSO. ppm) 7 81-7 73 (nr. (M ~ H)+ 99 I 14f t-142 2)i), 744 (m = 8 H, H), f)2 ts. 2) I). 5 75 (, ('a 3644. IH)43 ( =147 H IH)419r =I, 4Hr. I ti), 9 76 I . I H). 3 63 3 5 t I, I H), 3 49) (m=143 H, IH),29tl(a. II), sr)l) IH). ()3(s. )H). I Ju I 79 (m IHl. I 71 im = 84 Hz. IH) lt 3 )H .IMR ( (D:VIHz. DMSO. pprn) 5.9 5 76 im. (M + H)+ 18( 187 4H). 5 6u (m = 6 0 Hz. 4Hl 4 16 4 rf3 tnr. H). 4 ul Cr 3G) 3 : 87 tni IH) 379 ts, JHL 3 67 ls. 2Hl 359-3 I touttd . 6(r 0 " (m. H),3lul (m = 7tl Hz,3HI. 249(a. 3H) 4 (s, I HI. 2 14.2 rl) An 6Hl, I SOts, HI lr)4 IHRMR ISrlt) MHz. DMSO PPml 8 fl6 ts, IH). 6 94 (s, (M ~ H)+ 99 7 Cluirl Pab AC-(C 12tt

O'J I I)i), 6 7 (s. IH). 5 (d. I = 16 8 I I, H), I ( I. = 8 i ('a 379 I. Hz. IH). 4 74 (d l = 14 6 Hz IHI, 4 I .4 01 tnr. IH) '9 t'ound 37tl 9 (d. J = I) 8 Hz, IH). ') 76 (s. 3H! '1.7'I 'I 66 tm. IH!. 366348(m.2H) '!22 I (nt 2H).17! Is. Hi lfett, f=7 H .)H) lu IH IMR i3ttn MHz) 7 13-710 Inr, IHI, 6 84 ts. (M ~ H)+ 99 Cluirl Pab RD-(C 7ft-80 IH). 5 61 (s IH), 5 49 ts, JHL '4 is. IHl 4 81- Cac 4rf3 it 4 77 Im H) 466 (d, I = 159 Hz. IH) 4 rr7 (nt, I = forutd 4(r3 fi (t H, IH),391 (1. J = I I H% till, 74f»

5)i), 41 (t. 1 = 2 6 H . Ill), 3 tl te, IH't, 03 (s. JHI. 178 (s 2Hl

lt 6 iH .IMR ( (s) .VIHz. DMSO d6) 7.)4 7 4 lnb IH). (M+ Hj+ 99 3 7 3 7 ft (m. '!H) 5 66 (s IH). 5 48 (dd. J = 8 8. (.u Ca 3134, ti, IH), 4 5!2 (m, 2H). 442 (t. I = 15 I Hr. HI), 3.75 rdd. J = 13 6. 5 0 Hz, IH), 3 89-3 71 trn. 2H), 3.68-3 4 ttn. JHl 2 tl7-2 63 (m, 2HI, 'V ts, 3H). I 89 I 66 (m. 2H) 134-)14 (m )H) 107 i)i IMR ()tal M)I, DMSO db.pp, ».') 6 = (vt + H)+ 9 8 79 (a,lH),770il,i=8tH. )Hj, 4i(l„l= ('a 3438, 81 Hz, I Hl,. 67 (s, I Hl, 57. 52 tnr. I Hl. 547 (otlttd 344 0 (br s. H). 4 50 4 43 (m. I H). 4 11 (dd. I = 1) . 4.(t Hz. I Hl. 'I 91 'I 87 (m. I Ht. 3 80 3 67 (m. Hl, 3 6ti t A, I H), 1 99 (, 3 H) I 79 tb lub IH ".IMR (3vrl MHz. DMSO-d6 ppm) I 86 ts. IH) (M ~ H)+ 99 3 156-158 Sr) Is IH) 741 (6 .l = 8" Hz IHI, 7 Str.7 15 tm. Cac 32 4 IH). 7 f I (d J = 7 2 Hz IH!, 5.91 (s. IH). 5 7 (s forurd '125 ri Iti), 5(t(s. 2H) 427 (, 1= 133, » H .2)IL

4 if 3 Sfr (m, JH), 3 70 )4 I 21)l, I 99 (e.4H!, I 75 ts. IH) lt 3 iH .IMR( (s):VIHz. DMSO d6 ppntj 788 (4 )Hj (M+ Hj+ 99 G 189 )91 673 fs. IH) 5 (2 (s IH). 54 is, H). 5 I td J= Ca 392 7, 82 H, I Ill 468 (I, I = I 3 tl, IH) 4 ir) (m. I = 13 5 5 A Hz. IH). 3 tl9 (6 .l = 117 Hz. IH). 374- 362 tm IHl 3 f9342 lin, JHI. 2 ri6 Is. 3Hl. 199 is Hi 175(s.SHl ll(t i)i IMR ()tal MII, DMSO db. pp ) 9r)2 (a. IHL (vt + H)+ I fi)7 7.88 (a, IHL 6 77 (.. Illl, 7 49 (I, I = 16 7 H, 3) I!. ('a 4068, 5 -'. -5 19 (m. IH) 4 72 (d, l = 15 Hz. IHL 4 »9 (otlttd 4r f6 I (dd J = ll a. ( 0 Hz. IH). 3 bz (d. J = 11! Hz. )Hl 374348(m ')H) 28(q i=75Hz )H) tl7(s H),176(a,2H),it)4(l,l= 6)I, 111 IH IMR (3vrl MHz. DMSO-d6 ppm) 97tl ls. I Hl. (M ~ H)+ 158-16ft 729rd J=86Hz.lH).707(d..l= .6Hz,)H), Cac 3693 70)688(m.)H).56((s )H) 5475 l(m.)H!. forutd 169 I 4 68 (I, I = 15 il If . I H) 4 I) 94 fm. 1)tl. 2 88 (1,1=1171)r.lit).3783(tr,,'H't, 60 46 in& I Hl 198 (s, 3 H), I 8 -I 7t! Inr, Hl US 2019/0322658 A1 Oct. 24, 2019 242

-conti))rtov)

HP melon LC po nt De VMR LC;VIS Puny: enanr omen pur ty (')

I I IH 'uMR ()t)ft Ville, t)MSO d6, ppm) 7 ilk!s, l)11 (M + )lj+ ott 7 6.79 ia, IHL (.. Illl, 548 ie. SH), 27 19 ('a 4188, fmmd (m, 1nl. 4 69 (l. I = I I H, HI). 4 lt (ll, I =! 418 ! 5 ti Hf. Ill),! 94 ! 84 i, IHL! 76 64 fm. I)IL ! 64347 (m. '!H) flv ts 4H) 18!!17) rm. 2H). I 88 u 70 (m 4Hl = 11! IH .IMR ( (D:VIHz. DMSO d6 ppnt) 7 50 Id. J (M + H)+ A( f)8

7 7 Hz. I H). 7 35 ( t. 1 = 7 8 Hz. I H). 7 8 (Srs. H). Ca 3!lp 2 558(a. I H). '47(s. 2 H),476-476 Im I Hl, touttd Jt)9 I 436 Is.! H). 4 ()-416 Im I H) 394-39tt fm. I Hl. 3 3-36. Im. 2 H). 35 (brs, I H), 197 (s,3 H), I 76 fire. ') I = 114 1)l .IMR imltl VII, ('D)olk pp 1 6 66 I l. ll 8 (vt + Hj+ 218 tl, Hl, 6tH 6!la (m,0211), 5 (a, I H't, 19 fm. (1 434 0.

08 H), 5)m 19 (a. f)6 H).42tl 4- I . I Hl.42 t'ed 434 tt 4141 . Il4 H),4f)7 !771, H),! 7- 9 ( . H). )08 Im I H) '15 ts I H) 2. 'I ls. H11.9 (m 2 Hi 152 (s. 'I H) 115 IH VMR (3(lt):VIHz. DMSO d6 ppm) 7 94 7.88 (;VI + H)+ 94 4 ee = 98 20 in& 2H),677 is, IH). 6tl (s, IHl 549 is, Hl. 53tl Cac . 7tl I (s. IHl 4!8457 (m, IHr 4174 lu im. IHl. fotlttri 34tl I . 91-3 8 (m IH) 3 Sf)-34t! Int 4HI, ltt.l 9" (m. Ht, I 77 (s, 2H) 116 1)l .IMR i)fit) MII, t)MSO, pp ) 46 rs, I H), (vt + Hj+ 98 9 1481 0 674 ta, I H), 664 (, I H), 92 ts. I tli. »7 (a. I t(j. (1 447 0. (a, H), 2its,tH).47!I,IH),405(s, t'ed 447 tt I ll), , mite, I Il), 6 I ( , 4 )I), ! ! !rL I = 1) 7 Hz. Hl. 6 (s. '! H). 202 (m 3 H) 18)173 (m. Hf. 13! (s H) 117 IH IMR (3(lt):VIHz. DMSO d6 ppm) 7.14 (s. I H). (;VI + H)+ 904 ee = 978" I79 6 83 fs. ! H). ( 54 5 36 (m ! H) 5 'lf) ( (nt, I Hl. Cr 4!l62, 4.6 -4 63 itn. I H). 4 2-4 09 Im I H) 3 99- totlttri 4()6 : 9" tnr I H) 378-3.A (m, 3 H), 2 89 ts. 6 Hl. 'f3 Is. 3 H). I Su-I 67 Im 2 H) 118 IH VMR (3(a) MHz. DMSO-d6, ppm) 8 70 Is. I H). (M+ H)t 224 ce= 969'r 19ft 7 88 ta, I H), 6 78 (9 I H), 60 ts. I tli. 49 (a. — t(j. 544 5)2 im, I H), 4 6 (R f = 14 H . I H). 42tfa lti 0, I H), 97 87 (m I Hk 81 49 ( . Ht. 82(t,! Il),2ft! (..'tl. I 91.76(m, 119 IH .IMR ( f)):VIHz. DMSO. pprn) 7.41 7 (s. I Hl. (M + H)+ 982 rR.R) Welk 0 141 143 701 Is. I H). 5 62 (s. I H) 5 ('I ts Ht a 4 Ca'19 8 5 30 fm I H) 4 6) (d i = 15 0 Hz. I H). 4 16 (dd. iorutd 419 I J=i 5.50Hz IH14fl'!Sslm IH) )8 37 tnt. ')I H13 "-: 39 (m. 3 H). 20 (4,3 H), 191-172 (nt, I r) IH VMR (3(a) MHz. DMSO. PPm) 6.94 fs, - H). (M+ H)t 28 5 ce = If!0 At!- Iv 674 ta, I H), 664 (, I H), 91 ts. I tli. »7 (a. I t(j. (1 43 0. 549ia, H), 20ts,t H).470t, I H),41 t'ed 43 I I 4ftit . Hk)91 (. I H),! )40 I r,4)ll, 0-

(a. H), 1 7 6 ( r, 2 II), I ! 5 i . 3 ltl 121 IH .IMR( (D:VIHz. DMSO. pprn) I 'la rs. I H). (M + H)+ 964 ee = 387" !92 84 Is. I H) 798 (s. I H) 679 (s I Ht a 77 fls Ca'2()2 (m 4 Hi 473 4 49 (m. I H). 4 24 40u (m. H). iorutd 42() I 40034 (m.3H).203 la tH) 179ls H).1. 4

093 tni 6 H) I" IH IMR i3t!9 MHz. DMSO. ppm) 7 36 ts. I Hl. (M ~ H)+ 9" 6 cc = 95 156-160

6,." ts. I H). 6 61 Is. I H), 5 92 (s I Hl 4.54 is. I Hl. Cac 474(t 5.4 ts. 2 H). 5 25-5 18 Im I Hl 4 72-4 68 fouri6 474 r) (m. I H) 406-4 Au Inr, I Hl, '1-Rfl7 trn, I H) 6'M+ ! 67 3 5 (m. 3 H) 3 47 3 'l9 (m I H). 'I IA Afl ( .)HI, 7tt-60( r,ill),- tf)(a.311).1St) 1.72im. H),i 1(s)H) r)62r) (it . )IL () 48-t) 34 (trr. 2 H) 12! IH.IMR( (D:VIHz DMSO pprn) I 8) rs I H) H)+ 965 ee = 38! 4 !92 8 44 fs. ! H). 7 97 (s. I H) 6 79 ts I H!. 5 7'I 5 8 Ca 420 2

(m, 4 H l, 4 62 4 8 ( . I I I). 4 2tt 4 14 r,, - H), 3.95-391 itn. I H). 3 85-351 Im 3 H) 2 f13 (s. 3 Hl. 1.88-1 9 itn. '). I 33-1 07 Im 6 H) I 4 IH VMR (300:VIHz. DMSO. ppm) 704 (a I H). (M+ H)+ 96 5 ee = pa 7 4 18ft 182 6.78 is, I H),664ts, I H). 9) I, I H), tt(s,! Hl, ( a 4749, 548ia, H), 20 is,t H).47 t,)H),404( u d47 I Hk 3 96-3 77 (m. 2 H). 3 77-347 lm, 4 H) 341 US 2019/0322658 A1 Oct. 24, 2019 243

-vvn(tt)ttvv)

HP 9 LC polrrr'') Da VMR LC;VIS Puny: enanr omen pur ty

im I Hi 2 02 (s, 3 HI, I 77 (s. '). I 34 (s. Hl. = = i.if (I, I 6 6 H, H), 0 97 I I, I 6 6 H . 3 Hl I I iti IMR (rial MII DMSO,pp ) 723 rs, H), (M + Ht+ 9 8 I 5 t tip

6 6, I t. J = 7 2 Hz. 2 H). 6 lv (s 2 H) 4 Bv ls. I Hl. Cac 476 r) 4 67 fs. !H) 4 16 4 01 tm I H! '1.99 'I 47 inn 7 Hj torurd 476 tr 3 fs. ! H). I 84 (s. H) I 5 I '17 (nr. 'I Hl, I 17 I rrt 0, H), I 00 0 86 (m 3 H) 126 IH IMR (3url MHz. DMSO. ppm) 6 65 ts. I Hl. (M ~ H)+ cc = 95 16fr-162 6.63 Is.! H). 5 97 is. I H) 557 (s, I H), 549(s. '). Cac r)3 fr I Is. I H). 4 69 (d. J = )I (r Hz I H! 4 t!7 (ur. torrrrd 5()3 fl

Hl, 9A (), I H), 80.'!P (m, 12 H). 299 9(r

( . Hr, rl2 (s, ! H), I 77 ( . I tl. I 47 (a, 3 H) 127 IH VMR (3(A MHz. DMSOd6, ppm) 8 478 fr" (M+ H)t 6'5 19t!- frv (brs. I H). 6 65 (s I Hl 6 54 (s I H!. I.as (s. I Hj Cr 3614, I 44 fs. 2 H). ( 3(l I 08 (m I H) 4 8 I 4 6t! (nr, I Hl. torrrrd 161 I 42)atra 0, I H),4r)0 85 (m lci.)86379) im. " 3 H). 3 c is. 3 H). 3 51 (s 3 Hl I 9t! (s, Hl. 1.84- I AA rm 2 H) I 8 IH VMR (300:VIHz. DMSO. ppm) 7 2) (a H). (;VI + H)+ )56 IGA = ('a 6.67 i), I 7 H, H), 6 10 I - HL 4 80 (s. I 0). 477 0,

467(a,l H),4164trl I .I H).399 4, (m.7t(j. t'nct 477 tr '." (s. 3 H). I 84(s. 2 H), I 52-137 im 3 Hl, I 17 I ill (m. '! H). I tm fl 86 (rn I H)

129 IH .IMR ( (H:VIHz. DMSO d6 ppnr) 8 14 Ia I H). (M + H)+ 5 7 9 ra, I H), 6 64 (, 2 H), 6 10 ts. I Hi. 9t) s (r (1 416 8. (m. I H) 4 56-4 2tl lnt, .'I, 4 28-4.ii) ttn, I H) t'ourrd 416 I 4r)5-3 6 itn. 3 H). 376-35. (m I H) 22) ls. ! Hl. 20417 (m. 2 H). 159 113 im. 'I H) I 0 i)i .IMR (rial MII, DMSO dd. pp ) 8 82 8 78 (m. (M + H)+ 9rl 6 « = 98 0"6 I rv

Hl, 7 9A (a, I H), 6 76 (s. I H). »8 I . I Hl. I 48 ('a 4 is 2 Hl 534(s I H) 463-44t! Irrr, IH!,414 tdd. J = iorlrrri 4- I! 5u Hz. I H). '!90 (d. J = 117 Hz. I H). 381

34 fm 5 H) 338 '!3( tm Hl vl (a 3 H).

I 78 1 76 0, ') 131 IH IMR (3url MHz. DMSO-d6 ppm) I 61-1 19 (M ~ H)+ 98 - cc = 9 180 (m. I H) 858 is, I HI,Br!0 is, I H1,68 fs. I Hl. Cac 41tl 2 6'3 6 61 Is. H). I 90 I 87 (m I H) 5545 52 (m. I HI. torrrrd 418 I 4 60 4 57 (m. I H). 4 16 4 14 (m I H). '1 96 72 (m. Hl, 63 .'»4 (m, I H), 90 8 r . IH). 17(s, Hl, I 84-1 8" (rn. 2 H) tl 77.t) 61 frn, 4 H) 132 IH VMR (3(A MHz. DMSO. pprn) 6.70 ts, I Hl. (M+ H)t 8 ce = 94 3'r. 15- lt! 66 fs.lH).65(l(s. H) drl (s IH!.585(s.)HL Cr 460 9, ra, I ll),46111, I = 15 I II, I H), 4(6 ( I) mM 461 tr I Hl, 94) -0,6H),— 9 t' HI,-I is.)HI. 1.81 (s. 2 H). I 45 is. 3 H) ll! IH VMR (300:VIHz. DMSO. ppm) 7 '16 (a I H). (;VI + H)+ 97 ee = lrrrr 6 )58 ldrr 6 74 ts. I H). 6 65 (s. I H) 5 95 (s I HI a 8 (a I Hl. Cr 4769 548ia, H), 2 rs I H)47 t,) H)43 (s, t'ml 477 2 I HL4164rr (rn. I H). 39rr (d..i = 119 Hz, I Hl. :,.-." 48 (rn. 3 H). 3483 31 lrn, JHI R17 (t. I = 7 7 Hz, 3 H), (rp (s. 'I H). I 77 (s. H). I 35 (s Hl 134 IH '9MR ()r)fr VIHr, DMSO, ppm't 8 rB (a. I )IL (M + )lt+ 9tl I BIA 21 779ra, I H),577(,)H), 6tl 57fm.t c).a4 ii 416 1. (s. 2 H! 4 49-4 't4 int 3 Hl 4 10 i t t, I = 13 6. -!.7 t'ourrd 416 0 '! '1 Hz. I Hl. 397 378 (m. H). 62 id.J= I 9 Hz. I HI. '! 207 Id. J = I 4 Hz. H). I 82 (s H) I 43 I 3 ( . Hr 13 IH VMR (3(A MHz. DMSO. ppm) B.rl9 ts, I H) 7 8(l (M+ H)t 19- 21 is I Hl 5 77 (s I H) 5 68-5 7 lrrr, I Hl. "43 ts. - Hl. Cac 4(r 441 fd. J = )I 5 Hz I H) 4 lrl (dd I = 13 5. 47 toutrd 402 I

ti, I Hl, 98378(m,6 H), 67 54i . I H). f7ra, H),184(1, I=It)6H,-H) = 1)6 IH .IMR ( (H:VIHz. DMSO. pprn) 7.6'I (d. I I (M + H)+ 142 144

Hz. I H). 7. 4 id. I = 8 3, I Hz I Hl 7D6 I I,.l = Cac 4391 83 Hz. I H). I 63 (s, I H), 547 (s. 3 H). 459 (d J = torurd 439 I 145 Hz, I H!,42)M)0 (tn. I Hl 391 fd I = ll 7 Hz. I Hl. '! 8'I 'I 47 (m. 3 Hr. 268 (d I = I I Hz. I HI. 'A" (s.3 H).175(d.) = 15 Hz 8 Hl US 2019/0322658 A1 Oct. 24, 2019 244

-von(lnttvs)

HP melba LC pn nt De SMR LC;VIS Puny: enanr omen pur ty (')

I 'uMR I I 1 7 IH (I!!ft vi) lr, DMSO, ppm't ltt 18 I, H), f M + I)+ 184 0 8G tf 7.22(a,l H),679 is,t H). 94I,-H), I (c(. I= ('a 448 (('hu: 1OI&H lu SM') 794 llr. 2 I I). 4 23 4 !17 (, I II), 9- I I, I = I I 7 H, I II), 71 I I, ) = 1171(,91)l,! 16 (a. )Ih t)0 fs. 2 H). I 7( (s. H) 118 IH HMR (300:VIHz. DMSO d6 ppm 1('I K) 6 = (;VI + H)+ 998 7 9 fs. I H). 7 8'! 7 7 (m H) 7 (6 td J = ( 4 Hz. Ca 38 8. I HI.(98(brs. H).(87(d.J=(4Hz.lH) (9 fort(Cd 183 f)5 ibr s. I Hh 4 &5-449 Im. I H). 416-41 Im I Hl. 3.90-3 ( itn. 3 H). 36C!-3&6 (m I H) 320 ts." Hl. 179(bra, Ht 139 IH ".IMR (31!Cl MHz. DMSO-d6 ppm) 7.(1 ts, I Hl. (M ~ H)+ 99 fnurth lutma tsotncr 1411 f!-147 0 7.17 712 im, H), 6 (s. I H). ( 5 9 (m. t(). ('a 4. I. (* turn C hi:d p: 1 0 )) 4 7t! 4 44 0 , ' I), 4 1 7% It! (m I I Ij, 4 t 0 P. (m . =99( Hl, 84.'8 (m, H), — PD ts. I H). 2 03 (a. t(j. = I 88 I 68 0, H), I 61 ( I, I 6 9 H ldf IH HMR(400:VIHz. DMSO d6) 6761(d ! = 179 (M+ H)+ Hz. 2H!. 7 44 (d I = 8 3 Hz IH!, 6.(7 (s. IH). ( 9G Ca 448 25, is IHi 576 (d, I = ii)( Hz. IH!. (47 ts. IH! Jt fotutd 44g 2tt " is IH) 406 is, IH) 4 CH Id..l = 9 5 Hz. I HI. 8" (s. IHI 369 (s, Hh 2 0 Id. 1 = I!t! Hz. SHI, 18" is 2H) 141 IH IMR (40rl MHz. Met)7:utnl-d41 b 7 93 (d, I = I 8 (M ~ H)+ IDD sc nn i elututg tsontet H, IH), 7 77 (Id. I = 8 I, I 91)r. IH), 7 &G ld, I = ('a 4 7 0, (Sh('( lts! 'ol r m ) 8 'z, IHi, 61 -& 41 im. 3H) 432 (di, 1 = 136. fun(tel 4. 7 I ce = 98" (0 Hz, IHI. 41) '! 97 (m H!, 3.88 '1.7 (tn. Ht.! 6( (td I = )I 8. 'I 6 Hz IH!, GiJ 2 4 (ut. Hl, ' '6 (m. JH), 2 11 (a. JH), '!9 I 91 (m. Ht, 189 (s,)H) 14 IH ".IMR i4tltl MHz. DMSO.d6) 6 lt) f19 ts, IH). (M ~ H)t IDD sc nn i elututg tsontet 7 86 ts. IH) 7 (tl ld I = 8 ( Hz IH). 7 9 (d. J = lt ( Ca'12 8 (SFC IC lft olumn! H, IH), 6 6 (I. J = ( 7)fr. Ill), 84 is, 3HI. ((1 t'ml 412 1 = 9)'!

I = (a H),41!I M, 12 llr. IH), 92 I I, 1=12 Hz. IH). 37u (t I= 120 Hz, Hl. 3 4 la. IH!, 199 (s Ht I 7( (s, Hl 14! (10f MHz DVI(O d6) 67( (s IH!, 648 (s. IHj. (M + H)+ 974 first elutng mant orner ll( 117 67 I, I H), (6 (s I I I) 5 46 t, H), ( 14 (6, I = (1 74 1. t*tt . I I'K I( ) 98 Hz, IH!,47 Id. 1 = 138 Hz. IH),4001di. I = fouttcl 374 I 134 & I Hz. IH).3tlS(d .1=12 Hz, IHI. )4! Im H) 3 2 308 (m. H). (8 (r. J = 6.4 Hz. 2)ll, 01 (s. IH). I 114 I (8 t,eul 144 (lf(t MHC, 1&MSO d6) 69 ts. IH). 646 rs, IH'I, (vt + H)+ t!H 10( 5(ntt J= 162Hz 3H),(23(s,)H147 ld J= Cac . 741 ( luff( PAK IG) 1(1 Hz. IH!. 41 38 (m. 2HI 17( 144 tnt. 3Hj. fottttd 173 9 ! 11 fr.J = 83 Hz H) Rfl4(t,l = 82 Hz. H) Gt! 76 0 , I H ), 0 ( ( I I I ) I 76 !a, 14 IHRMRIJVD MHz. DMSO ppml 734 ts, IH). 6 (s, (M ~ H)+ 99, clurfl PAK IO 19 -197 IH). 5,6 (s 2H) 49( is, JHI 41 Is 2HI 3 91 hi, I = Cac 4!t I ll ( Hz IH) 365 (d 1= 12 Hz. IH). 36 34)l(m Hl. fotutd 4tl2 f) (.99 ia, Hh I 7 (a Jill 146 (lf(t MHC, 1&MSO d6) 11 I (0, IH), f - (6, I = (M + H)+ 1481 0 , 1Hz,lHi,6 9id.)=70Hz.)H),563(s,lH). Cac 3941 (49 fs. 2H! (24 (s IH).45( 424(m.4H), tl& (d fottttd 194 I I = I 6 Hz. iH) 3 7(t 3 40 tn, 3H) 'I (at (s. 3H), H), I 89 I 64 (m. 211)

147 IHRMR I Jut& MHz. DMSO ppm) 7 01 is, IH). 6 82 (s, (M ~ H)+ 1)n

IH). 5 8 (s IH), &47 ts,JHL 31 is. IHI 4 8 ts. JH). Cac 492 4 6 ld. J = 14 6 Hz IH) 4&14 (dd I = 11 4 (t Hz. I HI. 'I 89 492'ert(Cd I (R l=llgltr.)H), 74(s,(H),1( crll, I= 7. 9Hz,

46 idd, f = 5 7. 3 9 H . 41 I), - !1 ia. JH't, I 7G (d, I = 61 Hz,JHi 'I(3 148 IH .IMR ( (D:VIHz. DMSO d6 ppnt. K) 6 = 6 90 fs. I H). 6 '! (s. I H) ( (4 (s I H!. ( 46 (bt s. 1 Hl. '2 '8 0, I ll),486%82 (m 'llj,- 4." 467 (m. I H) 454-44tl lni, 1 Hl, 4 00 tdd I = 13 ( I " Hz. I Hh 3 9CIO 86 Im. I H). 3 69-3 48 Im, Hl. 2 07 la. 3 H!. I 99 (s. 3 H) I 7'I tbr s. 2 H).

149 )!I IMR (lilt) MII, t)MSO db) 7rD Ca, 1)tl 6 8, (M + H)+ 998 .)ut; I pal lm (a. )H), 8 (a. Ill), 471, JHI, t(. 1)ih 4 (9 ('a 417 0, id. I = l. 4 Hz IH), 407 tdd I = 134 lt Hz, IHI. tound 417 D US 2019/0322658 A1 Oct. 24, 2019 245

-uontn)ttuu)

HP melba LC po nt De SMR LC;VIS Puny: ensnr omen pur ty (')

= 88 1 I, I ll 7 II, !II). 3 gtt 3 41 rr, H). 2 01 (a. ;ti), 174 (6, 1 = 5!i II.. 2lii, t) 6r! (I, I =; I )I, 4H) I (t iti IMR;)f it) MII, t)MSO,pp ) I ur! (a lt!, 79il (ut + H)+ 98 8 I)9 )41 (s 2H) 7 58 (s, Hl. 7 10 (s. IH) 7 03 ts )H). 6 79 Cr 421 t), ld. 1 = 81 Hz '2H). 656 (s, )H). 596 ldd. I = 96 totutd 421 15 5 1 HZ, )Hl. 566 (S. )H) 512 ldd l=!6. 2 HZ. IH). 4 76 (d J = 14 5 Hz IH). 4 67 447 tm. H) 4184(lti (m. IH) 406395 Int 2HI,401.R86 lm. 3H). 3923 78 Im IH), -'9 ls, HHH 218(s. SH), 183(a. H) 127 (ddd, 1 = 15,64, 7 Hz ISH) I I IHBMR(30!) MHz. DMSO D201663 ts IHl.6.54(s. st st 97 Cluttl ART cellulose SB I 0 i)i), 86 (s. 2H). 5 4(t (s, III), 5 t)tt (a, Hj. 3 93 (m. I = 17.1, tl H, H), 3 68 (s. H). 3 t rs, IH), I 96 fa, )Hl. l.7f ia, 15 (Sti(t MH , t)uISO d6) 7 I 6 86 (, 4tlj, 67 (a. (M + )lt+ 998 firn) I niup,rto IH). 5 46 (s 3H). 4 5 (d. 1 = ls 7 Hz. 3H), 414 (dd. Ca 443 15, (Clutal ART cellul se HB) J=l,a Hz IH).'191(d.J=I tlHz.lH),'177 fottttd 443 I )4 Im H) 286(s. 'IH) 2ttl (s. 3Ht 176 (s, Hj I 99 I 4 IH ".IMR (3(al MHz. DMSO-d6 ppm, "53 K) 8 = (M ~ H)+ 97 first clututg cnattontcr 699(a. I H). 681(s. I H), H 61 ts I Hl H58 Mrs, 2 Hl, Cac 41!tt ( hurl pak IO-31 .34-7 30 itn. I H). 4 6u-4 5. Im I H) 4 (15 Md. t'ourid 417 r!

I = I ». 5 I H . I H), 3 M 3 51 I t, 8 tlj, -I I (a. 7 I 74 tbr s, Hl, tl 9. Is. 6 Hl )55 IH .IMR( (D:VIHz. DMSO d6 ppnt. 'IH3 K) 6 = (M + H)+ !! ) first elttt ng Hunter 66)fa.lH).66(l(S.)H) 57 (S )H!.554(a.)HH Cr 462 'J, iCheal ART cellulose HB) 461hrs,2 II), 72!t 717 im, I ltl,4 465 (m. I H) 412.4!ll Int, .'l, '!-R8» ttn, I H) 3.71-3 63 itn. I H). 3 btl-3 71 Im 3 H) 3 fH-2!8 Int. I Hl. 199 (s. 3 H). 174 tbrs. H) 140 ts. 'I Hl. 11 (I,)=pb, H) I 6 i)i .IMR (3(HI MII, ~ 0 u I ttt dr p (ut + H)+ DCI tn dcutcrnun oatdc solution ppml tenet:tttts t o Cac 4tt- tl rotamers) 6 = 786 (s. 0 'I H) 78tt(s. t) 7 H) 7. 7 (s. fouttd 4(12 I 1 Hl. 7 24 (s, 0 7 Hl. 6 39 (a, 0.7 H) H Ht3 ~ 86 lnt.

t t ( t 7 I ( 1 . 5 It ( . , !i 3 ) I ) . 5 3 8 4 I , ) I I ) . 7 ( I 4.94 (m "H) 436-42u Ini 17 H). 407O93 tni, 1.7 Hi, ." 84-3 73 (tn, 3 3 Hl, '3-3 58 (tn, I H l. 2 I Is. I Hl. (D (s. 0 9 H). I 96 I 8u tm. 2 H!. I 7 i)i .IMR (3(HI MII, DMSO dd.pp, ».'l 6 = (ut + H)+

6.61 is,l H),660tH,t H). 9-I', I H), 4(s,i 0), ('a 46 9. (('hu: I till * ll I H«SB) 546(bra, Hl, 2tl 5 17 ttn. I Hl 47 -46 fotlttcf 46 I (m I Hi 4(!4 3 84 tm. 4 H). 'I 69 I su(m. 4 H). 30) 98(m.)H).)97(s IH) 174tbts. Hj iatit, H),097(l J=96,)H)

I 8 IH ".IMR (3(al MHz. DMSO-d6 ppm, "53 K) 8 = (M ~ H)+ 99 fits't clttttttg 9 -97 cttattttotttcl'cittrttl LHO 36 ttn. 3 H). 567 (s I Hl 554- 49 Im. I Hl. Cac 4614 pak IE) 5 41 I br s. Hl. 4 50 (s. 2 H). 4 49 4 4 (m, I H) fottttd 461 I 4t!8(dd, I = li, I II, I Hi, iur!37 (m.')lh

.643 2 im, H), 88 (s. 3 H). 201 I . Itl. I 87 172 trn 2 H) 159 (iuf MHz DVIHO d6) 72fl (s IH!, 69i! (s. IHj. (M + H)+ 98 3 first slut ng mant omar 563 fs. IHi 5 (4 (s SH) 5 ltt(s, H). 463 td J= Ct 4t)5 tt )cheat ART cellul se SB) 14) llr. 111),4(!7 Ill, J = 134, 5!) Ilr. Ilf), 390 I) mM 404 I (d.)=117Hz, IH).372 Is. H),"»fltt,)=134 Hz. IHI. 2 u3 (s SHl, I 79 (s, JH) 16t IH HMR(300:VIHz. DMSO. ppm) 694(a IHj 6 )12 (;VI + H)+ 97 5 1st l(7 (a )Ht, 6 M, I = li I llr.)Hj, 1 ts. 1)I1.467 ('a 4 6 9.

(R I = ib H., lll),4 7 ia. H),4)4 86 I . )t(l. t'M 437 tt :,, tdd. J = I' 6. Iu I Hz, IH). 367 3 3(m. OH), 0 fs. )H! 179 ts SH) I t8 121(m.HH), till! (s.

t Hf

161 1 HSMR ()fttl Mtl, t)MSO, ppm) 7 14 I l. I = 16 H . It(j. (M + )lt+ 994 ftm I i»p rto 681 Is. IH) 55 (6 .)= 7(! Hz SHI, »6(s. SH) 467 ts. Cac 41tl I (ciural pack IGl IHi.41'dd 1= 13 .. 0 Hz, IH). 390 td. )=119 Hz. t'ourtd 417 9 IH).'174348(m 3Hl. 0 (a,3H).177(s. Hl 162 ()f(t MHH, DMSO d6) 7 !tt (a, IH). 7 4 (I. I = I I (ut + H)+

H, Hi, 5 8 ( . )H), 7 I! (a. SH), 464 t I, I = I ('a 4. (*hue( p. I I 3) Hz. IH). 443 (s 2H), 4 12 tdd, 1 = IR5. 4 9 Hz, IHl. fotlttcf 4- 0 US 2019/0322658 A1 Oct. 24, 2019 246

-conti)&tive)

HP me)un LC po nt De %MR LC;VIS Puny: ensnr omen pur ty (')

9)tt,f=)JJH.IH),37936 I &,2)tl,3 4ll, I = 11.& Hr, lll), - 87 Ia, H), ') tq, I = 7.6 H . H),179(a,JH),ltt4(l,l= 6)I,

16 (&f (1 MHC, 1&MSO d6) 7)9 7 r)7 rr, H) 8 ( „ (M + H)+ It)fr )0 IH). (44(s H),462(d, I = 16( Hz. IH). 4 6 Ca 4(82, (clural pack IGi 449 1m H) 44844) (m. H). 4)l tdd.J= I 4. fotutd 4(8 I ( 0 Hz, IHl. 'I 89 (d. J = ll 6 Hz IH), 3 7 3 4'I lu& 4H). Su (d J = I I I Hz, H). 2 t&fr la &H). I 97 186(nt 2H) 176 id, I = 83 Hz,4HI. 17&hl Im 3H)

164 i3&)A MHz DMSO-d617 31 Is. 7 17 ts IH). &9 I Pl!st cltttu&S 93-9 IH), (M+ H]t cue&It!outcr'clural :.. 's. IH) 5 45 (s 2H), . 38-5 29 (tn, IH). 4 69 Cac 36 pach IGl (R I = I & tl H., Ill), 4 tt6 id I, I = I . & I H . HI), & 9- I I, f = ll 8 lt, lit). 3 8 .'1!r,4HL 6 46 im. )H), 2 22 (a. Jl I), I 99 fa, H), I 76 (d. I = 6 6 H, 2) tl. I 67 (a, JH) 6'! 16( i30t )IHz DVI(0 d6,ppm) 912 ls I H) 7 f19 (a I Hl. (;VI + H]+ 90 7 Se ond elututg en mr omar 6( 673fs.!H).(4&(d J=lf&BHz &H) &2 (a C! 3(A&t (chas( pack IGi I Hl. 4 7 (d. J = I ( 4 Hz I H) 4 ll (d. I = 11.7 Hz. fotutd 149 I I Hh 39&f td I = ll 8 Hz, I Hl, '&-R4( ltn, 3 Hl. Is. 3 H). I 99 Is. 3 H) 176 (4, 2 H) 166 IHRMR(30&1 MHz. DMSO,ppnt) 851 ts. IH) 76 Is. (M+ H]t 99 ( Second lutme cnantion&et 16V IH). 639 fs 2H),602 is, IHI. 8 - 6 It&&. IH),460 Cac 41 I (clural pach IGl (a. II). 441 M, I = I( f) I fr. I I I), 4 % t) I . I = 1. t'ml 412) ,lltl.at)437 (m, H).37 (( . )=122. I I (. 4 8 Hr, )H), ! fttl (a. Jll), )6 fs, H). I 8 (f(. I = 46 H,J)tl 167 IH HMR (300:VIHz. DMSO d6) 846 (d I = I 9 Hz. (;VI + H]+ 90 ( first elur n anent orner I fl 122 IH). 7 8& (d I = I 9 Hz I HI. ( 7& (s, )H). 62 (s. Ca'121, cturil pa k IG IH). ()( (s SH).451(s, H). 4 7 is. IH1.417!dd. Iotuld 412 I J=l,&(Hz IH).'197(d.J=I)6Hz Hl.38u ldd J = 13 't. 10 7 Hz. IH), "»3 ts IH), 94 (s. SHI. 'u) (s SHl, I 77 (d, I = 37 Hz, JHI. 168 (Sttv MHz DMSO-d6) 7 I ld..! = 8.7 Hz. IHI. 699 (M ~ H]+ 98 4 fits't cltttlttg 89-91 ' cttattttotncl'CHIRBLPAK id. I = Hz IHl, 6 86 ( td, I = 8 6 2.6 Hz. I HI. Cac 3491 IGl &61, IH), 46 (s 2)I) &39 29 r, IH),464 id, I = 14 8 H, HI), 4 07 idd. I = I! 4, I H, IH). 94 t Sl A, IH),! 7() (tkL J = I &. I t2 Hz, 4H). .64. 49im,JH),2()0(a,&ll),l & (II, 1=84,4 Hz. 2H) 16& IH HMR (300:VIHz. DMSO d6 ppm) 7 (8 (s I Hl. (;VI + H]+ 98 9 Ch ral p&k IG 78(&f1 Strut! 646 fs. ) H). ( 74 (s. I H) ('ll fs I H!. 4 (9(d, I = Ca 379 8, ') 'I I ( 0 Hz, I Hl, 4 18 3 98 (m. I H). 87 77 (m. I Hl. fottttd 179 I :,,-." &9 (m. 2 H). 3. 7-344 lm, 2 H), 2 06 (s, 3 H), I&3 Is H) " 1&v i3&)0 MHz DMSO-d6,ppni) 7 t! (s IH),6(rl (s. (M+ H]t 98 Ctnral-pak-IG 7tl Ou- flu flu ID, ( 76 (a, 111), '&&2 (a. Ill), 4 &9 I I, I = 14 & I( (( 79 8. Ill), 4 IS& ttl I . IH). 3 tlv! 6 t I,)H), 3 6(t . 9 t'ml )79) (m, Hl 2 tl7 (a, &H), I 74 ( . JHi 't 17 I I )IS M!1 t&tltt MH, DMSO. pp 9 (G (a. I H!, 7 . 4 (s (M + H)+ 99. (I(,R) W Ik (tl 300 IH). 687 (s IH), ( (3 (d, I = 160 Hz. 3H). ( rs. IHL Ca 427 I, 4 6 ld J = I( I Hz IH) 44'I 406 tm. 'IH). 3 9A (d.! = fotutd 427 f& )17 Hz. )H) 379 3'!7 tm &H). 8( is. 3H),201 (s. )H). I 77 (d J = 6 0 Hz SH! 17'HRMR (30&1 11Hz. Metl&anni ppm) S.t!3 ts, tl(H) 79 (M+ H]t 1&u (s. 0 H) 643 fs 0&Hl 6VO (s, V(H), & 77 is. V.H). Cac 39 I 5 18 ts. A. H). 478-3. 7 lm. 2Hl 4.48-3 96 tm, 4H). fotlttc) . 9 D 3.9&-350 irn. JHl 316.3 flit (m,SHI, 30 td. I = 196 Hz 3Hi. I 88 fs 2H) 17) IHNI IR ( 00 MHz. DMSO ppm) Su) 7.41 (u& 2HI. (;VI + H]+ 90 Ch ral PaJ IG 732 (I, I = 7 7 H, IH). 7& t&. Iltl. & 4& (a,)Hi,4 I (a. ('a 444 I. 2)l),438 (d, 1= f&3 H lit) 42& ar)8 rna 1=1&R I t'ert 444 tt Hz. IH). 391 fd I= I 4 Hz IH1,383-3 76 tnt. 1= 124. lf Hz.)H).374360(m. iHI &6u&4 (nt.)H). '9 (s. ) H) '3 ts 3H). I 77 is, PH). )74 IH 'CMR (&t)ft Ville, DMSO d6) 74! (a. IH), 719 )M + )lt+ 996 ('hial thk (() lt)6 1(ttl (s. IHl 569 (s, IHL 54. Is. 3H),445 It, I = 16 Cac 36 I Hz. )HI. 413-3 39(m 7Hl, 40 is, 3H) 2 ti& ls fotlttc) 36- I )H). I 87 ! 64 (m SHI 17( ill .IMR (lilt) MII, t)MSO, pp ) 8 79 rs, l)ih 84tt (M + H)+ 9( (a. )H), 7 77 (m = 9 I H . Ill), 6& 0 = 9 -, I 8, Hr. ('a 3 64. IHI. 88 (s IHl, . 72 (s, IHI. 5 60 Is. 2HI, 42. fotlttc) 326 D US 2019/0322658 A1 Oct. 24, 2019 247

-con(It)&tbu)

HP melon LC po nt De bMR LC;VIS Puny: ensnr omen pur ty (')

(m = I! 2. 5 2 H, 2ll), aft! ( = I 4, 94 Hz, I Hi, .92 (m = 1&16 H, IH),! 64 tm = 12 8 H% H), — &'8 ts, H), I 87 (s. 111). I 79!a, IH)

176 iti IMR()fit)MII, t)MSO,pp ) zr)8 r, =131 (M + Ht+ 99! f'tu . I Ibd 1(t 110 )12 Hz. )H). 685 ts IH). & 61(s, IH). 5 &I (s. Hl, & 39 Cr 436 'J, 5 30 lm IH) 4 66 (m = 14 9 Hz, IH). 446 (s Hl. fo&U!d 43 6 f! dt) fs. IH) 415 395 tm PH). '191 (m = 121 Hz. IH). 'I 83 3 &I (m 3Hl. 03 (a, 3H). I 78 (m = 7 8. : 8 Hz, JHi, I!1(in = 69 Hz,!Hl 177 IH ".IMR i3&al MHz) 7 94-7 89 In&, )HI, 7 8 td. (M ~ H)+ 6!t- 67 I = 8 - Hz. IH) 7 43 (d .l = 8 0 Hz IHI, 69-5.62 Cac . 6. tl (m. IH), 4 &9 (d, I = 15 5 Hz. I H), 4 21-4 11 in!. !out!&i 363 8 iti), 9 (d,)=118)I,IH), 5tl, l=il bpz. H), »7 (I. J = 10 &! llr. Ill), 'l8 I 98 (, 31tl. i.bf is, 178. 'UMR ('8 t! I H ()i)ft Vll I,) 7 I! 7 i(i I . I Ill, 6 84 I, iM+ )(i+ otic is( )Uk kD 7tl 8() IH). 561 (s IH).! 49 (s, PH). 5 34 ts. IH). 481 Cfl'03 8

4 77 fm 2H) 4 66 ( t. 1 = I ( 2 Hz, IH). 4 07 im. 1 = fo&U!d 403 8 I! & 0 Hz. IH). 3 9) td l = 12 I Hz. IH). 3 74 (s 5HI. 34( (t .l= 6 Hz IH1,301&a. IH). 203 ls. 3H). I 78 ts 2H) 179 IHRMR 300 I IHz DMSO ppn&) 8 86 ts IH) 6 94 Is IH) (M+ H)+ 29 6 Clnr&l Pal, kG-3 6.71(a. IH) 552(s IH),547 (s, H). 5 6-51 lm, IHl. Cac 379 I

474 I = 149 If . )H).414)98 I . 89 f1, I = (I, 'Ill),! 11 9 Hz. IH) 3 76 td l = 09 Hz 3HI. - 66 (m IH). ! 6034 (m. iH) !42 !9 tn& 2H). 184 1.66 (m. Hl ! 1009 (m. ')H) 18(t ill 'UMR ()i)ft Vlllr, DMSO d6, ppm) 792!!, H), iM+ )(i+ 675 Is. I H). 5 6u Is. I H) 549 (s, 2 H), 5 36(brs, I H), Cac 37tl I 4 63 &d J = 14 8 Hz I H), 421-410 Im I Hl, !out!&i 37tl I ) 91 ld. J = ll 8 Hz. I Hl. 'I 81 3 47 (m. 4 H). 21 3 (a. SH!, I 78 (bia. 2 H) lti iti IMR i)fit)MII, t)MSO,pp ) 67! 6 9 (m, '), (M + Ht+ 599(n! 0 6 H). 57u ts. I H). 19(m, f!4 H), Cac 434r) 4 87 19 (s. 0 6 H), 4 I 4 11 (m. &! 4 H). 4 03 (m. I Hl. fo&U!d 434 I! !9 373 (m. 'I H). ') &2 tm Hl 97(m. I H).

— 28 ts, I H), 2 19 (n - H), I &9 I !, - (li, I 43 (n 2 182 IH IMR (3&el MHz. DMSO-d6 ppm) 8.67 &s, I Hl. (M ~ H)+ 95 c = 96 190

, 88 Is. I H). 6 79 Is. I H) 5 6!t (s, I H), 5 48 (s. H). Cac 39 I

'&22 ! (m. I H). 4 61 td. J = I & 4 Hz. I Hl, fort&!6 I 6'9&

4 1 8 4 08 (m, I H), 9 86 & . I H). ! 79 3

Hl, 82 (a, H), tt (s.! H). I 78 I . - Itl 183 IH VMR (3(a) MHz. DMSO-d6, ppm) 7 14 Is. I H). (M+ H)t ce= 986'r 179 6 84 fs. I H). ( &7 (s. I H) & 51 ts 2 H! & 40 & 6 Cr 4V62, (m I Hi 4 67 (d, 1 = I ( 0 Hz. I H). 4 17 (s. I Hl. fo&U!d 406 ;pbt870,IH), 78 ! (m)HL28tl(s.6Hl. &f3 Is. 3H) I tul (s 2 H) 184 IH IMR i3&al MHz. DMSO. ppm) 7 34 fs. I Hl. (M ~ H)+ 95 9 (R,RI Welk-0 14! t-142 7 01 ls. I H). 5 64 (s. 3 H) 5 31 5 45 lm I Ht. 4.61 Ca'19 8

(R I = 14 6 H'. I H), 4 16 (&bt, I = I! . 49 H, I Hi, t'ml 4191

.97 3 86im, I H), 8 51 & .4 HL206 (a. t(). I 91-1 79 (rn. 2 H) 18& IH.IMR( (M:VIHz. DMSO d6 PPn&) 87 869 Vn. (M + H)+ 93 6 I'osr eluuu8 s mer 17&! ! Hl. 79 (s. I H). 677 ts I H) & 60 ts. I Hl, &4lt Ca 4222, !Lua Cellulose 41 (s, H), 4 5!0(,)H),46)r&L I=148)I,I H), = 97 6'I 415 &dd J = 134 48 Hz, I Hl, '98htt& l&n, I Hl. 3.81-348 in!. 5 H). 3 39 tt, 7 = 60 Hz, 2 Hl Rul is H) 179176(m JH)

186 i)i .IMR i)fit) MII, t)MSO, pp ) 12 14 (a. I )Ih (M + Ht+ 9 « 180 ', =988."'7 8.6f is, I H), 7 W) ts, I H). 6 78 I I H), 6& (!, I Hl, ('a 418 5 48 ts. ') 37 ls. I H), 4 62 td, l = 149 Hz. tound 41tl I ') I Hl. 4 0 4 (!9 (m. I H). 9rl td. J = 11 8 Hz. I Hj. ! 83 348(m. 'I H). 288 ts I H) 03 ts. 'I Hl, 179 (s, H),074(I,J=68)I 2H) t)62(a )Il 187 IH IMR i3&al MHz. DMSO. ppm) 799-7 77 (n& H). (M ~ H)+ 3 36 itn. I H). 662 ts 05 H). 598- 8 un Cac 363 I f» Hl, &5 (s. 0 5 H), 4.94 (d, 1 = 144 Hz, 0 & Hl fo&U!d 163 I 432 409 (m, H),4t!8 74 t .! H).! 6 (I. I = ,Ill),221&(,&=! 9H, H),197164 ini 2 Hl US 2019/0322658 A1 Oct. 24, 2019 248

-conlunicx)

HP me)un LC po nt De XMR LC;VIS Puny: ensnr omen pur iy (')

IPH. IH 'SMR (lf)fl Vu(r, DMSO d6, ppm) 796 (d. I = )M + )I)+ satl 250 (.9 Hf. I I I), 7 tn I I I, I = tl -, I 9 H . 1111 7 61 (l. ('a 4 0 9.

I = 8 I 6 17 . )I 7 67 I H'), 4 5 ', nk ( I), ia. (s. Ill),41 (dd. J = I 6,4tl llf. IH),4()4 7) (u. )H!. ) 67 ') s'I (rn IH), 3. I (s. 'IH). )84 (s, 2H) 183 IH SMR (300:VIHz. DMSO. ppm) 10.1 (s. I Hj. (;vl + Hi+ 97 7 first elur n samer 184 fl 186 0 7 fa. I H). 6 8(l (S. I H) 5 74 (S 2 H!. 5 )4 (d, I = Ca'48 2, (Chna el ODH olrunn SI C) 8 Hz, Hl, 4 16 (d, I = 12.7 Hz. I H). 3 92 (d J = forurd 448 2 ee = lfff)', 11 Hz. I H). 382-344(m, 10 Hl Rlo(s, Hl. Lll-186 un "H) 17s id, l= 9 Hz, H) 190 IH VMR (sm) MHz. DMSO-d6, ppm) 8 3(f Id, J = (M+ Hie 140 0-142 fl (.9 Hz, IH), 811 Inf, I = 8 3, 2 fr Hz. IH). 7 . (d, Cac 3tltl 5 i=84H,IH), 8 (s.ill).)66!r,)=10,49 )1 ued )SS fr ll, IH), 4 (s. 2H)427 (fk I = 161 H, ln)414

( ..I=I 6. OH,IH) 19 I .I=104. 3nz, Hi, SS 75 (m. 10), i 661 atm. )H'), I ) 9 la. 3H) 2 f)6 ts 3H), 1.81 (m. J = 8.. 4 4 Hz. Hi 191 IH SMR(300:VIHz. DMSO d6 ppm) 7.s'I (s. I Hj. (;vl + Hi+ 90 8 tlurd slut ns sorner 14fl fl 142 0 , 36-729 (fn. 2 H). 62(s, I H),5 5-539 Inr,s H), Cac 4 ( olunnf 1 )ural pak ID)

4 off.4 46 ifn. 4 16-4 11 Inf, I Hl. L92-3 83 (m. toflrfri 4 4 9 ce = '). Iof.l'* " " I HL 3 84O 47 (m. 3 H). 3 ufl (4, H), 2 ufl (s, H), " 1.88-1 68 ifn. '). I 62 (d. I = 6 0 Hz, H) 192 (i( .IMR (1(al VII, DMSO dd. pp ) 1 (a. I )Ii (M + 0)+ I fr) !0

.'I I ('hu: I 748 7 4 0, '), 5 62 ( . I H) 5 fm. 3 Hl. mn p:6 H)) 4.6544(f(m, H),421&()2( .IH).40(38(l( t'ml 4 4') = 99 in),,sfi)460, H), 9( inh-fi(s.iu). 18 168(rn.2H).164ld.J=72Hz 1H) 133 )H.IMR( (n:VIHz. DMSO d6 ppnf) 751(a I H). (M + Hi+ 994 first elurns somer 135 0 I '17 fl 74 728 (m. 2 H). 5 62 ls I H) 5 SS 5 31 (m. 1 H). Ca'25 I (c lumn Chmlpak!D) 4 69 4 43 (m. 2 H). 4 17 4 1) (m. I HH 4 00 1 8 (m. forrrrd 424 95 ee = 39 5 I H). 3 83-'I 47 ifn. 3 H). 2 Su (s 3 H) 2 f!3 (s. 3 Hl. 191-17ff(m.2H).161(d J=6f!Hz SH) IH".IMRi4IHI MHz.DMSO-d6)6761(i, l=) 9 (M ~ Hi+ Hz. JH). 744 (d l = 8 3 Hz, IHl, 6.77 is, IH). 5 96 Cac 44tl

(s, 1)li. 76 (d. I = lf)5 11,1)l'), 5471. 10). 7 11 mn 448 20 (a. I 0!, 4 f!6 (a. I I I), 4 fn I I, I = 9 5 H, I 0). 3 tl2 (s, 1)li, 16J (s, II), 'l2 (I, I = r) tl H, ilt)„1 83 (a. 0)

1. Hk compound of formuia Ik each R's indcpcndcnlly hydrogen, or C,, ahphatic optionally substituted by 1-0) halogen: or two R'roups are optionally taken together with their intervening atoms to form a 5-8 membered partially (R '„ unsaturated Ihscd carbocyclic nng, HJXQ each of itz is independentiy hydrogen, halogen, CN, NOz, A'(O)OR. A'(O)N)t», NR2, N)t( (0)

(R )a R. NRC(O)OR. NRS(O)2R. OR. P(O)R„ SR. S(O)R. S(O)2R, S(O)(NH)R. S(O) 2NR„or R, or nvo R gmups are optionally taken together to form 0; or two R'oups are optionally taken together with their intervening atoms to foun a 8-8 mcmbcrcd saturated or a phannaceuticaliy acceptable salt thereof, wherein: spirocychc nng hdvuig 0-2 hetcronloms indcpcn- Ruig A is nng sclccted from phenyl, 4 5-7 mcmbcred dcnlly sclimled from niirogml. oxygml or sulliir: saturated or partially unsaturated carbocyclic ring, a each R's independently hydrogen„OH. or C» ali- 8-12 niembered satunuted or partially unsaturated blcy- phanc; ol clic heterocyclic nng having 1-2 heteroatoms indepen- two R'roups are optionally taken to ether to form dently selected fmm nitrogen, oxygen. or sulfur. 0 5-6 0: or niciilbcrcd hf:lfxodronlallc rnlg hdvnlg 1-1 hclclinltoills Ra in(IL7)endently selected from nitrogen, oxygen, or sul- nvo gmups are optionally taken together to form fur, or an 8-10 mcmbcred bicychc hclcroaronuitm ring CH,: or having 1-5 heteroatonls independently selected front nvo Ra groups are optionaliy taken together with their JlltrogCI). Oxy'gCO. Ol'111ful': intervening atoms to tiinn a 8-8 membered saturated US 2019/0322658 A1 Oct. 24, 2019 249

spirocyclic nng having 0-2 heteroatoms indepen- 16. The compound of claim 1. or a pharmaceutically dently ac)act&xi from iutrogcn, oxygmi or sulliir, or acccptablc salt thcrcof. whcrcui at least onc of R Is a 7-10 nvo R groups are optionally taken together with their membcrcd saturated fused bmyclic heterocyclic nng havuig intervening atoms to form a 5-8 membered satumted 1-2 hetematoms independently selected from nitrogen or bridged bicychc ring having 0-2 heteroatoms inde- oxygen pendently selected from nitrogen. oxygen or sulfur, 17.(canceled) each R is independently hydrogen or an optionally sub- 18 'I'he compound of claim I, or a phaniiaceutically men&- Rs 4-6 stituted youp selected from (', & aliphatic, a 3-8 acceptable salt thereof. wherein at least one of is a herod satumted or patt)a))y unsatumted monocyclic membered saturated monocyclic heterocyclic ring bavin carbocyclic ring. phenyL a 7-10 membered saturated 1-2 heteroatoms independentlyselected from nitrogen, oxy- spirobicyclic hctcrocyclic rin liavuig 1-2 hetcroatonm gen, or sulfur, optionally substituted 1-4 times by halogen, incl&7tendently selected from nitrogen, oxygen, or sul- OH, CH„~OCH„O. fur, a 7-10 mcmbcred saturated or partuilly unsaturated fused bicyclic heterocyclic ring having ] -2 heteroatoms independently selected from nitrogen. oxygen. or sulfur, a 4-8 membered saturated or partially unsatumted monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen. oxygen. or sulfur, or a 5-6 membcrcd monocychc hcteroaromatic mng having 1-4 hctcroatoms independently ac)ected from ilitl'OgL'll. Oxy'gCII. Oi'lllflll"I Ol': nvo R ~tops on the same nitrogen are optionally taken 19. (Cancel&xi) together with their uttcr&cnui atonm Io lhrm a 4-7 20. Thc compound of clmm 1, or u pharmaccuticdlly mcmbercd saturn&ink partially unsaturated. or hct- acceptable salt thcrcof. wherein at )cast onc of R's a 5-6 eroaryl nng havuig 0-3 hetcmatoms, ui addition to menibered monocyclic hetemaromatic ring having 1-2 het- the nitmgen. independently selected from nitrogen, eroatoms independently selected fmm nitrogen. oxygen. or oxycen and sulfur, optionally substituted with 1-2 sulhir. oxo groups: 21. (canceled) = is a single bond or a duublc bond, 22. Thc compound of clmm 1, or u pharmaccuticdlly X is ~), N(R), N(S(O)z(R)) S dcccpIabl& milt &helix)f, whcicln at lcast olu: of R is ~(O) S(O), S(O)z . CHC, CH(R') . or OR, wherein R is hydro en or C, s aliphatic C(RS)s 23. (Cancel&xi) m is 0, 1. or 2, 24. The compound of cLsim I, or a pharmaceutically n is 0. I, 2, 3, 4 or 5, and dcccpIabl& milt &helix)f, whcicln at lcast olu: of R is ~(O) p is 0. I„or 2. NR„whcrcui each of R is uidepcndcntly hydrogen, C, & Z 1 he compound of claim I, or a pharmaceutically aliphatic which is optionally substituted by a N(('I li),, acceptable salt thereof. ~herein Ring I& is phenyl. unsubstituted 3-6 membered sanirated nionocyclic carbocy- 3-6. (canceled) clic ring, or unsubstituted 4-(I membered satumted monocyclic heterocyciic ring lmving 1-2 heteroatoms indepen- 7. The compound of claun 1, ur a phamiaccutically acceptable salt thereof, wherein at least one of R's dently selected from nitrogen or oxygen, or tv o R taken (',, 4-7 mem- allpllatlc. togeIhcr with their uitcrvcning atoms to Ihnn a bered saturated and unsubsututixl ruig havuig 0-3 hcterod- 8. The compound of claun or a phannaccutically 1, toms, in addition to the nitrogen, independently selected acceptable salt thereof. wherein at least one of 8's i CI Is. from nitrogen, oxygen and sulfur 9. The compound of claun 1, ur a phamiaccutically 25. (Cmiccl&xf) acceptable salt thereof wherein at least one of 8's attached 26. The compound ol'ldun or a pharmaccutically to position 6 of the pyrimidine. 1, acccptablc salt thermif, whcrcin at least one of R's NR„ 10. Thc compound of claun 1. or a phannaccutically ol' (', whcrcin each is indcpmidmitly. acceptable salt thereof, wherein at least one of R is & h vill aliphatic, optionally substituted l-f times by halogen, o geo, 1-2 OH. NH,. OCH,. NH('(O)CHS. S(O)SCHS, C,, aliphatic vvhich is optionally substituted times by COOH, COCCH,. COICZH,, or N(CH.,)C(O) OH. CHS. 11. (canceled) 12. 'I'he compound of claim l. or a pharmaceutically acceptable salt thereof, wherein at least one of R's a 3-6 membered saturated monocyclic carbocyclic rin . 13. (canceled) 14. Thc compound of claun 1. or a phannaccutically acceptable salt thereof. wherein at least one of Rs is a 7-10 membered saturated spimbicyclic heterocyclic ring having unsubstituted 3-6 membered saturated monocyclic carbo- 1-2 heteroatoms independently selected from nitrogen or cyclic ring: oxygen. 4-6 membered saturated monocyclic heterocyclic ring 15. (canceled) having 1-2 heteroatoms independently selected from US 2019/0322658 A1 Oct. 24, 2019 250

nitro en or oxygen, which ic optionally substituted 1-2 37. (canceled) umes by CH,, ~H, C(O)OC(CH,)„or ~(O) 38 'I'he compound of claim I, or a phanilaceutically CH,: or acceptable salt thereof. wherein at least one of Ri is SR, (i niembered monocycllc heteroaromatic ring having 1-2 v herein R is unsubstinited C«aliphatic. heteroatoms independently selected from nitrogen, 39. (cmiccl&d) oxygen. or sulfur which is optionally substituted 1-2 4(). The compound of claini I, or a phaonaceutically umes by ~Hi or NHi. acceptable salt thereof, wherein at least one of R's S(O) 27. (canceled) R, wherein R is unsubstituted C,, el(phatic. 28. Thc compound of claun 1. or a phannaccutically 41. (cdncclcxi) ace& ptdblc salt thereoi; whcrcui at least one of R is NHC 42. Thc compound of clmm 1, or a pharmaccuticdlly w 1-3 (O)R. heraus R ls C, & ahphauc optionally subsututed acceptable salt thcrcof. wherein at least onc of R is S(O) tinies by halogen, ~)('Ii„N(('Ill)i, or Oil, 3-6 where is unsubstinited aliphatic or 3-6 membered 1R, R C, & membered saturated nionocyclic carbocyclic ring optionally saturated monocyclic carbocychc ring substituted 1-2 times by halogen or OH, or 4-6 membered 43. (cdncclcxi) 1-2 saturated monocyclic hetemcyclic ring bavin heteroa- 44. Thc compound of clmm 1, or a pharmaccuticdlly toms independently scliwted from nitrogen. oxy en or sulfur acceptable salt thcrcof. wherein at least onc of R is S(O) optionally subsututed 1-2 tunes by halogen, ~H, or (NH)R, wherein R is unsubstttutcd C, & allphauc. CH1. 45. (cdncclcxi) 29. (canceled) 46. The compound of chlim I, or a pharmaceutically 30. Thc compound of claun 1. or a phannaccutically acceptable salt thereof, wherein at least one of R" is S(O) acceptable salt thereof, wherein at least one of R is NI IC 1NRi. (O)OR. wherein R is unsubstituted (', aliphatic. s 47. The compound of claim 1. or a pharmaceutically 31. (canceled) acccptablc adit thcrcoi: wherein a(least onc ol'R is selccied 32. 'I'he compound of claim l. or a pharmaceutically irolll tlm gr&illP collslstulg ol: MHw MFw MH,CHH acceptable salt thereof. wherein at least one of R is NI IS (', M-=CH, (O)CR. wherein R is unsubstituted & aliphatic 33. (cdnccb:8) 34. 'I'he compound of claim l. or a pharmaceutically acceptable salt thereof. wherein at least one of Rs is OR, wherein R is: hydrogen, C,, aliphatic optionally substituted by a halogen. OH,

OH, RHi,

C(O)NHC, aliphatlc. COOH. ('(O)OC, ~ali- plrdtlr CN SOCCi daliphatic, or

(.)

&1 I'-6 niembered satumted monocyclic heterocyclic ring having 1-2 hctcroatoms independently selected from lutrogen or oxygen. 35. (canceled) 36. Thc compound of claun 1, or a phamiaceutically acceptable salt thcrcol', whcrcin at least onc of R ls P(O) Ri. ivherein each of R is independently unsubstituted (', „ allphatlc. US 2019/0322658 A1 Oct. 24, 2019 251

—clo)oH o~ 0

/ 0

Q G

0 US 2019/0322658 A1 Oct. 24, 2019 252

0 H 0 HO,

HO j.~ j..~. US 2019/0322658 A1 Oct. 24, 2019 253

-continued or a phamlaceutically acceptable salt thereof. wherein:

n's I or 2: and ~//— I&~S X..O OH R's halogen or aliphauc. // OC, 55 (cmlceled) 56. Thc compound of claim 54. or a pharmaccutically Rs acceptable salt thereof. Ivherein is halogen or ~)CI I aliphatic. 57 I'he compound of clainl 54. or a phannaceutically acceptable salt thereof, wherein R's Cl. 58 I'he compound of clainl 54. or a phannaceutically — C(0,1811 acceptable salt thereof, wherein R" is OCHC 59 (cmlceled)

48. 'I'he compound of claim l. or a pharmaceutically 60. A phamlaceutical composition comprisin a com- acceptable salt thcrcol, whcrcul at least onc oi R's C,, pound according to claim 1, or a pharnlaceutically accept- aliphatic. able salt thereof. and a pharmaceutically acceptable carrier, 49. The compound of claim 1. or a phamlaceutically attiuvtult, ol vchlclc. acceptable salt thereof. ~herein X is 0 50. 'I'he compound of claim l. or a pharmaceutically 61. A method for treating a cellular proliferative disorder acceptable salt thereof. v herein m is l. iu II ptltlelu colupllslllg adlulll&ti:llllg lo salil ptulclu a 51. The compound of claim 1. or a phamlaceutically compound according to cLaim 1, or a phamlaceutically acceptable salt thcrcol, whcrcul p is 0. acceptable salt thereof. or a pllannaceutical composition 52. Thc compound of claun 1, or a phamlaceutically thereof. acceptable salt thcrcof, whcrcin n is I, 2, 3, 4, or S. 62-64. (ctlllcclcil) 55. 'I'he compound of claim l. or a pharmaceutically acceptable salt thereof, wherein is a single bond. 65. A method tbr inducinu I:R stress in a patient in need 54. The compound of claim 1. or a phamlaceutically thereof, comprising aibninistenng to caid patient a com- acceptable salt thereof. wherein the compound is ofFormula pound accordin to clainl 1„or a phamlaceutically accept- SIII able salt thereof. or a phamlaceutical composition thereof. 66. A method for induculg thc unl'oldcd protcul response 0)PR) in a paimnt in aced thcrcof, compnsulg aihnuustenng VII to saul patient a compound according to claun 1, or a pllarmaceutically acceptable salt thereof. or a pharmaceutical composition thereof 1118 67. A method for causing calcium release from the endoplasmic reticulum (ER) via a putative Ca'hannel known as Wolfranun (WFSI) in a patient iu need thcrcof, comprising adnunisicnng to said patient a compound accorihng to claim I, or a pharnlaceutically acceptable salt thereof, or a !HP Iv pllarmaceutical composition thereof 68. (canceled) v v v