Ol'sin('HE Related U.S

Home , Benzododecinium bromide, Ridaforolimus

llIIlIlllIlIlIllIlIllIllIllIIIIIIIIIIIIIIIIIIIIllIllllIIlIllllllIIIlllIlIllIIIIIIIIIIIIIII US 20140275135A1 (») United States (12) Patent Application Publication (io) Pub. No.: US 2014/0275135 A1 GENOV et al. (43) Pub. Date: Sep. 18, 2014

(54) SAI.TS AND SOI.ID IJORVIS Olr (22) liiled: Msr. 13, 2014

ISOQUI Ij OLINONES AND COMPOSITION Ol'SIN('HE Related U.S. Application Data COMPRISIN(1 A'vD VIETIIODS SAME (60) Provisional application No. 61/789,740, lilcd on Mar. 15. 2013. (71) Applicant: Infinity Pharmaceuticals, Inc., Publication ('lsssilicstisn ('anibridge, MA (US) (51) Int. CL (72) Inventors Daniel G. GENOV, Boston. MA (US). Ct)7D 401//4 (2006.01) Louis GRENIER, Newton. )vLA (US). G/11N 31/16 (2006 01) Andrew u. IIA(IUI'., ( helmsford. MA (52) U.S. «L (J.JS); Alcsandcr Redvers 1(BERI.IN, CPC ...... Cd 7D 401//4 GP/Ãdh'168 ('anibridge (2013.01)1 ((iu); I.udouc Sylvsin (2013.01) Merc RENOU. Cambridge ((iB); 514/275: 544/324; 436/42 Susana DEL RIO GANCEDO, IJSV('...... Ctunbridgc (GB) (5 7) ABSTRACT Sohd fonus of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, phar- (73) Assigncc. Infinity Pharmaceuticslt, Inc., maceutical compositions, mid methods of treatment of dis- Ctunbridgc, MA ((JS) eases md conditions associated with kinase activity. includuig PL3 kinasc acuvity. arc descnbed hcrmn. Also providtxl hcrmn arc proccsscs for prcpanng compounds, solid fonna

(21) Appl. No . 14/209,842 thereof, turd phannaccutwsl compositions thereof Patent Application Publication Sep. 18, 2014 Sheet 1 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 2 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 3 of 54 US 2014/0275135 A1

95 90 85 80 75 /0

40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340'C FIG. 2A

1TA, 9.1880m9 Step -2.7575!, 100 -" '5'4m 95 =- 90= 85-. 25.9657K 2.385/mg 80~ 75 70 "I "I ' 9 . 9 7: 7 40 Ki 80 100 120 140 160 180 2i30 220~240 260 280 300 320 340'C FIG. 2B

04 12Ã00mo

40 60 80 100 120 140 160 180 200 220 240 260 280 'C FIG. 2C Patent Application Publication Sep. 18, 2014 Sheet 4 of 54 US 2014/027i135 A1

Wg -1

40 60 80 100 120 140 160 180 200 220 240 260 280 800 „20 340 C FIG. 3A

Wq -1

40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340'C

FIG. 3B letegrel - 24.41mJ - novelized -12,67Jg I 0neet 21 8.42 'C Wg -1

0.0

40 60 80 100 120 140 160 180 200 220 240 260 280 *C FIG. 3C Patent Application Publication Sep. 18, 2014 Sheet 5 of 54 US 2014/0275135 A1

0. /0

0,60 E Ã 0. 50

~ 0.40

4 0.30 Patent Application Publication Sep. 18, 2014 Sheet 6 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 7 of 54 US 2014/027i135 A1

R E

CCt

1 ! ! 1 T ! ! l ! ! lm CD CO (2& ~ ~ M CO CD ~ ~ C3 CG eX& LC) CFl CB CA CC CC CF& QO CO CQ CQ CO j 0$ Patent Application Publication Sep. 18, 2014 Sheet 8 of 54 US 2014/027i135 A1

Form 1

.'=orrn 1A After 24 hours standing Li ~

Form 1A After filtration

'l0 20 2 —Theta — Scale Patent Application Publication Sep. 18, 2014 Sheet 9 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 10 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 11 of 54 US 2014/027i135 A1

C CN j

i/3 p ~ C:i 93

t3 c& E lo o cudQ K V Patent Application Publication Sep. 18, 2014 Sheet 12 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 13 of 54 US 2014/027i135 A1

300

5 10 l5 20 25 30 35 40 8 -28Ideg) Patent Application Publication Sep. 18, 2014 Sheet 14 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 15 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 16 of 54 US 2014/027i135 A1

~ 8 8 8 8 g 8 8 8 8 ssmmwsIIIQN8IQQ88$8$88~ (""ivf103)v!) (SlLao0)93 Patent Application Publication Sep. 18, 2014 Sheet 17 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 18 of 54 US 2014/0278135 A1

";0)iep -0.89? 4Ã CA 3,!930ma -29. 3883e-03ma 1GG

Siep -12.48! &Xp -0.4110mg Siep 6.449'i8) 0.2'24mg

80 ~- -r 40 60 80 100 120 140 160 180 200 220 240 260 280 300 220 340'0 FIG. 13A

S)ep -1.0667'1) ! 63) 'ace CA 81 -65 88PPe-

8.8046/ 90~ .!a Sma 85~

80 -„!

40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 0 FIG. 138

Step -0.6189!. lCA 11,2966)mg — 69.997, e — 03!ai] ', 00

g)" ~ Step -14 6637/ -1.6481mg 90 -„

85-1

40 60 80 100 120 140 160 180 200 220 240 260 280 '0 FIG. 13C Patent Application Publication Sep. 18, 2014 Sheet 19 of 54 US 2014/027i135 A1

Wg -1 2,0

0',0 -0"

40 60 80 100 120 140 160 180 200 22G 240 260 280 300 220 340'"C FIG. 34A

40 60 80 100 12G 140 160 180 20G 220 240 260 280 00 32G 340'C

FIG. 34B

Wg -1; 0 09C'6200rlg -1-

2~ 'C 0 i.-e: 1 9 l.99 ~er'9 196 66'",.

40 6G 80 100 120 140 160 180 00 220 240 260 280 'C FIG. 14C Patent Application Publication Sep. 18, 2014 Sheet 20 of 54 US 2014/027i135 A1

0.60

~ 0.40 E

5 0X

0.25

~ 0,20

0.15

0 !0 20 30 40 50 60 70 80 90 x-RH(x) FIG. 15 Patent Application Publication Sep. 18, 2014 Sheet 21 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 22 of 54 US 2014/027i135 A1

1 Patent Application Publication Sep. 18, 2014 Sheet 23 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 24 of 54 US 2014/027i135 A1

co c)

I cD

CD cD CD CD cD cD CD cD cD '') C' ) Patent Application Publication Sep. 18, 2014 Sheet 25 of 54 US 2014/0275135 A1

Step -7./6?5,"r,. -0.393." Ii9

Step -9.9'i 842 -0.5'-2')

— — — — — — — r r r 1--r r r r-T r" r r r i r,, ] ] T 9 7 ] g I 1 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340"C FIG. 18A

40 60 80 100 120 140 160 180 200 ?20 '?40 260 280 300 320 340'&: FIG. 38B Patent Application Publication Sep. 18, 2014 Sheet 26 of 54 US 2014/027i135 A1

Wq -1 0.0 OSC ! 40„"Oreg btagra[ -43.34mJ — 0.4- ( aorraa[iz.d -3[296.:g -1 -06 ([, a 7 I .-"'aak [85.':.! 'C -1. 1 -1.2 -1A -r--"--r-- --v--r -T'--[-- r--f--&--T- T- 7--i-- --i--T - --T -r--[-- — T--t"- [--r--[--'- - i-- ["- T 40 60 80 100 120 140 160 180 20G 220 240 260 280 300 320 340 C FIG. 39A

1[/g --1 1,0

0.6 0.4 0.2 0.0 -0.2

40 60 80 100 12Q 140 160 180 200 220 240 260 280 300 320 340"C FIG. 19B Patent Application Publication Sep. 18, 2014 Sheet 27 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 28 of 54 US 2014/027i135 A1

(DCJEDCD&C)NCJN\DcD(-JCJED'.DER3 ]"T''T', 'T$ 'I (-JCIC)&D(- at ( I;t, T T T T i i 7 7TT, ar n&awaanac~nnac acianamnaconHC'BMOOf (SDIIJw"MM CVMCOI CGi'3M WC% C lMCM

(0/UllOJ) Ul ] Patent Application Publication Sep. 18, 2014 Sheet 29 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 30 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 31 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 32 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 33 of 54 US 2014/027i135 A1

a a

C! c «L «D F I«l canQ c c)

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V I ID «D I: I n- Patent Application Publication Sep. 18, 2014 Sheet 34 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 35 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 36 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 37 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 38 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 39 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 40 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 41 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 42 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 43 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 44 of 54 US 2014/027i135 A1

so'vent Posed in poiyrnonph ee(een

IP.I I I

THT

1-II!eTHI

I80E

iL 4eT

20 2 —Theta — Scoie FllG. 36 Patent Application Publication Sep. 18, 2014 Sheet 45 of 54 US 2014/0275135 A1

solvent used in, pollen&o:nh soreen I, I i&;;/ Met'&I-I/oni;ole I& /; (I

1 ~*

I ooetoritrile I g ) /& 00&0 »'.,'','„"':, ~) /t f"t '/

20 2 —Theta — Scale FIG. 37 Patent Application Publication Sep. 18, 2014 Sheet 46 of 54 US 2014/027i135 A1

.676 67.6 5'H------6 .6'IZ .6'06 '6 = .I I .6 6'6 = I RLl=~ 6'6 i =

.6'6 I—

'6'II'6 I = Patent Application Publication Sep. 18, 2014 Sheet 47 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 48 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 49 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 50 of 54 US 2014/0275135 A1

C10

FIG. 42 Patent Application Publication Sep. 18, 2014 Sheet 51 of 54 US 2014/0275135 A1

FIG. 43 Patent Application Publication Sep. 18, 2014 Sheet 52 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 53 of 54 US 2014/0275135 A1

Compound 1 Capsules 50 mg, 0.1N HCL, 50 rpm, 500 m::, n=5 1'l 0-— 100 90 f 80 70 -ta- Form 2 of Free Base Hydrate ~ Form 1 of blale!c Acid Salt — -a 1 Il T Form of Sulfuric Acid Salt 20. /1 10 0 0 15 M 45 60 75 90 Time 1,'min) FIG. 45A

Compound I Capsule 50 mg, pH=2.5 Pthalate Buffer, 50 rpm, 500 mL, n=5 'I 10 100 90 80 a 70 g 60 50 ~o 40 50 20 10 0 0 15 50 45 60 75 90 Time (min) FIG. 458 Patent Application Publication Sep. 18, 2014 Sheet 54 of 54 US 2014/0275135 A1 US 20]4/0275 [35 A] Sep. 18, 2014

SALTS AND SOLID FORMS OF signalin is involved in many disease states including allergic ISOQUINOLINONES AND COMPOSITION contact dermatitis. rheumatoid arthrit&s, osteoarthritis. COMPRISING AND METHODS OF USING inflammatory bowel diseases. chronic obstructive puhnonary TIIE SABIR disorder, psoriasis, inultiple sclemsis, asthma. disorders rcla&cd to diabetic complications, aud uii?anunatory ix&mpli- [0001] Tins application claims pnoniy u& U.S. Provisioi&al catious of &hc cardioi ascular sys&cm such as acu&c coro&wry Application No 61/709,740. filed Mar. 15, 2013. the entirety syndrome. of which is incorporated herein by reference [0007] Many inlubitors of P13Ks have been generated. While such compounds are often initially evaluated for their 1. BACKC&ROUND activity when dissol& ed in solution, solid state characteristics such as polymorplusm play an uuportaut role. Polymorplnc 'I [00(12J he activity of cells can be regulated by external forms of a drug subs&ance. such as m& inhib»or oi'P13K, can signals that stimulate or inhibit intracellular events. The pro- have different chemical and physical properties, includin cess by which stimulatory or inlfibitory si mals are transmit- crystallinity. melting point, chemical reactivity, solubility. ted ill&o alai w &till&1 a cell to cllclt ail il&traccllul»l rcspol&sc is dissolutmn rate, optical and mechanical properties, vapor referred to as signal transduction. Over thc past decades, pressure, and density I'hese properties can have a direct casciulcs of signal &ransducnon even&s have been clucuiutcd cffcc& on thc abili&y &o process or manufacture a drug sub- and found to play a central role in a variety of biological stance and thc drug produc&. Moreover, polymorphism is responses l)efects in various components of signal transduc- ofien a factor under regulatory review of the "sameness*'f tion patlnvays have been found to account for a vast number dn& products from various manufacturers For example. of diseases, includin numerous forms of cancer. inflamma- polymorphism has been evaluated in compounds such as tory disorders. mctabol&c disorders, vascular m&d ncuroi&al warfarin sodium, famotidine. and ranitidine Volyniorphisni discascs (Gaestcl ci al Current Medicinal C/&einis/ri (2007) can a i lect thc quality, sa 1cty, m&d/or eflicacy o I a drug producL such as a kinasc inhibitor. Thus, rcscarch directed towards 14.2214-2234). ingredients polymorphs ol PI3K uihibitors and processes I'or prcpanng [0003] Kurascs rcprcscnt a class oi importm» sigi&sling polymorphs ofPI3K inhibitors represents a siimificantly use- molcculcs. Kinascs can gcncrally bc class&lied into pro&mn ful field of investigation in the development of active phar- kinases and kinases, and certain kinases exhibit dual lipid maceutical (APIs). speciticities. Vroteil& kmases are ei&zymes that phosphorylate [0008] In addition, PI3K inhibitors have been used to treat other proteins and/or then&selves (i e . autophosphorylation) venous diseases and disorders u& humans (c.g., u& clin&cal Protein kinases can be generally classified into tluee inajor tnala). For the production ofa drug sub s&ance &n&cndcxi Ibr use groups based upon theirm'Iotasubstrate '2, utilization; tyro sine kino sea in humans, current flood Manufacturing Practices ((IMP) are wluch predonunantly phosphoryla&c substra&es on tyrosinc applicable. Procedures need to be in place that can control the rcsalucs (c.g., erb2, PDCiF receptor. EGF rcccptor, YEGF levels of impurities and ensure that API products are pm- receptor. src. abl), serine/threonine kinases which predom&- duced &vhich consistently meet their predetermined specifi- nantly phosphorylate substrates on serine and/or threonine cations. Thug a signiticant need exists for a pmcess to prepare residues m'lb&C I . A'I'IL I )NA-VK. (e g., ATM, Akt), P13K mlubi&ors suitable for human usc, par&icularly on a and dual-specificity kinases v.hich substrates phosphoryiate conuncrcial scale, that is, inter aha, safix scalablc, cflicien&, on tyrosine. serine and/or threonine residues. economically viable. an&for having other desirable proper- [0004] Lipid kinases are enzymes that catalyze the phos- ties Among other entities. disclosed herein are polyniorphic phorylation oflipids These enzymes, and the resultin phos- forms of F13 K inhibitors &vhich address these needs and pm- phorylated lipids and lipid-derived biolo ically active vide exemplary advantages. organic molccules play a role u& many diffcrcn& physiolo ical proccsscs. u&cluduig cell prolifcrauon, migra&um. adhesion, 2. SUMMARY and diffbrentiation Certain lipid kinases are membmne asso- [tgl()9J Provided herein are salts and solid forms of a con&- ciated and they catalyze the phosphorylation of lipids con- pound of formula (I) (also referred as Con£ I herein), tained in or associated with cell membrm&es. I:xan&ples of sohd forn&s ofthe salts. and methods of synthesi zine the salts such enzymes include phosphoinocitide(s) kinases (e... PI3- and solid forms. kinases, P14-Kinases), diacylglycerol kinases. and sphin- gosllu: kil&uses. 3-kinases ix&nstitute a [0005] Phosphoinositide (PI3Ks) Meo unique and conserved fanuly ofintracellular lipid kinases that phosphoryla&c the 3uGH group on phosphatidylux&artois or phosphoinositides. The P13K family compnscs 15 ku&uses with distinct substrate specificities, expression patterns. and modes of regulation 'the class I V13Ks (pl lflou p110[1, p110K and p1107) are typically activated by tyrosine kinases or Ci-protein coupled receptors to generate a lipid product termed PIP„which engages downstream eflectors such. as those in the Akt/PDKI pa&hway, mTGR. thc Tec Iiun&ly kinascs. and the Rho family GTPascs. Thc class II nnd 111 VI)Ks play a key role in intracellular tratficking, through the synthesis of VI(3)V and Vl(3.4)P2. QY [0006] The PI3K signaling pa&hway is onc ol'hc laos& highly mutated systems in bun&an cancers. V13K signaling is also a key factor in many other diseases in humans. V13K US 20]4/0275 [35 A1 Sep. 18, 2014

[00101 The solid forms provided herein include. but are not characteristic substantially identical to the reference sigrm- hnliled lo, hv'Brutes, Bnhvdlulcs, solvalcs, as well ils ixvslBI torv chiildclcnsltc uuhcalin lhc presence of lhc solid foun nl and mnorphous forms. Thc solul lilnns prov idml herein arc thc malcnal. useful as active pharmaceutical ingredients tbr the preparation of tilrnndations for use in aninlais or lnunans. 'I'lnis, 3. INCORPORATION BY REFERENCE embodiments herein encompass the use these solid forms of [0017] All pubhcauons. patents, and pa)cut applications as a hnal drug product Certain embodiments provide solid mentioned ul llus spcciticalion arc herein ulcorporalcd by with fonna useful in making firml dosage forms improved reference in their entireties and to the same extent as if each properties, c g., powder tlow propcrues, compuction proper- individual publication, patent. or patent application w:Is spe- ties, lablcting slabihly and excipicnl properties. propcrtics, cifically and individually indicated to be incorporated by compatibility properties. anlona others, that are needed for reference. manufacninng. processing, fomndation and/or storage of final drug products. Certain embodiments herein provide 4. 13RIIII'IIS( l(IPI'ION OI'I I III I)RAIYINGS pharmaceutical compositions comprising a single-component crystal foun. a multiple-component crystal foml, a [0010] FIG. IA, FIG. IB, and FICi. IC provide rcprcscntd- sulglc-conlponcnt Bnlolphoiis folnl dnd/ol B nlulnplc-conl- tivc X-ray powder diffraction (XRPD) pa u crns of a solid I'onu poncnl amorphous I'onn compnsulg lhc compound of Ibr- composing Form I of a sulfuric acul suit of Compound 1. mula (I) and a phannaceutically acceptable diluent, excipient [0019] FIC). ZA, FIG. 2B, and FICi 2C provide representa- Or CIITlel tive thermal gavimetric analysis (TC)A) thermograms of a [0011] Provided hcrcin arc methods lilr prc)tamt a sohd sohd form composing Foml I of a suit)inc acid sall of Com- filrm of a salt of('ompound I, ore solvate thereof; comprising pound I I'IC) (a) contacting ('ompound I with an acid in a solvent system or [IH)20J FI(i 3A, 111(i 313, and 3('mvide representa- exposing a material composing a salt of Compound I to a tive diiferential scanning calorimetry (DSC) themlograms of solvent system; and (b) producing and/or recovering the solid a solid form comprising Foml I of a sulfuric acid salt of foun of the salt of Compoiuld I from the mixnire resulted Conlpoiind 1. i)urn slap (a). [IH)21J FI(i 4 provides a representative gravimetric vapor [0012] Provided herein are methods for preparing a solid sorption (()YS) plot of a solid filnn comprising liornl I of a form of a Iycc base of Compound I, or a solvulc thereof, sulhiric acid salt of Compound I comprising (a) exposing a ma)coal comprisulg a sall or free [0022] FIG. 5A and FIG. 5B provulc reprcsmllalivc FT-IR base of Compound I to a solvent system, and (b) producing spectra of a solid form comprismg Iiorm I of a sulfuric acid andior recovering the solid form of the free base of Conl- salt of ('ompound I pound I from the mixture resulted front step (a). [0023] FIC). 6 provides a representative overlay plot ofthe ol'a [0013J In certain embodiments. step (b) cmnprises one or XRPD patterns ol'Form I A and Form I sulfunc acid sall more ofthe following steps (i) cooling a solution containing of Compound l. a salt or free hase of('ompound I; (ii) adding an anti-solvent, [0024] FIC). 7 provides a representative overlay plot ofthe with or without a cooing step. to cause precipitation of a solid XRPD patterns ofForm IB and Foun I of a sulfunc acid salt material comprising a salt or free base of C'ompound I, (iii) of Compound 1. cviipoi'iitulg (c.g., slow cvBpoldlton or Iasl cvdpoldfion) [IH)25J FI(i SA provides a representative 'I'(iA thenno- solution contmmng a salt or free base of Compound I: (iv) gram of a solid form comprising Iiorm 113 of a sulfuric acid slurrying a matenal compnsing a salt or free base of Conl- salt of Compound 1. pound I in a solvent system: and (v) subjectinu a nlatenal [0026] FIG. SB prus ides a rcprcsentauvc DSC thcnmi ram comprising a salt or free base ofCompound I to maturation in of a solid filnu composing Form I B of a sul fun c acul salt of a solvent system. ('ompound I

[0014J Provided herein are also pharmaceutical conlposi- [0027] FIC). 9 provides a representative overlay plot ofthe tions. sin le unit dosage fornls, dosing regimens and kits XRPD patterns ol Foml I and Foml 2 ofa sul fun c acid sall ol'onlpoiind comprising the salts and solid forms. 1. [0015J Provided herein are also methods tier treating. pre- [IH)2SJ Fi(i 10 provides a representative XRPI) pattern ofa venting, and managing various disorders usia the composi- sohd form comprising Form 3 of a sulfuric acid salt of Com- tions. salts. and solid forms The methods comprise adminis- pound I tering to a patient in need of such treatment or management a [IH)29J Fi(i 11A and III(i 1113providerepresentative T()A )hei'iipcinuxlllv'ifccnvc dnlounl of a sah ol sohd Iona pro- and I)S(: thernmgmms of a solid form comprising liornl 3 of s idcd herein. Further provided arc mclluxls of prevmllulg a sulfuric acid salt of Compound I various diseases and disorders, which comprise adnlinister- [0030] FIG. 12A, FIG. 12B, and FICi 12C provide rcprc- ing to a patient In need of such prevention a pmphylactically smllalivcXRPDpallcrnsofa solidl'onncompnsulg Form I of effective amount of a salt or solid form pnlvided herein a maleic acid salt of ('oinpound 1. [0016J Provided herein are also methods tilr analyving a [0031] FIC). 13A, FIG. 13B, and FICi. 13C pmvide repre- material for the presence or amount of a solid form pnlvided sentative TCIA thennograms ofa solid foml comprising Foml herein, comprising providing a material comprising a com- I ol B nlaiclc acid mdl oi Conlpoiuld I. pound of formula (I), or a salt, solvate. or solvate of a salt [IH)32J FI(i 14A. 111(i 14)3, and III(i 14C provide repre- thereof, or a mixture Iherixlf, aml usulg a cluudctcrizanon sentative DSC thermograms of a solid form comprising Foml method to detennulc whclhcr a signatory characteristic asso- I of a maleic acid salt of Compound 1. ciated with lhc sohd form is present m lhc nuucrial by com- [0033] FIG. 15 provides a rcprcscnlalivc CiVS plot of a paring the characteristic obtained from the nlaterial v ith a sohd filrm comprising Iiorm I of a maleic acid salt of('onl- reference signatory characteristic; wherein the existence of a pound I US 20]4/0275 [35 A1 Sep. 18, 2014 3

[0034] FICi. 16A and FICi. 16B provide representative FT- [0058] FICi. 40 provides a representative DSC themlogmlm IR spectra of a solid I'onn composing Form I ol'a malcic acid ofa solid iona compnsulg Fomi 6 ol'a frcc be ac ol'Compound salt ol'Compound l. I. [0035J I'l(i. 17A and ill(i. 17I3 provide representative [(H)59J FI(i 41 pmvides a representative (iVS plot of a XRPD patterns of a solid filrm comprising I'onn I of an sohd fornl comprising I'onn 6 of a free hase of Compound I 1.2-ethanedisulfonic acid salt of ('ompound l. [0060] FICi.42providesaviewofamoleculeofCompound [0036] FICi. 18A and FICi 18B provide representotive TCiA I in a single crystal of an acetonitrile solvate (Form 5) of themiograms of a solid form comprising Form I of an 1,2- Compound l. ctlnmcdisulfomc acid salt of Compound 1. [0061] FIG. 43 provalcs a lieu ofpartof the crystal puck- [0037] FIG. 19A and FIG. 19B provide rcprcsentativc DSC ulg of thc acctonitrdc so)vote (Foun 5). thermograms of a solid form comprising Iiorm I of an 1.2- [(H)62J Fl(i 44 provides an overlay ofthe experimental and ethanedisulfonic acid salt of ( ompound 1. calculated X RPI ) patterns ofan acetonitrile solvate (I 'orm 5) [0038] FICi. 20 provides a representative overLay plot ofthe of Compound 1. XRPD patterns ofForm I, Form 2. Foun 3. and Form 4 of an [0063] FICi. 45A and FICi. 45B provide representative com- 1.2-ethanedisulfonic acid salt of ('ompound l. parison of dissolution rates of free base hydrate, Form I of [0039] FIG. 21A provnlcs a rcprcscntauvc XRPD paucrn bis-sulfunc acid monohydratc salt, and Form I of mono- of a solid form composing Form I of a hydrocldoridc salt of malcic acid salt of Compound I ('ompound I [(H)64J Fl(i 46 provides representative comparison ofpar- [0040J I'I(i.2) I3 provides arepresentativeXRPDpatternof ticle sire distribution of 1iorm I of his-sulfilric acid monohy- a solid filrm compnsing Iiorni 2 of a hydrochloride salt of drate salt, and liorm I of mono-maleic acid salt ofCompound ('ompound I I [0041] FICi.22 providesarepresentativeXRPDpatternofa so)xi fomi comprising Foun I of an isctlnonate salt of Com- 5. DETAILED DESCRIPTION polillil I . [0042J I'l(i.23 provides arepresentativeXRPI)patternofn 5.1 Detinitions solid form comprising I'orm I of a free base of( ompound I [0065] Unless dclined otherwisc, all tcclu»cdl mid scien- [0043J I'l(i. 24 pmvides a thermogranl representative'I'(iA tifi temls used herein have the same meaning as is conmionly of a solid filrm Form I of a free base ofCompound comp n sing understood one of skill in the art. I. by [0066] As used in thc spccilication and claims. thc sui uldr [0044] FIG. 25 provides a representative DSC thcrmogrmn folio d, dn allil thc lllcl oiled riublcnci:s Ulllcss fhc ofa solid form compnsing Fonu I ofa frcc be ac ofCompound plural contcxl clearly dw(aics otherwise. I [0067] When ranges are used herein for physical proper- [0045J I'l(i. 26 provides a repmsentative (iVS plot of n ties. such as molecular weight. or chemical properties, such as solid form comprising I'orm I of a free base of( ompound I chmnica I fomndac, all combulations and sub comb usa nona of [0046] FIG.27providcsarcprcscntauvcXRPDpaucrnofa ranges aml specdic embodiments thcrcin nrc intcndcd to bc so)xi form compnsing Form 2 of a free base ofCompound l. ulcludcd. As usixl hcrmn, thc terms "about" and '*approxi- FICi. 28 provides a representative TGAthennogram [0047] nmtely" v'hen used in coiubination with a nunlenc value or of a solid filrm Form 2 of a free base ofCompound comp n sing mange of values mean that the value or mange of values may I. deviate to an extent deemed reasonable to one of ordinary [0048J I'l(i. 29 provides a representative 1)SC thermogranl skill in the art. within experimental van ability (or within a liorm e, of solid form comprising 2 ofa free base ofConlpound statistical cxpcnmcntal error), and thus the numcnc value or I. range of values can vary from, for cxamplc. bctwccn 1% and [0049] FIG. 30 provides a rc7ncscnrdtivc GVS plot of a 15%, bctwccn 1% and 10%o. between 1%o nnd 5%, between so)xi form compnsing Form 2 of a free base ofCompound l. 0 5% and 5%. and benveen 0.5% and 1%, of the stated [0050] FICi.31 providesarepresentativeXRPDpatternofa nunleric value or range of values As disclosed herein. every solid fomi compnsin Form 3 of a)Fee hase ofCompound l. instance ~here a numeric value or range of values preceded [0051] FIG.32 provides arcprcscntauvcXRPDpaucrnofa by the tenn "about'* also includes the embodiment of the solid form comprising I'orm 4 of a free base of( ompound I given value(s). For example, '*about 3'y discloses thc [0052] FICi. 33 provides a representative TGAthennogram cmboduncnt ol thc tempcraturc bmng "3'y The terms ofa solid form compnsing Fonu4ofa frccbascofCompound '*about" and "approximately" arc used completely inter- I. clmngeable throughout the disclosure 'I'he term "between" I'l(i. [0053J 34 provides a representative 1)SC thermogranl includes the endpoint number on both limits ofthe range 1 sor ofa solidfilrmcompnsing Form4ofa freebaseofCompound example, the range described by "bett( een 3 and 5** is inclu- I. sive of the numbers "3" and "5'1 As used herein, a tilde (i.e.. [0054J I'l(i. 35 provides a repmsentative (iVS plot of n '* —") proccduig a numcncal l slue or range ofvalues uidica res solid form comprising I'orm 4 of a free base of( ompound I '*about" or '*approxinnitclyy [0055] FICi. 36 and FICi. 37 provide represenmtive overLly [(H)68J As used herein. and unless othenvise specified, plots of thc XRPD pnuems of Form 5 of a Iiec base of "a eat*'r "biologically active agent** or "second active Compound l. agent" refers to a biological, pharmaceutical, or chemical [0056] FICi.38 providesarepresentativeXRPDpatternofa compound or other moiety. Non-limiting cxtunplcs include solid fomi compnsin Form 6 of a)Fee hase ofCompound l. sunplc or complex organic or ulorganic moleculca. a pcpudc. [0057] FIG. 39 provides a rcprcscntauvc TGA thcrmogrmn a protein. an ohgonuclcxitidc. an antibody, an antibody deriva- of a solid form comprising liorm 6 ofa free base ofConlpound tive, antibody fmlgment. a vitamin derivative, a carbohydrate, I a toxin, nr a chemotherapeutic compound Various coni- US 20]4/0275]35 A1 Sep. 18, 2014

pounds can be synthesized, for example, small molecules and [0074] As used herein, and unless otherv ise specified, the oltgomcrs (c.g., oltgopepudcs aml obgonuc)cxtttdcs). Bnd tenn '*cffi:clivc amount" or "therapeutically clfbclivc sv'albo)le olgaillc coulpoUiuls basixl ou vatloils core suuc- amount" rcfcrs lo an muount of a compound dcscnbcd hcrcin tures In addition. various natumsl sources can pmvtde con&- tint is sufficient to effect an intended application or effect, pounds filr screening, such as plant or aniinal extracts. and the including, but not limited to. disease treatment. as defined like. A skilled artisan can readily reco mize that there ls no herein. The therapeutically effective amount can vary limit as to the stnlctumsl nature of the a eats of the present depending upon the intended application (in vitro or in vivo). disclosure. or the subject and disease condition being treated, e.g.. the [0069] As used herein, and unless otherwise specified, the weight mid agc ol lhc sub)ccl, the seventy ol lhc discase term "agonist" refers to a compound having Ibe ability to condition, the miuulcr of aibninislralion. and Ihc bkc, wluch imlialc or enhance a biological funcuon ol a largcl protein, can be detemlined by one ofordinary skill in the arr. 'I'he tern& ts bclhcr by enhancing or ilu )mung lhc aclivtly or cxprcssion can also apply to a dose that ivi)1 induce a particular response of lhc target protein Accordulgly, Ihe term *'Ugontsl" is in target cells. e... reduction ofplatelet adhesion and/or cell defined in the context of the biological role of the target ml ration. The specific dose will vary depending on the par- pmtein IVihile agonists provided herein can specibcally inter- ticular compounds chosen, the dosing regimen to be fol- act v ith (e.g . bind to) the target. compounds that initiate or lowed, tshether il is aibnirusterixl in combulauou with other enhance a biological activity ofthe target protein by intemct- compounds, linung of;ubninistrattou, thc tissue lo wluch il is in with other members ofthe signal transduction pathway of administered, and the physical delivery system in which it is wluch Ihc target protcu»s a member arc also spccdicully curried inc)udcx) ts ithin tlus dclinilion. [0075] As used herein. mid unless othcrwisc spixilicd, lhc [00'70] As used hcrcin, and unless olherwtsc spcctlicd. thc terms "treatment", "treatin ", "palliating'* and "arneliomst- eradic- tenns "antagonist" mid "inhibitor" are used interchangeably, ing" are used interchangeably herein. and refer to an approach and )bey refbr lo a compound having Ibe ability to mlubil a for obtaining beneficial or desired results. including, but not biological function of a target protein, whether by inlubiting limited to. a therapeutic benefit and/or a prophylactic benebt. the activity or expression of the target protein Accordingly, ln one embodiment, therapeutic benefit means eradication or the temls "mltagonist** and "inhibitors** are defined in the amelioration ol'hc underlying disorder being tres)cd. In onc context of the biological role of the tar et protein Wbt)e cmboduucnt, a )hempen tie bcnelit ts Bchtcvcd with thc anlagomsts providixl herein can spccilically us)creel with ationn or amelioration of one or more of the physiological (c.g.. bind to) lhc target, mimpounds that inhibit a btolo ical symptmns associated with the underlying disorder. such that activity ol Ihc target protein by ullcraciing with olhcr mem- an impmvement is observed in the patient, notwithstandin bers of the a)gita) transduction patlwvay of which the target that the patient can still be afilicted with the underlying dis- pmtein is a member are also specifically included wit)un tlus order. For prophylactic benefit, the compositions can be debnition. In one embodiment, a biolo ical activiry inhibited adnuuistcrcd lo a patient al nsk ol dcvcloping a parucular by an antagonist is associated with the development, growth, discase, or lo a patient reporlmg oue or more ol Ihc physi- or spread of a tumor, or ml undcsirixl umnunc rcsponsc, c.g., ological symptoms of a disease. even though a diagnosis of as iuaulfcslcd lu BUloiuuuUlu: dlswssc. tlus disease can or cannot have been made [0071] As used herein, and unless otherwise specified. Bn [0076] As uses) hcrmn, and unless olbcrwisc specilicd, a Bull-cailccr agent . Bull-IUulor agent 01 chcutolbct'Bpcu- "therapeutic effect" encompasses a therapeutic benefit and/or tic agent" rcfcrs to any agni) usclul in Ihc Ircauncnt ol a a prophylactic benefit as described herem. A pmphylactic neoplastic condition One class of anti-cancer agents cons- effect includes delaying or eliminating the appearance of a prises chemotherapeutic agents. As used herein, and unless disease or condition. delaying or eliminating the onset of Othetwise specibed, "chemotherapy" nleans the administra- svulplouls of B iliscasc 01'ondition, slowiug, balling, ol tion of one or more chemotherapeutic drugs and/or other rcvcrsulg thc progression of a disc;isc or comb)ion, or Bny a ents to a cancer patient by various methods. includin combmation thereof. intravenous. oral. intramuscular, inlrapcnloncal. infravcsical, [0077] As uses) bcrctn, and un)css othcrw isc specilicd, "sig- subcutmlcous, transdcrmal, buccal, or utba)alton or in thc nul transduction" is a process during which stimulatory or )oral of B supposiloty. ulhibtlory signals arc lr;msmttlcd into and within a cell lo [0072] As used herein, and unless otherwise specified. the elicit an intracellular response A modulator of a signal trans- term "cell prob femstion" refers to a phenomenon by lvluch the duction pathway refers to a compound which moduhstes the cell number has changed as a result of division. In one activity of one or more cellular pmteins mapped to the same embodiment. this term also encompasses cell growth by specific signal transduction pathway A modulator can au- which the cell morpholocy has changed (e... increased in mcut (agomst) or suppress (antagonist) lbc acuvity of a sig- size) consistent w lib a prolllcrBllvc st+ra). naling ulolcclllc. [00'73] As used hcrcin, and unless olherwtsc spcctlicd. thc [0078] As used herein, and unless otherv ise specified, the tenn *'co-aibninistrauou." "adnnmslcrcd ul combululton tenn "sclccuvc inlubttion" or '*sclccuvcly udubtt" as applied with and their grammatical equivalents, encompasses to a biologically acuvc agent refbrs lo the agent's ability lo administration of two or more agents to an animal either selectively reduce the target signaling activity as compared to simultaneously or sequentially. Jn one embodiment, both off-tar et sifts)ing activity, via direct or interact mteraction a ents and/or their metabolites are present in the animal at the with the target same tnuc. In one cmboduncnt, co-aibnuuslratton ulcludcs [IH)79J As used herein. and unless Otheiwise specified. the simulnmcous administration in scparatc compost)tons, term "tn vivo" refers to an event that takes place in a subject's adnumstration el diffi rent )uncs ul scqtaratc compost t ious, or body. administmltion in a composition in which both agents are [IH)80J As used herein. and unless Otheiwise specified. the prcseltt. term "in vitro" refers to an event that takes places outside of US 20]4/0275 [35 A1 Sep. 18, 2014

a subject's body. For example. an in vitro assay encompasses ing the surface of a solution with Bn implement to induce any assay run outsulc of a subiecl assay. In vtlro assuys compound precipitation), and distillat&on techniques lqecov- encompass cell-based essays u& wluch cells alive Or dead arc enn one or more compounds can involve preparation of a employed. In one embodiment, in vitro assay& also encon&- salt, solvatc, hydrate, chclatc or other complcxcs of Ihc same. pass a cell-free assay in which no intact cells are employed. then collecting or separating as described above. [0081[ "gublecf'o which administnltion i ~ contemplated As us&xi hcrcul, a *'phanuaccut&cally acccptablc includes. but is not limited to, humans (i.e.. a male or female [0085] form" of a disclosed Fom&OIB (I) includes, but is not limited of any Bge group. e.g., B pediatric subject (e, infbnt, cluld, m&1&s. chc- adolescent) or adult subject (c g., young udult, middle-aged to. plmnnaccut&cally acceptable hydrates, solvatcs, adult or semor adult)) and/or other primates (c.g., cynomol- lates, non-covalent complexes, isomers. prodrugs, and isoto- gus monkeys, rhesus monkeys). manunals. includm com- p&cally labclcd dcriiativcs ther&x&f, m&d nuxturcs Ihcrmif. mercially relevant mammals such as cattle, pins, horses, I lence, the terms "chemical entity" and "chem&cal entities" sheep. goats, cats, and/or dogs; and/or birds, including cons- also encompass plmnuaceutically acceptable salts, hydrates. mercially relevant birds such as chickens. ducks, geese, quail, solvates, chelates, non-covalent complexes, isomers, pm- and/or turkeys. dn&gg and isotopically labeled derivatives. and n&ixtures [0082] As used herein, and unless otherwise specified, thereof. In some embodiments. a phannaceutically accept- '*red&ation therapy" means exposing a pat&cnt, usmg routine able fom& of a disclosed Fomlula (I) includes a salt, a solvate. methods andcompos&uons known iolhcpract&&&oner,&orudu&- or B hydrate thereof. tion mnitters such as alpha-particle emitting radionnclides [0086] In certain embodunents, thc phannaccutically (e .. actinium and thonum radionuclides), lov linear energy acceptable foml is a phanuaceutically acceptable salt As transfer (i,l 91 ) radiation emitters (e o .. beta eniitters). conver- used herein, the term "phanuaceutically acceptable salt" sion electron emitters (e.g., strontium-89 and samarium-153- refers to those salts lvhich are, within the scope of sound EDTMP). or h&gh-energy radiation. including without limi- medical judgment, suitable for use in contact with the tissues tation. x-rays, gamma rays. m&d neutrons. of subjects without undue toxicity. irritation. allergic [0083] As used hcrcu&, the term "comb&mng" rcli:rs to rcsponsc and thc like. and arc conunm&surete w&th a rcason- bung&ng onc or more chcnucal ca&ilies in&o assoc&ation w&th ablc bcnclit/msk ratio. Phannaccuticdlly Bcccptablc salts arc another one or more chemical entities. (:Ombining includes well known in the art i&or example, lierge et al describes the pmcesses of addmg one or more coinponnds to a solid, plmrmaceutically acceptable salts &n detail in 9 I'l&uriiiucea- liquid or gaseous mixture of one or more compounds (the /icdl Sr/Cares (1977) 66 1-19 Pharmaceutically acceptable same or other chem&cal entities), or a liquid solution or nnd- salts ofthe compounds provided herein include those derived tiphasic liquid mixture. The act of combinin includes the from su&table inorganic and organic acids Bnd bases. Inor- ploccss 0& processes of 01&c 0& &nore co&upi&i&luis Iciicl&llg gan&c acids from wluch salts can be dcrii ed include, bui Brc (c.g.. bond fom&ation or clcavagc, sall li&rmat&on, solvatc not linutixi to, hydrochlonc ac&d, hydrobrom&c ac&d, sulfunc formation, chelation, or other non-bond altering assoc&ation) acid. Bitnc acid. phosphonc seal, and thc hkc Orgaiuc acids with one or more compounds (the same or other chen&ical from which salts can be derived include, but are not limited to, entities). The act ofcombining can include alteration ofone or acetic acid. propionic acid, glycolic acid. pyruvic acid, oxalic more compounds, such Bs by isomerization (e... mutomer- acid. maleic acid. malonic acid, succinic acid. fumaric acid. ization, resolution of one isomer from another. or nlcemiza- tartaric acid. citric acid, benzoic ac&d, ciiummic acid, man- Iion). dchc amd, mcthancsulfonic ac&d, ethm&esullonic acul. p-Iolu- [0084] As used hcrmn, thc tenn '*recovcnng" includes, but cncsulfonic acid, sal&cylic acid. and thc 1&kc Exmuplcs of is not lunitcd to, Ihc action of obtauung onc or morc com- phum&accul&cally acceplablc. nontox&c Bc&d add&uon &aim arc pounds by collection during andior after a pmcess step as salts of an amino group fora&OI w&th imlrganic acids such as disclosed herem, and the action of obtaining, one or n&ore hydrochloric acid, hydrobromic acid, phosphoric acid, sulfu- compounds by sepamtion of one or more compounds fmm ric acid and perchloric acid or with organic acids such as one or more other chemical entities d&uin and/or after a acetic acid. oxalic acid, maleic acid, tartaric acid. citric acid. process step as d&scloscd hcrcu&. Thc tcm& '*collcmuon" rcfcrs succ&n&c ac&d or malumc ac&d or by usu& other methods us&xi to mly action(s) known u& the an for dus purpose. including, u& Ihc art such as ion exchm&gc. Other pharmaccutically but not linutcd Io, liltrauon. deem&un a mother liquor from a dcccptdblc sails include ad&pate, algumtc, Bscorbatc, aspdr- solid to obtam one or more compounds. and evaporatiim of tate, benzenesulfonate. besylate, benzoate, b&sulfate, borate, liquid media in a solution or other n&ixture to afi'ord a solid, butynlte, camplxlnlte, cainphorsulfonate, citnlte, cyclopen- oil. or other residue that includes one or more compounds. tanepmpionate, di luconate. dodecylsulfate, ethane- The solid can be crystall&ne, acrystalline. partially crysmlhne, sulfonate. formate. fumarate, glucoheptonate. glycerophos- dlllolphous, col&mill&Jig ollc ol 11&olc pi&lvlllolphs, B powdcl, ph'd&C, gluCO&u&IC, hC&u&S&illa&C, lleptalloate, hCXBI&oa&0, granular, of varying paruclc ~ ides, of umform part&clc s&zc,VBI)'n hydroiodidc, 2-hydroxy-cthancsulfona&c, lactobionaic. lac- dlllollg 0lhCI cia&dc&Olla&les k&low &1 &11 I he &O'I. Au 011 Ciill tate, lmiratc, Im&ryl sulfate. malatc. malcatc, malonatc, mcth- color and viscosity, and include one or more solid foun& as anesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, a hetemgeneous mixture. among other characteristics known oleate, oxalate, palmitate, pamoate. pectinate, persulfate, in the art. The tenn "separation" refers to any action(s) known 3-phenylpropionate, phosphate. picrate. pivalate, propionate. in the Brt for tlfis purpose. includin, but not limited to, stearate, succinate, sulfate, tartrate. th&ocyanate, p-toluene- isolating onc or morc compounds lrom a solutton Or mixlurc sulfoimtc. undecanoatc, valcrate salts, m&d Ihc 1&kc. In some using, for example, sccdcd or acedlcas crystal h zalain Or other cmboduncnts, organic acids Ibom v&luch salts can bc dcnvixl proc&p&talion Icclu»ques (c.g., addu&g un Bnt&-solvenl lo a u&cludc. for example, acct&c acid, prop&on&c ac&d, glycol&c solution to induce compound precipitation; heating a solu- acid, pymvic acid. oxalic acid. male&c acid, nlalonic acid, tion, then cooling to induce compound precipitation; scratch- succinic acid, fumaric acid, tartanc acid, citric acid, benzoic US 20]4/0275 [35 A1 Sep. 18, 2014

acid, cinnamic acid. mandelic acid, methanesulfonic acid, verted under physiological conditions or by solvolysis to a ctlumcsulioruc acid. p-tolumlcsulioiuc acid, wilicylic acid, biologically active compound desvnbcd herein. Tlms, thc and thc like. tenn '*prodrug" rclbrs to a precursor of a biologically active [0087] PharlIIBcciltlcallv dcccptdblc salts dcrivcd from compound that is pharmaceutically acceptable A prodrug appropriate bases include alkali metal, alkaline earth nletal, can be inactive when administered to a subiect. but is con- ammonium and N+((', dalkyl) -salts Inorganic bases front verted in vivo to an active compound, for example, by which salts can be derived include. but are not limited to, hydrolysis. hi some embodiments, the prodrug compound sodium, potassium. lithium. anunonium. calcium. ma ne- offen offers advantages of solubility, tissue compatibility or Siuttl. Iroll, LIUC. CoppCI; illanganCSC, JIUUIIUU111, Jnd thC llkC. dclaycd release In a manunalimi or unism (scc, c g., Bund- Organic bases I'rom w luch salts can bc denvcd uicludc, but arc gard, H.. Design ofProdrugs (1985), pp. 7-9, 21-24 (Elscvier. not htuitcd to. pnmary. secondary, and tertiary amines, sub- Amsterdam). A discussion of prodrugs is provided in I iigu- stituted amines, includmg naturally occurring substituted clu, T., et al.. "Pm-drugs as Novel Delivery Systenlsy A.C 8 amineg cyclic amines, basic ion exchange resins, and the like, Symposium Series, Vol. 14, and in Bioreversible Carriers in examples include, but are not limited to. Isopropyiamtne, Dru Desi ul, ed. Edward B. Roche, American Phamlaceuti- cal Association and Pergamon Pres~, 1987, both ofwhich are trimethylamine. diethylamine, triethylamine, tripropy- " lamulc, and cthanolaminc In some embodiments, thc phar- ulcorporatixi ui full by rcii:rcncc hcrcin Thc term "pmdru maccutically acccptablc base addiuon suit is;ulunonnun, Is uBo meant to include any ixiva lently bonded cam era. w luch potasslilill. sodiUUI, calclUUI, ol nlagncsllinl sJIB. Rcplcscll- release the active Iiorinula (I) in vivo lvhen such prodrug is tative alkali or alkaline earth metal salts include sodiunl, administered to a mammalian subject Prodrugs of an active 1 i thtllln, potBisiUIU, c,'lie iUBI, tu,'lglleslUm. Inlil, vine, coppcn compound, as described herein, can be prepared by modify- man anese, aluminum, and the like. Further phamiaceuti- ing functional groups present in the active Formula (I) in such cally acceptable salts include, when appropriate. nontoxic a way that the modifications are cleaved. either in routine dlnnloluiinl, IIIIB(ixlldi) Blnnlonltllll. Jnd BUIIUC CBtlonS mampulation or ui vivo, to thc parent active compound. Pro- fornuxl using co untcrions such as halide, bydmxulc. carboxy- drugs include compounds whcrcul a hydroxy, amino or mcr- is to that. the late, sulfate, phosphate, nitrate, lower alkyl su 1 gnri (e and aryl capto group bonded any group when prodnlg of sulfimate Organic bases fmin which salts can be derived the active Formula (I) is administered to a manlmalian sub- include. filr example. primary, secondary, and tertiary ject, cleaves to form a free hydroxy, free amino or free mer- amines, substituted amines including natumlly occurrin capto group. respectively. Examples of prodrugs include. but substituted amines, cyclic amines, basic ion exchan e resins, are not limited to. acetate, fonnate. and benzoate derivatives and thc like, such as Isopropylamuic, trimcthylammc, dicthy- of iin Blcolloh oi Bcctanlldc. fonudluldc. dnd bcnLalllldc liinlinc, tllcth)'IBnllnc, tnpropvlaluinc, dnd ctllalnlliinlinc. In dcnvativcs ol an aminc functional group ul thc acuvc com- some embodunmlts, thc plrdrmaccuticdlly ucccptablc base pound, and the like. Other examples of prodrugs include addition salt is chosen front ainmonium, potmsium, sodiunl, compounds that coinprise NO, NOz, ONO. or calcium. and magnesium salts l3is salts (i.e, tv o counteri- ~)NOz moieties Prodnigs can typically be prepared using ons) and higher salts (e.g.. tluee or more counterions) are v ell-known methods, such as those described in Bttrgcr's encompassed within the meaning of phamiaceutically Mcdicinai Cgcinisiri and DnigDisco verv, 172-178, 949-982 acceptable salts. (Manfred E. Wo ill cd., 5 th cd., I 995), and Design of Pro drags [0088] Inaddiuon, if a compound of die present disclosure (H. Bundgaard ed., Elscliier. Ncw York. 1985). is obtained as mi acid addition salt, thc I'rce base cun bc [0091] For example. if a disclosed compound or a phannd- obtained by basifying a solution of the acid salt Conversely, ceuticaliy acceptable form of the compound contains a car- if a pmduct is a free base, an acid addition salt. particularly B boxylic acid functional group, a prodntg can comprise a pharmaceutically acceptable addition salt. can be produced plmrmaceuti cally acceptable ester formed by the replacement by dissolving the free base in a suitable organic solvent and ofthe hydrogen atom of the acid ~cup v ith a group such as treating the solution with an acid. in accordance with conven- (Ci C's)alkyl. (CB-C„)alkanoyloxymethyl, I -(all anoyloxy) tional procedures for preparing acid adihtion wilts from base ethyl luiving irom 4 to 9 carbon atoms, I -methyl-I -(all anoy- compounds Thosv. skilled in thc art will recognize various loxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbo- synthetic methodologies that can bc used to prcparc non-toxic nyloxymcthyl havuig from 3 to 6 carbon atoms, pharmaceutically acceptable addition salts I-(alkoxycarbonyloxy)ethyl having fmm 4 to 7 carbon [0089J In certain embodinlents, the pharmaceutically atonlg I -methyl-I -(alkoxycarbonyloxy)ethyl having fmm 5 acceptable form is a "solvate** (e.g., a hydrate). As used to 8 carbon atoms. N-(alkoxycarbonyl)aminomethyl bavin herein, the term "solvate" refers to compounds that further from 3 to 9 carbon atoms. I -(N-(alkoxy carbo nyl)amino)ethyl include a stoichiometnc or non-stoichiometric amount of huving from 4 to 10 carbon atoms. 3-phthalidyl. 4-cmtono- solvent bound by non-covalent uitcrmolcx:ular forces. Thc lactonyl, ganuua-butyrolacton-4-yl, di-N,N (C,-CC)alky- solvatecan be ol'a disclosed compound or a phannuccuticully lanuno(Cz-C,)alkyl (such as [3-dimcthylaminocthyl), cdr- acceptable salt thereof Where the solvent i ~ v ster. the solvate bamoyl-(C, -('.z)alkyl, N.N-di(C,-Cz)alkylcarbamoyl-(C,- is a "hydrate" Phanuaceutically acceptable solvates and ('z)alkyl and piperidino-, pyrrolidino- or morpholino(( z-Cs) hydrates are complexes that. for example. can include I to allzyl abolut 100, or I to about 10, or one to about 2. 3 or 4. solvent [0092] Similarly, if a disclosed compound or a pharmaceu- or water molecules. In some embodiments, the solvate can be tically acceptable form of the compound contains an alcohol '*com- a clmniml solvatc. It will bc understood that die tenn funcuoiuil group. a pro drug can bc formed by the rcp1acement pound" as used hcrcin cnixlmpasscs ihe compoiuid and sol- ofthc hydrogen atom of thc alcohol group with a group such vates of the compound, as well as mixtures thereof as (C, -Ci)alkanoyloxymcthyl, 1-((C, -Cd)alkattoyloxy)ethyl. [0090J As used herein, and unless othelwise spemtied, I -nlethyl-(((',-Cs)alkanoyloxy)ethyl((',-Cs)alkoxycarbo- "prodrug" is meant to indicate a coinpound that can be con- nyloxymethyl, N ((',-Cs)alkoxycarbonylaminonlethyl, US 20]4/0275 [35 A1 Sep. 18, 2014

sUcctllovl. (Ci Co)alkanoyl, ix-amino(CI C4)alkanoyl. Bty)a- include all such possible isomer~, including racemic mix- cyl and ix-aminoacyl, or 0-anunoacyl-0-ummoacyl. where (Urea, optically'Ubs(Bnnilllv pUic fornls Jnd uucinu:ihatc each 0-auunoacyl group is indcpcndcntly sclcclcd from thc nuxturcs. Optically active (R)- and (S)-isomers can bc pre- naturally occurring I -amino acids, P(O)(OI I),, P(O)(O pared, for example. using chiral synthons or chiral reagents, ((:I-('o)alkyl)z or glycosyl (the radical resulting from the or resolved using conventional techniques removal of a hydroxyl group of the hemiacetal form of a [0097] As used herein, and unless otherv ise specified, the carbohydrate). tenn "stereomerically pure" means a composition or sub- [0093] If a disclosed compound or a phamlaceutically stance that comprises one stereoisomer of a compound and is acccptablc foml ol thc Formula (I) ulcorporalcs an lunule substimtially frim of other stcrcoisomcrs ol that compound. funcuonal group, a prodrug can bc formed by t)torcplaccmmlt For cxamplc, a stercomcncally pure composition of a com- of il hy'dtogcn Btonl ul thc Bnllnc groUp wllh B gt'UUp such its pound having one chiral center will be substantially free of R-carbonyl, RO-carbonyl. NRRucarbonyl where R and 8're the opposite enantiomer 0 f the compound. A stereomerically composition of a compound having two chiral centers each independently (( I ( io)alkyl, (( H-CO)cycloalkyl, ben- pure zyl. a nahlral 0-aminoacyl or natural coaminoacyl-natural v ill be substantially free of other stereoisomers (e.g., diaste- xx-aminoacyl. C(OH)C(O)OY'herein Y's H, (C,-C,) reoisomers or enantiomers, or syn or anti isomers, or cis or alkyl orbmlzyl, M(OYS)Y'whcrmnY is (C,-CJ) alkyl mid trials lsontxrs) of thc conlpoUnd. A (vplcal stcrconlcilcallv Y's (C, -Co)alkyl, carboxy(C, -Ccjalkyl, annno(C, -CJ)ulkyl pure compound compnscs greater than about 80 percent by or mono-N ordi-N,N (C,-CO)alkylanunixilkyl, C(Y ) weight of mle stereoisomer of the compound and less than Y'vherein Y is I I or methyl and Y's nlono-N or di-N, about 20 percent by weight of other stereoisomers of the N ((',-( &)alkqylamino, nlorpholino. piperidin-I-yl orpyrro- compound, greater than about 90 percent by weight of one lidin-I -yl. stereoisomer ofthe compound mid less than about 10 percent [0094] In certain embodiment~. the phamlaceutically by weight ofthe other stereo isomers ofthe compound. greater acceptable form is an isomer. "Isomers" are different com- than about 9S percent by weight ol'nc stcrcoisomcr of thc pounds that have thc same molecular liinnula. '*Slcrcoiso- compound and less than about 5 percent by weight of thc other isomers the or than about 97 ntcrs Sic'sonlci's thBI differ onlv ul Ihc v Hy lhc Btonls Hrc stereo of compound. greater arrangedin space Asusedherein.theterm "isomef'includes percent by weight of one stereoisomer of the compound and any and all geometric isomers and stereoisomers. Iior less than about 3 percent by iveight ofthe other stereoisoiners example, "isomers*'nclude geoinetric double bond cis- and ofthe compound. trans-isomers, also termed E- and Z-isomers: R- and S-enan- [0098] As used herein, and unless otherv ise specified, the tiomers: diastereomers, (d)-isomers and (1)-isomers, racemic tctnl cnanllolncilcBlly'ine ntcans a stcrconlcilcallv pule mixtures thcrcof, and other mixtures thereof as Ibllm w i(inn composition of a compound having onc or morc clura I center the scope of tlus disclosure. (s). As used herein, and unless otherv ise specified, the [0095] SubstitUcnts Bround J carbon-xalbon iliIUblc bond [0099] excess'* excess** alternatively can be referred to as "cis" or "tranC'here "cis'* terms "enantiomeric and "diastereomenc are com- represents substituents on the saine side of the double bond used ultcrclmngcably hcrcin. In some cmboduncnts, and "trans'* represents substituents on opposite sides of the pounds with a single stcrcoccntcr can be rcfi:rrcd to as being in "enantiomeric excess," and those with at least two double bond. The arrangement of substituents around a car- present 7 stereocenters can be referred to as being present in "diaste- bocyclic ring can also be designated as "cia** or mans." The excess" I'or "enantioineric tenn "cis" reprcsmlts substitucnm on lhc same snlc of thc reomeric example. the term excess" is well known in the att and is defined as plane of thc ring, mid thc tenn "trans" rcprcscnl s su be 1 ilu cuts on opposite sides of the plane of the ring Mixtures of con&- pounds wherein the substituents are disposed on both the II'f O — COIIC Of Hi same and opposite sides of plane of the ring are designated c sc ot 4+mac of' "cis/trmls." [00961 "Enantiomers" are a pair of stereoisomers that are non-supcrimposablc mirror uuagcs of ouch olhcr. A mixture [0(00J I lnls, the term "enantlomeric excess" is related to of il pau of cnannonlcrs ln Bnv pioportlxul can bc known Js 11 the term "optical purity" in that both are measures ofthe same '*raccmic" nuxturc. Thc term "( )" is used to dcsignatc a phenomenon. The value of ceil ill be a number from 0 to 100. racemic mixture lvhere appropriate. "1)iastereoisomers" are zero being racemic and 100 bein enantiomencally pure. A stereoisomers that lmve at least two asynunetric atoms. but compound which in the past migtt have been called 98% which are not mirror-images of each other. The absolute optically pure is now more precisely charac ten zcd by 96% cc. stereochemistry is specified according to the Calm-In old- A 90/4 cc re(kola thc pri:Hence 01 98% ol onc cnantlonlcr and Prclog R-S system. When a Formula (I) ls an cnantlomcr, thc 5% of the other(s) in the material in question. stcrcochmnistry at each chirogcluc carbon can bc speci(lcd by [0101] Some compositions described herein contain an mtlmr R or S. Rcsolvcd compounds whose absolute conligu- cnantiomcnc cxccss ol'at least about 80%, 75%. 90%, 9S%. ration is unknown can be designated (+) or (— ) depending on or 99% ofthc S clmntiomcr. In other words, the composilions the direction (dextro- or levorotatory) which they rotate plane contain an clmntlomenc excess of thc S cnanuomcr over thc polarized light at the wavelength ofthe sodium D line. Certain R enantiomer. In other embodiments, some conlpositions of the compounds described herein contain one or more described herein contain an enantiomeric excess of at least asynunctnc ccntcrs and cml time give nsc ni clrultiomcrs, aboUt S0%. 75!o. 90/4, 98%, or 99% of the R enantiomer. In diasterxximcrs, Bnd other stcrcoisomcric liinns tluit can bc other ~ords. the compositions contain an enantiomeric dclincd. ul terms of absolute stcrcochcmistry at each asym- excess of the R enantiomer over the S enantiomer. metric atom, as (R)- or (S)- 'I'he present chemical entities, [0(02J For instance, an isomerienantiomer can. in some pharmaceutical compositions and methods are meant to embodinlents, be provided substantially free of the corre- US 20]4/0275 [35 A1 Sep. 18, 2014

spondin enantiomer, and can also be referred to as "optically isotopicallyenrichedatoms.Forexample. compoundshavin cnrichcxf," *'eiranuomcncally cnnchcdy "cnunuomcncully thc prcscnt structures except for thc rcplaccmcnt of a hydro- pure" mid '*non-racmnicy as used interchangeably hcrcin. gen by a dcu(comn or tntnim. or the replacemmit of a carbon 'I'hese terms refer to conipositions in which the percent by by "C- Or ''-enriched carbon. or the replacement of a weight of one enantiomer is greater than the amount of that nitrogen by "N- or '-enriched nitmgen. or the replacement one enmitiomer in a control mixture of the racemic composi- ofan oxygen by '-. "00 "0-, or "0 enriched oxygen, or tion (e.g.. greater than about I: I by weight). For example. Bn the replacement of a chlorine by "C I-, 'C f 0 or "Cl-enriched enantiomerically enriched preparation of the S eiusntiomer, cldorme, are within the scope ofthis disclosure. meims a preparation of Ihc compound havuig greater tluin [0106] In one embodiment. the compounds of the present about 80sgs by weight of thc S cnantiomer rclativc to thc R disclosure can also contain uiuiatural proportions of atomic enantiomer. such as at least about 75% by weight, further Isotopes at onc or morc ol atoms that constitute such com- such as at least about 80% by w:eight In some embodiments, pounds. For cxamplc, thc compounds can bc radiolabchxl the enricluuent can be much greater than about 80%v by with radioactive isotopes. such as, for cxumplc, tntium ('H). weight, providing a "substantially enantiomerically iodine-125 ('I), or carbon-14 (') Certain isotopically- pure** eiuichedy "substantially enantiomerically or a "sub- labeled disclosed compounds (e.g., those labeled with 'I I and stantlallv lion-raccnnc prcpBIB(ion, whicli rcfbls 10 plepiii'B- ') are useful in compound and/or substrate tissue distribu- tions of compositions wluch have Bi least ubout 85% by tion essays. Tritiated (i.e., H) and carbon-14 (i.e., ') iso- weight of one enantionier relative to other enantiomer. such topes can allov: for ease of preparation and detectability. as at least about 90'%y weight, and further such as at least Further, subs(itution with hcavu:r Isotopes such as deutcnum 95% by iveight In certain embodiments. the cnmpound pro- (I c., H) can afford cer(ain Ihcrapcuuc advantages rcsulnng vided herein is made up ofat least alxiut 90% by weight( ofone from greater metabolic stability (e g, increased in vivo lmlf- enantiomer. In other embodiments, the Fomiula (I) is made up life or reduced dosage requirements) Isotopically labeled of at least about 98%, 98%, or 99% by weight ol'onc cnunti- disclosed compounds can generally be prepared by substitut- omcr. ing an isotopically labeled reagent for a non-isotopically

[0103J I inantiomers can be isolated from nscemic mixtures Labeled rea ent. In some embodiments, provided herein are by miy method known to those skilled in the art. includin compounds that can also contaui unnatural propornons of clural high pressure liquid clu orna(op aphy (HPLC). Ihe for- atomic isotopes a( one or more of atoms (frat consututc such mauon and crystalhrauon ol'hiral malta, or prcparcxf by compounds. All isotopic variations of compounds of the asynunctuc syntheses. Scc, for cxamplc, E»an(in»icrs, Rnce- present disclnsure, whether radioactive or not, are enconi- mates and Resolutions (Jacques, Ed., Wiley In(crscicncc, passed within the scope of the present disclosure. Neiv York. 1981); Wden et al . I'htrahertrnn 33 2725 (I')77), [0107J As used herein. and unless othemise specified. the Rterenchcmistry n/ (arhun ('nuifinunrts (E I, Eliel. I:d., terms "solvent "organic solvent or "inert solvent" each MCGraw-Hill. NY, 1962): and Jn hiet nfRetniving:I gents and mean a solvent inert under the conditions ofthe reaction bein Optical Rcsniuiinns p. 268 (E L. Eliel, Ed., Univ, of Notre described in conjunction therev ith, including. without limi- Dmuc Press, Notre Dame. Ind. 1972). tation, bcnzenc, toluene, acctonitulc, ethyl acctatc, Isopropyl [0104J In certain embodinients, the pharmaceutically ace(etc. hcxancs, heplanes, dioxunc, Iclrahvdmfiiran acceptable form is a tautomer As used herein. the term "tau- ('*THF"), dimcthyllbrmanude ("DMF"). dimcthylacctmuulc tomer" is a type of isomer that includes two or more inter- ("l)MA*'), chlorofiirm. meihylene chloride (dichlo- convertable compounds resulting from at least one fomial roniethane), diethyl ether. methanol, butanol. methyl t-butyl mipation of a hydrogen atom and at least one chan e in ether ("MTBE", or "TBME"), 2-butanone ("MEIC'), N-me- I alcncy (c.g., a single bond to a double bond, a topic bond to thylpyrrolidone ("NMP"), pyridine, and the like. Unless a suiglc bond, or vice versa). "Tauiomcnzatuin" uicludcs spccilicd 10 the conirary. thc solvents used In rcacIions pmtotropic or proton-shift tautomerization, which is consid- dcscribcd herein arc inert org;mic solvmits. Unless spccitiixl ered a subset of acid-hase chemistry PPrototropic tmitomer- to thc con(cary, fiir each gr;mi of a liminng reagmit, onc cc (or ization" 0 r "proton-shi ft tauto meri ration" involves the nugra- ml.) of solvent cmistitutes a volume equivalent. tion of a proton accompanied by changes in bond order The [0108] As used herein. and unless otherwisc specilied. exact ratio of the tautomers depends on several factors, '*phamiaccutically acceptable carrier" or "phannaccutically includmg temperature, solvent, and pH. Whcrc tautomenza- acceptable excipient" include~ any and all solvents. disper- tion is possible (c... ui solunon), a chemicul cxfutlibrium of sion media, coatings, antibacterial and antifiingal agents, iso- tautomers can be reached 'I automerizations (i e.. the reaction tonic and absorption delaying agents and the like. The use of pmviding a tautomeric pair) can be catalyzed by acid or base, such media and agents for pharmaceutic a fly active substances or can occur without the action or presence of an external Is known in thc art. Excep( maofar as any convminonal ntcdfra a ent. Exemplary tautomerizations include. but are not hm- or agent is uicompaublc with thc active Ingrcihcnt, Its use in ited to. keto-to-enol; amide-to-imide: lactam-io-luctiin, thc Ihcrapcunc compositions ofthe present disclosure Is con- cnaminc-to-inunc, and cnanunc-to-(a drfli rent) cnummc tmi- templated. Supplementary active Ingredients can also be tonlcilzafions. An cxBnlplc ol kcto-ciiol LsutonlcIIZBIIon Is incorporated into the compositions. the intercom era ion ofpentmie-2,4-di one and 1-hydroxypent- [0109] As used herein and unless otherwise specified, the 3-en-2-one tmitomers Another example oftautomenzation is tenn "solid fomi'nd related terms refer to a physical fiimi phenol-keto tautomerization. Another example of phenol- v hich is not predominantly in a liquid or a gaseous state. keto tautomerization is the interconversion of pyridin-4-ol Sohd forms may be crystalline. umorphous or mixtures and pyridin-4(1 H)-one tautomers. thereof. In particular embodunents. sohd forms may bc liquid [0105] As used hcrcin, mid unless othcrwisc spcctficsf, ctystais structures depicted herein are also meant to include con&- [0110J In some embodiments, a solid form provided herein pounds which differ only in the presence of one or niore is a single cnmpnnent or multiple component solid form A US 20]4/0275 [35 A1 Sep. 18, 2014

"single-component** solid form comprisin a compound of a difficult to filter and &sash free of impurities. and particle formula consiam essentially of Ihc compound of Ihc Ionmrlu. sliapc and size disuibution might bc diffi:rent bclwccn poly- A "multiple-compo&&i:iil soli&1 for&i& co&rip&is&rig a ci&&lip&&uiiil &iso&pl&a). of a fi&rnnda comprises a significant quantity of one or nlore [0114] As used herein and unless otherwise specified, the additional such as ions and/or molecules, v ithin the species, tenn "solvate" snd "solvated," refer to a crystal form of a solid form. For example. a crystalline nmltiple-component substimcc which contauis solvent. The term "hydmtc** and com- solid form comprising a compound of a formula further '*hydrated** rclbr to a solvalc wherein thc solvent comprises prises one or more species non-covalently bonded at reguLar water. "Polymorphs of solvares" refers to the existence of posit&or&s m thc crystal lalucc. A multiple componcnl solid more than one crystal form fi&r a particular solvate composi- form provided herc&n may be a co-cryslsl. tion. Similarly, "polymorphs of hydrates** refers to the exist- [0111[ As used herein and unless otherwise specified, the ence of more than one crystal form for a particular hydrate term "crystalline** and related term~, when used to descnbe a composition. The tenn "desolvated solvate,** as used herein. substance, modification, material. component or product refers to a crystal form of a substance which may be prcparrxl maim thai the substance, moddicauon, malcnal, componmil by'ciiioviiig ilia soli ciil frorii a solvale. or product rs subslaul&ally crystalline as deism&rncd by X-ray [0115] As used herein and unless otherwise specified, the d&ITrsclion. Sec, c.. Resrisgrasr The Science arri/Pracrree of tenn "smorphousy '*amorphous I'onny and rclalcd terms /'/iarmirrv. 21" edition, I rppuicott, Williams and Wilkins, used hcrcui, mean thai Ihc substance, componm&1 or product 13altimore, Md (2005), /he (i&rile&/ Srarei Pharmarapeia, ui is as dclcnninrxl 23m edition. 1843-1844 (1995). question nol subsiantially crystalluic by X-ray diffractim& In particular. the term "amorphous form" [0112] As used heraus and unless othes wise spccificd, thc describes a disordered solid fi&rm, i e, a solid form lacking "crystal fonna" fi&rms tenn and rclalcd terms rcii:r to soltd long mnge crystalline order. In certain embodiments, an that are crystalline. (:rystal fern&s include single-component amorphous form of a substance may be substantially free of crystal and forms multiple-component crystal forms. and other ium&rphous fonna and/or crystal fonna. In other include, but are not hmited to. polymorphs. solvates, cmboduucnts, an mao rpho us form of a substance may contain hydrates. and other molecular complexe~. as well as salts, less than aboul 1%, 2!w 3 /w 4%, 5%. 10%, I 5%, 20%, 2S%. solvates ofsalts, hydrates of salts, other molecular complexes 30%, 35%, 40%, 45'/ or 50% of one or more other mnor- of salts, mid thereof. In ccrisui embodimmits, a polymorplw phous forms and/or crystal forms on a weight basis. In certain crystal form a bc substantially free unor- of substance may of embodiments. an amorphous form of a substance may be phous forms and/or other crystal fonna In certain embodi- physically and/or chemically pure. In ce&tain embodiments. ment~. a crystal form of a substance contain less than may an amorphous form of a substance may be about 99/o, 98%. about I/h. 2%. 3%, 4%, 5%. 6%, 7/o. 8%. 9%. 10!w 15%, 97%, 96%, 95%, 94!w 93!w 92!o. 91!o or 90% physically "/s, 50'/s 200I&, 25 30%. 35%. 40%, 45% or of one or more and/or chemically pure. gravimetr- amorphous forms and/or other crystal fomis on a we& ht basis. In certaui cmboihmcnts, a crystal Ii&rm ol'a substuncc [0116] Teclmiques for characterizing crystal forms and may bc physically mid/or chem&cally pure. hi ccrtmn embodi- amorphous forms uiclude. but arc not lun&tcd to. thermal ment~. a crystal form of a substance may be about 99%. 98%, gruvunclric mialysis (TCIA), d&ITercnual scanning cslonm- 97% 96% 95% 94% 93% 92% 91% or i)0% physically clry (DSC), X-ray pov, dcr diifractomctry (XRPD), and/or chemically pure. icc vapor sorption ((iVS), single-crystal X-ray diffracton&- vibrational e infrared and Raman [0113] As used heraus and unless othes wise spccificd, thc etry, spectmscopy. g., (IR) solid-stateand reso- tcnns **polymorphsff "polymorph&c lorn&a" and rclalcil lcrms spectroscopy. solution nuclear magnetic nance optical hcrcui, ref) r to two or morc crystal lorms thai co&nial csscn- (NMR) spectroscopy, microscopy, hot stage opt&csl nucroscopy, scaruung electron nucroscopy (SEM). ti ally of the same molecule, melecules or iona I ike different ckctron crystallography and qumiulalivc analysi ~ . part&clc crystal forms. different polymorphs may have differentphysi- s&zc analys&s surface arcs analys&s, solubililv mea- cal properties such as, for example, meltin temperatures, (PSA), surements, dissolution measurements, elemental analysis and heats of firsion. solubihties, dissolution rates and/or vlbm- Karl l&ischer analysis ( haracteri stic unit cell paran&eters tronsl spectra, ss a result ol Ihc arrangcmcnl or confi&nnulron may be determined using one or more teclmiques such as, but not of Ihc moleculcs and/or iona ui Ihc crystal lanicc. 11&c diffcr- limited to. X-rsy diffraction and neutron diffraction. includ- cnccs m phys&csl properties may aITcs:t plurnnacculical uig single-crystal drffracuon and powder diffracuon. Tcch- parameters such as storage stability, compressibility and den- niqucs useful for mialyzing d&ffracl&on dale include sity (important m fi&rmulation and pmduct manufacturing), powder profile such as cld rclinmncnt, and dissolution rate (an important factor in bioavaiLsbihty). rciincmcnt, Ricli winch msy be used, e to diffraction assocmted with a Differences in stabihty can result fhom changes in chemical g, analyze peaks single phase in a sample comprising more than one solid reactivity (c.g., dilTcrenual oxidation, such that a doss c fi&mi discolors more rapidly when composed ol onc polymorph phase. Other methods useful for analyzing powder diffraction data include ruiit cell indexing, which allows one skill in than when compnscd of another polymorph) or mccluuucal of the art to determine unit cell parameters fmm a sample com- changes (e 8,. tablets cnimble on storage as a kinetically posing pov, dcr. favored polymorph converts to a thermodynamically nlore crystalline stable polymorph) or both (e.g., tablets of one polymorph are [0117] In some embodiments. the solid fonna, e.g.. crystal more susceptible to breakdown at high humidity). As a result or amorphous fomls, described herein are substantially pure. of solubility/drssoluuon d&ffi:rcnccs, ui lhc extreme csee, &.c., substantially free of other solul forms and/or ol'ther some solid-&laic trans&nous may rcsull &n lack oi potency or, chmnical cou£s. conlauung less thun about 2S%, 20%. al thc other extrcme, toxicity. In addition, Ihc physical prop- 15%, 10%, 9%. 8%. 7!w 6%, 5%, 4%, 3/w 2% 1%, 0.7S%. erties maybe important in processing (for example, one poly- 0 5%, 0 25% or 0 I '/ percent by weight ofone or n&ore other morph might be more likely to form solvates or might be sohd fi&rms andior of other chemical compounds US 20]4/0275 [35 A1 Sep. 18, 2014 10

[0118] Solid fomis may exlubit distinct physical character- butyL sec-pentyl. iso-pentyL tert-butyl, n-pentyl, neopentyl.

&ratio&i da&B &1&a& Brc uiiiquc &0 B pa& &&cola& solkl lorn&, st&el& &is n-hcxyl, scc-hcxyl, n-hep&yl. n-Cetyl, n-diuyl, n-undccyl. the crystal fonna dcscubcd herein. Thcsc cluuactcuzation d(xlccyl, iuid &hc like. data may be obtained by various techniques knov n to those [0122] The tenn "alkenyly as used here&n, dcnotcs skilled in the art. including for example X-ray powder dif- monovalent group derived fmm a stnlight- or branched-clmin fraction, differential scanning calorimetry, thermal y lvimet- optionally substituted aliphatic mmety having at least one ric analysis. and nuclear magnetic resonance spectroscopy. carbon-carbon double bond by the removal ofa single hydro- The data provided by these techniques may be used to identify gen atom. In certain embodiments, the all enyl group a particular solnl form. One skilled &n dic ar& can dctcnmnc employ&xi in thc invention contains 2-6 carbon a&orna [C.g.. w bc&her a solid form &s onc of'hc fonna described herein by C, i alkcnyl]. In certain cmbodimcnts, thc alkcnyl group clmracterization performing one of these techniques and employ&xi in thc uiven& ion cont au&a 2-5 carbon atoms. In some determining whether the resulting data "matches" the refer- embodinients, the alkenyl group employed m the invention ence data provided herein, wluch is identified as being char- contains 2-4 carbon atoins In another embodiment. the alk- acteristic ofa pariicular solid form. ( 'haracterization data that enyl group employed contains 2-3 carbon atoms Alkenyl ''&uatches" those of a reference solid form is understood by groups include, for example. ethenyl, propenyL butenyl. those skilled in the ar& to m&rrcspond &o &hc same solid fi&no as l-mc&hyl-2-bu&cn-l-yl, and &hc like. the rcfcrmicc sol&d form. In whc&hcr da&B *'match," analyzing [0123] The term "alkynyly as used hercui. refers &o a a skill in the art person ofordinary understands that particular monovalent group dcm cd from a stra igh&- or brmichcd-Chain characterization data points may vary to a reasonable extent optionally substituted aliphatic mmety having at least one while still describing a g&ven solid forin, due to, for example, carbon-carbm& triple bond by the removal of a suigle hydm- experimental error and routine sample-to-sample analysis gen eton&. In certain embodiments, the alkYnyl gmup [0119] The solid forms provxhxl hcrcui may bc crystnllute, employed in the invention contains 2-6 carbon atoms 1e.g.. amorphous, or an &n&crmedia&c li&nn. Thc crystal fi&rnm Cz, alkynyl]. In certain embodiments, the alkynyl group described herem, therefore, may have varying degrees of employ&xi in thc uiven& ion cont au&a 2-5 carbon atoms. In some crystallinity or lattice order The solid forms described herein cmboduucnts, thc alkynyl roup c&nploycxf ui &hc uivcnuon are not limited by any particular de ree of crystallinity or contains 2-4 carbon atoms In another embodiment, the alky- lattice order, and may be 0-100% crystalline. Methods of nyl group employed contains 2-3 carbon atoms Representa- ilctcililiiiiiig flic dcgrLO of cNS&all&i&i&v Bro kiiowii &0 &i&use of tive aliynyl gmups include. but are not limited to. ethynyl, ordinary skill in thc. such as those dcscnbcd in Sury uraray- 2-propynyl (propargs li. I-propynyl, and the lil e. anan. R., X-Ra) Power Di//nocto&nett), Physwal Character- [0124] The tenn "aryl*'sed alone or as part of a larger ization ofPharmaceutical Salts. I I (i I irittain, I iditor. Mercel moiety as in "aralkyl", "aralkoxy*k or "aryloxyalkyl'2 refers l)ekkter. Murray I hll, N .I, 1995, pp. IN7-199. which is to monocyclic and bicyclic optioirally subsu&u&ed nng sys- incorporated herein by reference in its entirety. In soine oi' tems havuig a &otal i& c to tw clvc nng mcmbcrs, whcreui a & embodiments, the solid forms described herein are about 0. 5, least one ring in the system is aromatic and wherem each ring 10.15.20,25.30,35,40,4S.50,55,60,65,70,7S.80,85,90, in the system contains three to seven ring members. In some 95 or I 00!o crystalline. embodiments. "aryl*'efers to monocyclic and bicyclic [0120J l)efinitions ofspecific fiinctional groups and chmni- optionally substituted ring systems bavin a total of six to cal tern&a are described in more detail below. For purposes of twelve nng members (e.g., C, „aryl], wherein at least one this invention. the chemical elements are identified in accor- nng ui thc system is aronuitic mid whcreui each ruig in &hc dance v ith the Penodic Table ofthe Elements. CAS version, system con&auis tluco &o sci cn ring mcmbcrs. Thc term "aryl" Hmidbook of Chemistry and Physics, 75m Ed.. insnlc cover, nmy be used interchangeably v ith the tern& "lryl ring". In and specific Iiuict&onal groups are gcncrally dclincd as certain embodiments 0 f the present invention, "aryl" refers to described therein Additionally, genenll principles of 0&genic an aromatic rin system v.hich includes, but not limited to. chemistry. as well as specific functional moieties and reactiv- phenyl. biphenyL naphthyl, anti&mcyl and the Iil e, v hich may ity. are described in Organic C:hemistz!s, 'I'homas Sorrell, bear one or more sub stituents. Also included v ithin the scope I)niversity Science Books, Sausalito. 1999: Smith and March of thc tenn *'aryl'*, as it is uscxf hcreui, m a group in which Bn 5m March's .4dvnnced Organic C7&emistry, Edition. Jolui Broil&&itic riiig is l&Ised & 0 0&ic or iiiorc &&oil.Broil&a& ic Ililgs, s&1 el& W&icy g Sons, Inc., Ness York, 2001, Larock, Comprehensive as indanyi. phthalimidyl. naphthimidyl, phenantriidinyl, or Organic Fransfornzz&ti ons. VCH Publishers, Inc.. Ncw York, tetrahydronaphthyl, and the like 19N'); ( Szzzne &dethtzds nit&e- arruthers. Modern OTOrgnnii .5] [f)125J I he terms "heteroaryl" used alone or as part of a 3'" ris, Iidition. ('ambridge Iiniversity Press, Can&budge, Llr er moiety. e.g., "hetemaralkyl*k or "heteroaralkoxy". 1 9N7. refer to optionally substituted groups having 5 to 10 rin [0121] The tenn '*alkyl," as used hereui, rcii:rs to sa&ura&Lxf, a&orna. prclcrably 5, 6, or 9 ring a&orna, having 6, 10, or 14 x straight- or branched-chain optioiially substi&uted hydrocar- ch:etio&is sl&B&ed iii a cv'clic iitriivx a&id liaviiig. iii Bid&&&oil &0 bon radicals dcnved from an al&phauc moiety coil&B&i&i&&8 carbon a&orna, from onc to live hctcroa&orna. In some embodi- tern& "hetemaryl" bet&veen one and six carbon atonis (e g, ( 1 s slkyl] bv ment~, the refers to optionally substituted removal of a single hydmgen atom In some embodiments, gmuPs as defined above having 6 to 10 ring eton&s (e g., Cs,s the alkyl group employed in the ini cation contains 1-5 carbon heteroaryl]. The tern& "heteroatom** refers to nitrogen. oxy- atoms. In another embodiment, the all yl group employed gen, or sulfur, and includes any oxidized form of nitrogen or contains 1-4 carbon a&orna. Iu sill other cmbodnncn&s. thc sulfur. Bml any quatcnuzcd Ibnu ol' bas&c n&trogcn. He&- alkyl group contains 1-3 carbon atoms. In yct another croaryl groups include. wi&hou& lunitatiou, &hicuyl, furanyl. cmbodimcnts, thc alkyl group con&aine 1-2 carbons. pyrrolyl, imnlazolyl, pyrazolyl. tnazolyl, tctrazolyl. Examples of alkyl radicals include, but are not limited to, oxazalyl, isoxazolyl, oxadiazalyl, thiazalyl, isothiazolyl, methyl. ethyl, n-propyl, isopmpyl, n-butyl. iso-butyl. sec- tluadiazolyl, pyridyl, pyridazinyl. pyrimidinyl, pyrazinyl, US 20]4/0275 [35 A] Sep. 18, 2014

indolixinyl, purinyl, naphthyridinyl. and pteridinyl. The independently selected from nitrogen, oxygen, or sulfur. or. tcnns '*hctcroaryl" and "hctemar-", ss used hcrcui, also notwithstanding the definition above. two independent occur- include groups in w luch a hctcroaromatic ring is fused to onc rences of R=. taken together v ith their intervening atom(s). or more aryl, cycloaliphatic. or hetemcyclyl rings, where the form a 3-12-mcmbcrcd saturated. partially unsaturated, or radical or point of attachment is on the heteroaromatic ring aryl mono- or bicyclic rin having 0-4 heteroatoms indepen- Non-limiting examples include indolyL isoindolyl. ben- dently selected lrom nitrogen, oxygen, or sull'ur. which msy zothienyl. benzofuranyl, dibenzofumnyl, indazoiyL benzimi- be substituted as defined beloiv dazolyl, benzthiazolyl, quinolyl. isoquinolyl. cinnohnyl, phthalaxinyl. quinazohnyl, quinoxahnyl, 4H-qumohzuiyl, [0128] Suitable monovalent substitucnts on R'or the ung carbazolyl, acndinyl. phenazinyl, phcnuthiazuiyl. phenox- formed by taking two indepmident occurrences ofR'ogether azinyl. tetrahydroquinolinyl, tetrahydroisoquinolinyl. and with their uitervcning atoms), arc indcpmulmitly halogen. pyrido[2,3-bJ-1,4-oxazin-3(411)-one A heteroaryl gmup (CI I )c R, -(haloR ), ~CI lz)c zOI I, (('I lz)o zOR may be mono- or bicyclic. The term "heteroaryl" may be used (CHz)o zCH(OR )z; 0(haloR ). CN. N„(CH,) interchangeably v ith the terms "heteroaryl ring", "heteroaryl z( (0)R (( I I )wz( (0)OI I (( I Iz)c ( (0)OR group", or "heteroaromatic'3 any of which terms include (CI I,)i, zSR, (CI I )o zSI I, (Cl iz)o,NI Iz. ~Olla)i, rings that are optionally substituted. Thc icmi'*hctcroaralkyl" NHR+. (('H.)„zNR . NO,. SiR+,, C(0)SRw,. refers to an alkyl group subsuhitcd by u hctcrouryl. whcrmn C(0)SR . (C, s straiuht or branched allylene)C(0) the alkyl and bete re sty 1 portions independently are optionally OR . or SSR wherein each R is unsubstituted or where substitmed. prcccdixl by "halo" is substituted only with one or morc [0126J As descnbed herein, coinpounds of the invention hulogcns, and is uidcpcndcntly sclcctcd from C, z alipllatlc.

I Vli I I pit or a 5-6-membered satunsted, may contain "optionally substituted" nioieties In umiensl. the 0(( )c i

term "substituted**, v hether preceded by the temt "option- partially unsatututed, or aryl ring having 0-4 heteroatoms ally*'r not, means that one or more hydrogens ofthe desi- independently selected from nitrogen, oxygen, or sulfur. Suit- able divalent substituents on a saturated carbon atom of R'nclude natcxl moiety urc replaced with a suitable substituent. UnIcssIlla)'ave iitllcrwisi: lililli:sti:il, all optlollallv siibstlnltcil gi'tiilp 0 and S. a suitable substituent at each substitutable position ofthe [0129] Suitable divalent substitucnts on a satumtcd carbon gnuip, and when more than one position in any uiven stmc- atoni ofan "optionally substituted" group include the follow- ture may be substituted with more than one substituent ing 0, sk NNR"z. NNI IC(0)Its, NNI I('(0) selected from a specified group, the substituent may be either OR'", NNI IS(0)zl&'L NIts. NOR". 0(C(R'z)), the same or different at every position. Combirmtions of sub- sO . or S(C(Rvz))z sS, wherein each indePendent stitumits inn i stoned by this uiv cation are prcii rably those tlmt occurrence of R's selected from hydrogen, C,, aliphatic result in thc formation ol'table or chemically feasible com- which may be substituted as dclincd below, or an unsubsti- 'I "stable", pounds. he term as used herein, refers to con&- tutcd 5-6-mcmbcrcd saturatcxl, partially unsatumtcd, or aryl pounds that are not substantially altered when subjected to ung having 0-4 hetcroatoms independently sclcctcd I'rom conditions to allow fiir their pmduction, detection, and. in nitrogen, oxygen, or sulfur Suitable divalent sub stituents that certain embodiments. their recovery, purification, and use for are bound to vicinal substitutable carbons of an "optionally one or more of the purposes disclosed herein. substituted" grouP include: 0(CRuz)z 30, wherein each [0127] Suitable monovalent substituents on a substitutable independent occurrence of R" is selected from hydrogen. carbon atom of mi **optionally substituted" group arc inde- C, s aliphatic wluch may bc substituted as dclincd below, or pendently halo i:n, (CHz)„zR', (CHz)o zOR; 0 an unsubstitutcd 5-6-membered saturated, parually unsatur-

(CHz)o C(0)OR', (CH,)„CH(OR',, (CH,)o,SR', ated. or aryl nng hating 0-4 hctcroutoms indcpcmlcntly (Cl iz)umph, which may be substituted with R': (Cl lz)o selected frmu nitrogen, oxygen. or sulfur zO(CI Vh which may be substituted with R, Iz)„, [0130[ Suitable substituents on the ahphatic group of Rv CH CHPh, which may be substituted with R": NOz, include halogen, R, -(haloR ). OH. OR . 0(ha-

CN; N, (CH„)c sN(R ),; (CHz)i, zN(R )C(0)R, loR ). CN, C(0)OH, C(0)OR, NH„NHR N(R )C(S)R (CHz)c.sN(R )C(0)NR " N(R )C(S) NR „. or NOz. whercui each R is unsubstitutcd or NR"„(CH )o zN(R')C(0)OR".I N(R')N(R')C(0)R', whcrc preccdixl by *'halo" is substituted only with onc or N(R )C(0)OR', )N(R ')C(0)NR'N(R')N(R more halogens, and is independently (', aliphatic, (Cl is)o~C(0)R: ~'(S)R ': (('I I,)i, zC(0)OR', z I Vli 0(( I I )ii i pit or a 5-6-membered satu usted, (0)SIRu (Clla)o ol'n (( Ilz)o~( (( Iiz)os( (0)OSiR,; partially unsaturated, or aryl ring having 0-4 heteroatoms 0('(0)R': OC(0)(CH,)„SR . SC(S)SR'; (CH,)„ independently selected from nitrogen, oxy en. or sulfur. SC(0)R; (CHz), C(0)NR",: C(S)NR,: C(S) SR', SC(S)SR". (CHz)„OC(0)NR'z ~0(D)N(OR ) [0131] Suitable substitumits on a subsututable muogcn R', M(0)C(0)R, M(O)CHzC(0)R'; C(NOR')R', "optionally subsututcd" group include R . NR'z, (CH,)o SSR, (CH,)o S(0),R'. (CH,)o,S(0) M(0)R', M(0)ORt. M(0)C(0)Rt, C(0)CH C(0) OR'; (( l l )„OS(0) l4', S(()) NR'; (('l l ) ~S R S(0)zlkt* S(0) Nlttz. ( (S)NR z ( (Nl l)NR " (0)R: N(R )S(0)zNIT: N(R )S(0)zk: N(01& ) or N(R )S(0)zR; ivherein each R is independently R '(NH)NR z P(0)zR P(0)R z OP(0)R hydro en, Ci s aliphatic ivhich may be substituted as defined OP(0)(OR'„SiR,I (C, 4 straight or bmnched alky- belov. unsubstituted OPh. or an unsubstituted 5-6-mem- lcnc)0—N(R ),: or (C, s stcmghtorbmnchcd)alkylcnc)C bcrcd saturated, parually unsaturated, or aryl ring havuig 0-4 (0)0 N(R')z. whercui each R'uy bc substitute as hctcroatoms uidcpcndcntly selecuxl Irom nitrogen, oxygen. dclincd below and is uidcpcndcntly hydrogcrs C, r aliphatic, or sulfur, or, notwithsi;mdmg thc dclinition above. two inde- ( I'z Vll ~)(( I I )o i Vli, ol a 5-6-lilelnbered saturated, pendent occurrences of ICL taken together with their interven- partially unsaturated, or aryl ring having 0-4 heteroatoms ing atom(s) form an unsubstituted 3-12-membered saturated, US 20]4/0275 [35 A1 Sep. 18, 2014 12

partially unsaturated, or aryl mono- or bicyclic ring bavin [0136] The solid fonna provided herein are useful as active 0-4 hctcroatoms independently sclectixl Irom mtrogcn, oxy- phumtaccuncal Ingrcdtcnts for thc prcparanon ol'ormula- gen, 01'tilfur. tions for use in animals or humans. Titus. embodiments hcrcin R" [0132] Suitable substituents on the aliphatic roup of are encompass thc use 0 fthe ac solid forms as a 1 i os I drug product. independently halogen, I(O, -(haloR ), OI I. OR Certain embodiments provide solid fonna useful ut malong O(haloR ). ~'N, C(O)OI I. ('(O)OR . NI II, littal dosage I'orms with uuproicd properties, c.g., powder NHR, NR „or NOI, whcrcut each R Is unsubstt- tlov properties, compaction properties. tableting pmperties, tuted ortt here preceded by "halo'* is substituted only with one stability properties, and excipient compatibility pmperties, or more halogens, and is utdependently ('t~ aliphatic, among others, that are needed for manufacturing, processing„ 5-6-membered Cl lsph, ~)((:Ill)c,ph, or a saturated, formulation andlor storage Of final drug products. ( ertain 0-4 partially unsaturated, or aryl nn having hctcroatonw embodintents herein provide pharmaceutical conipositions independently selected from nitrogen, oxygen. or sulfur comprising a single-component crystal form. a ntultiple- component crystal fomt, a single-component amorphous I'orms, l&orni ~ 5.2 Salts. Solid and Solid of Salts form and/or a multiple-component amorphous foun compris- the compound fornnila and a pharmaceutically [0133] Potcnual plrdmtaccuncal solxls utclude crystalline ing of (I) soluls and amorphous sobds. Amorphous sohds arc churac- acceptable diluent, excipient or carrier. terized by a lack of long-range structural order, whereas crys- [0137] Solid I'onn andrclatcd tenns rcfi r to a physical I'onu talline solids are charactenzed by structural periodicity 'I he which is not predominantly in a hquid or a gaseous state desired class of pharmaceuucal solxl depends upon thc spc- Sohd forms may be crystalline. amorphous or mixtures cdic application, amorphous sohds arc somctimcs sclcclcd on thereof. A "single-component" solid form comprising a par- the basis of. e g., an enhanced dissolution profile. wlule crys- ticular compound consists essentially of that compound. A talline solids may be desirable for pmperties such as. e g., "nuiltiple-component" solid fomt comprising a particular physical or chemical stability (see, e g., 8 R Vippagunta et conlpotuld coul poses that conipound Bnd d slgulfii aut qtldu- and&or al., gdu Drag Dell v Rev., (2001) 48:3-26, L. Yu. &Idv. Drag ttty of onc or more tuldittonal spccics, such as Ious molecuies, within the solid form. 'I he sohd forms provided Deli v: Rev., (2001) 48:27-42). A change in solid fonu may herein may be crystalline. amorphous. or an intermediate affect a variety of physical and chemical properties, which form. The crystal forms described herein. therefore. may have provide benefits or drawbacks in pnlcessinu. fornuila- may varying degrees of crystallinity or lattice order. The solid tton, stability and btoavatlability, among other unportmtt forms described herein are not limited to any particular pharmaceutical chamlcteristics dcgrcc of crystalliruty or lauicc Order, and may bc 0-100% [0134J Whether ciystalfine or ainorphous, potential solid crystallutc. 11 Pathods of dctcrnuning the degree of crystallinity are known to those of ordinary skill in the, such as those forms of a pharmaceutical compound may utcludc singlc- described in Suryanarayanan. R, N-Rav I'nut r Iam- component and multiple-component solids. Single-compo- Di[frar ctr v. Physical Chamlcterization ofPharmaceutical Salts, H. G, nent solids consist essentially of the pharmaceutical com- Brittain, Editor. Mercel Dekkter, Murray Hill, N. I.. 1995, pp. pound in the absence of other coinpounds Variety among 187-199. wluch is incorporated herein by reference in its sulglc-conlpont:nt crvs(Blhuc ulatcilals nlav potcunBllv Iiilsc cnnrcty. In some cmbodimcnts, thc sohd fonna dcscnbixl from the phenomenon of polymorphism, wherein multiple hcrmn are about 0, 5, 10. 15. 20, 25, 30, 35, 40, 45. 50. 55. 60. three-dimensional arrangements exist for a particular phar- 65, 70, 75. 80. 85, 90. 95 Or 10()% crvstalline. maceutical e 8 et compound (see, g, 8 l3yrn el, Salldgtaie [(H38J Solid forms may exhibit distinct physical chanlcter- Cgemls(D of Drags, (1999) SSCI, West Lafayeuc). ization data that are unique to a particular solid fomt. such as [0135] Additional diversity among the potential solid the crystal forms described herein. These characterization du(a bc obtautcd 1 anous tcclmtques known to Ihosc filrms Of a pharmaceutical coinpound Inay arise from the may by skilled in thc art. utcludutg I'or cxamplc X-ray powder dil- possibility of mulnplc-component sohds. Crystallute sohds fracnou. itlfcrcuttal scduntug cd loilnlctiy, (hernial gi dv uuct- comprising two or morc ioiuc spccms Brc tcnned salts (sul ric analysis, and Iniclear magnetic resonance spectroscopy e.g., Haadbaal af'Pfiamuareariral Salrsi Properties Selec- 'I'he data pmv id ed by these techniques may be used to identifi& Iii&a aad (Ire, P I I Stahl and (2 (t Wermuth, Eds, (2002), a particular solid form. One skilled in the art can determine Wiley, Wcinheun). Additional types of nnilnplc-component v hether a solid form is one ofthe fomts described herein by soluls tits 1 nuiy potentially olpcr other properly improvmncnls pcrfonnnlg oue of thcsc chatactcnzBnon tcchutqtlcs dud for a pharmaceutical compound or salt thereof include, e dc( crnnning whether the resuitmg data Is **substanually simi- hydrates. solvates, co-crystals and clathrates. among others lar'* to thc rcfbrcncc data provided hcreut, which Is ulcnutiixl as characteristic a particular solid fornt. ('hanlcter- (scc, c.g.. S. R. Byrn ct al, Solid Stare Cbemlstri af Drags, heing of ization data that is "substantially similar" to those a refer- (1999) SSCI, West LBfdy'ctlc). Morcovcn ultlltiplc-compo- of ence solid fomt is understood by tlxlse skilled in the art to nent crystal fonna may potentially be susceptible to polymor- correspond to the same solid form as the reference solid form. wherein a given nndtiple-component phism. composition In analyzutg whether data Is "substantially suntlarP a person utay'xist tu niorc lian ouc thrcc-dtulcnslonal ci)'stBllluc ofordumry skill in Ihc art understands Ihat particular charac- arrmtgmncnt. Thc discovery ol'ohd lorms Is ol'reat unpor- terization tkita points may vary 10 a reasonable extent wlnlc tance in the development of a safe. elfective, stable and mar- still describing a given solid filnn, due to, filr example, ketable pharmaceutical compound experimental eiror and mutiite sample-to-santple analysis US 20]4/0275]35 A1 Sep. 18, 2014 13

[0139] In some embodiment~. provided herein are solid 80% to about 99.5i'c. greater than about 85% to about 99.5%. loci&is of a coiiipoU&id of loitiiida (I). grcdtor than about 90!c Io about 99.S%, grcatcr than about 95% to about 99.5%. greater titan about 96% Io about 99. S%. greater than about ')7'%o about 99 5%, greater than about 9N% to greater than about &8).5%, greater than about &8)'rl to Mco aboUt 99.5% ot'nore. [0143[ As used herein and unless otheovise specified, the term "I onmila (I)" includes (8)-2-ammo-4-((I-(8-(2-meth- oxypyridin-4-yl)-l-oxo-2-phenyl-l.2-dihydroisoquinolin-3- yl)ethyl)amino)pyrimidine-5-carbonitrile in its imide tau- tomcr shown below as (1-1) and in its lac)un tmitomer shown below as (1-2).

Mco QY)

or a salt. solvate (e.g . hydrate), or solvate of a salt thereof, or a mixture thereof. In one embodiment. the solid form of a compound ofI'onnula (I) cd&i bc d cry sl all&tie f&iriiic SI piirt&Jlly crystalluic lonn. an amorphous lonn, ore mixture ofcryslal- line form(s) and/or amorphous forni(s). In one embodiment, pmvided herein is a solid forni comprising a crystalline forni ofa compound offormula (I), ore salt, solvate (e g., hydrate), or solvate of a salt thereof. or a mixture thereof. [0140] The compound of lbmiula (I) has a chemical Burne of (S)-2-annno-((I-(8-(2-mcthoxypyndm-4-yl)-I-oxo-2- Mco phenyl- 1.2-dihydroi soquinolin-3-yl)ethyl)ainino)pyrinu- 'I dine-5-carbonitrile he compound offornnila (I) i ~ pnivided in the cLass of molecules described in US2013/0053362, the entirety of which is Incorporated herein by reference. [0141] In some embodiments, Ihc Formula (I) is a racmnic mixture of (S)- and (8)-isoniers In other embodimmits. provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example. the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 610!c, about 6S%, about 70%, about 75/c. about 80%, about 85!c, about 90%, about 95%, about 96/c. about 97%, about 9N%, about 99%, about 99.5'%, or more ln other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about ')9 5%, [0144] In some embodiments, provided herein are salts of greater than about 60% to about 99.5'!c. peeler than about thc compound of formula (I), or a solvatc (c g., hydmtc) 65;c to about 99 5%. greater than aixiut 70% to about 99 5%, thereof. In some mnboduncnts, thc sal& is n salt ol'i X. greater than abou& 75% Io about 99.5%, grcatcr than about wherein X is 11 I'I, ilr, I, I(SO,. or l(FOB. &vherein R is alkyl, 80% to about 99 S%, renter&han abou185%1o about 99 S%, aryl, substituted aliyl, or substituted aryl ln one embodi- greater than about 90% to about 99 5%, greater than about ment, the salt is a phannaceutically acceptable salt. In some 95% to about 99 5%. greater than about 96% to about ')9 5%, embodiments. provided herein is a salt of the compound of greater than about 97% to about 99 5%, greater than about fornnila (I). ~herein the salt is a hydrobromic acid salt. a 98; c to greater than about 99 5'!c. greater than about 99% to hydrocldonc acul salt. a sulfuric acid sall, nn 1,2-ctlianc dis- aboiut 99.5ic, or more. Ulloiiic dcid sdln a p-lohlciic SUlfoiiic acid sall, a iiicll&J&ic [0142] In o&hcr embodimmits. Ihe compound nux&urc has sulf&onic acid salt, an oxalic acid salt, a 2-hydroxy ethane- an (R)-enantiomeric purity of greater than about 55%, about sulf&onic acid salt (i.e . an isethionate salt). a l,-sspartic acid 60%, about 65%, about 70%, about 75'!! . about NO'%. about salt. a maleic acid salt. a phosphoric acid salt, or an ethane 85;c, about 90%, aboUt 95%, about 91)%. about 97%. Shout sulfonic acid salt. 98;c, about 99%. aboUt 99.5% or more. In some other [0145] The compound of formula (I) has at least two basic cmbodimcnts, thc compound mixture has an (R)-cnantio- nitrogen atoms with a pKB value of about 3.5 and about 4.2, menc cxccss of renter than about 55icc Io about 99.S%, rcspcctivcly. Without bcuig lnnitcd by any pnrticular theory. greater than abou& 60% Io about 99.5%, grcatcr than about ui some cmbodimcnts, thc acids arc assoc&a&ed wi&h the basic 65% to about 99 5%. greater than about 70% to about ')9 5%, nitrogen of the pyrimidine ring of the compound of formula greater than about 75% to about 99 5%, greater than about (I); in other embodiments, Ihe acids are associated w:ith the US 20]4/0275 [35 A1 Sep. 18, 2014 14

basic nitrogen of the pyridine ring of the compound of formula (I): and yet in other cmbodimcnts, ihc acids arc nssoci- S.h a lcd w it h both o I'he basic nitrogen of the pynmidure ring and the basic nitmgen of the pyridine ring of the compound of fiirnnda (I). [0146] Also provided hcrcin are solid lonns of a salt of thc compound of fiirmula (I), or a solvate (e.g . hydrate) thereof In one embodiment, the solid fiirm provided herein i ~ Form I, B Form 12M Form I B, Form 2, Form 3. or an amorphous foun of HO OH a sulfuric acid salt Compound or a mixture thereof. In of I, I I Pdinnphosl t.'I onc cmbodimcnt. the solid I'onn prov Bled hcrcui Is Form I, or X;POi Hio an mnorpho us form of a malcic acid sall u1 Compound I, or a I-BuOHiH20 fiinn mixture thereof In one mnbodimcnt, the solid provided 2i nook up nnd herein is I'orm I, Iiorni 2, I'orin 3, liorni 4, or an amorphous fiirm of an 1.2-ethanedisulfonic acid salt of ('ompound 1. or a mixture thereof. In one embodiment. the solid fomt provided herein is Form 1. Form 2. or an amorphous fomt of a NH hydrochloride salt of Compound 1. or a mixture thereof. In onc cmbodimcnt. the solid I'onn prov Bled hcrcui Is Form I, or an amorphous form of nn isctlnonatc salt of Compound I. or a mixture thereof [0142] Also provided herein arc solid Iiinns ol'a Ibec base Meo QY of thc tximpouud of formula (I), or n solvatc (e.g.. hydrutc) thereof In one embodiment. the solid forin pnivided herein is B:leo liorm l. Iiorm 2, liorm 3. Iiorm 4, I orm 5, liorm 6. or an I BOB amorphous form of a free base of Compound I. or a mixture 2I nude eolni on thereof. [0148] In some embodiment, a solid foun provided herein is a soli etc of a Ibcc base or sall of Compound 1. In onc cmbodimcnt, the solvdtc is a hydrate. h:Hi [0149] In some mnboduncnts, provided hcrcm is a phamui- ceutical composition coinprising a solid forin of a conipound of formula (I) Meo

IB Meo

NO QYl [0151[ In one embodiment. ~olid forms pmvided herein are usehd in the pmduction ofmedicinal preparations and can be or a salt. solvate (e.g . hydrate), or solvate of a salt thereof, or obtained by means of a crystallization process to produce a mixture thercol, und ouc or more phurmaccuucally accept- crystulluiclidifyingg nnd semi-crystalline forms or u solidilicauon pro- able cxcipients. In some cmbodimcnts, provided herein is a cess to obtain thc amorphous Ibnn. Iu ccrtnui emboduucnts. pharmaceutical composition comprising, a therapeutically thc crystallization is carried oul by cithcr gmierating a com- effective amount ofa solid forni ofa compound offin rmula (I), pound of Formula (I), or a salt thereof, in a reaction mixture or a salt. solvate (e.g . hydrate), or solvate of a salt thereof, or and recovering a solid form from the reaction niixture, or by a mixture thereof, and one or more pharmaceutically accept- dissolvin a compound of Fomtula (I), or a salt thereof, in a able excipients. solvent. optionally with heat, followed by crystallizing/so- [0150] In onc mnboduncnt, as depicted in Scheme I below, the product by cooling and/or by the addiuon of dn Compound I is prcparcd ui Iwo steps frum (S)-3-(I-amiuo- anti-solvent I'or a pcnod oflunc. Thc crystallization or sohdi- cthyl)-8-chloro-2-phcnylisottuutolin-I(2H)-onc in tv,o steps. licuuon can bc followed by drying cerned oul under con- 'I'he preparation of ('ompound I has also been reported in trolled conditions until a certain solvent or water content is US2013,'0053362 reached in the end solid fiirm. US 20]4/0275 [35 A1 Sep. 18, 2014 15

[0152] In some embodiments, provided herein is a method ment, Compound I used in step (a) is a crystalline form of of prcpaung a sollil fonu of a conlpoiulil oi fbuuUIS (I): Compound I, c.g., Foml 1. Form 2, Fonu 3, Foun 4, Form 5, or Foml 6 ofa frix: base ofCompound I, or a mixture Ihcrixlf. In one enlbodiment, Compound I used in step (a) is substantially pure In another embodiment, ('ompound I used in step MSO (a) Is a crude material after synthesis ofCompound I, wherein the crude material is optionally treated with activated carbon. [0156] In some embodiments, pmvided herein are methods for prcpuring a sohd form of a salt oi'ompound I, or d sol vale Ihcl co f: conlpllslug (il) exposing s nlstcildl conlpl ising a salt of ('ompound I to a solvent system; and (b) producing and/or recovering, the solid filrm of the salt of ('onlpound I from the mixture resulted from step (a). [0157] In some embodiments, pmvided herein are methods for preparing a solid form of a free base of Compound I. or a rorno sol vale Ihcl co f: conlpllslug (il) exposing s nlstcildl conlpl ls- QYI ulg a salt or from base ofCompound I to a solvent systcmi and (b) pmducing and/or recnvering the solid form of the free base ofCompound I froin the mixture resulted from step (a) [0158J In certain embodiments, step (b) comprises one or or a salt. solvate (e.g . hydrate), or solvate of a salt thereof, or more ofthe folloiving steps; (i) cooing a solution containin a mixture thereof ln one embodiment. the method comprises a salt or free base ofCompound I: (il) adding an anti-solvent. I'I vering a solid form as a 1 i rat solid litnn a cr synthesisrecove-of with or w uhout a cooling stcgb to cause prcmipitauon of a solid a compound of Formula (I). or a salt thereof. In another material composing a salt or frcc base of Compound I, (ni) embodiment. the method comprises recovering a solid fornl evaporating (e.g . Sloiv evaporation or fast evaponltion) a as a transition fmm a prior solid form of a compound of solution cmltaining a salt or free base of ('ompound I; (iv) iiormula (I). or a salt thereof. (e 5, first recovering a hrst solid slurrying a material comprising a salt or free hase of ('onl- foun of a compound of Formula (I). or a salt. solvate (e pound I in a solvent system; and (v) subjecting a material hydrate). or solvate of a salt thereof. and converting the comprising a salt or free base ofCompound I to maturation in redd Iirst solid fonu to a six ond solnl Iilrm under suitublc d solvent sy'aleut. conditions). Trdnsiuons Ibom onc solid form ul another src within the scope of the disclosure. In one einbodiment, such 5.2.1 Sulfuric Acid Salt oi'Compound I transition processes can be used as a manufacturing. metlxld [0159J In some embodiinenti. provided herein is a sulhiric filr obtaining a solid form for the production of medicinal acid salt of Compound 1. It is contemplated that a sulhiric preparations.

acid salt of Compound I can exist in a variety of solid filmls.

[0153] In some mnboduncnts, provided hcrcm;uc methods Such sohd forms include crystallulc sohds, such as polymor- for prc7tartng s sohd I'oun of a adit of Compound l. or a phs, solvatcs and hydra(ca oi'crystallulc sulfuuc acid salt oi'onlpoiind solvate thereof: comprising (a) contacting Compound I v ith I, as well as ilnlolphoUs sollils, ol nuxlUrcs an acid in a solvent system or exposing a material comprising thereof. All such solid forms of sulfiiuc acid salt of ('onl- a salt Compound I to a solvent system: nnd producin of (b) pound I are cmltemplated under the present invention. and/or recovering the solid form of the salt of Compound I [0160] As uscxf herc. Snd unless otherwisc spccdicd, Ihc Ihi: rcsUltcil flout flout aux(lire step (a). tenn '*a sulfuric acid salt" rcfcrs Io a salt compnsulg at least [0154J In some embodiments, provided herein are methods ouc countcnon dcnvcd from sulfuuc acid (HsSOS). A coun- filr preparing a solid form of a salt of Compnund l. or a teriim derived frmu sulfuric acid include, but are not liinited solvate thereof: comprising (a) contacting Compound I v ith to. I ISOS (e.g . hydmgen sulfate. hydmsul fate. or bisulfate) an acid in a solvent system, and (b) producing and/or recov- and SOSC (e.g., sulfate). The molar ratio of the cation to the ering the solid form of the salt of ('ompomld I from the coutnerion derived from sulfuric acid in a sulfuric acid salt mixture resulted Irom step (a). can bc any rauo known ul Ihe art. Exemplary molar rauos [0155J In one embodiment. provided herein are methods ulcludc. but are not linntcxf to. shou( 1.2 (i.c., bis-sufi'uric acid filr preparing a solid form of a salt of Compnund l. or a salt), about I:I (i.c., mono-sulfunc acid salt), mid about 2:I solvate thereof; comprising (a) mixing (I) a mixnire of('om- (i e, hemi-sulfuric acid salt). 'I he term "a sulfiiric acid salt" pound I in a tirst solvent and (ii) a mixture of an acid in a includes all forms ofthe salt. including, but not limited to. an sicond solvent, and (b) producing and sor rcmovcrin thc sohd amorphous foml, a crystalline foml, an anhydrous foun. a form oi'hc salt of Compound I from thc mixture resulted solvate foml (e.g., a hydrate form), of the salt, or a combina- from step (a) Thc lira( solvent and Ihe second solvent can bc tion or nuxturc thereof. different or the same In one embodiment, the tirst solvent is [0161 J In one embodiment. provided herein is a solid fornl anisole In annther embodiment, the first solvent i ~ anisole/ comprising a sulfuric acid salt of ('nmpound I, or a solvate MeOH. In one embodiment. the hrst solvent is anisole/MeOH (e ., hydrate) thereof. In one embodiment, provided herein is (ca. 6/4 v/v). In one embodiment. the second solvent is a a solid form comprising a solvate of a sulfuric acid salt of solvent that dissolves thc acid. In onc embodiment. Ihc sec- Compound 1. In onc cmbodimcnt, provided hcreul is a solid ond solvent is a solvent that dissolves thc acid at RT in no form composing a hydrate oi' sufi'uuc acid sall of Com- morc than 100 volumes. Iu one cmbodunent, thc almond pound l. In onc cmbodimmu, provided herein is a solid I'onu solvent is I'I Ill In one embodmlent, ('ompound I used in step comprising a crystalline form of a sulfuric acid salt of ('onl- (a) is anamorphous form ofeonlpound I In anotherembodi- pound I, or a soivate (e g . hydrate) thereof In one embodi- US 20]4/0275 [35 A] Sep. 18, 2014 16

ment, provided herein is a solid form comprising B crystalline ments. the solid form is characterized by 7 of the peaks. In fornl of a so 1 vs to of B sill fil lie acid salt ofConlpoitad I . Ill onc some cmbodimcnts. thc solid I'onn is charsctcnzcd by 9 ofthc cmbodimcnt, providixl hcrcul is a solul form comprisul a pmiks. In sonic cnlbixllnlcnts, thc solid fornl is charBcicrizixl crystalline form of a hydnlte of a sulfuric acid salt of Conl- by 11 of the peaks In some embodiments, the solid form is pound 1. In one embodiment, the sulfuric acid salt of Conl- clmracterired by 13 of the peaks. In some embodiments. the pound I is a sulfate salt. In another embodiment, the sulhiric sohd form is characterized by all of the peaks. acid salt ofCompound I is a bisulfate (i.e.. hydmsulfate) salt. [0168] In some embodiments. provided hcrcul is a solid [0162] In some embodiments. the molar ratio ofCompound form comp n sing a su 1 fur w. acid salt ofCompound I having an I to sulfuric acid in thc solul form ranges Irom Shout 2.1 to XRPI) pattern comprisin peaks at approximately 10.7. 12 4, about I:2. In oue mnboduncnt, thc molar ratio is about 1.2 and 23 6 degrees 2H In certain embodimentm the solid fornl (i e, bis-sulfiiric acid salt) In another embodiment, the molar further comprises peaks at approximately 19.2 and 204 ratio is about I: I fi e., mono-sulfiiric acid salt). In yet another degrees 20. In certain embodiments, the solid form fhrther embodiment. the moLar ratio is about 2; I [i.e., hemi-sulhiric comprises peaks at approximately 17.7 and 22.2 degrees 20. acid salt). In onc cmboduuent, thc sohd Ibnn comprises peaks at [0163] In some embodiments. the molar ratio ofCompound approximately 10.7, 12.4. 14.2. 17.7, 18.4, 19.2, 20.4, 21zk I to thc solvent/water in thc solxl form ranges Ibom about 2.1 21 7, 22 2. 23 0. 23 6. and 24 7 degrees 2H to about I:2. In one embodiment. thc molar ratio is about 1.2 [0169] In some embodiments, the XRPD peaks above (de- (i e, bis-solvate/hydrate) In another embodiment, the molar grees 20 peaks) are when analyzed using copper Kct radia- ratio is about I: I (i.e, mono-solvate'hydnlte) In yet another tion. embodiment. the molar ratio is about 2: I (i e, hemi-solvate/ [(317()J In some embodiments. provided herein is a solid hydrate). form comprising a sulfuric acid salt of Compound I, wherein [0164] In one embodiment. the hydrate ofthe sulfuric acid the solid form is characterized by an XRPD diffmlction pat- salt of Compound I is a monohydraie of a bis-sulfurm ucid tcm v luch matches thc XRPD paucm prcsmltixl ul FIG. IA. salt oi'Compound l. FIG. I B, or FIG. IC.

[(3 171 J A representative thermal gravimetric analysis Form I of Sulfunc Acid Salt ol'Compound I [TCIA) curve of the sulffiric acid salt of Compound I is FICr. B [01651 In some embodiments, provided herein is Form I of provided in 2su ivhich exhibits weight loss of alxlut the sulfuric acid salt of Compound I. In one embodunent, 2.70/o ofthc total sample w eight upon heating I'rom about 30 Form I ofthe sulfunc acul salt ol'Compound I is a crystallulc to about 220'. Without being lunitcd by any parucular bis-sulfuric acid mouohydratc salt of Compound 1. In some theory, thc w eighl loss corresponds to loss of about I cxluiva- cmbodimcnts, Form I ofthe sull'uric Beni salt ofCompound I lent of water. is substantially free of amorphous sulhlric acid salt of Conl- [0172] Another representative thermal gravimetric analysis pound l. In some embodiments, I'orm I of the sulffiric acid [TCiA) curve of thc sulihric acid salt of Compound I is salt of Compound I is substantially free of other crystalline provided ui FIG. 2B. wluch exhibits a wci Jit loss of about fonna (i.e., polymorphs) of the sulfuric acid salt of ('om- 2.76/o ofthc total sample w eight upon heating I'rom about 30 pound l. In some mnboduncnts, Form I oi'he sulfuric ucid to about 220" ( Without being limited by any particular salt oi'ompound I is substanually free of ogler salts of theory, the v;eight loss corresponds to loss ofabout I etiuiva- Compound 1. In some cmboduncnis, Form I oi'hc sulfunc lent of water. acid salt of( ompound I is substantially free of the free base [0173] Yct another rcprcscntauve thermal gravimctnc ('I'GA) I ofCompound 1. In some embodiinents, florin I ofthe sulhiric aimlysis curve ofthe sulfuric acid salt ofCompound acid salt of Compound I is provided as substantially pure is pmvided in 111G. 2(, which exhibits a weight loss of about Form I of the sulfuric acid salt of Compound l. In one 2 7591 ofthe total sample weight upon heating front about 30 embodiment. Form I ofthe sulfuric acid salt of('ompound I to about 220" C. Without being limited by any particular is a sulfate salt. In another cmboduncni, Form I ofthc sul func theory, the v eight loss corresponds to loss ofabout I etiuiva- acid salt ofCompound I m a bisulfate [i.c., hydrosulfale) salt. lcnt of Outcr. [0166] Representative XRPD patterns of Form I of the [0174] In some embodiments. pmvided herein is a solid sulffiric acid salt of Compoiuld I are provided in FICI IA, form comprising a sulfuric acid salt of Compound I, wherein FIG. IB, mid FIG. IC. thc solid foml is charactcrizcd by a TCiA thcnuogmm wluch [0167J In some embodinlents, pmvided herein is a solid ma tclms the TGA thennogrmu pres cntcd in FIG. 2A, FIG. 2 B. form comprising a sulfiinc acid salt of Compound I charac- or ill(i 2(L terized by XRPD peaks located at I, 2, 3. 4, 5, 6, 7. 8. 9, 10, [0175] A rcprcscntauvc differcnual scanlung caloruuctry 11, 12. 13. 14, 15, or all ofthe followin ~ or approximately the [DSC) thcrmogram of thc sulfuric acid salt ol'Compound I is following positions 8.1, 10.7, 10.9, 12.4, 13ek 14.0, 14 2, presented in 11IG 3A In some embodiments, provided herein 14.8, 15.1, 16.0. 16.3, 17.6, 17.7. 18.4, 18.6, 18.7, 19.2, 20 4, is a solid foml comprising a sulfunc acid salt ofConlpound I 21.4, 21.7, 22.2, 23.0, 23.4, 23.6, 24.2, and 24.7 dcgrccs 20, that exhibits a thermal event. as characterized by DSC, with a plus or minus 0 10 In some einbodiinents, provided herein is peal temperature of about 151'. and/or an onset tempera- a solid form compnsing a sulfiiric acid salt of ('ompound I ture ofabout 133" C. Without being limited by any particular characterized by XRPD peaks located at I, 2. 3. 4. 5, 6. 7, 8, theory, thc thermal event with a peak temperature of about 9. 10. 11. 12. or all of the following or approximately the 151" C. and/or Bn onset temperature ol'about 133'. corre- following positions 10 7, 12.4, 14.2, 17.7, 18.4, 19.2, 20 4, sponds to dehydration of the solid form 21.4, 21.7. 22.2, 23.0, 23.6, and 24.7 degrees 20. plus or [0176] Another rcprcscntauic diffi:rential scaruung calo- mulus 0.10. In some embodiments, ihc sohd form is clmrac- nmctry [DSC) thcmlogram of'the sulfunc acid salt of Com- terized by 3 of the peaks. In some embodinlents, the solid pound I is presented in I'IG 3B In some enlbodiments, form is characterized by 5 of the peaks. In some embodi- pmvided herein isa solid fbrm compnsing a sulfuric acid salt US 20]4/0275 [35 A1 Sep. 18, 2014 17

ofCompound I that exhibits a thermal event, as characterized m&xin (I) a mixture ofCompound I in a first solvent and (ii) by DSC. wtth a peak tcmpcrature of about 153'. and/or an a mixture of sulfur&c ac&d in a second solvent, mid (b) pro- onset Icmpcrature of about 128" Co or» Ith a peak tempera- duculg andior recovcrulg Form I of the sulfunc ac&d salt of ture of about 223" ('nd/or an onset temperature of about ('ompound I from the mixture resulted front step (a). 219" ('. In some embodiments, pmvided herein is a solid fornl [t)182J In one embodiment. Step (a) is conducted at a tenl- a acid salt ('ompound I thm exh&bits comprising sulfunc of perature ranging from about 20" ('o about 100" ( . front themlal events. as chamcterized by DSC, with a peak tem- about 30" ('. to about 80" ('., or from about 40" C. to about 60" 153" perature of about C. and/or an onset temperature of C. In one embodiment. step (a) is conducted at about 50" C. about 128'.. and with a peak tcmpcrautrc of about 223'. In one embodiment. the molar ratio Compound I and/or ml onset Imnpcrature ol'about 219'. Without being [0183] of to sulfuric acid in ranges from about I:1.5 to alxlut limited by any particular theory. the thermal event wtth a peak step (a) 1.3. In one cmboduncnt, tlm molar ratio ranges from about temperature of about 153" ( anrgor an onset temperature of abolut 128" C. corresponds to dehydration of the solid form. 1.1.8 to about 1.2.5. In onc embodnncnt, Ihc molar ratio mlnges from about I 1.9 to about I:2 4 In one embodiment, Without bein limited by any particular theory, the them&el the molar ratio ranges fmm about I 2 to about I 2.2 In one event &lith a peak temperature of about 223'. and/or an embodinlent, the molar ratio is about I:2 2 onset tcmpcraturc of about 219'. corresponds to melt/ d&ssoctauon of thc sol&d foun. [t)184J In one embodiment. the material comprising a sul- [01771 Yet another representative differential scannin func acid salt of Compound I in step (a) comprises at least calorimetry (DSC) thcnnogrmn of thc sulfuric acnl salt of one non-Foun I foml of a sulfuric ac&d salt of Compound l. Compound I is prcscntcd in FIG. 3C. In some embodunmlts, In onc cmbodimcnt. tlm non-Form I form of a sulfunc acid pmvided herein is a solid form cotnprising a sulfuric acid salt salt ol'Compound I is Foml IA, Form I B, Form 2, Foml 3, or ol'a ofCompound I that exhibits a thertnal e& ent, as characterized an amorphous form sulfuric acnl salt of Compound l. In by DSC. with a peak temperature of about 161', and/or an another embodiment, the material comprising a sulfuric acid onset temperature of about 133" ( '.. or &vith a peak tempem- salt of('ompound I in step (a) comprises Itorm I of a sulfuric ture of about 222" C. Und/or an onset temperature of about acid salt of Compound I and one or more impurities. 21 8'. In some ambo dnncn& s, prov alod hcrmn is a so ltd fbml [0185] The solvent system (c g., the solvmlt system result &xi comprising a sulfunc acid salt ol Compound I tlutt exh&btts front thc nltxnlg ol thc 01st solvent anti thc second solvent) thermal events. as charactenzed by DSC, with a peak tens- may bc a mono-solvent system or a multi-solvent system, I.c.. perature of about 161" ('. and/or an onset temperature of a b&nary, tertiary, or greater solvent system In certain embodi- abolut 133'o and with a peak temperature of about 222" C. ment% step (a) ant(tor step (b) are conducted in a non-anhy- and/or an onset temperature of about 218'. Without bein drous condition. Where the conchtions are non-anhydrous. limited by any particular theory, the themlal event with a peak v ater can be present in trace amounts, or in amounts less than tcmpcraturc ol'about 161' andior an onset tempcraturc of about 1% by vohunc ol solvent, or present as water vapor. In about 133'. corresponds to dehydrauon of thc sohd foun. certain cmbod&ments. thc solvent system Is a non-anhydrous Vt'ithom being limited by any particular theory, the them&el solvent system. In cert ma ambo dunml to, w ster can be present event with a peak temperature of about 222''nd/or an as a co-solve&&t (or anti-solvent). for example, in an an&Cunt 218" onset temperature of about C. corresponds to melt/ mlnging from about I'i to about 50% I &or example. water can dissociation of the solid form. be present in about 5%, about 10'/o. about 15%, about 20%. [0178J In some embodinlents, pmvided herein is a solid aboUt 25%, about 3@%. about 35%. about 40%. about 45%. form comprising a sulfuric acid salt ofCompound I, wherein and about 50% by volume of'solvent. In crrta&n emboduucnts. the solid form is characterized by a DSC thermogram which w ster can bc pre&cut in mnounts equal to or grwtlcr than aboul matches die DSC thcrmogram presented in FIG. 3A, FIG. 3B, 50% by volume of sob cnt. For example, water can be present or FIG. 3C. in about 55%, about 60%, about 65%, about 70%, about 75%, [0179] A representative gravimetric vapor sorption (CiVS) about 80%, about 85'%. about 90%. about 95%, and up to isotherm of thc sull'unc ac&d salt ofCompound I Is prcscntcd 100% by volume of solvent. In cermin embodiments. liquidol'hc in FICI. 4. In one embodiment. provulcd hcrcul &s a sohd fbml v ater is present in a nntlti-solvent system, for example, in an comprising a sulfunc acid salt of Compound 1. whcrcul thc amount ranging from about 10'!o to about 50% by volume solid form is charactenzed by a (iVS i anthem& which nlatches solvent system. In ccrtaul cmboduncnts, hqu&d water Is the (iVS isotherm presented in Ill(i 4 plcscnt ul a n&UI&l-solvent sy'steal, nl an anloUU& cqtlal Io ol [0180] Representative FT-IR spectra of the sulfuric acid greater than about 50'%y volume of the solvent system. In salt ofCompound I are presented in FIG. 5A and FICi. 5B. In certain etnbodiments. &vater can be present as water vapor or one embodiment, prov&ded herein is a solid form comprisin ambient hluuidity a sulfunc acid salt of Compound I, whcrem thc sohtl form Is [0186] In one cmboduncnn thc not&-water solvent &s a char w tenzed by an FT I R spectrum whwh matches the FT IR water-miscible solvent. For example, hqu&d water can bc spectrum presented in I'I(i 5A or I'l(i 5B prcscnt in an amount of'about I'!o, about 2%, about 3%, about [0181J In one embod&ment, provided herein i ~ a metlxld for 4%, about 5%, about 6%, about 7%, about 8%, about 9%, preparing ltorm I of the sulfuric acid salt of ('ompound I about 10%. about 15%, about 20%. about 25%, about 30%, comprising (a) contacting Compound I with sulfuric acid In a aboUt 35%, about 4(F%o. aboUt 45%. about 50%. about 55%. solvent system or exposing a material comprisin ~ a sulhlric about 60%, about 65;o. about 70%. about 75%. about 80%. acid salt ofCompound I to a solvent system. mid (b) produc- about 85%, about 90%, about 95%. about 96%, about 97%. ing and/or recovcrul Form I of thc sulfunc acid salt of about 98%. about 99'/o. or about 100% by volume ol'hc Compound I lrom thc m&xturc rcsultcd lrom slop (a). In onc solvent syslem. In one cmbodimcnt, hqutd water is pre&cut in embodiment. provided herein is a method for preparing ltornl an amount ofbetween about 10% and about 50'%y volume I of the sulhtric ac&d salt of ('otnpound I compri ~ ing (a) ofthe solvent system. US 20]4/0275]35 A1 Sep. 18, 2014 18

[0187] In one embodiment, the solvent system (e., the a mixture of sulfuric acid in a second solvent: (2) cooling the solvent system resulted from Ihc mixing ol Lhe lirst solvent rcsuhcd nuxturc, and (3) optionally sublcctlng lhc nuxturc Io and thesccond solvent) compnscs water ands water-miscible maturation. In onc emboduncnt, thc lirst solvent Is amsole/ solvent, e g., (, -( o alcohol. acetone. acetonitrile. amnng oth- I:tOI I. In another embodiment, the first solvent is EtOI I In ers In one embodiment. the water-miscible solvent is an another embodiment. the first solvent is acetone In one alcohol, e.g., C,-CJ alcohol In one embodiment. the water- embodiment. the second solvent is 11 ater. In another embodi- miscible solvent is a Cs-Co alcohol. In one embodiment, the ment, the first solvent is anisole/EtOH and the second solvent water-miscible solvent is ethanol. I-propanol, 2-propanol, is water. In another embodiment, the hrst solvent is EtOH and I-butanol. 2-butanol, t-butanol, or ethylcnc glycol. In onc thc second solvent is water. In another embodiment, Ihc lira( cmbodimcnto the ratio ol'water and watermisclblc solvmlt in solvent is acetone and Ihc second solvent is water. a solvent system provided herein is about 50 I, about 40 I, [0191] In onc embodiment. thc solvent system (c.g.. Ihc about 30:1. about 20 1. about 10 I, about 9: I, abouts 1. about solvent system resulted from the mixing of the lirst solvent 7:I, about 6:I, about 5:I, about 4:I, about 3:l. about 2:I, and thc siwond solvent) is anon-anhydrous solvent system. In aklut I; I, about I:2. about I:3, about I:4. about I 5. about one embndiment, the solvmit system comprises water and an I:6, about I:7. about I:8, about I:9. about I:10. shorn I:20, alcohol In one embodiment, the solvent system comprises about I: 30, about I 40, or about 1. SO vov. In onc emboduncnt, v ater mid a C,-('o alcohol. In one embodiment. the solvent thc rano of wBIcr dnd watcl-1111sclblc sLilvenl in 11 solvent system comprises water and EtOH. In one embodiment, the system provided herein is fronl about 50 I to about I I, froni amount of water in the solvent system ranges from about 1% about 40 I to about I I, froni about 30 I to about I 1. froni to about 20%, from about 2'!o Io about 17.5%, I'rom about 3% about 20 I to about I I, froni about 10 I to about I 1. froni to about 15%, lium about 4'!o Io about 12.5%, or fmm about aklut 9: I to about I: I, fmm about 8; I to about I:1. from about 5% to about 10%, by vnlume nf solvent In one embodiment,

7: I to about I: I, from about (u I to about I:1. from about 5: I the anl cunt of I itOI I in the solvent system ranges from about I'rom to about I. I o about 4 I to about I: l. Irom ubout 3.1 to 20% to about 99%, from about 20'io to about 90%, from alxlut about 3:1. Ikom about 2.1 Io about 1. 2, from about I: I to about 20% to about 80%, from about 25'io to about 70%, from alxlut I 4, from about I I to about I:5, froni about I:I to about I 6, 25% to about 60%, from about 25% to about 50%, or from fmm about I I to about I 7, from about I:I to about I:8. froni about 30% Io about 40o!o. by iolume of solvent. In onc about I:I to about I 9, from about I I to about I 10. froni cmboduucnt, thc solvent system is a water/ELOH nuxturc. In aklut I: I to about I:20, fmm about I: I to about I:30. fmm one embodiment, the snlvent system is a water/IitOI I mix- aklut I:I to about 1.40. or from about I;I to about I:50 v/v. ture, wherein the amount nf water in the solvent systeni hl ollc cnlboduncin, thc solvcnl svstcnl colnprlses v,iitcl; Bn ranges from about 3% to about 15% by volume of solvent. In alcohol. mid a non-alcohol solvent. another embodiment. the solvent system is a water/EtOH/ [0188J In certain embodiments. step (b) cmnprises one or amsole mixture. In one embodiment, the solvent system is a more ofthe following steps: (i) coolin ~ a solution contninin water/EIOH/iulisolc mixture, wherein thc amount ofwater in a sulfuric acid salt ofCompound I: (ii) addio an anti-solvent, thc solvent system ranges from about 3% Io about S% by 1itOI I w 1 th or without a coo 1ulg s kgb Lo cause prccip its Ium ol a solid volume of solvent. and the amount of in the solvent ma(coal compnslng a sulfuric acid salt uf Compound I: (ui) system ranges from about 30% to about 40% by volume of cvilpoi'iltlng (c.g., slow cvBpoldttoll or last cvdpoldfloll) solvent. solution contaming a sulfuric acid salt of ('ompound I: (iv) [0192J In one embodiment, the cooling tempemsture ranges slurrying a material comprising a sulfuric acid salt of (:oni- from about — 20" (: to about 5''. In one embodiment. the pound I in a solvent system; and (v) subjecting a mntenal cooliilg temperature is about 5'. In one embodiment. the comprising a sulfuric acid salt of ( 'ompound I ro matunstion cooliilg time is at least 4 hours, at least 8 hours, or at least 24 in a solvent system In onc cmbodimcnt, step (b) further hours comprises secdulg with a Form I ol a sulfunc acid salt of [0193] In one embodiment, the maturation is conducted Compound l. In one cmboduncnt, step (b) furlhcr composes v ithin a temperature range from about 0" C. to about 70" C.. a sonication step from abou I 10" C. to about 60' .. or from about 20'. (room [0189] As used herein, and unless otherwise specified, the tcmpcraturc) to about 50'. In onc cmboduncnt, Ihc matu- term "mahiratioif* refers to a process of crystallization, ration is comluctcd Bi(inn a tempcraturc range lrom about whcl'cln B Illatcrtal coinpllsulg Bn Jlllorphoiis solid forln, II 20" ('room temperature) to about 50" C In one embodi- gcl-like form, un oily form. or other low crystallulc Ibrms of ment, the maturation is conducted for at least 4 hours, at least a compound is kept at a certaui tempensture or within a certain 8 hours. at least 24 hours. at least 48 hours, or at least 72 hours. temperature range fora certain period oftinle, with or v ithout ln another embodiment, the maturation is conducted lilr alxlut stirring, to allow the said amorphous solid form. gel-like 4 hours, about 8 hours. about 24 hours, about 48 hours, or form. oily foml, or other loss crystalline forms of the com- about 72 hour~. pound to crystallize. A maturation process is normally con- [0194] In one embodiment, Form I of a sulfuric acid salt of iluctcd ul il solvcllt svsn in ALBBIOI Jtlollploccss Inil)'lvolvc Compound I is prcSIarcd by evaporation of a solution of d sublcctmg Ihc matcnal to onc or more hcatulg cycle(s) sulfuric acid salL of Compound I in MIBK, followed by [0190J In one embodiment, provided herein i ~ a metlxld for nmturation in I-l3uOI I preparin Form I of the sulfuric acid salt of Compound I [0195] In one emboduncnt, Form I ol'a sull'uric acid salt of comprising (I) contacting Compound I with sulfuric acid in Compound I is prcSIarcd by evaporation of a solution of d a solvmlt system, (2) txlohng Ihc resulted nuxlurc, nixl (3) sulfuric acid salt of ('oinpound I in 2/Me'I I II( followed by optionally sublccung Ihc nuxturc Io maturution. In onc inn(ill 1tluli ill;LCetoile cmbodimcnto provided hcrcul is a method lor preparing Foml [0196] In one emboduncnt, Form I ol'a sull'uric acid salt of I of the sulfuric acid salt of Compound I comprising (I) ('ompnund I is prepared by cooling a solution of a sulfuric mixin (i) a mixture of('ompound I in a first solvent and (ii) acid salt of ('.Omponnd I in acetone/ivater. In one embodi- US 20]4/0275 [35 A1 Sep. 18, 2014

ment, the volume ratio ofacetone to water is about 9:1. In one Without being limited by any particular theory, the weight cmbodimcnt, thc coolulg tcmpcraiure &s about 5'. In onc loss corresponds to loss oi'olvent. In some emboduucnts. cmbodimcnt, thc solution is opt&onally seeded with Form I of provided hcrcui is a solid form composulg a sull'uric acxl salt a sulfuric acid salt of ('ompound I of('ompound I, wherein the solid form is characterized by a [01971 In one embodiment, Foun I of a sulihric acid salt of 'I'(iA thenmlgnsm which matches the 'I ()A thermognsm pre- ( 'ompound I is prepared by slow evaporation of a solution of sented in FIG. SA. a sulfunc ac&d salt ofCompound I ui EtOH/THF (ca. 5/I v/v). [0206] A rcprcscntauvc differcnual scaniung caloruuctry [0198J In one embodiment, iiorm I of a sulfuric acid salt of (I )8(') thermos am ofthe sulfuric acid salt of ('ompound I is ('ompound I is cooling a solution of a sulhiric i prepared by presented in I IG. 813. In some embodiments, provided herein acid salt ofCompound I in MEK/THF (ca. 5/I v/v), followed is a solid foun comprising a sulfuric acid salt ofCompound I by nuiturauon that exhibits a thermal event. as characterized by DSC, with a

[0199J In one embodiment, iiorm I of a sulfuric acid salt of peal temperature of about 58" C and/or an onset temperature 'orm ('omponnd I is prepared by hydration of I 2 of a sulhiric of about 35'.. or vnth a peak tcmpcrature of about 129'. acid salt of Compound I and/or an onset temperature of about 110'. In some [0200] In onc embodnncnt, Fonu I of thc sulfunc ncid salt embodinlents, pmvided herein is a solid fornl con&prising, a Coll&poli&id I is stable aficr storage a&40 C /75% RH Rir of 50'. up sulfuric acid salt of( ompound I that exhibits thermal events, to I lveek as characterized by DSC, with a peak temperature of aixlut [0201] In one embodiment, Form I of the sulfuric acid salt 58" C and/or an onset temperature of about 35" C., and with of Compound I is stable aller nuiturauon between RT to a peak temperature ofabout 129" C. and/or an onset tempera- for 5 days ui ethanol, 2-propanol, I-propanol. I-butanol, ture of about 110'. In some mnboduncnts, provxlcd hcrcin 2-butanone, MII3K. acetone. ethyl acetate, anisole, anisole/ IS a Solid foll&1 Coll&pl&S&llg a sillfUI&C dC&il adit Ol CoillpOUI&d 1. 'I'13M) methanol (50/50 v/v), toluene, isopropylacetate, „ wherein the solid film& is characterized by a I )8('hem&Co rani 'I 2-methyl-i-propanol, I II', 2-propanol/water (90/H) v/v). or which matches the DSC thermogram presented in! I(i 813 anisole/TBME (50/50 v/v). In another embodiment. Fomi I of the sulfuric acid salt of Compound I is stable ofter inatu- Form 2 of Sulfuric Acid Salt of Compound I ration bctwccn RT to 50'. Ii&r s days in MeOH. [0202J All of the combmations of the above embodinients [t)207J In some embodiments, provided herem is! Omi 2 of are micompassed this mvention. by the sulfuric acid salt of ('ompound I In one embodiment, iiorm 2 ofthe sulfuric acid salt of('ompound I is a crystalline Form IA of Sulfuric Acid Salt of Compound I anhydrous bis-sulfiiric acid salt of Compound 1. [0203] In some embodiments. provided herein is Form IA [t)208J In one embodiment. I'orm 2 ofthe sulfuric acid salt ofthe sulfuric acid salt of Compound l. In one embodiment, of ('ompound I is prepared by dehydration of iiorm I ofthe Foun IA of thc sull'uric acid salt of Compound I is prepared sulfuric acid salt of Co&upound 1. In one embodunent, Iiorni by subjecting an amorphous sulfunc acid salt oi'Compound I 2 of the sulfuric acid salt of Compound I Is prepared by to maturation ui acctonitnle. In one embodiment, the crystal- dehydmstion of Form I ofthe sulftmc acid salt ofCompound linity of I&orm IA of the sulfuric acid salt of Compound I I at approximately 180'. In some embodiments, Form 2 of decrease~ after standing at 13'I'or 24 hours An overlay plot of thc sulfunc acid ol'Compouixl I is unstable at ambmnt con- representative XRPD patterns of Form IA and Form I ofthe ditions In mle embodiment. I'orm 2 of the sulfuric acid of sulhiric acid salt ofCompound I is provided in FICr'. 6. In one ('ompound I converts to I'orm I ofthe sulfuric acid of ('on&- cmbodimcnt, providixl hcrcui is a solnl form comprisui a pound I by hydnstion sulihric acid salt of Compound I, wherein thc sohd filrm is [0209] An overlay plot ofrcprcsentat&vcXRPD paucrns of char;mtcnzed by ml XRPD d&lfraction pancrn winch matches iiorm 2 and I onn I ofthe sulfuric acid salt of('ompound I is the Xl(PD pattern presented in ill(i. 6 (botto&n pattern). pmvided in FIG 9. In one embodiment. provided herein is a sohd form comprising a sulfiinc acid salt of ('o&npound I, Form I B of Sulfuric Acid Salt of ('ompound I v herein the solid fonu is characterized by an XRPD ditfrac- [0204J In some embodiments, pmvided herein is I'onn I B tion pattern which matches the XRPD pattern presented in ofthe sulfuric acid salt of Compound l. In one embodiment, FIG. 9 (the second mid/or thc tlnrd paucm from thc top). Form IB of the sulfuric acid salt of C'ompound I is prepared by sloiv evaporation of a solution of a sulhiric acid salt of Form 3 ol Sulfunc Acnl Salt of Compound I Compound I in an anisolc/MCOH/THF nnxturc solvent. An ol crlay plot ofrepresentative XRPD put terna oi'Foun I B and [0210] In some embodiments, provided herein is Fomi 3 of iiorm I of the sulfuric acid salt of ( ompound I is provided in thC SUlfU&1C dC&li Salt Of Coll&poll&Id I. Ill Ol&C Clllbodlll&C&lb ill(i. 7. In one embodiment, provided herein i ~ a solid forni 11'unc Form 3 o f the su acid salt ofCompound I Is a cry& ta1 1uic comprising a sulfunc acid salt of C'ompound I, wherein the bis-sulfunc acid salt of Compound I In some emboduucnts. solid form is characterized by an XRPD diffraction pattern iiorm 3 ofthe sulfuric acid salt of('ompound I is substantially which matches the XRPD pattern presented in FICr'. 7 (top free ofamorphous snlfiiric acid salt of Con£ I In some pat&em). embodiments. Fomi 3 ofthe sul fun c acid salt ofCompound I [0205] A representative thermal gravimetric analysis is substantially free of other crystalline fomis (i.e, polymor- (TGA) mirve of the sulfuric ac&d salt ol Compound I is phs) ol lllc sii Ill&&le acid salt oi ColllpoU&ld 1. Ill so&ac I:I&&bod&- provided in FIG. SA, which cxhib&ts a weight loss of about ments. Form 3 of U&c sulfunc acid salt of Compound I is 357% oflhc total sample weight upon hcaung from about 30 substimtially frcm of other salts ol'ompound I In some to about 100" (', and a weight loss ofabout 2 3t)% ofthe total embodinlents, I ono 3 ofthe sulhiric acid salt of( ompound I sample v eight upon heating fm&n about 100 to about 170" C is substantially free of the free base of ('ompound I In some US 20]4/0275 [35 A1 Sep. 18, 2014 20

embodiments, Form 3 ofthe sulh&ric acid salt ofCompound I sulhiric acid salt of Compound I, wherein the solid iiimi is is prox idcd as substanually pure Fomi 3 ol'hc sulfuric uc&d charactcnzcd by a DSC thcnnogram w h&ch ma&elms thc DSC salt ol'Compound l. thcmiogram prcsentcd ui FIG. 11A or FIG. I IB. [0211] A representative XRPD pattern of Form 3 of the [0220] In one cmboduucnn provided hcreui is a method for sulhiric acid salt of Compound I is pro&ided in FICI. 10. preparing ltorm 3 of the sulfiinc acid salt of Con£ I [0212] In some mnboduncnts, pmv&dcd herein &s a sol&d comprising (a) contacting ( ompound I with sulfiinc acid in a fiirm comprising a sulfiinc acid salt of Compound lcharac- solvent systetn or exposing, a material con&prising a sulh&ric terized by XRPI) peaks located at I, 2, 3, 4, 5, 6, 7. N. 9, 10, acid salt of Compound I to a solvent system: and (b) produc- 11, 12. 13. 14, 15, or all ofthe followin ~ or approximately the ing mid/or recovering Form 3 of the sulfuric acid salt of following positions 6.8. 7 7, 9.7. 10.4, I I.N. 12.4. 13 7. 14 I, Compound I lrom dic m&xturc rcsultcd from step (a). In onc

15.5, 15.8, 183. 19.3, 20.9, 21.7. 22.1, 22.8, 24.0, 24.6, 24 9, cmboduucnt, provided herc&n is a method for prepanng Fonu 25.3, 25.7. 26.8, 27.1, 27.6, and 28.4 degrees 20. plus or 3 of the sulfuric acid salt of ('ompound I comprising (a) cmbod&ments, hcrmn &s a sol&d muius 0.10. In some provided nuxing ( I) a mixture of('ompound I in a first solvent and (ii) fiirm comprising a sulfiinc acid salt of Compound I charac- a n&ixture of sulfuric acid in a second solvent: and (b) pm- terized by XRPI) peaks located at I, 2, 3, 4, 5, 6, 7. N. 9, 10, ducing and/or recovering Fomi 3 of the sulfuric acid salt of 11, 12. 13. 14, 15, or all ofthe followin ~ or approximately the Compound I from the mixture resulted fmm step (a). following positions 6.8. 104, 11.8. 12.4, 13.7. 15.5. 15 8, [0221] In one embodiment. step (a) is conducted at a tem-60''n 18.3, 193, 20 9, 21.7, 22.8. 24.6. 24.9. 253, and 25.7 de rees pcraturc rm&ging from about 20'. to about 100'., I'rom 20. plus or m&nus 0.10 In some cmbodimcnts, the solnl fi&mi about 30'. to about 80'., or Ikom about 40'. to about is cl&Brac&ended by 3 ofthc peaks. In some mnboduncnts, thc one embodiment. step ('a) &s conducted at about 50" C. solid fit nn is charactenzed by 5 ofthe peaks In some embodiment~. the solid form is characterised by 7 of the peaks In [0222] In one cmbodimcnt, the molar rat&o ofCompouml I embodime- some embodiments. the solid lorn& is characterized by 9 ofthe to sulfuric acid in step (a) ranges from about I I 5 to about peaks. In some embodiments, the solid form is characterized I 3 In one embodiment, the molar ratio ranges from about by 11 of the peaks. In some embodiments. the solid form &s I:1.8 to about I;2.5. In one embod&ment, the molar ratio char;mtcnzed by 13 of the peaks. In some cmbodmicnts. thc ranges from about I:1.9 to about I:2.4. In one embodiment. nu&lar 1. 2 solnl form &s charactcnzcd by all of thc peaks. thc ratio r urges from about to Shout 1.2.2. In onc [0213] In some embodiments, provided herein is a solid cmboduucnt, thc molar ratio &s about I:2.2. form comprising a sulfuric acid salt ofCompound I bavin an [(1223 J I he solvent system (e g., the solvent system resulted XRPD pattern compris&ng peaks at approxnuatcly 137. 15 5, from the mixing of the first solvent and the second solvent) and 20.9 dcgrccs 20 In cc&tain cmboduncnts, thc solid fi&mi may be a mono-solvent system or a multi-solvent system, i e.. further comprises peaks at approxuuately 24.6 mid 24 9 a b &nary. tertiary. or greater solvent system. In certain degree~ 20. In certain embodm&ents, the solid form h&rther ntsts. step (a) i&ndtor stc7& (b) are conducted u& a non-at&hy- comprises peaks at approximately 11 8 and IN.3 degrees 2H ilrous co&ld&t&o&1. Micro tile co&id&t&ons Brc t&o&l-d&lllvdroi&s, In one embod&ment. the solid form comprises peaks at water can be present &n u ace amounts, or &n amounts less than approximately 6 8, 10.4, 11.8. 12.4. 13.7. 15.5, 15.8. 18 3, about 1% by volume of solvent, or present as water vapor In 19.3, 20.9, 21 7, 22 8, 24 6, 24.9, 25.3. and 25.7 degrees 20. certai&i etnbodiments. the solvent syste&n is a non-snhydmus [0214J In some embodiments, the XRPD peaks above (de- solvent system. In certain emboihments, water can be present grees 2 Hpeaks) are when analyzed using copper ICC& usdi ation as a co-solvent (or anti-solvent). for example, in an amount [0215] In some mnboduncnts, pmv&dcd herein &s a sol&d rang&ng from a boui 1% to about 50%. For example, we ter can form compnsing a sull'uric acnl salt ofCompound I, whcrmn bc prcscnt in about 5'/w about 10/w about 15%. about 20%. thc sohd Iot&11 is charactcnzcd by an XRPD diffract&on pat- about 25%, about 30%, about 35%. about 40%, about 4S%. tern &vhich matches the XRPI) pattern presented in 1&l(i. 10. and about 50% by volume of solvent In certain enibodiments, [0216] A representative thermal gravimetric analys&s water can be present in amounts equal to or greater than about (TGA) mirve of the sulfuric ac&d salt ol Compound I &s 50% by vohune of solvent. For example, water can be present provided m FIG. IIA, which exlub&ts a weight loss of about in about 55'!w about 60%, about 65 io, about 70%, about 75%. 4. I 9% of the total sample w c&ght upon hcatuig from about 30 about 80%, about 85!w about 90/w about 95%, and up to to about 150' 100% by volume of sob cnt. In ccrtau& cmboduncnts, liquid [0217] Another rcprcscntativc thermal gravunetric mialys&s ware& B prcscnt ul B &i&UI&&-solve&&t svstc&l&, lor cxa&&&pic, ul a&1 (I'CIA) curve of the sulfiiric acid salt of ('ompound I &s amount ranging frmn about 10'%o about 50% by volutne of pmvided in I&l(i. I I B, which exhibits a weight loss of about the solvent system. In certain embodiments, 1&qu&d water is 7 28 % ofthe total sample weight upon heating from about 30 present in a nn<i-solvent system, in an amount equal to or to about 220' greater than about 50 is by volume of the solvent system. In [02 INJ In some embodinients, pmvided herein is a solid certain mnbod&ments. water can be prcscut as water vapor or form comprising a sulfuric acid salt ofCompound I, wherein ambient luimid&tv. the solid foun is characterized by a TCiA thermogram which [(1224J In one embodiment. the non-water solvent is a matches the TCiA thennogram presented in FRi. I IA or FICi. water-n&iscible solvent i&or example, liquid water can be 11B. present in an amoiuit of about I "is, about 2'ib, about 3%, about [0219] A representative d&fferential scanning caloritnetry 4%. aboUt 5'!w about 68(&, about 7'ib, about 8%, about 9%. (DSC) thennogram ol'thc sullbnc acid salt ofCompound I &s about 10%, about 15%, about 20%. about 25%, about 30%. prcscntcd ui FIG. IIA. Another rcprcscntauve d&ffcrcnt&al about 35%, about 40%, about 45%. about S0%, about 5S%. scatutuig calorimetry (DSC) thcrmogram ol thc sulliinc uc&d about 60%, about 65%, about 70%. about 75%, about 80%. salt of ('ompound I is presented in I&l(i I II3. In some about 85%. about 90'%, about 95%. about 96%, about 97%, embodiments, pmv&ded herein is a solid form comprising a about ')8'i, about 99%. or about 100% by volun&e of the US 20]4/0275 [35 A] Sep. 18, 2014 21

solvent system. In one embodiment. liquid water is present in to about 15%, from akiut 4"i[ to about 12.5%. or from aixiut an amount ofbctwccn about IO'%nd about 50% by volume 5% to about 10%, by volume of solvmit. In one cmbodimenk of thc solvent system thc mmiunt of E!OH ut thc solvent system ranges from about [0225] In onc embodnnmit, the solvent system (c.g, thc 20% to about ')')'i, from about 20'%o about 90%. from about solvent system resulted from the niixing of the first solvent 20% to about 80'i, from about 25'%o about 70%. from about and the second solvent) comprises water and a water-nu ac ible 25% to about 60%, from about 25% to about 50%, or from solvent, e, C r-Cs alcohol. acetone. acetonitrile, amon oth- about 30% to about 40%, bv volume of solvent. In one ers. In one embodiment, the water-miscible solvent is an embodiment. the solvent system is a water/EtOH mixture. In alcohol. c.g., Cr-Cs alcohol. In onc embodiment, die wutcr- onc cmboduncnt, thc solvent systmn is a water/EtOH mix- miscible soli en! is a Cs-Cs alcohol. In unc cmbodnncnt. thc ture, whcrcin thc iunount oi'ater in thc solvent system water-nusciblc solvent w ethanol, l-propanol, 2-propanol, mnges from about 3% to about 15% by volunie of solvent I -butanol. 2-butanol, t-butanol, or ethylene glycol In one [0229] In one embodiment, the cooling temperature ranges embodiment. the mtio ofwater and water-miscible solvent in from about -20" C. to about 5'. In one embodiment. the a solvent system provided herein is about 50: I. about 40:I, cooling tcmpcraturc is about 5'. In onc cmbodimcnt. thc akiut 30: I. about 20: I, about 10: I, about 9: I, about 8 1. about cooling tune is at least 4 hours, at Ic ist 8 hours, or at least 24 7.1, about 6:I, about 5:I, about 4:I, about 3.1, about 2.1, hours about 1.1, about 1.2, about I:3, about 1.4, ubout 1.5, about [0230] In one embodiment, Foun 3 ofthe sulfiiric acid salt 1.6, about I:7. about 1.8, about 1.9, about 1.10, about I:20, ofCompound I converts to Form I ofthe sulfuric acid salt of about I:30, about I 40, or about I 50 v/v In one embodiment, Compound I after maturation in 10% water/EtOH betvveen the ratio of ivater and water-miscible solvent in a solvent RT and 50'. Ior 3 days. In one cmboihmcnt. Form 3 oi'hc system provided herein is from about 50:I to about I: I, fmm sulfuric acid salt of Compound I converts to Form I of thc akiut 30; I I 1. 40;I to about I:I, fmm about to about fmm sulfuric acid salt of Compound I afier maturation in anisole I'rom I'rom about 20.1 to about 1.1, about 10.1 to ubout 1.1, between Ill'and 50" I: for 3 rLsys about 9: I to about 1.1. I'rom about 8. I to about 1. I, from about 7.1 to about I: I, from about 6.1 to about 1.1, lrom about 5.1 Anmrphous Sulfuric Acid Salt of Compound I to about I 1. from about 4 I to about I:I, from about 3 I to about 3: 1. from about 2 I to about I 2, fmm about I: I to about [0231] In some embodiments. provided herein is an amor- I t4, from about I: I to about I:5, ibom about I: I to about I:6, phous sulfunc acid salt of Compound l. In one cmbodimenL from about I I to about I 7. from about I: I to about I:8, fmm thc umorphous suliunc acid salt oi'Compound I is prcparixl about I:I to about 1.9, from about i.l to about 1.10. I'rom by evaporation of a soluuon oi' suliiinc acul salt oi'om- about 1.1 to about 1.20, I'rom about I.i io ubout 1.30, I'rom pound I in a solvent. In one embodiment, the solvent is about I: I to about I 40, or from about 1.1 to about 1. 50 v/v. MeOI I ln one embodiiuent, the amorphous sulfuric acid salt In one elnbodilnent. the solvent system comprises water. an of Compound I contains about 0.3 equivalent of MeOH. alcohol. and a non-alcohol solvent. [11232J In one embodiment, the amorphous sulfuric acid [0226J In certain embodiments. step (b) cmnprises one or salt of ('ompound I remains as amorphous sulfunc acid salt more ofthe following steps: (i) coolin ~ a solution contninin ofCompound I afier maturation between RT to 50" C, for 24 a sulfuric acid salt of Compound I; and (ii) adding an mtti- or 48 hours in toluene. DCM, THF. EtOAc, BuOAc. TBME. solvcnt, with or without a cooluig step, io cause precipitation dioxane. IPA. or DIPE. of a solid matcnal compnsuig a sulfunc acid salt of Com- pound I &.2.2 Maleic Acid Salt of Compound I [0227J In one embodiment, provided herein i ~ a metlxid for preparing iiorm 3 of the sulfuric acid salt of Compound I [0233] In some embodiments, provided herein is a maleic comprising (I) contacting Compound I with sulfuric acid in acid salt ofCompouixl 1. It is contcmplatcd theta malcic acid a solvent system, and (2) adding an anti-solvent and/or cool- salt ofCompound I can exist in a variety of sohd lbnus. Such in the resulted mixture. In one embodiment. provided herein sohd forms include crystalline solids, such as polyinorphs, is a method for preparuig Form 3 of ihe sulfunc acid salt of solvates and hydrates of crystalline maleic acid salt of Coni- Compound I compnsing (I) mixing (i) a mixture of Ciilll- pound I, as well as amorphous solids. or mixtures thereof All ponnd I in a first solvent and (ii) a mixture of sulfuric acid in such solid fomts of maleic acid salt of Compound I are a second solvent; and (2) adding an anti-solvent and/or cool- contemplated under the present invention. in the resulted mixture. In one embodiment. the first solvent [11234J As used here. and unless otherwise specified, the is EtOH. In one embodiment. the second solvent is water In tenn "a maleic acid salt" refers to a salt comprising at least one embodiment, the first solvent is EtOH and the second one counterion derived from maleic acid (cis-HOO('H solvent is water. In onc cmbodimcnt, thc method docs not CH COOH). A coun!enon dcnved from malcic acid comprise a maturation step. In one cmbodimmit, thc unti- uicludc. but arc not limited to, cis-HOOC/~OH CH solvent is iitOI I COO ) mxl cis- OOCMCH CHMOO . Tlic molar mtio [0228J In one embodiment, the solvent system (eg, the of the cation to the coutnerion derived from nialeic acid in a solvent system resulted from the niixing of the first solvent nmleic acid salt can be any ratio known in the art I ixempLsry and the second solvent) is a non-anhydrous solvent system. In molar ratios include. but are not limited to. about I;2 (i.e.. one embodiment, the solvent system comprises water and an bis-maleic acid salt), about I: I (i e.. mono-maleic acid salt). alcohol. In onc mnboduncnt, thc solvent system composes and about 2: I (i.c., hemi-malcic acid salt). Thc term "a maleic water;md a Cs-Cs alcohol. In one embodiment. thc solvmtt acid salt" includes all fomis of thc salt, uicluding, but nut system comprises water and EtOH. In onc cmbodimcnt, thc lllllltcil to. all alllorpilous fortll, a crystallulc loml, atl allliv- amount ofivater in the solvent systein ranges fnim about 1% dmus forni, a solvate fiimi (e g., a hydrate form). of the salt, to about 20%, from about 2"I to about 17 5'!! . from about 3% or a combination or mixture thereof US 20]4/0275 [35 A1 Sep. 18, 2014 22

[0235] In one embodiment, provided herein is a solid fomx characterized by 13 of the peaks. In some embodiments. the comprising a malcic acid sall of Compound I, or a solvatc sohd form is charac&ended by all of thc peaks. (cg.. hydrate) thcrcof. In ouc cmboduncnt, provided herein is [0241J In some embodiment~. provided herein is a solid a solid form composing an anhydrous maleic acid salt of form comprising a maleic acid salt ofCompound I having an ('ompound I In one embodiment. provided herein is a solid XRPD pattern comprising peaks at appmximately 9.0. 16.0. form comprising a crystalline form of an mxhydrous maleic and 22.6 degrees 20. In certain embodiments, the solid fomx acid salt of Compound 1. In one embodiment. the anhydrous further compnscs peaks at approximately 18.6 mxd 244 maleic acid salt ofCompound I is an anhydrous mono-maleic dcgrccs 20. In ccrtaux cmbodnnents. the sohd I'orm further dCid BBII. comprises peaks at approximately 12 9 and 13 0 degrees 20 [0236] In some embodiments, Ihc molar rano ofCompound In one embodiment, the solid form comprises peaks at 1 to maleic acid in the solid fornx nsnges fmm about 2:I to approxunately 6.2. 9.0, 12.4, 12.9, 13.0, 13.4, 14.6, 16.0. about I:2 In one embodiment, the inolar nstio is about I 2 18.0. 18 6, 19.6, 22.6, 23.5, and 24 4 degrees 20 (i.e., bis-maleic acid salt). In another embodiment. the rnoLxr [0242] In some cmboduncnts, the XRPD peaks above (de- ratio is about 1.1 (i.e., mono-maleic acid salt). In yet another grees 20 peaks) are ivhen analyzed usmg copper K&x radia- embodiment. the molar ratio is about 2: I (i.e.. hemi-maleic tion dCid BBII). [0243] In some embodiments. provided hcrcux is a solid [0237] In some embodiments, Ihc molar rano ofCompound for&xi Coillpllsillg B util)C1C BC&El salt Of Coixlpoxlxid I, WllCrChl 1 to Ihe solvent/mater in the solid form ranges from about 2 I thc solid fonu is charac&coded by au XRPD diffraction pat- to about I:2 In one embodiment, the moLsr ratio is about I 2 tern which matches the XRPI) pattern presented in FI(i 12A, (i e, bis-solvate/hydrate) ln another embodiment, the molar 1&1(x 12B, or I'l(x 12C ratio is about I: I (i.e, mono-solvate/hydrate). In yet another [0244] A rcprcsentativc them&el gravimetnc mxalysis embodiment. the moLar ratio is about 2: I (i.e.. hemi-solvate/ (TCiA) curve of thc malcic acid salt ol'ompound I is pro- hydrate). vided in FI(1. 13A, v inch exhibits no substnntial weight loss upon heating from about 30 to about 170" (L. and which Form I of Malcic Acid Salt of Compound I exhibits a v'eight loss of about 12.48'%f the total sample v 170 to 220" C [0238J In some embodiments. provided herein is 1&orm I of eight upon heating from about about Without the maleic acid salt of Compound l. In one embodiment, bein limited by any patt)en)ar theory, the weicht loss corre- Io Ihc Form I ofthe maleic acid salt of ( 'ompound I is a crystalline sponds dissociation of solid form. anhydrous mono-malmc acid salt of Compound 1. In some [0245J Another representative thermal gravimetric analysis cmbodimcnts, Form I ol'he malcic acul salt ofCompound I ('I'(iA) curve of the maleic acid salt of ('ompound I is pm- is substmxtially lycc of iunorphous mdlcic acid salt of Com- vided In FI(f. 13B, which exhibits no substantial weight loss from about 30 to about 170" C. pound I In some embodiments, liorm 1 ofthe maleic acid salt upon heating ofCompound I is substantially free ofother crystalhne forms [0246J Yet another representative them&el gravinxetric (i.e., polymorphs) of the maleic acid salt of Compound I In aimlysis ( I'(iA) curve ofthe maleic acid salt of ( ompound I some embodiments, Form I of the maleic acid salt of ('om- is provided in I'l(i 13(L xvhich exhibits no substantial iveight 170" pound I is substantially 1rcc of other sails of Compo uxxl 1. In loss upon hestia from about 30 to about C. some emboduumxts, Form I ol'hc malcm acid salt of Com- [0247] In some embodiments. provided hcrcux is a solid pound I is substantially free ol'hc frcc base ofCompound 1. foun comprising a maleic acid salt of ('ompound 1. &vherein In some embodiments, I'orm I of the maleic acid salt of the sohd form is characterized by a I'(iA thermogram which 'I'(iA ('ompound I is provided as substantially pure 1&orm I of the nmtches the thermognsm presented in Ii)(i 13A, l&l(i maleic acid salt of Compound l. 13B. or FICi. 13C. [0239] Rcprcscntauvc XRPD paucrns ol Form I of thc [0248] A rcprcscntauvc differcnual scanrung caloruuctry malcic acid salt of Compound I arc provided ux FI( L 12A, (l)S(') thennogram of Ihe maleic acid salt of ('ompound I is

li1(i. 12B, and I'I(i presented in Fl(i 14A In some embodiments. provided In some embodiments,12('0240] provided herein is a solid herein is a solid tixrm comprising a maleic acid salt of ('on&- form comprising a maleic acid Balt ol Compound I charac- pound I that exhibits a thermal event. as characterized by ter&a&xi by XRPD peaks located at I, 2, 3. 4, 5, 6, 7, 8. 9, 10, DSC, xvith a peak temperature of about 196'. and/or an I'o1 ox&set tcmpcrature of about Without lunitcd I 1. 12. 13, 14, I 5, or all of thc low uxg or approx muitcly thc 191'. being by fixlloxving positions: 6 2, 9 0, 11 3, 11 7, 12 1, 12 '), 13 0, dJx)'iirtlC uhix theory. IRC (11Cmlal Cvcxit w 1&11 a pCak I C&IipCxd- 134, 144 14 6. 16 0 168. 17 5, 18 0, 18 3 18 6, 196. 19 8, ture of about 196" C and&or an onset temperature of about 20 3, 213, 21.7. 22 6, 23 2, 23 5, and 24 4 dep ees 20. plus or 191" C. corresponds to melndissociation of the solid fornx minus 0.10. In some embodiments. provided herein is a solid [0249] Another rcprcscntauic dilTi:rent&el scaruung calo- form comprising a maleic acid Balt ol Compound I charac- rimetry (DSC) themxogram of the maleic acid salt of ('on&- ter&a&xi by XRPD peaks located at I, 2, 3. 4, 5, 6, 7, 8. 9, 10, pound I is presented in lxl(i 14B. In some enxbodiments, I l. 12. 13, or all of the followuxg or approximately Ihc fol- provided herein is a solid form comprising a maleic acid salt loxving positions 6 2, 9 0, 12 4, 12 9, 13.0, 13.4. 14 6. 16 0, ofCompound I that exlubits a thermal event. as characterized 18 0, 18.6. 19.6. 22.6. 23.5. and 24 4 degrees 20. plus or by DSC. xvith a peak temperature of about 19(e C. and/or an minus 0.10. In some embodiments, the solid Iixrm is charac- ox&set tcmpcrature of about 191'. Without being lunitcd by terized by 3 of the peaks. In some embodiments, the solid dJx)'iirtlC uhix theory. IRC (11Cmlal Cvcxit w 1&11 a pCak I C&IipCxd- form is charac(cured by 5 of the peaks. In some embodi- ture of about 196" C and&or an onset temperature of about ments. Ihc solid lonn w chamctcnzcd by 7 ol Ihc peaks In 191" C. corresponds to melndissociation of the solid fornx some mnbodimcnts, I he solid form is clrdractcriBed by 9 ofthc [0250] Yct am&ther rcprcscntauve &hlTcrcntial scanxung peaks In some embodiments, the solid form is clxaracterized calorimetry (DSC) thenuogram of the maleic acid salt of i by 11 of the peaks In some embodiments, the solid form is ('ompound 1 is presented in 1 1(i. 14('n some enxbodiments, US 20]4/0275 [35 A] Sep. 18, 2014 23

provided herein is a solid fomi comprisin ~ a maleic acid salt v ithorv,ithoutacoolingstep.tocauseprecipitationofasolid ofCompound I ihai cxlubiis a ihcrmal cvcni, as chamctenzcd material comprismg a nuilcic acid salt oi'ompound 11 (ni) by DSC. with a peak icmpcraiure of about 197'. and/or an evaporating (c.g., slow eiaporaiion or fast evaporation) a onset temperature of about 1&)2" ( Without being limited by solution containing a maleic acid salt of ('ompound I; (iv) any particular theory, the thernial event with a peak tmnpera- slurrying a material coinprising a maleic acid salt of Coni- ture of about 197" C. and/or an onset temperature of about pound I in a solvent system; and (v) subjecting a material 192" C. corresponds to melt/dissociation ofthe solid fomi. comprising a maleic acid salt ofCompound I to maturation in [0251] In some mnboduncnts, pmvidml herein is a solid a solvent system. In one embodiment. step (b) fiirther com- form comprising a maleic acid salt of Compound I, v herein pnscs scixling with a Fomi I of a malcic acul salt oi'om- the solid form is characterized by a DSC thernxiuram which pound l. In onc cmbodnncni, step (b) further comprises a matches the DSC thermogram presented in FICi. 14A, FICi. sonication step. 14B, or FIG 14C. [0259] In one cmboduncnn provided heraus is a method for [0252] A rcprcscntativc gravimetnc vapor sorpuon (Gs/S) prcparuig Form I oi'hc maleic acid sall of Compound I isotherm of the maleic acid salt of Compound I is presented comprising (I) contacting, ( ompound I with maleic acid in a in lilti. 15. In one embodunent, provided herein i ~ a solid solvent system; (2) cooling the resulted mixture; and (3) foun comprising a maleic acid salt of Compound I, wherein optionally subjecting the mixture to matumtion In one the solid form is characterized by a GX S isotherm which embodiment. provided herein is a method for preparing Fomi matches the GVS isotherm presented in FIG. 15. I of the maleic acid salt of Compound I comprising (I) [0253J Representative lrlilR spectra ofthe maleic acid salt nuxing (i) a mixture of Compound I ui u lirst solvent and (ii) of Compound I are presented m I IG 16A and Fl(i 16I3 In a nuxturc of malcic acid in a second solvent, (2) cooluig ihc one embodiment, provided herein is a solid form comprisin resulted mixture; and (3) optionally subjecting the mixture to a maleic acid salt of Compound I, wherein the solid forin is nmturation In one embodiment, the first solvent is anisole. In char w tenzed by an FT I R spectrum whwh matches the FT IR another embodiment, the first solvent is MIBK. In one spectrum prcsentcd in FICi. 16A or FIG. 16B. embodiment. the second solvent is THF. In another embodi- [0254J In one embodiment, provided herein i ~ a metlxid for ment, the second solvent is IPA In another embodiment. the preparin Foun I of the maleic acid salt of Compound I socond solvent is EtOH. In onc cmboduncnt, thc lirst solvent comprising (a) contacting Compound I with maleic acid in a is MIBK and thc second solvmii is THF. In miother embodi- solvclli svstclll or i:xposlllg d lllaii:rial collipllslllg a lliillclc ment, the first solvent is anisole and the second solvent is acid sall ofCompound I to a solvent sysiem. mid (b) produc- 'll II In another embodiment, the first solvent is anisole and ing and/or rccovcring Fomi I oi'the maleic acid salt of Com- the second solvent is EtOH. In another embodiment, the hrst pound I from the mixture resulted front step (a) In one solvent is anisole and the second solvent is IPA. embodiment. provided herein is a method for preparing liorni [t)26()J In one embodiment, the cooling tempemture ranges I of the maleic acid salt of Compound I comprising (a) from about -20" C. to about 5'. In one embodiment. the mixing (I ) a mixture ofCompound I in a first solvent and (ii) cooliiig temperature is about 5'. In one embodiment. the a mixture of maleic acid in a second solvent: and (b) produc- cooling tune is ai least 4 hours, ai Ic ist 8 hours, or ai least 24 ing and/or rccovcring Fomi I oi'the maleic acid salt of Com- hours pound I from thc mixture rcsulicd from step (a). [0261] In one embodiment, the maturation is conducted [0255] In one embodiment, step (a) is conducted af a imn- witlun a tcmpcraiure range from about O'. io about 70'., pcraiurc ranging from about 20" C. to uboui 100'.. from from about 10" C. to about 60' .. or from about 20'. (room about 30" ( to about 80" C.. or from about -10" C to about 60" temperature) to about 50" ( ln one embodiment. the matu- ('n one embodiment. step (a) is conducted at about 50" ('0256] mtiion is conducted within a tempemture mange fmni about In one embodiment. the molar raiio ofmulcic acid to 20" C (room temperature) to about 50" C In one embodi- ('ompound I m step (a) mnges fmin about OA I to about 3 I ment, the maturation is conducted fiir at least 4 hour~, at least In one embodiment. the ma Lsr ratio rano as from about 0 4 I to 8 hours. at least 24 hours. at least 48 hours, or at least 72 hours. about 06:I, from about I I to about I 3 1. or from about 2 I In unothcr embodiment. the mature non is conduct ixl for about to about 2.4:l. In one embodiment. the moLsr mtio ranges 4 hours, about 8 hours. about 24 hours, about 48 hours, or from about 04:I to about 0.6:1. In one embodiment. the about 72 hour~. molar ratio is about 0 5: 1. In onc cmboduncni, thc molnr rutio [t)262J In one embodiinent, liorm I of a maleic acid salt of ranges from about 1.1 to about 1.3.1. In one mnbodimcnt. thc ('ompound I is prepared by evaporation of a solution of a molar ratio is about I I: I In one einbodiinent. the molar ratio maleic acid salt of Compound I in MeOH/THF, followed by ranges from about 2 I to about 2 4 I In one einbodiment. the maturation in TBME. molar ratio is about 2 2 I [0263] In one embodiment, Form I of a maleic acid salt of [0257J In one embodiment. the material compri ~ ing a Compound I is prcparcd by cxiohng a solution of a malcic maleic acid salt of Conipound I in step (a) comprises at least acid salt ol Compound I in MIBK/THF. In one cmbodimenL one non-Form I form of a ma laic acid salt of Compound 1. In thc volume ratio ofMIBK io THF is about 9.1. In onc embodi- one embodiment. the non-Form I form of a mal eic acid salt of ment, 1iorm 1 of a maleic acid salt ofCompound I is prepared ('ompound I is an amorphous form of a mnleic acid salt of by cooing a solution of a maleic acid salt of ('onipound I in Compound 1. In another embodiment, ihc matenal mmipns- 2-butanone/MEK. In one embodiment, Form I of a maleic ing a maleic acid salt of Compound I in step (u) compnscs acid salt of Compound I is prepared by cooling a solution of liorm I of a maleic acid salt of Compound I and one or niore a malcic acid sall of Compound I ui ethyl acctaic. In onc impurities cmboduucnt, Form I of a malcic acid salt of Compound I is [0258] In ccrtaui embodiments, step (b) rximpnscs cilia or prcparcd by cooluig a solution of a mulcic acul sall of Com- more ofthe following steps (i) cooling a solution containing pound 1 in Ml iK In one embodiment. I'orm I ofa maleic acid a inaleic acid salt of Compound I: (ii) adding, an anti-solvent, salt of ('ompound I is prepared by cooling a solution of a US 20]4/0275 [35 A1 Sep. 18, 2014 24

maleic acid salt of Compound I in anisole/THF. In one embodiment. the amorphous maleic acid salt ofCompound I cmbodimcnt, thc coolulg tcmpcrature is ubout 5'. In onc contains about 0 9 ctluivalcnt ofmalmc acid and/or about 0 6 cmbodimcnt, thc solution is optionally seeded with Form I of equivalent of lVICOH. a maleic acid salt of ('onlpound I [(3272J In one embodiment. the amorphous maleic acid salt [02641 In one embodiment. Form I of a maleic acid salt of of ('ompound I converts to I'orm I of the nlaleic acid salt of 50" ('ompound I is prepared by maturation of an amorphous Compound I after maturation beuveen RT to C. for 3 days malcic acid salt ofCompound I ul I-butunol. In onc embodi- in l-butanol, 2-butanone, MIBK, ethyl acetate, anisole. tolu- ment, Form I of a malmc acnl salt ofCompound I is prepared ene. isopropylacetate, 2-methyl-I-propanol. 2-MeTHF. or by mature uon of'an amorphous ma1cic ucid salt ofCompound aci:tonltrllc. 1 in 2 butanone In one enlbodiment, I'orm I of a maleic acid 5.2.3 1.2-Ethanedisulfonic Acid Salt of Compound I salt of ('ompound I is prepared by inaturation of an anxlr- phous maleic acid salt of Compound I in MIBK. In one [0273] In some embodiments, provided herein is an 1,2- embodiment. Form I of a maleic acid salt of Compound I is cthancdisulfonic acid salt of Compound I. It m contcmplatixl prepared by maturation of ml amorphous mulcic acid salt of that tm 1.2-cthanedisulfonic acid sall of Compound I can Compound I ul ethyl acctatc. In one cmbodunmlt, Form I of exist in a variety of solid forms. Such solid forms include a nudcic acid salt ofCompound I isprcpuredbymaturauonof crystalhne solids, such as polymorphs. solvates and hydrates an amorphous maleic acid salt of('oinpound I in anisole In of crystalline 1.2-ethanedisulfilnic acid salt of Compound l. one embodiment, liorm I of a nlaleic acid salt of Conlpound as well as amorphous solids, or mixtures thereof. All such I is prepared by maturation of an amorphous maleic acid salt sohd fomls of 1.2-ethanedisulfilnic acid salt of Compound I of Compound I in toluene. In one embodiment. Form I of a arc contemplated under thc present invention. malcic acid salt oi Compound I is prcparcxl by maluration of [(3274J As used here. and unless othenvise specified, the an;mlorphous malcic acid salt of Compound I m isopropy- tenn "a 1.2-ethanedisulfonic acid salt** refers to a salt com- hmctatc. In onc cmbodunmlt, Form I of a malcm acid salt of prising at least one counterion derived from 1.2-etlmnedisul-

('ompound I is prepared by maturation of an amorphous fonic acid (HO.,S CHsCHs SOsH). A counterion derived maleic acid salt of ('ompound I in 2-methyl-I-propanol. In from 1.2-cthanedisulfonic;mid include, but arc not limilcxi to. one embodiment, Form I of a maleic acid salt of Compound

HO1S CHsCHs SO, and O,S~HsCHs SO, . Thc I is prepared by maturation of an amorphous maleic acid salt molar ratio of the cation to the coutnerion denved from 1.2- of Compound I in 2-McTHF. In onc cmboduncnt, Form I of ethanedisulfonic acid in a 1.2-etlmnedisulfonic acid salt can a nudcic acid salt ofCompound I isprcpuredbymaturauonof lel'nd be any ratio known in the art. Exemplary molarratios include. an amorphous malcic acid salt ofCompound I in acctomtnlc. but are not limited to. about I;2 (i.e, bis-1,2-ethanedisulfonic In one embodiment. the maturation is conducted betv een acid salt). about I:I (i.e., mono-l,2-ethanedisulfonic acid about 50" C for about 3 days salt), and about 2. I (i.e .. hemi-1. 2-cthancxt 1 su I fonic acid salt). [0265] In one cmboduncnt, Form I ofthe nudcic acid suit of Thc tenn "a 1,2-c tinned i su l fomc acid salt" includes all forms ('ompound I is stable after storage at 30" ('/75% Rl I for up ofthe salt, including. but not limited to. an amorphous tbrm, to I lveek a crystalline form, an anhydums form, a solvate form (e o.. a [0266] In one cmboduncnt, Form I ofthe nudcic acid suit of hydmste form), of the salt, or a combination or mixture ('ompound I is stable after maturation between IO'o 50" C thereof. [0275] In onc embodiment. provided hercul is a solid I'onu fiir 3 days in I -but anni. M I 1 3 K. ethyl acetate. an i sole, an i sole/ methanol (50/50 v/v), toluene, isopropylacetate, 'I'13MI „ comprising an 1,2-etlmnedi sulfonic acid salt o f('oinpound I, 2-methyl-l-propanol, or anisole/TBME (50/50 v/v). or a solvate (e g., hvdrate) thereof In one embodunent, provided herein is a solid form comprising a solvate of an 1.2- [0267J Inoneembodinlent,liorm 1 ofthemaleicacidsaltof ethanedisulfonic acid salt of Compound 1. In one embodi- ('ompound I corn erts to liorni 2 of the free base of Conl- ment, provided herein is a solid form comprising a hydmste of pound I after maturation between RT to 50" C. for 3 days in an 1,2-cthancdisulfonic acnl salt oi'ompound 1. In onc 2-propanol/water (90/10 v/v) or acetic acid/water (25/75 v/v). cmboduucnt, provided hcrcin is a solid lbml compnsing a [02613[ Inoneembodinlent,liorm 1 ofthemaleicacidsaltof crystalhne form ofan 1.2-ethanedisulfimic acid salt of ('onl- ('ompound I converts to Form 5 of the fbee hase of ('ompound I, or a solvate (e . hydrate) thereof In one embodi- 50" g pound I after maturation between RT to C. for 3 days in ment, provided herein is a solid form comprising a crystalline ctlumol. 2-propanol, i-propanol, acetone, THF, or EtOH/wa- form of a solvate ofan 1,2-ethanedisulfonic acid salt ofCom- ter (90/10 1/v). pound 1. In one embodiment, provided herein is a solid foml [0269] In one embodiment. Form I ofthe maleic acid salt of compnsing a crystallulc form of a hydrate oi'n 1,2- ( 'ompound I converts to an amorphous compound offormula cthancdisu1fonic acid salt oi'ompound 1. (I) aficr maturation bctwcml RT to 50'. for 3 days in [0276] solventIn some embodiments. the molarratio ofCompound 2-butanonc or MeOH. I to I-2-ethane disulfonic acid in the solid form ranges from [02701 All of the combirmtions of the above embodiments about 2. I to about 1.2. In onc cmbolhmcnt. (hc molar ratio is are mlcompasscd by tlus invention. about 1.2 (i.c.. bis-1,2-cthanedisulibnic acid salt) In another cmboduucnt, thc molar ratio is about I I (i.c., mono-i,2- Aluorphous Mali:lc Aciil Salt of Colupoulld I ethanedisulfonic acid salt) In yet another embodiment. the molar ratio is about 2 I (i.e, hemi-1,2-ethanedisulfimic acid [02'71] In some embodiments, provided hcrcul is an nnor- salt). phous maleic acid salt of Compouml I. In one emboduncnt, [0277] In some cmbodimcnts, the molar ratio of'Compound the amorphous ma laic acid salt o fCompound I is prepared by I lo thc 'water in thc sohd form ranges from about 2: I evaporation of a solution of a nlaleic acid salt of('ompound I to about I:2 In one embodiment, the molar ratio is about I:2 in a solvent In one embodiment. the solvent is MeOI I. In one (i e, bis-solvate/hydrate) In another embodiment. the molar US 20]4/0275]35 A] Sep. 18, 2014 25

ratio is about I: I (i.e, mono-solvate/hydrate). In yet another sohd form comprises peaks at approximately 7.9, 10.3, 12.7. cmbodimcnt, the molar ratio is about 2: I (i.c., hemi-solvatc/ 14.3. 17.2, 18.1. 18.3. 18.7. 19.2. 20 5, 21.2. 21.9, 22.4, 22.8. hydrate). and 23 3 dcgrccs 20. [0278J In one embodinient, the hydrate of the 1.2- [0283] In some embodiments, the XRPD peaks above (de- ethanedisulfonic acid salt of Compound I i ~ a hydrate of a grees 20 peaks) are when analyzed using copper Kct radia- mono-1,2-ethanedisulfomc acid salt of Compound 1. In one tii111. embodiment. the hydrate ofthe 1,2-ethanedisulfonic acid salt [t)284J In some embodiments. provided herein is a solid of ('ompound I is a monohydmte of a mono-1.2-ethanedis- foun comprising an 1,2-ethanedisulfonic acid salt of ('oni- ulliilllc acid salt ol Compound 1. pound 1. wherein the solid form is chamcterized by an XRPD diffraction pattern which matches the XRPD pattern pre- Form I of 1,2i Ethanedisulfonic Acid Salt of ('ompound I smitcd in FIG. 17A or FIG. 17E( [02'79] In some embodiments. providcdhcrcin is Form I of [0285] A representative thermal gravimetric analysis the 1.2-ethmiedisulfonic acid salt of ('oinponnd I In one (TGA) curve of the 1,2-ethanedisulfonic acid salt of Com- I embodiment. I'orm I of the 1.2-ethanedisulfonic acid salt of pound is pruvuk:d in FIG. 18A. which exhibits a weight loss I'rom ( 'ompound I is a crystalline hydrate of mono-1.2-ethanedi - ofabout 7.79% of ihc total s miplc weight upon heating su lkin acid salt ofCompound 1. In some embodiments. Fomi about 30 to about 220'. Without being limited by any I of tlm 1.2-ctlranixlisulfonic acid salt ol Compound I is particular theory, the wei ht loss corresponds to loss ofwater substantially I'rcc of tunorphous 1,2-cilmnmlisulfomc ucid and/or solvent salt of Compound I ln some cmbodunents. Form I of thc [t)286J Another representative thermal gravimetric analysis 1.2-ethanedixulfimic acid salt of('onipound I is substantially ('I'(iA) curve of the 1.2-ethanedisulfonic acid salt of ('oni- i free of other crystalhne fonna (i e., polymorphs) of the 1.2- pound I is provided in 1 1(i 1813, which exhibits a weight loss ethanedisulfonic acid salt of Compound l. In some embodi- ofabout 3.67% ofthe total sample weight upon heating from ments, Form I of the 1,2-ethanedisulfonic acid salt of ('om- about 30 to about 110" C. and a weight loss ofabout 3.06% of pound I is substantially free ofother salts ofCompound I. In thc total sample weight upon heating lbom about 110'. to some cmboduncnts. Form I of thc 1,2-ctlmncdisulfomc ucid about 220" C. Without bcuig limited by miy particular theory. salt of Compound I is substantially lrcc ol'hc frcc base of the weight losses correspond to loss of water andior solvate ('omponnd 1. In some embodiments. Iiorni I of the 1.2- [0287] In some embodiments. provided hcrcui is a solid ethanedisulfonic acid salt of ('ompound I is pnivided as form composing an 1,2-cthmiedisulfonic acid salt of Com- substantially pure Form I ofthe I.2-ethanedisuliiinic acid salt pound I, wherein the solid form is characterized by a T(iA of Compound l. therniogram which matches the 'I (iA thermogmm presented [0280] Rcprcscntauvc XRPD paucrns ol Form I of thc in FIC). ISA or FR). INB. 1.2-ethanedixulfimic acid salt of('onipound I are pnivided in [t)288J A representative differential scanning calorimetry li1(i. 17A and li1(i. 1713 (DS(') themiogram of the 1,2-ethanedisulfonic acid salt of [0281] In some mnboduncnts, pmvidml herein is a solid Compound I is presented in F ICi. 19A. In some embodiments. form comprising an 1,2-cthancdisulfonic acid salt ol Com- provided herein is a solid form comprising an 1,2-ethanedis- pound I clmractcnzcd by XRPD pmiks lucated ut l. 2, 3. 4, 5, ulkinic acid salt ofCompound I that exhibits a thermal cvenb 6. 7. 8, 9. 10. 11, 12. 13, 14, 15. or all of the following or as charactcnzcd by DSC. with a peak tcmpcraturc of about approximately the following positions 7.9, N 5, 103, 10 7, 130" C. andior an onset tcmpcrature ol'about 125'., or widi 11.0, 12.4, 12.7, 14 0. 14.3. 15.3, 15.9. 17.2, 17 4, 18.1. 18 3, a peak temperature ofabout 185" ( and/or an onset tempera- 184, 18.7 19 2, 20.5. 20.6. 21.2. 21.5. 21.9. 224. 22.8. and ture of about 163" C. In some embodiments, pmvided herein 23.3 dcgrixs 20, plus or mimis 0.10. In some embodunmits, is a solid form comprising an 1,2-ethanedisulfonic acid salt of provided hcrmn is a solid I'orm compnsuig an I,2-ctlmnuits- Compound I that exhibits thermal events, as characterized by ulfonic acid salt of Compound I charactcrizcd by XRPD DSC, vvith a peak temperature of about 130'. and/or an peaks located at 1. 2, 3. 4, 5, 6. 7, 8, 9. 10, I I, 12, 13. 14. or all oimct tcmperaturc ofabout 125'.. and with a peak tcmpcra- of the fiillowmg or approxmiately the followina positions turc ol about 185'. mid/or an onset tcmperaturc of about 7.9, 1020 12.7. 14ab 17 2, 18 I, 18.3, 18.7, 19.2, 20 5. 21 2, 163" ('itlmut being limited by any particular theory, the 21.9, 22.4, 22 8, and 23.3 degrees 20, plus or minus 0.10. In thernial events correspond to loss of water and/or solvent. some mnbodimcnts, the solid form is cireractcrizcd by 3 ofthc [0289] Another rcprcscntauic dilfi:rential scaruung calo- peaks. In some embodiments, thc solid form is chamctenzcd rimetry (DS(') themnogmm of the 1,2-ethanedisulfonic acid by 5 of thc peaks. In some cmbodimcnts, die sohd Ibnn is salt of Compound I is presented in lil(i. 1913 In some characterized by 7 of the peaks In some einbodiments, the embodiments. provided herein is a solid form comprising an solid fiiun is clmractenzed by 9 ofthe peaks In some embodi- 1.2-ethanedisulfonic acid salt of Compound I that exlgbits28'., a ments, the solid form is characterized by 11 of the peaks. In themis I event. as charac t crizcd by D SC. w ith a pmik t cmpcra- some embodiments, the solid form is characterized by 13 of turc of about 53'. and/or an onset tcmpcraturc ol'about tiie peaks. 111 solllc cillbodllllcllts, tile solid loilli is cllal actcl- or with a peak tempcraturc of about 193'. and/or an izcd by all of the peaks. onset teniperature of about 16N" ('n some enibodiments, [0282J In some embodinients, pmvided herein is a solid pmvided herein is a solid fiirm comprising an 1,2-ethanedis- foun comprising an 1.2-ethanedisulfonic acid salt of ('om- ulfonic acid salt ofCompound I that exlgbits thermal events. pound I having an XRPD pattern comprising peaks at as characterized by DSC, with a peak temperature of aixiut approximately 10.3, 12.7. and 23.3 dcgrccs 20. In certmn 53' and'or an onset tcmpcraturc of about 28'., aml widi cmbodimcnts, the sohd fonu further compnscs peaks at a peak tcmpcraturc ol about 193'. and/or an onset tcmpcra- approximately 14 3 and 18.1 dcgrccs 20. In ccrtuui embodi- turc ofabout 168'. Without being limited by miy parucular ments. the solid forni fiirther comprises peaks at approxi- theory, the thermal events correspond to loss of water and/or mately 17.2 and 21 9 degrees 20 In one einbodiment. the solvent US 20]4/0275]35 A] Sep. 18, 2014 26

[0290] In some embodiments, provided herein is a solid Compound I comprising (I) contacting Compound I with form comprising an 1,2-cthancdisulfonic acid salt oi'Com- 1,2-ethancdisulfoiuc;mid in a solvent system, (2) cooling thc pound I, whcrmn the solid liirm is cftaractcnzcd by a DSC rcsuhcd nuxturc, and (3) optionally sub)ecting thc nuxturc to thermogram which matches the DSC thenuogram presented nmturation In one embodiment. provided herein is a method in lil(i. 19A or Iii(i 19I3. for preparing iiorm I of the 1.2-ethanedisulfonic acid salt of [0291] Inonccmbodunmit, provided hcrcm is a method Ibr Compound I comprising (I) mixing (i) a mixture of Com- preparing liorm I of the 1,2-ethanedisulfonic acid salt of pound I in a hrst solvent and (ii) a mixture of 1,2-ethanedis- ('ompound I composing (a) contacting ('ompound I v ith ulfonic acid in a second solvent; (2) cooling the resulted 1.2-ethanedisulforic acid in a solvent system or exposing a nuxturc, and (3) optionally subjecting the mixture to matu- material comprising an 1,2-ethanedisulfonic acid salt of ration. In one cmboduucn( thc Iirst solvent m E(OH. In onc 'I Compound I to a solvent system, aml (b) producuig;uid/or embodinient, the second solvent is I lli In one embodiment, 'I'I rcwovcring Form I of thc 1,2-cihmiedisulfomc acid salt of the first solvent is I itOI I and the second solvent is lli Compound I Irom thc mixture rcsultcd Irom stclt (a). In onc [0297] In one embodiment, the cooling temperature ranges embodiment. provided herein is a method for preparing liorni from about -20" C. to about 6'. In one embodiment. the

I of the 1,2-ethanedisulfonic acid salt of ('ompound I con&- cooliitg temperature is about 6'. In one embodiment. the prising (a) mixing (I) a mixttue of ('ompound I in a first cooling tune is at feast 4 hours, at Ic ist 8 hours, or at least 24 solvent and (ii) a mixture of 1,2-ethanedisulfonic acid in a hours second solvent, and (b) pmducing and/or recovering Forin I [0298J In one embodiment, the maturation is conducted ofthc 1.2-cthancxftsulfontc acid salt ofCompound I from thc within a temperature range from about 0" C. to about 70" ( mixture resulted Irom step (a). from about 10" C to about 60" ( . or from about 20" C. (rooni temperature) to about 50" C. In one embodiment. the matu- [0292] In one embodiment, step (a) is conducted at a tclll-60''n pcraturc ranging from about 20" C. to about 100'.. from ration is conducted within a tempemsture range from aixiut about 30'. to about 80'.. or from about 40'. )o about 20' (room tcmpcraturc) to about 50'. Iu onc embodi- one embodiment. step (a) is conducted at about 50" ('0293] ment, thc maturation is conducted for at least 4 hours, at least In oue cmboduncnt, thc molar ratio of 1.2- 8 hour~, at I east 24 hours, at least 48 hours, or at least 72 hours In another embodiment. the maturatmn is conducted for about ethanedisulforic acid to ('ompound I in step (a) ranges front 4 about 0.4: I to about 3: I In one einbodiinent, the molar ratio lmurs, about 8 himrs. about 24 hours, about 48 hours, or 72 ranges from about 0 4 I to about 0.6 I, from about I: I to about hours. aboiut 1.3: I. or from about 2: I to about 2.4:l. In one embodi- [0299] In one embodiment, Form I of an 1.2-etlmnedisul- I a solu- ment, the moLar ratio ranges from about 0.4: I to about 0.6: l. fonic amd salt of Compound is prcparcd by cooluig In onc muboduucnt, thc molar ratio is about Orh I. In onc tion oi'n 1.2-i:thancdisuli'oiuc acid salt oi'ompound I in I/'ll cmbodimcnt, the molar ratio ranges from about 1.1 to about MeOI If In one embodiment, iiorm I ofan 1,2-ethanedisulfonic acid salt of ( ompound I is prepared cooling a I 3 I fn one embodiment. the molar nstio is about 1.1 I. In by acid salt ( I one mubodiment. the molar ratio ranges from about 2 I to solution of an 1,2-ethanedisulfonic of oinpound about 2.4:1. In one embodinient, the molar ratio is about in EtOH/THF. In one embodiment. the volume mstio ofEtOH 2.2:l. to THF is about 18:l. In one embodiment, the cooling tempcraturc is about In onc cmboihmcnt. the soluuon is [0294J In one embodiment, the material cmuprising an 1.2- 5'. optionally seeded isith Form I of an 1,2-ethaucdisulfomc ethanedisulfonic acid salt of Compound I in step (a) com- acid salt of Compound I prises at least one non-Form I Iiimi of an 1.2-ethanedisul- In mie embodiment, iiorm I an 1.2-ethanedisulfonic acid salt of Compound l. In one embodiment, the non- [0300[ of

fonic acid salt ('ompound I is evaporation Fonn I form oi'n 1,2-cthanedisulliimc acid salt of of prepared by of a solution ofan 1.2-ethanedi sulfonic acid salt ofCompound I

Compound I is an amorphous liirm of an 1.2-ctluincdisul- in MIBK. followed by maturation in I-BuOH. fimic acid salt of ('ompound I In another embodinient, the [0301] In onc embodiment, Fomi I of thc 1,2-cthancdisul- material comprising an 1,2-etlmnedisulfonic acid salt of 40''/75'8 fonic acid salt of Compound I is stable after storage at ('ompound I in step (a) coniprises liouu I of an 1.2- I(f I for to I iveek ethanedisulfonic acid salt of Compound I and one or more up impurities. [0302] Ail of the combinations of the above embodinients are encompassed by this invention [0295] In cermin embodiments. step (b) comprises one or more ofthe following steps: (i) coolin ~ a solution contaiuin liorm 2, I onu 3, and iiomi 4 of 1,2-fithanedisulfimic Acid an 1,2-ethanedisulfomc acid salt ofCompound I; (ii) addio Salt of Compound I an mitt-solvent, st ith or without a cooling step, to cause precipitation oi a solid ma)coal comprism an 1.2-ctluincdisul- [0303] In some cmbodimcnts, provided herein is Form 2 of fimic acid salt of ('ompound I; (iii) etaporating (e g, slow the 1,2-ethanedisulfonic acid salt of ('ompound 1. In one evaporation or test evaporation) a solution containing ail 1.2- embodinient, I onu 2 of the 1.2-ethanedisulfonic acid salt of ethanedisulfonic acid salt of Compound I: (iv) slurryin a Compound I is prepared by heating Form I of the 1.2- material comprising an 1,2-ethanedisulfonic acid salt of ethanedisulfonic acid salt of Compound I to about 100-140" ('ompound I in a solvent system; and (v) subjectin a mate- C. rial compnsing an 1,2-cthaucdisulfoiuc acid salt of Com- [0304] In some embodiments, provided herem is! omi 3 of pound I to maturation ui a solvent systmn. In onc embodi- the 1,2-ethanedisulfonic acid salt of ('ompound 1. In one ment, step (b) fiirther comprises seeding with a Fonu I of an embodiment. Fomi 3 of the 1.2-ethanedisulfonic acid salt of 1.2-ethanedisulfimic acid salt of ('ompound I In one Compound I is prepared by heating Form I of the 1.2- embodiment. step (b) further comprises a sonication step. ethanedisulfonic acid salt of ('ompound I to about 220" C. [0296J In one embodiment, provided herein i ~ a metlxid for [0305] In some embodiments, provided herem is! omi 4 of preparing liorm I of the 1,2-ethanedisulfonic acid salt of the 1,2-ethanedisulfonic acid salt of ('ompound 1. In one US 20]4/0275]35 A] Sep. ]]], 2014 27

embodiment. Form 4 of the 1.2-ethanedisulfonic acid salt of (3) optionally subjecting the mixture to maturation. In one

Compound I is prepared by hcaung Form I ol'hc 1.2- cmboduucnt, provided hcrcin is a method for prepanng Fonu cthili&ixllsidfol&lc ac&it wilt ol Col&lpol&1&d I to about 220'. I of thc hydrochloudc salt of Compound I cou&pnsing (I) fi&llo&ved by cooling hack to about 25" ('0306] nuxing (i) a mixture of ('ompound I in a hrst solvent and (ii) An overlay plot ofrepresentative XRPD patterns of a n&ixture of hydrochloric acid in a second solvent, (2) cooling Form I, Fom& 2. Form 3, and Form 4 ofthe 1.2-ethanedisul- the resulted mixture: and (3) optionally subjecting the mix- fonic acid salt ol'Compound I &s provided u& FIG. 20. In onc ture to maturation. In one embochment, the first salient is cmbodimcnt, provided hcrcin ispatterna solnl li&nn compnsing an MeOH In one embodiment, the second solvent is THF. In one 1.2-ethanedisulfienic acid salt of ('oinpound 1. wherein the cmboduucnt, the lirst solvent is McOH and the second sol- solid fi&nn is chanscterized by an XRPD diffraction pattern vent is THF. which matches one ofthe XRPD presented in FICI. 20. [(O13J In one embodiment, the cooling tempensture ranges from about — 20" C to about 5''. In one embodiment. the 5.2.4 Hydmchloride Salt of Compound I coolii&g temperature is about 5'. In one embodiment. the coolii&g time is at least 4 hours, at least 8 hours, or at least 24 In some is a [0307J embodiments. provided herein hydro- hours. chloride salt of('ompound 1. It is conten&plated that hydro- a [0314] In onc cmbodimcnt, thc man&ration is conduct&xi cldoride salt of Compound I can exist in a variery of solid witlun a tcmpcrature range from about O'. to about 70'., fonna. Such solid fom&s include crystalline solids. such. as from about 10" C to about 60" ( . or from about 20" C. (roon& solvatcs and hydrates of crystalline hydrochlo- polymorphs. temperature) to about 50" ( in one embodiment. the matu- ride salt of Compound as well as mnorphous solids, or I, nstiion is conducted within a tempensture mange fmn& about mixtures thereof All such solid fi&rms salt of of hydmchloride 20" C, (room temperature) to about 50" C. In one embodi- ('ompound I are conten&plated under the present imention ment, the maturation is conducted fi&r at least 4 hour~, at least [0308] In onc embodnucut, prov&dcd herein is a solid fi&m& 8 hours. at least 24 hours, at least 48 hours, or at least 72 hours. comprising a hydrochloride salt of ('ompound I, ore solvate In another embodiment. the mature uou is conduct&xi for about (e ..hydrate) thereof. In one einbodiment, provided herein is 4 lmurs, about 8 himrs. about 24 hours, about 48 hours, or a solid fom& comprising a solvate of a hydrochloride salt i&f about 72 lmurs ('ompound I In one embodiment. provided herein is a solid [(O15J In one embodiinent, liorm I of a hydrochloride salt ('om- foun comprising a hydrate of a hydrochloride salt of ofCompound I is prepared by slow evaporation of a solution mnbodimm&t, &s a fi&m& pound I. In one provulcd herein solid of a hydrochloride salt of Compound I in MeOH. In one comprising a crystalline form ol a hydrochlondc wilt ofCi&im- cmboduucnt, Fonu I of a hydrochloude salt ol'Compound I pound 1. or a solvate (e hydrate) thereof In one embodi- g, &s prcparcd by slo&s evaporation of a solutiou of a hydrochlo- ment, provided herein is a solid form comprising a crystalline ride salt of ('ompound I in MeOI I/I I lli In one embodiment, fi&rm a solvate of a hydrochloride salt of Compound I In of 1&orm I of a hydmchforide salt of('ompound I is prepared by one embodiment, provided herein is a solid form comprisin slow evaporation of a solution of a hydrochloride salt of a crystalline form of a hydrate of a hydrochloride salt of Compound I in MeOH/THF/water. Compound l. [0316] In one embodiment, Form I of a hydrochloride salt [0309] In some embodiments. the molar ratio ofCompound ofCompound I is prepared by coolu&g a solutiou ol'a hydro- I to hydrochloric acid in the solid foun ranges from about 2: I chlondc salt of Compound I in anisolc. Iu onc cmbodimenb to about I:2. In one embodiment, thc molar ratio is about 1.2 1&orm I of a hydmchforide salt of('ompound I is prepared by (i.c., bis-hydrochlondc sall). In m&other embodiment, thc cooling a solution of a hydrochloride salt of ('ompound I in molar ratio is about I I (i e . mono-hydmchloride salt). In yet water. In m&e embodiment. the coohng occurs at about 5' another embodiment. the meLsr ratio is about 2: I (i e., hmni- for about 24 hour~. In one embodiment. Fom& I ofthe hydro- hydrochloride salt) chior&de salt of Compound I prepared by the method pro- [0310J In some embodiments. the inolarnstio ofCon£ vided hcrcin has a lov, crystallinity.

I to the solvent/mater in the solid form ranges from about 2 I [(O17J In m&e embodiment, I'onn I of the hydrochloride to about I:2 In one embodiment, the molar ratio is about I:2 salt of ('o&upound I deliquesces after stowage at 40" ('750( (i.e., bis-solvate/hydrate). In another embodiment, the rnoLsr RH for up to I week. ratio is about I: I (i.is, mono-solve&et]&ydratc). In yet another cmbodimcnt, the molar ratio &s about 2: I (i.c., hemi-solvatc/ Foun 2 of Hydrochloride Salt of Compound I hydrate). [0318] In some cmbodimcnts, provided herc&a &s Form 2 of the hydrochloride salt of Compound I A representative 1&orm I of I lydmchloride Salt of Compound I XRPI) pattern of 1&om& 2 of the hydrochloride salt of ('on&- [0311J In some embodiments. provided herein is liorm I of pound I is provided in FICI. 21B. In one embodiment. pro- the hydmchloride salt of Compound I A representative vided herein is a solid foun comprising a hydrochloride salt of XRPD pattern of Form I of the hydrochloride salt of ('om- Compound I, wherein thc solid I'oun is charactcuzcd by an pound I is provided in FICI. 21A, In one embodiment. pro- XRPD diffraction pattcm which matches the XRPD pa ben& vided herein is a solid fom& comprising a hydrochloride salt of prcscutcd in FIG. 21B. Compound I, w hcrcin thc solnl li&nn &s charactcrizcd by an [0319] In one embodiment. provided herein is a method for XRPD dilfraction paucm wluch matches 0&c XRPD paucrn preparing Form 2 of the hydrochloride salt of Compound I presented in I'l(i 21A compnsing (I) contacting Compound I with hydrochlonc [0312] Inonccmbodunm&t, provided hcrcm is a method lbr acid in a solvent system: (2) cooling the resulted mixturci and preparing Form I of thc hydrochlonde salt of Compound I (3) optionally sublcctu&g thc mixture to maturation. In onc comprising (I) contacting ( ompound I with hydrochloric embodin&ent, provided herein is a method for preparing 1&orn& acid in a solvent system; (2) cooling the resulted mixture: and 2 of the hydrochloride salt of ('ompound I comprising (I) US 20]4/0275]35 A1 Sep. 18, 2014 28

mixing (i) a mixture of Compound I in a first solvent and (ii) ratio Is about I: I (i.e., mono-solvate/hydrate). In yet another a mixture ofhydrochlonc acid ui a second solvent I (2) cooling cmboduucnt, thc molar ratio is about 2. I (T.c., hemi-solvate/ the resulted nuxuirc, and (3) opuonally subjecting Ihc nux- hydrate). ture to maturation In one embodiment. the tirst solvent is 2-Me'I'111'n one embodiment, the second solvent is Tl 11( In Form I ol Isetluonatc Sall of Compound I one embodiment. the first solvent is 2-Me THF and the second [0328] In some embodiments, provided herein is Fomi I of solvent is THF the Isetlfionate salt of Compound l. A representative XRPD [0320] In one embodiment. the cooling temperarure ranges puttcm of Fomi I of tlm iscthionatc salt of Compound I is lrom about — 20'. to about S'. In onc cmbodimmit, thc provided in FICT. 22. In onc mnbodimmit, provided hcrcui is a cooluig Iempcraturc is about S'. In onc embodiment, thc sohd finn comprisuig mi isethionate sall of Compound l. time is at least 4 hours, at least 0 hours, or at least 24 cooling ditfnsc- foui's wherein the solid form is characterized by an XRPI) tion pattern which matches the XRPD pattern presented in [0321] In one embodiment, the maturation is conducted FICT. 22 within a temperature range from about 0" C. to about 70" ('., [0329] In one cmboduucnn provided hcreui is a method for from about 10" C. to about 60" C., or from about 20" C. (room prcparuig Form I of the iscthioimtc salt of Compound I tcmpcraturc) to about 50'. In one cmbodmicnt. thc matu- comprising contacting ('ompound I with 2-hydroxy- ration is conducted within a IcmpcraIurc rungc lrom about (I) ethanesulfonic acid in a solvent system, cooling the 20" ('room tempensture) to about 50" C. In one embodi- (2) resulted mixture; and the mixture to ment, the maturation is conducted for at least 4 lxiurs, at least (3) optionally subjecting maturation. hi one embodiment, provided herein is a method 0 hour, at least 24 hours. at least 4g hours, orat least 72 hours for prcparuig Form I of the iscthioimtc salt of Compound I In another embodiment, the maturation is conducted for about composing mixing (i) a mixture ol Compound I ui a Iirst 4 hours, about g hours, about 24 hours. about 4g hours. or (I) solvent and a nnxturc 2-hydroxyethancsu1fonic acid in about 72 hours. (it) of a second solvent; (2) coolin the resulted mixture; and (3) [0322] In one cmboduncnt, Form 2 ol a hydrochlondc salt optionally subjecting the mixture to maturation of ('ompound I is prepared by cooling a solution of a hydro- [0330] Inoneemboduncnt, Ihccooluigtmnpcraturcranges chloride salt of ('ompound I m 2-Me'I'111'n one embodi- — ment, the cooling occurs at about 5" ('. fiir about 24 lxiurs. from about 20'. to about 5'. Iu onc cmbodimcnt, Ihc cooling temperature is about 5''. In one embodiment. the [0323] In one embodiment, Form 2 of the hydrochloride cooling time is at least 4 hours, at least 0 hours, or at least 24 salt of ('ompound I is a mono-hydrochloride salt. hours

5 2.5 1sethionate Salt of ('ompound I [0331J In one embodiment, the maturation is conducted within a temperature range from about 0" C. to about 70" ( In some embodimcntsT provided hcrem is an [0324] from about 10" C to about 60" ( . or from about 20" C. (rooni isctluonate sall of Compound l. II is contcmplufcd that an temperature) to about 50" C. In one embodiment. the matu- isethionate salt of ('ompound I can exist in a variety of solid ration is conducted within a tempemature range from alxiut fiirms. Such solid fiirms include crystalline solids, such as 20' (room tcmpcraturc) to about SO'. Iu onc embodi- polymorphs. solvates and hydrates of crystalline isethionate ment, Ihc maturation is conducted for at least 4 hours, at least salt ofCompound 1. as well as amorphous solids. or mixnires 0 hour~, at least 24 hours, at least 40 hours, or at least 72 hours thereof. All such solid forms ofisethiormte salt ofCompound Inanotherembodiment.thematuratmnisconducted forabout I arc contcmplatcd under Ihc present uivcnuon. 4 lmurs, about g himrs. about 24 hours, about 4g hours, or [0325J In one embodiment, provided herein is a solid forni about 72 hours. an a solvate comprising isethionate salt of Compound I, or [0332J In one embodiment. Iiorm I ofan isetluonate salt of (e.g.. hydrate) thereof. In one embodiment. provided herein is Compound I is prepared by slow evaporation of a solution of a solid fomi comprising a solvate of an isethionate salt of an isethionate salt of Compound I in MeOH. Compound l. In onc embodiment, provtdcx! hcrem is a solid [0333J In one embodiment, I'orm I ofthe isethionate salt of form comprisuig a hydrate of an isethionatc salt of Com- Compound I deliquesces after storage at 40" C./75% RH for pound 1. In one embodinient, pmvided herein is a solid forni up to I weeiv comprising a crystalline form of an isethionate salt of Coni- pound or a solvate hydrate) thereof. In one embodi- I, (e.g., 5.2.6 Free Base of Compound I ment, provided herein is a solid form comprising a crystalline form of a solvste ofan is ethiormte salt of Compound 1. In one [0334] In some embodiments. provided herein is a free hase cmbodimcntT providixl hcrcui is a solul form comprisui a of Compound 1. It is contemplated that a I'rce base of Com- crystalluic form of a hydrate ol an isctiuonutc sall ol Com- pound I can exist ui a variety ofsolid fonna. Such solul fonna pound I include crystalline solid~, such as polymorphs, solvates and [0326] In some embodiments. the molar ratio ofCompound hydnstes of crystalline free base of Compound I, as well as I Io 2-hydroxycthancsulfonic seal in Ihc solul liinn ranges amorphous solids. ormixtures thereof All such solid forms of thorn about 2 I to about 1.2 In onc cmbodimcnfT Ihc ntolar free base ofCompound I are contemplated under the present ratio is about 1.2 (T.c. bis-isclhiooatc sall). In another invention. embodiment. the molar nstio is about I I (i e, mono-i sethion- [0335] In one embodiment, provided herein is a solid fomi ate salt). In yet another embodiment, the molar ratio i ~ about comprising a free base of Compound I, or a solvate (e... 2: I (i.e.. hemi-Isethionate salt). hydrate) thereof. In onc cmbodimcnt, provided hcrcin is a [0327] In some embodiments, Ihcmolur ratio ofCompound sohd form comprisuig a solve(a ol'a free base of Compound I to thc solvent/stater in thc solal form ranges Ibom about 2.1 1. In onc embodiment. provided henna m a solid form com- to about I:2 In one embodiment, the mohsr ratio is about I 2 prising a hydrate of a free base of ('ompound 1. In one (i e, bis-solvate/hydrate) ln another embodiment, the molar embodinient, provided herein is a solid form comprising a US 20]4/0275 [35 A1 Sep. 18, 2014

crystalline form of a free base of ('ompound 1. or a solvate mately 5.0. 7.6, 11.4. 12.2, 13.5, 15.1. 16.8. 19.9, 20.6, 21.1.

(c. g.. hydrate) thcrcof. In ouc cmboduncut, provided herein & s 22.4. 23.1, 23.7, 24.6. m&d 25.2 dcgrccs 20. a sol&d fom& m&mpnsu&g a crystallu&c form of a solvatc of a [(1342] In some embodimentg the XI(VD peaks above (de- free base of Compound I In one e&nbodi&nent. pn&v&ded grees 20 peaks) are when analyzed using copper Kc& radia- herein is a solid form con&prising a crystalline form of a 3 au&. hydrate of a free base of Compound l. [0343] In some cmbod&ments. provided hcrcu& is a solid [0336] In some embodiments. the molar ratio ofCompound foun cmnprising a free base of ('ompound I, wherein the I to the solvent/water in the solid foun ranges from about 2: I sohd form is chamcterized by an XRVD diffmction pattern to about I:2. In one embodiment. &hc molar rat&o &s about 1.2 v hich matches the XRPD pattern presented &n FIG Z3. (&.c., b&s-solve&a/hydrate). Iu another embod&ment, thc molar [(1344] A representative thermal grav&metric analysis ratio is about I: I (&.e, mono-solvate'hydmte) In vet another ('I'(iA) curve of the free base of ( ompound I is provided in embodiment. the molar ratio is about 2: I (i e, hemi-solvate/ FICi. 24, which exhibits a tv eight loss of about ).9)'44 of the hydrate). total sample &veight upon heatin from about 30 to about 130" C. Without being linn&Ox) by any particular th&x&ry. thc wc&ght l&orm I of l&ree l3ase of ('ompound I loss corrcspomls to loss of water Iu some emboduucnts. [0337J In some embodiments. provided herein is l&orm I of prov&dcd herein &s a sol&d form tx&mpns&ng a free base of the free base ofCompound I In one embodiment. Form I of ('ompound 1. wherein the solid form &4 characterized bv a 'I'(iA 'I the free base of Compound I is a crystalline semi-hydrate of thenm&gmm which matches the (iA thermogmm pre- ('ompound l. In some embodiments. Fom& I ofthe free base sented in FIG. 24. ofCompound I &s substm&u ally fr&m ofamorphous free base of [(1345] A representative different&al scanning calorimetry Compound l. Iu some embodiments, Form I of d&e Ikce base (DS(') thennogmm of the free base of Compound I is pre- ofCompound I &4 substantially free ofother crystall&ne forms sented in FICi. Z5. In some embodiments, provided herein is a (i e, polymorphs) of the free base of ('on£ I In some sohd form comprising a free base of Compound I that exhib- embodiments, Form I of the free base of Compound I &s &ts u thermal cvcnt, as charactcrizcd by DSC, w&th a peak substantially free of salts of Compound I. In some embodi- tcmpcraturc of about 27'. m&d/or an onset tmnpcraturc of ments, Form I of the free base ofCompound I is provided as about 25" (', or &vith a peak temperature of about 172" C substantially pure Form I of thc frcc base ol'Compound l. and/or an onset temperature of about 161" C In some [0338J In one embodiment, I'orm I of the free base of embodin&ents, pmvided herein is a solid forn& con&prising, a ('ompound I is a hydrate. wherein the molar mtio of C'om- free base of Compound I that exhibits thermal events. as 27" pound I to the water ranges from about I:0.5 to shorn I:0 Ci characterized by DSC, with a peak tempemture of about (i.e., semi-hydrate). In one embodiment. the molar ratio of C. and/or an onset tcmpcrature of about 25'., and with a Compound I to the water &s about I:0.6. peak tcmperaturc of about 172'. and/or an ormet tcmpcra- 161" [0339J A representative XRVD patterns of l&orm I of the ture ofabout ('ithout being limited by any particular free base of Compound I is provided in FIG. 23. theory, the thermal events correspond to loss ofwater. In some embodin&ents, is a forn& a [0340] In some mnboduncnts, pmv&dtxl herein &s a sol&d pmvided herein solid con&prising, free base of Compound wherein the solid form is chamc- form compri su&g a fr&m base ol'Compo uml I charac tensed by I, XRVD peaks located at I, 2. 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, terized by a DSC thennogram which matches the DS( 'her- &n FIG. 25. 14. 15. or all of the following or approximately the following mogram prcscntcd acct & positions: 5 0, 7,(u 9.9. 10.7, 11.4, 12.2, 13.0, 13.5, 14.0, 14 5, [0346] A representative gravimetric vapor sorpt&on (C)VS) 15.1, 15.9, 16.4, 16 8. 17.7. 18.1, 19.1. 19.9, 20.6, 21.1. 21 7, isotherm of Compound I is presented in FICi. 26. In one 224, 23.1, 23.7. 24.6, m&d 25.2 degrees 20, plus or m&nus cmboduucnt, provided hcrcin is a sol&d lbm& compnsing a 0.10. In some embodnucnts. prov&ded hercu& is a solid fbm& fr&m base of Compound 1. whcrcu& thc solul form &s charac-

comprising a fr&m base of Compouml I character&z&xl by terized by a (iVS isother&n &vhich matches the (iVS isothern& XRVD peaks located at I, 2. 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, presented in Fl(i 26 14. or all of the following or approximately the follov ing [0347] In onc mnboduucnt, Fom& I of thc frcc base ol''ompound pos&t&ons: 5.0. 7.6, 11.4, 12 2, 13.5, 15.1. 16.8. 19.9. 20 6, I is prepared by adding an anti-solvent to a solu- 21.1, 22.4. 23.1. 23.7. 24.6. and 25.2 degrees 20. plus or tion ofCompound I in a solvent system In one embodiment, mu&us 0.10. In some cmbod&ments, &hc sohd form is clmrac- the solvent system is a mixture of c ac& d and water. In one tcr&z&xt by 3 ol'hc peaks. In some mnbodunents, thc sol&d embodiment. the solvent system is acetic acid/water ( I /I v/v) . form is charac&cured by 5 of the peaks. In some embed&- In one embodiment, the anti-solvent is NH4OH. In one ments. the solid form is characterized by 7 of the peaks In cmboduucnt, Form I of the free base of Compound I &s some mnbodiments. the solid fom& is chamcterized by 9 ofthe prcparcd by add&ng NH4OH to a solut&on ol'Compound I in 4 peaks. In some embodiments, the solid form is characterized nuxture of acetic acid and &vater In one embodiment. 1&or&n I by 11 of the peaks. In some embodiments. the solid form &s ofthe freebaseof('ompound I is prepared by adding N114011 clmr;mtcnzed by 13 of the peaks. In some cmbodm&cnts. thc to a solution of Compound I in a mixture of acct&c acid and solul form &s charactcnzcd by all of thc peaks. v ater, v herein pH ofthe resulted mixture is about neutral. In [0341J In some embodin&ents, pmvided herein is a solid one embodiment, preparation of Form I of the free base of form comprising a free base ofCompound I having an XRPD Con£ I docs not u&volvo a n&au&rat&on step. pattern comprising peaks at approximately 11.4. 16.8, and [0348] In one embodiment, Form I of the free hase of 19.9 dcgrecs 20. In certain mnboduncnts, thc sohd form fur- Compound I converts to Form 4 ol'hc I'rcc base of Com- ther compnses peaks at approxuua rely &.0 and 7.6 dc rccs 20. pound I by dC&ydration. In onc cmboduncnt, thc dchydrat&on In certain embodunm&ts, thc solid li&nn lurther compnscs occurs from about 40 to about 75'. In onc cmbod&mene peaks at approximately 22.4 and 23.7 degrees 20 In one 1&orm I ofthe free base ofCompound I converts to! Om& 3 of embodiment. the sol&d form comprises peaks at approxi- the free base of ('ompound I by hydmtion In one embodi- US 20]4/0275]35 A1 Sep. 18, 2014 30

ment, the hydration occurs in a range ofabout 80-90% RH. In mately 9.1. 10.9, 12.3, 15.0, 16.8, 17.8. 19.3, 20.7, 21.9. 24.9. onc cmbodnncnt, Fonu I ol'thc free base ol Compound I is 25.6. 26 8, 27.2, and 27.5 dcgrccs 20. stable aficr storage al 40 C./75% RH for I week. In another [IO56J In some embodimentg the XRPI) peaks above (de- embodiment. I 'orm I ofthe free base I converts ofCompound grees 20 peaks) are ivhen analyzed usmg copper Krx radia- 25" to 1iorm 3 ofthe free base ofCompound I after storage at non. ((/93% RH for I week [0357] In some embodiments. pmvided herein is a solid [0349] In one embodiment, Form I of the free base of form compnsing a free base of Compound I, whcrcin lhc ('ompound I converts to Form 6 of the fbee hase of C'om-

sohd form is charactcrizcd by an XRPD diffraction paucnx pound I aller nialutallon in scene acul/walcr (1.1) for 72 hour'. which matches the XRPI) pattern presented in 111(i 27. [0350] All of the mimbinations ol'hc above mnbodimcnls [0358] A representative thermal gravimetric analysis are mxcompassed by this mvention. (TCIA) cxxxve of the free base of Compound I is provided130'. in FICI. 28, which exhibits 0 tv eight loss of about 3.04% of the to Form 2 of Free Base of Compound I total sample weight upon heating from about 30 about Without being linxxtcxl by any purticulur thixiry. thc weight [0351] In some embodiments.providcdhcrcinis Form 2 of loss corresponds to loss of water In some enxbodiments, the frcc base ofCompound 1. In onc embodiment, Form 2 of pmvided herein is a solid fixnn comprising a free base of the free base of('ompound I is a crystalline mono hydnxte of Compound I, wherein the solid form is characterized by a ('ompound 1. In some embodiments. I orm 2 ofthe free base TCIA themxogram xvhich matches the TCIA thermogram pre- ofCompound I is substantmlly free ofmnorphous free base of sented in FI(f. 28. ('ompound In some embodiments. Fomx 2 the free base l. of [0359] A rcprcscnlauvc differcnual scanxung caloruuctry ofCompound I is substantially free ofother crystalline forms (l)S(') thennognxm of the free base of Compound I is pre- thc Ibcc base of Compound In some (i.c., polymorphs) of l. sented in Fl(i. 29 In soine embodiments. pmvided herein is a cmbodimcnts, Form 2 of thc free base ol Compound I is sohd form comprising a free base of Compound I that exhib- substantially free of salts of Compound I ln some embodi- '0 its a thermal event, as characterized by DSC. with a peak ments. I un 2 of the free base ('ompound I is provided as of temperature of about 60" C, and/or an onset temperature of substantially pure Iiorm 2 of the free hase of Compound I about 26'.. or wuh 0 peak tcmperuturc ol'bout 182'. [0352] In one embodiment, Form 2 of the free base of and/or an onset temperature of about 172'. In some C'om- ('ompound I is a hydrate. wherein the molar mtio of embodinxents, pmvided herein is a solid fornx conxprising, a I pound to thc water ranges from about I:0.5 lo about I:0 8. free hase of ('.ompound I that exhibits thermal events. as In onc embodiment, thc molar rano of Compound I to thc characterized by DSC, with a peak tempemxture of about 60" w alcr is about 1.0.8. C. und/or an onset temperature of about 2(e C.. and with a [0353J A representative XRPD patterns of liorm 2 of the peal temperature of about 182'. and/or an onset tempera- free base of ('ompound I is provided in I'l(i 27 ture of about 172'. In some mnboduncnts, provxlcd hcrcin [0354J In some embodinxents, pmvided herein is a solid is a sohd lorm compnsing a free buse of Compound l. foun comprising a free base ofCompound I characterized by wherein the solid fix mx is characterized by a I )8('he mt 0o ran& XRPD peaks located at I. 2, 3, 4, 5, 6. 7, 8, 9. 10. 11, 12. 13, which matches the DSC thermogram presented in! I(i 29 14, 15, or all ofthe following or approximately the followin [0360] Arcprcsenlatiicgravimetncvapoursorpnon(GV/S) posuionm 9.1. 10.9, 12 3, 15.0, 16.1, 16.8, 17.8. 18.1, 18 3, isotherm of Compound I is prcscntcd ux FICI 30. In onc 19.3, 20.1, 20.5. 20.7, 20.8, 21 5. 21.9, 22.4, 22.7, 23.9, 24 9, embodinxent, provided herein is a solid form comprising a 25 6, 26.2, 26 8. 27 2, and 27.5 degrees 2H, or minus plus free hase of ('ompound 1. ivherem the solid form is charac- 0 10. In some embodiments. provided herein is a solid fornx terized by a CITS isotherm which matches the OVS isothemx comprising a free base of Compound I characterized by presented in FICI 30 XRPD peaks located at I. 2, 3, 4, 5, 6. 7, 8, 9. 10. 11, 12. 13, or all of the follov ing or approximately the following posi- [IO61J In mxe embodiment, I'orm 2 of the free base of tions. 9.1, 10.9, 12.3, 15.0, 16.8, 17.8. 19.3. 20.7, 21.9, 24 9, ('ompound I is prepared by adding an anti-solvent to a solu- 25.6, 26.8, 27.2, and 27 5 degrees 20, plus or muxus 0.10. In tion of Compound I in a solvent system, followed by matu- some mnbodiments. the solid fomx is chanxcterized by 3 ofthe ration. In one embodiment, the solvent system is a mixture of peaks In some embodiments, the solid form is clmracterized aci lic 'icid ting waxer. hl one enlbodinlcnl, lhc solvent x) su nx by 5 of the peaks. In some embodiment~, the solid form ls is ucclic acid/waxer (I/I v/v). In onc cmbodimmu, the anti- characterized by 7 of the peaks. In some embodiments, the solvcnt is NHsOH. In onc cmbodunmu, Form 2 of thc free solid form is characterized by 9 ofthe peak~. In some embodi- base of Compound I is prepared by addmg Nl lsOI I to a ments. Ihc sohd form is characlcnzcd by 11 of lhc peal s. In solution of('0mpound I in a mixntre ofacetic acid and ivater, some muboduucnls. thc sohd liirm is cfmmctcnzcd by 13 of followed by matxuation. In one embodiment, Form 2 of the the peaks. In some embodiments, the solid fbrm is character- free base of Compound I is prepared by adding NHsOH to a ized by all of the peaks solution ofCompound I in a mixture of acetic acid and water. whcrcin the resulted nuxture is about ncutml, follow ixl [0355J In some embodinxents, pmvided herein is a solid pH of by maturation. In onc cmbodimmxl, the malurauon is con- foun comprising a free base ofCompound I having an XRPD ducted at about 90" ( for about 5 to about 24. or about 10 to pattern comprising peaks at approximately 9.1. 10.9. und 16 8 niboitt I 5 houi'1 degrees 20. In ccrtuux cmbodimcnts, Hxe solid Iiirm further comprises pcuks at approxuualely 17.8 mxd 24.9 degrccs 20. [0362] In onc emboduucnt, Fomx 2 of lhc frcc base ol'ompound In certain embodunmus, thc solid liinn lurther compnscs I is stable after storage at 40'./75% RH I'or I peaks at approximately 195 and 26.8 degrees 20 In one week or after storage at 25" C..193% Rl I for I week. In one embodiment. the solid form comprises peaks at approxi- embodinxent, without being limited by any particular theory, US 20]4/0275 [35 A1 Sep. 18, 2014 31

Form 2 of the free base of Compound I is a channel hydmte. [0369] In some embodiments. pmvided herein is a solid In a cluuuicl hydrate, water can easily muvc ui und out of thc form comprising a frcc base ofCompound I characlcrizcd by crvslal la&neo. XRPD peaks loca&cd at 1. 2. 3, 4. 5, 6, 7. 8, 9, 10, I 1. 12, or all

[0363J In one embodiment, I'orm 2 of the free base of of the following or approximately the following positions ('ompound I corn erts to liorni 5 of the free base of Con&- 49 73 10.6. 113 120 14.4 149 152 169 177 20.0 pound I a[ier matumtion in a solvent. In one embodiment, 21.9. and 24.(i degrees 20, plus or minus 0.10 In some solvent is E&OH. acetonitrile, EtOAc, Acetone, MIBK. IPA, embodiments. provided herein is a solid form comprising a EtOH/5%& water, IPAc, or l-butanol, or a mixture thereof In free base of Compound I characterized by XRPD peaks onc cmbodimcnn the maturation is pcrli&nncd bctwcmi RT local&x! Ot l. 2, 3, 4, 5, 6. 7. 8. 9. 10, or all ol'he Ihllowuig or and 50'. I'or 5 days Iu ouc cmboduncnl, Fomi 2 of thc free approximately lhc follow&ng positions. 4.9, 7 3. 10.6, 11.3. base of ('ompound I is stable after matunution in EtOI I/water 14 4, 14 '), 16.9, 17 7, 20.0, 21.9. and 24 6 degrees 20, plus or (I I) between R'I to 50" ('or 5 days. nunus 0 10. In some embodiments. the sohd fiirm is charac- 2 3 [0364] In one embodiment, Form of the free base25'. of terized by of the peaks. In some embodiments, the solid ('ompound I is stable after maturation in acetic acid/water form is characterized by 5 of the peaks In some embodi- ( I: I ) for 72 hours. In another embodiment. Form 2 ofthe free ments. the solid form is characterized by 7 of the peaks. In base ofCompound I &s stable after maturat&on in waters& some cmbodimcnts. thc solid I'onn is charsctcnzcd by 9 ofthc for about 40 hours. In ycl another cmboduncnt, Form 2 of pL"Iks. Ill so&1&C C&ilbixliil&CI&ls, ll&C solid for&11 &s CllaraCICrizixl the free base of ('ompound I is stable after matunstuoa in by 11 of the peaks In some embodiments, the solid form is water at 90" ('. for about 40 hours In yet another embodi- clmracterived by all of Ihe peaks ment, Iiorm 2 of the free base of Compound I i ~ stable after [0370[ In some embodiment~. provided herein is a solid maturation in acetic acid/water (I:3) at 25" C. for about 40 form comprising a free base of Compound I having an XRPD hours. In yet another embodiment, Form 2 ofthe thee bose &1f pattern comprising peaks at approximately 7.3. 10. 6, and 11 3 Compound I partially couvcns lo Form 6 ol thc friu base of dcgrccs 20. In ccrlaui cmbodnnenls. the sol&d I'orm furlhcr Compound I uftcr mature)&on ui water at 90'. Ii&r about 40 compnscs peaks a& approximately 4 9 und 20.0 degrccs 20. In houi's certain embodiments. the solid form Iiirther comprises peaks [0365J In one embodiment. I'orm 2 of a freebase of Con&- at approximately 21 ') and 24 6 degrees 20 In one embodi- pound I is prepared by maturation of I'orm I of a maleic acid ment, the solid form comprises peaks at approximately 4 9, salt of Compound I in 2-propanol/water (90/10 v/v) In one 73. 10.6. 11.3. 14.4. 14.9, 16.9. 17.7, 20.0. 21.9, and 24.6 embodiment. Form 2 of a free base of Compound I is pre- degrees 20 pared by malurution of Form I ol'a malcic ac&d sah of Com- [0371] In some cmboduncnls, the XRPD peaks above [dc- pound I in acetic acul/water [25/75 v/v). In one emboduncul, grccs 20 peaks) arc when mialyzcd us&ng copper Ku rad&a- the maturauon is performed between R'I'o about 50" ('or tion about 24 to about 72 hours. [0372[ In some embodiment~. provided herein is a solid [0366] In one embodiment, Form 2 of a Ibee base of('om- fonu cmuprising a free base of ('ompound I, wherein the pound I is prepared by w&ohng a solut&on of a mulmc acid salt sohd form is characterized by an XRPD diffraction pattern of Compound I ui 2-butmioneiwalcr. In onc emboduncul, v hich matches the XRPD pattern presented in FIG 31. Iiorm 2 of a free base of ('ompound I is prepared by cooling [0373] In onc cmboduncnt, Form 3 ol'a Ihcc base of Com- a solution of a maleic acid salt of Con£ I in I-butanol/ pound I is prepared by hydration of Form I ol'a frcc base of water. In one embodiment, I'orm 2 of a free base of Con&- ('ompound l. In one einbodiment. Iiorm 3 of a free hase of pound I is prepared by cooling a solution of a maleic acid salt ('ompound I is prepared by subjecting Iiorm I of a free base of Compound I in ethyl acetate/mater. In one embodunent, of ('ompound I to a condition of 25" ('93% RI I fiir about a Form 2 of a Ihcc base of Compound I &s prepared by cooling v eek. a solution of a malmc acul sall of Compound I ui anisolc/ [0374] In one embodiment, Form 3 of a free base of Com- water. In one embodiment, the cooling temperature ranges pound I is prepared by hydration of Form 6 ol'a frcc base of fmm about — 20" C. to about 5' In one enibodiment, the Compound 1. In onc cmbodimcnn Form 3 of a frcc base of cooling temperature Is about 5' In one enibodiment, the ('ompound I is prepared by subjecting Iiorm 6 of a free base cooling time is at least 4 hours. at least 8 hours. or m least 24 of ('ompound I to a condition of 40" ('75% RI I fiir about a hours. week. [0375] In onc cmboduncnt, Form 3 ol'a Ihcc base of Com- Form 3 of Free Base of Compound I pound I is prcparcd by evaporation ol'a solus&on ofa free base of ('ompound I in dioxane. followed by maturation. In one [0367J In some embodiments. provided herein is l&orm 3 of embodinient, the maturation is conducted between Rl'nd the free base ofCompound I In one einbodiinent. 1&orni 3 of 50" ('. for about 48 hours In one embodiment. the solid forni the free base ofCompound I is a crystalline hydrate of('om- prepared by the metlmd contains both Form 3 and Form 5 of pound I. In some embodiments, Form 3 of the Ibee base of a free base of Compound I. Compound I is substanually free of amorplx&us Ihce base of [0376[ All of the combinations of the above embodinients Compound l. Iu some embodiments, Funn 3 of Hie Ihce base are encompassed by this invention ofCompound I Is subslaul&ally free of u ther crysfalluic fi&rms (i e, polymorphs) of the free base of ('on£ I In some I&orm 4 of I ree l3ase of ('ompound I embodiments, Iiorm 3 of the free base of Compound I Is substantially free of salts of Compound I. In some embodi- [0377] In some cmbodimcnls, provided herc&n &s Form 4 of ments, Form 3 of the free base ofCompound I is provided as thc fr&u base ofCompound 1. hi onc mnboduncnl, Form 4 of substantially pure Form 3 of the free base of Compound l. thc Ihcc base ofCompound I is a cryslalluic anhydrous Com- [0368J A representative XRPD patterns of l&orm 3 of the pound l. In some embodiments, l&orm 4 of the free base of free base of ('ompound I is provided in I'l(i 31 ('ompound I is substantially free of amorphous free base of US 20]4/0275 [35 A1 Sep. 18, 2014 32

('ompound l. In some embodiments. Fomi 4 ofthe free base about 51" ('.. or with a peak temperature of about 173" C. ofCompound I is substaut&ally free of 0&hcr crys &allure fi&rms and/or an Onset temperature of about 162'. In some (i.c., polymorphs) of thc lbcc base of Compound l. In some cmboduucnts, pruvulcd lmrcin is a solid I'orm compnsuig 0 embodiments, Iiorm 4 of the free base of Compound I is free hase of ('.ompound I that exhibits thermal events. as substantially free of salts Of Compound I In some embodi- clmracterized by DSC, with a peak tempemsture Of about N3" ments, Form 4 of the free base ofCompound I is provided as C. and/or an onset temperature of about 51" C.. and with a substantially pure Form 4 of the free base of Compound l. peal temperature of about 173'. and/or an onset tempera- [03'78] A rcprcscntauvc XRPD paucnw of Form 4 of thc ture of about 1(i2" C. In some embodiments. provided herein free base of ('ompound I is provided in I'l(i 32 &s a sol&d lorm compnsing a free base of Compound l. [0379] In some embodiments, provided herein is a solid whcrcin the solul fomi is characterized by a DSC thcnmi ram form comprisuig a frix base ofCompouiul I charac&ended by which matches the DSC thermogram presented in! I(i 34 XRPD peaks located at I, 2. 3. 4, 5, 6, 7, 8, 9, 10. 11, 12, 13, [0385J A representative gravimetric vapour sorption ((iVS) 14. I l. OI'lll 01 fili: follow&Jig 01 dpproxilllatCIV tl&C fr&liow&Jig isotherm of Compound I is presented in FICi. 35. In one positions: 5.0, 7 4, 10 7 11 I, 11 5, 11 8, 13.0, 13 N 14 5, embodiment. provided herein is a solid form comprising a 15 4 16 4 16 7 17 5 ii) I 200 21.7 22.2. 22 4 23 2 and free base of Compound I, wherein the solid form is chamsc- 23.9 degrees 20, plus or minu~ 0.10. In some embodiments, tcrizcd by 0 GVS isotherm whwh matches thc CiVS isothcnu provided herein is a solid form comprising a fice base of prcscutcd in FIG. 35&. ( 'ompound I characterized by XRPD pealx located at I. 2. 3, [0386J In one embodiment, I&orm 4 of a free base of('on&- 4. 5, 6, 7, 8. 9. 10, 11, 12, 13, 14, 15, or all of thc fi&ll owing or pound I is prepared by dehydration of liorni I of a free base approximately the followuig pos&uons. 5.0, 7.4, 10.7, 11 I, ofCon£ I In one einbodiment, Iiorm 4 of a free base of I I 5, I 1.8, 13 0. 14 5, 17.5. I i) I, 20 0, 21 7, 22 2, 22.4. 23 2, Compound I is prepared by heating Form I of a free base of and 23 9 degrees 2H. plus or niinus 0 10 In some embodi- Compound I to about or over 80" C. ments, the solid form is characterized by 3 of the peaks In [0387] In Onc cmboduncnt, Form 4 ol'0 lbcc base of Com- some embodiments. the solid f0mt is characterized by 5 ofthe pound I is prepared by dc-solvauon ol'Form 6 of a lbcc base peaks. In some embodiments, the solid form is characterized ofCon£ I In one einbodiment, Iiorm 4 of a free base of by 7 of thc peaks. Iu some cmbodimcnts, die sohd Ibnn is ('0mpound I is prepared by heating Iiorm 6 of a free base of char;mtcnzed by 9 of thc peaks. In some cmbodunenls, tile ('ompound I to about or over 100''0388] solid fiirm is characterized by 11 of the peaks In some In one embodiment, Form 4 of a free base of Com- embodiments, the solid form is chamscterized by 13 of the pound I is prepared by maturation ofan amorphous fkee hase peaks. In some embodiments, the solid form is characterized ofCompound I in water. In one mnbodunmit, the mature&&on by all of the peaks. &s pcrliinncd bcnvccn RT to about 50'. for about 24 to about [0380J In some embodinients, pmvided herein is a solid 72 hours. form comprising a free base ofCompound I having an XRPD [0389J All of the combinations of the above embodinients pattern comprising peaks at approximately 11.1. 11.5, and are encompassed by this invention 20.0 dcgrecs 20. In certain mnboduncnts, thc sohd form further compnscs peaks at approximately 7.4 and 21.7 dcgrixs Iiorm 5 of I ree 13ase of ('ompound I 20. In ccrtmn mnbodunmits, thc solid lorn& further compnscs [0390] In some cmbodimcnts, provided herc&a &s Form 5 of 11 In peaks at approximately 5.0 and 8 degrees 20. one thc frix base Of Compound 1. hi onc mnboduncnt, Form 5 of solid form comprises at embodiment. the peaks approxi- the free hase of ( ompound I is a crystalhne solvate of ('on&- 10.7. mately 5.0. 7 4, 11.1. 11.5, 11.8. 13.0. 14.5. 17 5. 19 I, pound l. In one embodiment. I'orm 5 of the free base of 20.0, 21.7, 22 2, 22 4, 23 2, and 23.9 degrees 20. Compound I is a crystalline IPAc solvate of Compound l. In [0381J In some embodiments, the XRPD peaks above (de- another embodiment, Form 5 ofthe free base ofCompound I grees 20 peaks) are v hen analyzed using copper Ko msdia- is a crystalline acetonitrile solvate of Compound I. In some tion. cmboduucnts, Form 5 ol'he free base of Compound I is [0382J In some embodinients, pmvided herein is a solid substimtially lrcc olqunorphous frcc base ol'Compound l. In form comprising a free base of ('ompound I, wherein the some embodiments, I&orm 5 of the free hase of ( ompound I solid form is characterized by an XRPD diffraction pattern is substantially free of other crystalline fiirms (i e, polymor- wluch matches thc XRPD pat&em prcscntcd ui FIG. 32. phs) of the free base of Compound 1. In some embodiments. [0383] A representative thermal gravimetric analysis Form 5 ofthe free base ofCompound I is substantially fkee of

(T(fA) curve of the free base of Compound I is provided in salts of Compoiuid l. In some embodiments. Form 5 of the FIG. 33, which cxlubits a we&ght loss Of about 1.54% of thc frix base ol'ompound I is prox idcd as substantially pure total sample 0 eight upon heating lbom about 30 to about I 30''Vi&bout Form 5 ol thc free base of Compound l. being limited by any particular theory. the v eight [0391] In one embodiment. the molar ratio ofCompound I loss corresponds to loss Of about 0 4 equivalent of ivater. In to the solvent in the solid form ranges from about 2: I to aixiut some embodiment~, provided herein is a solid fomi compns- 1.2. In onc cmbodimcnt, thc molar rauo &s about I:2 (i.c.. in 0 free base of Compound 1. wherein the solid form is bis-solvatc). In anodicr emboduuent, the molar rat&o is about characterized by a TCIA thermogram which marches the T(IA 1.1 (& c., mono-solvaic). In yet another embodiment. &hc thennogriun prcsmitcd ui FIG. 33. molar ratio is about 2 I (i e . hemi-solvate) [0384] A representative differential scanning caloninetry [0392] In one embodiment. the solvent is MeOH. In one (DSC) thcmlogrdill of fili: lrci: bdsi: ol'iillipiiullil I is prc- cmboduucnt, thc solvent is E&OH. In ouc cmboduncni, thc scntcd in FIG. 34. In some cmbodimcnts, prov&dcd herein is a solvent is acct On&In lc. In one mnbodimcnu the solvent &s ethyl solull'onn compnsin a frcc base ofCompound I that exhib- ace&etc In onc emboduucnt, thc solvent is sec&one. In onc its a thermal event, as characterized by DS(1 with a peak embodin&ent, the solvent is M II)K. In one embodiment, the temperature of about N3" ('nd/or an onset temperahire of solvent is '113MI! In one embodiment, the solvent is US 20]4/0275 [35 A] Sep. 18, 2014 33

2-MeTHF. In one embodiment. the solvent is THF In one one embodiment. Fomi 5 of a free base of Compound I is cmbodimcnt, thc solvent is DCM. In unc cmbodimcnt. thc prcparcd by maturauon of mi amorphous free base of Com- solvent is IPA. In onc cmboduncut, the so1vmit is DME. In onc pound I usMIBK. In one mnbodimmit, Foun 5 ol'a I'rce base embodimenL the solvent is I)CM and/or MeOI I In one of ('ompound I is prepared by matumtion of an amorphous embodimenL the solvent is litOII andior v ster In one free hase of Compound I in 'I I3Mli In one embodiment, embodiment. the solvent is THF and/or water. In one embodi- Form 5 of a free base ofCompound I is prepared by matura- ment, the solvent is acetonitnle and/or water. In one embodi- tion ofan amorphous free base ofCompound I in 2-MeTHF. ment, the solvent is IPAc. In one emlxidiment. without bein ln one embodiment. Form 5 of a free base of Compound I is lunited by any particular theory, Form S ol'hc free base of prcparcd by maturauon of mi amorphous free base of Com- Compound I is onc or morc tsostructuml solve(as. pound I in THF. In one cmbodimenL Form 5 ol'a frcc base ol''ompound [0393] RcprcscntauvcXRPDpaucrns ofForm 5 ofthe free I is prepared by maturation ofan amorphous free base of Compound I are provided in FIG. 36 and FIG. 37 base of ('ompound I in D('M. In one embodinient,! orm 5 of [0394] In some embodiments, provided herein is a solid a free base of Compound I is prepared by matumtion of an form comprisuig a friw base ofCompouml I charac(cured by amorphous free base of Compound I in IPA. In one embodi- XRPD peaks located at I, 2. 3. 4, 5, 6, 7, 8, 9, 10. 11, 12, 13, ment, Foun 5 of a free base of Compound I is prepared by 14. I l. or'lll ol tilt: follow illg oi approxilllatclv tile ftillowlllg maturation of an amorphous frcc base ol'ompound I in positions: 6 5, &) 0,9.4. 10.0.10 5, 107, 11 3, 11 7,12 I, 12 '), DME In onc embodiment. Form 5 of a free base of Com- 13 I, 14 0, 14 5. 15 5, 15 8. 160, 16 6, 17 3, 17 5, 17 7. IN 0, pound I is prepared by maturation ofan amorphous free base 18.5, 18.9, 19 I, and 19.4 degrees 20, plus or minus 0.10. In of ('ompound I in DCM,'MeOI I [I:I] In one embodiment, some embodiment~, provided herein is a solid fomi compns- 1iorm 5 of a free hase of ( ompound I is prepared by matura- ing a frcc base ol'Compound I clmracterizcd by XRPD peaks tion of an amorphous free base ofCompound I in EtOH/5% located at I, 2. 3,4, S. 6, 7, 8, 9. 10. 11. 12, 13, 14, orall ufthe v ater. In one embodiment, Form 5 of a free base of Com- following or approxunatcly thc following positions. 6.5. 9 0, pound I is prepared by maturauon ofan amorphous free base 9 4. 10.0. 10.5. 10.7. 12 9, 15 5, 15 8, 1(i 0, 17 3. 17 7, IN 5, ofCompound I ui THF/5% water In onc mnboduncnt, Form 18 9, and 19/4 degrees 20, plus or minus 0.10 In some 5 of a free base of ('ompound I is prepared by maturation of embodiments, the solid form is characterized by 3 of the an an)orpheus free base of ('ompound I in acetonitrile/5% peaks. In some embodiments, the solid form is characterized water. In one embodiment, I'orm 5 of a free base of ('oni- by 5 of thc peaks. In some cmbodimcnts, die sohd Ibnn is pound I is prepared by maturation ofan amorphous thee hase char;mtcnzed by 7 of thc peaks. In some cmbodunents, tile of Compound I in IPAc. In one embodiment. the maturation solul form is charac tensed by 9 ofthc peaks. In some embodi- is pcrliinncd between RT to about 50'. for about 24 to about ments. the solid foun is characterized by 11 of the peaks In 72 hours. some embodiments. the solid forin is clmmcterized bv 13 of [0399] In onc cmboduncnt, Form 5 ol'a Iycc base of Com- the peaks. In some embodiments, the solid fiirm is character- pound I is prepared by maturation of I iorm 2 of a free base of ized by all of the peaks. ('ompound I in I/tOi I In one embodiment, liorm 5 of a free [0395J In some embodinients, pmvided herein is a solid base of ( ompound I is prepared by maturation of I'orin 2 of form comprising a free base ofCompound I having an XRPD a free base of Compound I in acetonitrile In one embodi- pattern comprising peaks at approximately 9.0. 10.5. and 18 9 ment, Foun 5 of a free base of Compound I is prepared by degrees 20. In ccrtaui cmbodimcnts, die solid Iiirm further maturation of Form 2 of a frow base of Compound I in ethyl comprises peaks at approximately 9.4 and 15.S degrees 20. In ace(etc In onc cmbodnncnt. Form 5 ol' free base of Com- certain embodiments. the solid fiirm further comprises peaks pound I is prepared by maturation of I iorm 2 of a free base of at approximately 10 0 and 16 0 degrees 20. In one embodi- ('ompound I in acetone ln one embodiment, I'orm 5 of a free ment, the solid fiirm comprises peaks at approximately 6 5, base of ( ompound I is prepared by maturation of I'orin 2 of 9.0, 9.4, 10.0, 10.5, 10 7, 12.9, 15.5, 15.8. 16.0. 17.3. 17 7, a free base of Compound I in MIBK ln one embodiment. 18.5, 18.9, and 19.4 de rees 20. Form 5 of a free base ofCompound I is prepared by matura- [0396J In some embodiments, the XRPD peaks above (de- tion of Form 2 of a free base of Compound I in IPA. In onc grees 20 peaks) are v hen analyzed using copper Ko mdia- cmboduncnt, Form 5 of a Iycc base of Compound I is prc- tion. purcd by maturation of Form 2 of a I'rce base ofCompouml I [0397] In some embodiments, provided herein is a solid in I:tOI I/5'i water In one embodiment, I'onn 5 of a free base 'onn form comprising a free base of ('ompound I, wherein the of('on)pound I is prepared by maturation of I 2 of a free solid form is characterized by an XRPD diffraction pattern base ofCompoiuid I in acetonitrile/5% water In one embodi- w luch matches onc or more of thc XRPD puucms prcscntcd ment, Foun 5 of a free base of Compound I is prepared by in FIG. 36 or FIG. 37. maturation of Form 2 of a frcc base of Compound I ui IPAc. ol'a [0398] In one embodiment. Form 5 of u frcc base of Com- In onc cmbothmcni, Foun 5 free base of Compound I is ol'a pound I is prcparcd by maturation of an tmiorphous frcc base prepsred by maturation ofForm 2 Iycc base ofCompound I I-butanol ln is of Compound I in McOH. In onc cmbodimcnt, Form 5 of a m one embodiment, the maturation performed between R'I'o about 50''. fiir about 24 to about 72 free base of ('ompound I is prepared by niaturation of an hours. amorphous free base of Compound I in EtOII In one embodiment. Form 5 of a free base of Compound I is pre- [0400] In one embodiment, Form 5 of a free base of Com- pared by maturation ofan amorphous free base ofCompound pound I is prepared by cooling a solution of Form 2 of a free I ui acctomtnlc. In onc mnbodimcnt, Form 5 of a Ibec bnsc of busc of Compound I in cldorolbnn. follow cd by maturauon. Colllpoiilld I is prc)tered by maturauon ol'mi amorphous free In onc cmbothmcni, Foun 5 ol'a free base of Compound I is base ol'ompound I ui ethyl acctatc. In one emboduncnt, prcparcd by cooluig a solution of Form 2 of a frix: base of liorm 5 of a free hase of Compound I is prepared by niahira- ('ompound I in 'I'Ill'n one embodiment, liorm 5 of a free tion ofan amorphous free base of ('ompound I in acetone. In base of ('ompound I is prepared by cooling a solution of US 20]4/0275 [35 A1 Sep. 18, 2014 34

Form 2 of a free base of Compound I in DCM. In one Compound I is substantially free of salts of Compound I. In cmbodimcnt, Form 5 ol' free base ol Compound I hs prc- some cmbodimcnts, Form 6 oi'he frcc base of Compound I parcd by rxholing a soluthon of Form 2 of a iyec base of hs provhdcd as substanthally pure Form 6 of thc I'rcc base of ('ompound I in D('M/Me011 (I:I) In one embodiment, ('ompound I ihorm 5 of a free base of('ompound I is prepared by cooling [0406] In some embodiment, Form (i of the free base of a solution Form 2 a free base Compound I in MeOH/ of of of Compound I is an acetic acid solvate. In one embodiment. anisole. In one embodiment, the coolin ~ temperanxre ranges Form 6 of the free base of Compound I hs an acetic acid —20" 5" C. from about C. to about solvutc, whcrcin Ihe molar retro of Compound I to thc accuc B Com- [0401] In one embodiment. Form 5 of frcc base of acid ranges ibom about 1.0.4 to about 1.0 6. In one embodi- pound I Is prepared slow cvaporanon of a solutxon of Fomx by ment, the molar ratio of Compound I to the acetic acid is 2 of a free base of Compound I in 2-Me'1111; followed by about I:0 5 (i.e, hemi-solvatei maturation. [04021 In one embodiment, Form 5 of a fice base of('om- [0407] A representative XRPD pattern ofForm 6 ofthe free FICI. pound I is prepared by maturation ofForm I of a malehc acid base of Compoxuxd I are pmvided in 38 salt of Compound I in EtOH. In one embodiment. Form 5 txf [0408] In some cmbodhments. provided hcrcux is a solid a free base ofCompound I Is prepared by mantra thon of Fomx foun comprising a free base of('ompound I characterized by I of a malcic achd salt ol'Compound I ux 2-propanol. In onc XRPI) peaks located at I, 2, 3. 4. 5, 6, 7. 8. 9, 10, 11, 12, 13, embodiment. Ihorm 5 of a free hase of ('onxpound I Is pre- 14. 15. or all ofthe folloxvin or approximately the iixllowin pared by maturation of I'orm 1 of a maleic acid salt of( on)- positions: 4.9. 7.2, 10.6. I I.l, 12 0, 12.2, 14.6. 15.3. 16.6. pound I in I-propanol In one enxbodinxent, lhorm 5 of a free 17.3. 18.1. 18.7. 19.4, 20.2. 21.0, 21.2, 22.2. 23 4, and 23.9 base of Compound I is prepared by matumtion of Fonu I of dcgrccs 20, plus or minus 0.10. In some cmbodimcnts, pro- a maleic acid salt ofCompound I in acetone. In one embodi- vhdcd hcrcin is a solid form compnshng a free base of Com- ment, Form S of a lycc base ol'Compound I Is prepared by pound I characterized by XRPI) peaks located at 1. 2, 3, 4, 5, maturation of Fonu I ol'a malchc acul salt ol Compound I In 6, 7, 8, 9, 10, 11, 12. Cr all ofthe following or appmximately 'll l1 'n one embodiment, ihornx 5 of a free base ofConxpound the following positions: 4.9, 7.2, 10 (b 11.1. 14.6, 18,1, 18,7 I is prepared by matunxtion of I'orhn I of a maleic acxd salt of 19.4. 21.0. 21.2. 22.2. 23.4. Bnd 23.9 de rees 20. plus or ('ompound I in lhtOII/water(90/IOCA) In one embodiment, muxus 0.10. In some embodiments, the sohd form is chamc- the maturation hs performed betxveen RT to about 50" C. for tcrizcd by 3 ol thc peaks. In some embodnucnts. thc solid aboxut 24 to about 72 hours. form is characterized by 5 of thc peaks. In some cmbodi- [0403J In one embodiment. I'orm 5 of a freebase of Con)- mentg the solid form is characterized by 7 of the peaks In pound I is prepared by cooluxg a solution of a maleic acid salt some embodiments. the solid form is chamcterized bv &) ofthe of Compound I hn ethanol. In one embodiment. Form 5 of a peal s. In some embodiments. the solid foun is characterized free base ofCompound I is prepared by cooling a solution of by 11 of the peaks. In some embodhments, the solid form is a maleic acid salt of Compound I in ethanol/water. In one characterized by 13 of the peaks. In some embodiments. the cmbodimcnt, Form 5 ol' free base ol Compound I hs pre- sohd form Is charactcnzed by all of thc peaks. pared by cooling a so lu u on of a ma 1 etc acid salt ofCompound [0409J In some embodiments. provided herein is a solid I in 2-butanone/water In one embodiment, lhorm 5 of a free foun comprising a free base of('ompound I having an XRPI ) base of ('ompound I is prepared by cooling a solution of a pattern comprising peaks at approximately 7.2. 10. 6, and 11.1 maleic acid salt of('ompound I in ethyl acetate/water In one degrees 20. In certain embodiments, the solid form fhrther embodiment. Form 5 of a free base of Compound I is pre- comprises peaks at approximately 14.6 and 18.1 degrees 20. paredbycoolin asoluthonofamaleicacidsaltofCompound In ccrtaux cmbodmxcnts. the solid form further comprises I in ouc S a Ibce amsolc/water. Iu mnboduncnt, Form of base at 4.9 mxd 22.2 dcgrccs 20. In onc oi'a peaks approxhmatcly of Compound I is prc)xarcd by rxhohn B soluthon malchc embodinxent, the solid form compnses peaks at approxi- acid salt of ('ompound I in anisole/MeOII/water In one nmtely 4.9, 7 2. 10.6. I I I, 14 6, 18.1. 18 7. 19 4, 21 0, 21 2, embodiment. Ihorm 5 of a free hase ('onxpound I Is pre- of 22 2, 23 4. and 23 I) deg,ress 20 pared by cooling a solution of a maleic acid salt ofConxpound I in MEK. In one embodiment. the coolin tempenxture [0410] In some cmboduncnts, the XRPD peaks above (de- ranges from about — 20" C. to about 5" C, In one embodunent, grees 20 peaks) are xvhen analyzed usmg copper Krx radia- the coohng tcmperaturc ha about 5'. In one cmbodhmcnt. thc tion coohhxg Ilhxxh: ls Bl IcBst 4 lxouhs, BI least 8 lxouhs, thr BI IcBsl 24 [0411] In some cmbodhments. provided hcrcux is a solid I hours form compnsing a free base of Compound I, whcrchn Ihc [04041 All of the combinations of the above embodiments sohd fonu is chanxcterized by an XRPD diffnxction pattern are encompassed by this invention. which matches the XRPI) pattern presented in lhi(i 38. [0412] A rcprcsentativc thcmxal gravhmetnc mxalyshs Form 6 of Free Base of Compound I (TCiAI curve of Ihc frcc base of Compound I is provhdcxi in [0405J In some embodiments. provided herein is lhorm 6 of lhl(i 39, which exhibits a wei ht loss of about 3 05% of the the free base ofCompound I In one ehnbodihnent. thorn) 6 of total san)pie v'eight upon heating, from about 30 to about 60" the free base of Compound I is a crystalline acetic acid C.. a v ei ht loss of aboxut 3.(i3% of the total sample weight solvate ofCompound 1. In some embodiment~. Fomx (h ofthe upon hestia from about 60 to about 130" C.. and a weight free base of Compound I hs substantially lrcc ol'amorphous loss of about 2.14% of Ihc Iouhl sample wchght upon heathng free base of Compound l. In some cmbodunents, Form 6 of from abou I 130 to about 200'. Wh thou t being hmt ted by Bny the frcc base of Compound I hs substanually frhm of other purthcular theory, Uxc wchght losses corrcspond Io loss of crystalline forms (i e, polymorphs] ofthe free base of Con)- about 0.5 equivalent of acetic acid In some enxbodiments, pound I in some embodiments, lhorm 6 of the free base of pmvhded herein is a solid fixnn comprising a free base of US 20]4/0275]35 A1 Sep. 18, 2014 35

('ompound I, wherein the sohd form is characterized by a solvent oft-BuOH and stater. In one embodiment. amorphous TGA thcrmogram which matches the TGA thcrmogrmn prc- frlm base of Compuund I prc)lated by frlmzc-drying (c.g.. scntcd in FIG. 39. lyophilization) of a solution of a I'rcc berne ofCompound I in [0413J A representative differential scanning calonmetry a mixed solvent of t-13uOI I and water is a t-llu011 solvate In (DS(') thermogmsm of the free base of Conipound I is pre- one embodiment, the t-13UOI I solvate of the amorphous free sented in FICi. 40. In some embodiments, pnivided herein is a base of Compound I contains about 10%s to about 40%. or solid fomi comprising a free base ofCompound I that exhib- aboUt 20%S to about 35%, of I-BuOH by molar ratio. its a thermal event, as clmracterized by DS('. with a peak [0419] In one embodiment. the amorphous free base of tcmpcraturc of about 49'. mid/or dn onset Icmpcraturc of Compound I is prepared by cvaporauon of a solution of a free shou(27'., with a peak tcmpcralure ofabout 131'.;uid/or busc of Compound I m DMSO. an onset tempemsture of about 111" ( . with a peak tmnpera- [042(IJ In mie embodiment, amorphous free base of ('oni- ture of about 173" ('nd/or an onset temperature of about pound I converts to liorm 6 of the free base of ('oinpound I 165" C.,orwithapeal temperatureofabout184'C.and/oran after maturation in acetic acid/w ster (I: I ) for 72 hour~. onset temperature of about 175" C. In some embodiments, provided herein is a solid form comprising a Ibee base of Mixture of Solid liorms of ('ompound I or Salts '!'hereof. Compound I that cxlub its themis 1 cvcnis, as charactended by [0421] In certain embodiments. provided herein are com- DSC. with a tmnpcrature ofabout and/or an onset peak 49'. positions compnsing morc than onc solid fonna of Com- temperature ofabout 27" (', with a peak temperature ofabout pound I. Ur a salt. solvatc (c.g., hydrate), or solvate ol a sall I 31" C. ancgor an onset temperature ofabout 111' . with a thereof. Such solid Ibnns use ludo, but are not limited to, Form peak temperature of about 173''. anrgor an onset tmnpera- I of a sulhlric acid salt of('ompound I, I 'orm I A of a sulhlric ture of about 1(15" C., and with a peak temperanire of about acid salt of ('ompound I, I'orm 113 of a sulfuric acid salt of 184" ( '. and/or an onset temperatiue ofabout 175'. Without Compound 1. Form 2 of a sulhiric acid salt of Compound l. bcuig linuuxl by any particular Ihcory. Ihc Ihcnnal events Form 3 of a sulfuric acid salt of Compound I, an amorphous corrcspond to loss ol'bout 0.5 ctiutvalcnt ol'scene acid. In sulhiric acid salt ofCompound 1. Fomi I of a maleic acid salt some embodiments, provided herein is a solid form cmnpns- ofCompound I, anamorphous malcic acid sah ofCompound ing a free hase of ('ompound 1. wherein the solid form is I, Form I ofan 1,2-cthmiedi sulfonic acid salt ofCompound 1. characterized a DS('hermogmsmnfl which niatches the DSC by liorm 2 of an 1,2-ethanedisulfonic acid salt of Compound I, themiogram presented in FICI. 40. liorm 3 of an 1,2-ethanedisulfonic acid salt of Compound I, [0414] A representativegravimetric vapoursorption(CIVS) Form 4 of an 1.2-ethanedisulfotuc acid salt of Compound l. isotherm of Compound I ls prescntcd in FIG. 41. In onc an amorphous 1.2-ethanedisulfomc acid salt ofCompound l. cmbodimcnt, providlxl hcrcui ls a solnl form comprisui a Form I of a hydrocldoride salt of Compound I, Fomi 2 of a free base of ('ompound I, wherein the solid form is charac- hydro cidondc salt ofCompound 1. ml tunorphou s hydrochlo- terized by a (IVS isotherni which matches the (3VS i sotherni ndc sall ol Compound 1. Form I of an lscthionate sall of presented in I'l(i 41 ('ompound I, an amorphous isethionate salt ofConipound I, [0415[ In one embodiment, Form 6 of the free base of liorm I of a free base of ( ompound I, liorni 2 of a free base ('ompound I is prepared by maturation of amorphous free ofCompound 1. Form 3 of a free base ofCompound I, Form base of Compound I in aceuc acidiwatcr (1.1). In onc 4 of a free base of Compound 1. Form 5 of a free base of cmbodimcnt, Form 6 ol'hc frcc base of Compound I is Compound 1. Fomt 6 of a free base of Compound I, or an prepared maturation 'orm I of a freebase ofConipound by amorphous free base ofCompound 1. I in acetic acid/water (I I). In one embodiment, the niahira- [0422J In mie embodiment, provided herein is a composition is performed between Kl'o about 50" C for about 72 tion comprising Form I of a sulfuric acid salt ofCompound I hours. and at least one other solid foun of Compound I, or a salt. [0416] In onc mnboduncnt, Fonu 6 of thc lbec base of solvate (e.g., hydrate). or solvate of a salt thereof. In one ('ompound I corn erts to liorni 4 of the free base of Coni- cmboduncnt, thc ratio of Form I of a sulfunc acid salt of pound I desolvation In one embodiment, the desolvation by Compound I lo Ihe total amount of other solid fonna ui Ihc occurs at about 100" C. In another embodiment, the desolva- composition is greater than about I:1. greater than about 2: I, tion occurs at 0% RH In one embodiment, Fomi 6 ofthe free greater tlmn about 3 I, greater than about 4 I, greater than base of Compound I convert~ to Form 3 of the free base of about 5: I, greater than about 6.1, yester than about 7:l. Compound I after storage at elevated hunndity conditions greater than about 8: I, or eater than about 9: I (c.g.. 40 C./75% RH for about a wcck). In onc emboduncnt, y [0423] In onc emboduncnt, provided hcrmn m a composi- without being limited by any particular theories, liorni 6 and tion comprising liomi I of a maleic acid salt of ('ompound I liorm 3 of the free base of ('onipound I are isostnictumsl and at least one other solid form of ('ompound I, or a salt, solvate/hydrate solvate (e.g., hydrate). or solvate of a salt thereof. In one [0417] All of the mimbinations ol'hc above mnbodimcnts embodiment. the mstio of Form I of a maleic acid salt of are micompasscd tlus invention. by Compound I lo Ihe total amount of other solid fonna ui Ihc composition is greater than about I: I, renter than about 2: l. Amorphous Frcc Base of Compound I grcatcr limn about 3.1, grcatcr than about 4.1, grmitcr Ihdn [0418] In some embodiments, provided herein is an amor- about 3:I, greater than about 6 I, greater than about 7:I, phous free base of Compound I. In one embodiment, the greater than about 8: I, or greater than about 9 I amorphous frlm base ol'ompound I ls prcparml by freczc- [0424] In onc emboduncnt, provided hcrmn m a composi- drying (c.g., lyoplullzatlon) ol' soluhon of a lhec bnsc of tion compnsing Form I of a free base ol'Compound I and at Compound I In one embodiment, the amorphous frcc base of least cite olllci solltl foml of ConlpoUilil I, or d sdh, solvatc ('ompound I is prepared by freeze-drying (e g., lyophiliza- (e g., hydrate), or solvate of a salt thereof. In one embodi- tion) of a solution of a free hase of Compound I in a nuxed ment, the composition comprises liorm I of a free hase of US 20 14/0275 [35 A1 Sep. 18, 2014 36

( 'ompound I and Form 2 of a lbee base of ('ompound 1. In [0427[ In one embodiment, provided here&n is a composi- another mnbodimm&t, the composition composes Fom& I of a t&on composing Form 4 of a free base ol'Compound I and at free base of Compound I and Form 3 ol a frcc base of least ouc othe& sol&tl fern& of Con£ I, or d adit, solve&a ('ompound 1. In another embodiment. the composituoo cons- (e g., hydrateb or solvate of a salt thereof. In one embodi- prises 1&orm I of a free base of ( ompound I and I orn& 4 of u ment, the composition comprises 1&orm 4 of a free hase of free base of Compound 1. In another embodiment. the com- Compound I and Form I of a free base of Compound l. In position comprises Fom& I of a free base ofCompound I and another embodiment, the composition comprises Fern& 4 of a Form 5 of a free base of Compound l. In another embodi- free base of Compound I and Form 2 of a free base of ment, thc compos&uou composes Form I ol a Ibcc base of Compound l. In another mnbodimm&t, the compos&uon com- Compound I and Form 6 of a free base of Compound l. In poses Form 4 of a free base of Compound I and Form 3 of d another embodiment, the con&position co&nprises l&oun I ofu free base of ('ompound 1. In another embodiment. the con&- free base of Compound I and an amorphous free base of position comprises 1&orm 4 of a free base of ('ompound I and ( 'ompound 1. In one embodiment. the ratio ofForm I of a free Form 5 of a free base of Compound l. In another embodi- base ofCompound I to the total amount ofother solid forms ment, the composition comprises Form 4 of a free base of in the composition &s peater than about I:I, greater than Compound I and Form 6 of a free base of Compound l. In about 2.1, greater than about 3.i, grcatcr tlmn about 4.1, another cmboduuent, thc composition comprises Form 4 of a greater than about 5.1, grcatcr than about 6:1. greater tlu&n fr&m base of Compound I m&d an amorphous free base of about 7:1. rester than about 0: I, or greater than about &hi ('ompound I In one embodiment, the ratio of I 'nun 4 ofa free [0425J In one embodiment, pmvided herein is a con&posi- base of('o&upound I to the total amount of other solid forms in is than about I 1. than tion comprising 1&orm 2 of a free base of Compound I and at the cmnposition greater greater least one other solid form of Compound I, or a salt. solvate about 2:I, greater than about 3.1, yester than about 4:l. (e.g.. hydrate), or solvate of a salt thereof. In one embodi- greater than about 3:I, greater than about 6 1. greater than ment, the composit&on comprises Form 2 of a free base of about 7:1. grcatcr tlmn about 0: l. or grcatcr thm& about 9.1. Compound I and Form I of a free base of Compound l. In [04201 In onc emboduucnt, prov&dcd barmn m a composi- another mnbodimm&t, the composition composes Fom& 2 of a t&on composing Form 5 of a free base ol'Compound I and at free base of Compound I and l&orn& 3 of a free base of least one other solid form of Compound 1. or a salt, solvate ('ompound 1. In another embodiment. the composituoo cons- (e g., hydrateb or solvate of a salt thereof. In one embodi- prises 1&orm 2 of a free base of ( ompound I and I orn& 4 of u ment, the composition comprises 1&orm 5 of a free hase of free base of Compound 1. In another embodiment. the com- Compound I and Form I of a free base of Compound l. In position comprises Fom& 2 of a free base ofCompound I and another embodiment, the composition comprises Fern& 5 of a Foun 5 of a frcc base of Compound l. In another embed&- fr&m base of Compound I and Form 2 of a fr&m base of ment, thc compos&uou composes Form 2 ol'a Ibcc base of Compound l. In another mnbodimm&t, the compos&uon com- ('ompound I and I'orm 6 of a free base of ('ompound l. In prises Form 5 of a free base of ('ompound I and 1&orm 3 of a another embodiment, the con&position co&nprises l&oun 2 ofu free base of ('ompound 1. In another embodiment. the con&- free base of Compound I and an amorphous free base of position comprises 1&orm 5 of a free base of ('ompound I and ( 'ompound 1. In one embodiment. the ratio ofForm 2 of a free Form 4 of a free base of Compound l. In another embodi- base ofCompound I to the total amount ofother solid forms ment, the composition comprises Form 5 of a free base of in thc composit&on &s greater than about I:1. grcatcr tlu&n Compound I and Form 6 of a Ibcc base ol'Compound l. In about 2.1, greater than about 3.i, grcatcr tlmn about 4.1, another cmboduuent, thc composition comprises Form 5 of a greater than about 5 I, greater than about 6:1. greater than free base of Compound I and an amorphous free base of about 7:1. rester than about 0: I, or greater than about &hi ('ompound I In one embodiment, the ratio of I 'nun 5 ofa free [0426J In one embodiment, pmvided herein is a con&posi- base of('o&upound I to the total amount of other solid forms in is about than tion comprising 1&orm 3 of a free base of Compound I and at the composition ~eater than I:I, greater least one other solid fom& of Compound 1. or a salt, solvate about 2:I, greater than about 3.1, yester than about 4:l. (e.g.. hydrate), or solvate of a salt thereof. In one embodi- grcatcr tlmn about 5.1, grcatcr than about 6.1, grm&tcr than ment, thc compos&uou composes Form 3 ol a Ibcc base of about 7:1. grcatcr tlmn about 0: l. or grcatcr thm& about 9.1. Compound I and Form I of a free base of Compound l. In [04291 In onc emboduucnt, prov&dcd barmn m a composi- another mnbodimm&t, the composition composes Fom& 3 of a t&on composing Form 6 of a free base ol'Compound I and at free base of Compound I and l&orn& 2 of a free base of least one other solid form of Compound 1. or a salt, solvate ('ompound 1. In another embodiment. the composituoo cons- (e g., hydrateb or solvate of a salt thereof. In one embodi- prises Form 3 of a free base of Compound I and Fomt 4 of a ment, the composition comprises Form 6 of a free base of free base of Compound 1. In another embodiment. the com- Compound I and Form I of a free base of Compound l. In pos&t&on composes Fonu 3 of a frcc base ofCompound I and another cmboduuent, thc composition comprises Form 6 of a Foun 5 of a frcc base of Compound l. In another embed&- fr&m base of Compound I and Form 2 of a fr&m base of ment, thc compos&uou composes Form 3 ol'a Ibcc base of Compound l. In another mnbodimm&t, the compos&uon com- ('ompound I and I'orm 6 of a free base of ('ompound l. In prises Form 6 of a free base of ('ompound I and 1&orm 3 of a another embodiment, the con&position co&npri sea I&oun 3 of u free base of ('ompound 1. In another embodiment. the con&- free base of Compound I and an amorphous free base of position comprises Foun 6 of a free base of Compound I and ( 'ompound 1. In one embodiment. the ratio ofForm 3 of a free Form 4 of a free base of Compound l. In another embodi- base ofCompound I to thc total amount ol other sol&d fbrms ment, thc compos&non comprises Foun 6 of a lbcc base of in thc composit&on &s greater than about I:1. grcatcr tlu&n Compound I and Form 5 of a Ibcc base ol'Compound l. In about 2.1, greater than about 3.i, grcatcr tlmn about 4.1, another cmboduuent, thc composition comprises Form 6 of a greater than about 5 I, greater than about 6:1. greater than free base of Compound I and an amorphous free base of about 7:1. rester than about 0: I, or greater than about &hi ('ompound I In one embodiment, the ratio of I 'nun 6 ofa free US 20]4/0275]35 A1 Sep. 18, 2014 37

base ofCompound I to the total amount ofother solid forms 18.4. 18 7, 19.2, 20.5, 20.(i, 21.2, 21.5, 21.9, 22.4. 22.8. and in Ihc composition is greater thun about I:1. grcalcr lluin 23.3 dcgrccs 20. plus or muius 0.10. about 2.1, greater than about grcatcr &lian ubout 4.1, 3.i, [0436] In one embodiment, the method is for analyzing a greater than about 5 I, greater than about 6:1. greater than material for the presence or amount ofForm I ofthe free base about 7:1. rester than about 8: I, or greater than about '):I of Compound 1. In one embodiment, the characterization method is XRPD. In onc mubodnucnl, thc charactcnzal&on 5.2 7 Methods for Anaiyzin ~ Material method is XRPD, and thc signatory charactcri ~ nc is XRPD [0430J In some embodiments. provided herein are also peaks located at 1. 2, 3, 4, 5. 6. 7, 8, 9, 10. 11, 12. 13, 14, 15, methods for analyzing a material for the presence or amount or all of the following or approximately the following posi- of a solid form provided herein, comprisin tions: 5.0. 7.6. 9.9, 10.7, 11.4. 12.2, 13.0. 13.5, 14.0. 14.5. providing a material comprising a compound of fomiula (I], 15.1. 15.9„ 16.4. IG.S, 17.7, 18.1. 19.1, 19.9, 20 (i, 21.1, 21.7. or a salt, solvate, or solvate of a salt thereof. or a mixture 22.4. 23.1. 23.7. 24.6, and 25.2 degrees 20, plus or minus thereof: and 0.10 using a characterization method to determine whether a si- [0437] In one embodiment, the method is for analyzing a natory cl&aracteristic associated with the solid ii&rm is present material for the presence or amount ofForm 2 ofthe free base in the nuilcrial by companng thc charac&enatic obtained from of Compound l. In onc mubodnucnl, the charactcnzal&on the malcnal with a rcfcrnicc signatory cliaraclcnsuc, method is XRPD. In onc mubodnucnl, thc charactcnzal&on wherein the existence of a characteristic substantially ident&- method is XRPD, and thc signatory charactcri ~ nc is XRPD eel Io thc refbrmicc s&gus lory charac tens tw. uidmales die prcs- peaks located at 1. 2, 3, 4, 5. 6. 7, 8, 9, 10. 11, 12. 13, 14, 15, ciici: of &lie solid for&&i i&i &lie ilialcilal. or all of the following or approximately the following posi- [0431] In one embodiment, the method further comprises tions: 9 I, 10.9, 12.3. 15.0, 16.1, 16.8. 17.8. 18.1, 18.3, 19.3. sclccting a batch as a result oi'lhc dclcrminal&on based upon 20.1. 20.5. 20.7. 20.8, 21.3. 21.9. 22.4, 22.7, 23 9, 24.9, 25.6. companson to lhc reference atm&dard. In one embodiment, thc 26.2. 26 S, 27.2, and 27.5 dcgrccs 20. plus or muius 0.10. method further comprises making a determination regarding [0438] In one embodiment, the method is for analyzing a the quality of the matenal. In one embodiment, the metlu&d material for lhc prescncc or amount of Form 3 ofthc frcc base fi&rther comprises making a determination whether to use the of Compound l. In onc mubodnucnl, the charactcnzal&on material in the manufacturing of a pharmaceutical compos&- method is XRPD. In onc mubodnucnl, thc charactcnzal&on tion. In one embodiment, the method further comprises mak- method is XRVD, and the signatory characteristic is XRVI) ing a dctcnmnation whether to use Ihe material for &rearing a peaks located at I, 2, 3, 4, 5. 6. 7. S. 9. 10. I I, 12, or all ofthe P13 K &acxliated disorder. following or approximately the follow in positions: 4.9, 7.3. [0432] In one embodiment, thc clmracterization mctlx&d is 10.6. 11 3, 12.0, 144, 14.9 15.2, l(i.9, 17.7, 20.0. 21.9. and one or more of XRVD, T(izu DSC, (ipg. I "l)IR, or NMR 24.6 dcgrccs 20. plus or muius 0.10. [0433J In one embodiment, the method is for u analynng [0439] In one embodiment, the method is for analyzing a material the or I orm I for presence amount of ofthe sulhiric material for lhc prescncc or amount of Form 4 ofthc frcc base character- acid salt of Compound 1. In one embodiment, the of Compound l. In onc mubodnucnl, the charactcnzal&on characterization method is XRPD. In one embodiment, the method is XRVD ln one embodiment, the characterization ization method is XRPD, and thc is s&gmilory charactenstic method is XRVD, and the signatory characteristic is XRVI) XRPD peaks located at I, 2. 3. 4, 5, 6, 7, 8, 9, 10. 11, 12, 13, peaks located at 1. 2, 3, 4, 5. 6. 7, 8,nfl9, 10. 11, 12. 13, 14, 15, 14. 15. or all of the following or the following approximately or all of the following or approximately the following posi- positions 8 1. 10.7. 10 9. 12 4. 13 3, 14 0, 14 2, 14 N, 15 I, tions: 5.0. 7.4, 10.7, 11.1. 11.5, 11.8, 13.0. 13 8, 14.5. 15.4. 16 0, 163, 17 6. 17 184. 18 6, 18 7, 19 204, 21.4. 21 7, 7, 2, 16.4. IG.7, 17.5. 19.1. 20.0. 21.7. 22 2, 22.4, 23.2, and 23.9 22.2, 23.0. 23.4. 23.6. 24.2. 24.7 20. and degrees plus or dcgrccs 20. plus or muius 0.10. minus 0.10. [0434] In one embodiment, the method is for analyzing a [0440] In onc embodiment. Ihc method is for analyzui a malcnal for Ihe prcsmicc or amount oi Form I of Ihc male&c material for lhc prescncc or amount of Form 5 ofthc frcc base acid sall of Compound 1. In one cmboduncnl, Ihc character- of ('ompound 1. In one embodiment, the characterization ization method is XRVD. In one en&bodin&ent, the character- method is XRVD ln one embodiment, the characterization ization method is XRVD. mid the sigimtory cl&aracteristic is method is XRPD. and the signatory characteristic is XRPD s 6. 9. XRPD peaks located at I. 2, 3, 4, 5, 6. 7, 8, 9. 10. 11, 12. 13, peal located at I, 2, 3. 4, 5, 7, 8, 10, 11, 12. 13, 14, 15. 14, 15, or all ofthe following or approximately the followin or all of the following or approximately the following posi- positions: 6.2. 9.0, 113, 11 7, 12.4, 12.9. 13.0. 13.4. 14 4, tions: 6.5, 9.0, 9zk 10.0. 10.5. 10.7. 11.3, 11.7. 12.1, 12.9. 14.6, 16.0, 16.S. 17.5, 18.0, 18 3. 18.6, 19.6, 19.8, 20.3. 21 3, 13.1. 14.0, 14.5. 15.5. 15.8. 16.0. 16 6, 173. 17.5, 17.7, 18.0. 21.7, 22.6, 23.2. 23.5, mid 24 4 degrees 20, plus or minus IN 5, IN 9. 19 1. and 19 4 degrees 20. plus or minus 0.10 0 10. [0441] In onc embodiment. Ihc method is for analyzui a [0435J In one embodiment, the method is for analynng u nmterial for the presence or amount 'orm 6 ofthe free base material for the presence or an&cunt of i&urn& I of the 1.2- of ('ompound 1. In one embodiment, the characterization ethanedisulfonic acid salt of Compound 1. In one embodi- method is XRPD. In one embodiment, the characterization ment, the characterization method is XRPD. In one embodi- method is XRPD. and the signatory characteristic is XRPD ment, the characterization method is XRPD, mid thc peaks loca&cd at I, 2, 3,4, 5. 6. 7, 8, 9, 10. 11, 12, 13, 14, i5, sigitalory clraractcrislic is XRPD peaks locutcd at l. 2, '3. 4. 5, or all of the followuig or approxuualely Ihc following posi- 6. 7. 8, 9. 10, 11, 12, 13, 14. IS, or all of lhe ibllowuig or tions: 4.9. 7.2, 10.6, 11.1. 12.0. 12.2, 14.6, IS.3, 16.6, 17.3. approximately the following positions 7.9, N 5, 103, 10 7, IN I, 18 7, I') 4. 20 2,21 0,21.2. 22.2,23 4. and 23 9 degrees 11 0, 12 4, 12 7. 14 0, 14 3. 15 3, 15 9, 17 2, 17 4, 18.1. IN), 20, plus or u&il&us 0.10 US 20]4/0275 [35 A1 Sep. 18, 2014 38

6. PH orRMICCEUTIC orl COMPOSITIONS [0447] Preparations for such pharmaceutical compositions arc well-known m the art. Scc, e.go Anderson, Pluhp O.. [0442] In some embodiments,providedhereinarephnmta- Knobcru James E., Troutmmt, Wilham 0, eds., IIaudhoal of ceutical compositions comprising a compound provided (7iairal l)tug l)ata.'I'enth I.dition, Mc(rraw-I hll,2002; Pratt hcrcnl, oi an enon(tonlcr. a nnxnuc ol onanltonlcls, ol and '1'aylor, eds, I'rituipler af')rug Arttirra, Third I(dition, mixture of two or more dtastcrcomcrs thcrcolj or a phamui- Churchill Livingston. New York. 1990: Katzung. edo Basic ceuucally acccptablc form thereof [c.g., phannaccuttcully atrd C7iuicai Phanaacalagv, Tv'elfth Edition, McCrraw Hill. acceptable salts, hydrates. solvates, isomers, prodntgs. and 2011: Croodman and Ciilman, edso The Pharatai'alagiral isotopically labeled derivatives), and a pharmaceutically Busis af Therapeutics, Tenth Edition, McGraw Hill, 2001; acceptable excipient, diluent, or carrier, inclnding inert solid Retui ugtaus Plutruuicetai ca/ Sciences, 20th Ed . Lippincot( diluents and fillets, sterile aqueous solution and various Willoiams; Wilkins, 2000; Martindale. 7/te I;.rtru Pharraa- organic solvents, permeation enhancers, sofubiliznrs and trrpuera, 1'hirty-Second i(dition ('I'he Pharmaceutical Press, adtuvants. In some embodiments, a pharmaceutical compo- London. 1999): all of winch are Incorpomsted by reference sinon dcscribcd herein utcl ud ca a second a c1 ivc agmt I such as herein in their entirety. Except insofar as any conventional an additional themspeutic agent, (e 8, a chemotherapeutic exciptent medium is incompatible with the compounds pro- agent) vided herein, such in by producing mty undcsirdblc biological effect or otherwise Interacting ut a dcletcrious marutcr with (i.l. Formulations any other componentfs) of the pharmaceutically acceptable composition, the excipient'ause is contemplated to be within [0443] Pharmaceutical compositions can be specially for- the scope of this disclosure mulated for administration in solid or liquid fiirm, includin those adapted lbr thc following. oral aihnunstranon, lbr [044NJ In some embodiment~, the concentration of one or more of the compounds provided in the disclosed pharma- cxanlplc, drcnchcs [aqUi UUS CI non-aqueous sohltlons or sus- ceutical compositions is to or less than about 100%. pensions), tablets (e 8, those targeted for buccal, subbngual, equal and systemic absorption), capsules, boluses, powders. gran- about 9)0%, about S0%, about 70%. about 60%, about 50%. ules, pastes for application to the tongue. and intraduodenal about 40%, about 30%, about 20%. about 19%, about 18%. routes; parenteral adnunistration, including intravenous, about 17%. about 16%, about 15%. about 14%, about 13%, about 12'iu about 11'%, about 10%. 9%. 8%, intraarterial. subcutaneous, Intramuscular. intrnvascular, about about about 7%, about 6%. about 5%, about 4%, about 3%. about httl'Upon(one'Il CI'lfUSIOU as, ior cxdnlplc, a stclsh: solUUOU 1%o. 0.4'io, aixiut or suspmtsion, or susuiincd-rclcasc lirnnulation: Iopical 2%. about about OB%, about about 0.3%, application, for example, as a cream, ointment, or a con- 0.2%, aboUt 0.1%, about 0.09%, about 0.08%. aboUt 0.07%. about 0.06%, abou(0.05%, about 0.04'/o, about 0.03%, about trolled-release patch or spray applied to the skin: intravagi- 0.02%, about 0.01%. about 0.009%, about about nally or intrarectally, for exarople, as a pessary. cream, stent 0.008%, 0 007ori, about 0 006'r(. about 0.005'%, about 0 (X)4'ri, about or foam; sublingually: ocularly: pulmonarily: local delivery 0 003%, about 0 002%, about 0 001%. about 0.(X)09%, about by catheter or steat: intrathecally, or nasally. 0 0(X)N%, about 0 0007%, about 0 0006%, about 0.(X)05%, [0444] Examples of suitable aqueous and normqueous car- about 0.0004%. about 0.0003oio, about 0.0002%, or alxiut riers wluch cmt bc mnploycd in phanndccutical compositions 0.0001% vv/w, tv/v or v/v. htchulc water, ethanol. pol)'Ols [sUch as glvcclol. plopvlcnc glycol, polyethylene glycol. and the like), and suitable mix- [0449] In some embodiments, the concentmstion of one or tures thereof. vegetable oils, such as olii e oil, and injectable morc of thc compounds as provided hcrcin Is greater than about 9)0%, about S0%, about 70%. about about 50%. organic eaters, such as ethyl oleate Proper tiuidity can be 60%, about 40%. about 30'!o. about 20%, about 19.75%, about maintained, for example, by the use ofcoating materials, such 19 50%, about I') 25%, about 19%. about IN 75%. about as lecithin. by the maintenance ofthe required particle size in IN 50%, about IN about 18%. about 17 75%. about the case ofdispcrsions. mtd by thc use of surfacIants. 25%, 17.50'!o. about 17.25;o. about 17%. about l(i.75/o. about [0445] These compositions cmt also comma adfuvants such 16.50'!o. about 16.25;o. about 16%. about 15.75'/o. about as prcservativcs. w ctnng agmtls, emulsifying agents, dispers- 15.50%, about 15.25%, about 15%, about 14 75%, about ing agents, lubncants, and/or antioxidants. Prcvcntion ol'hc 14.50%, about 14.25%, about 14%, about 13 75%, about action of microorganisnts upon the contpounds descnbed 13.50%, about 13.25%, about 13%, about 12 75%, about herei n can be ensured by the inclusion ofvarious antibacten el 12 50oi, about 12 25%, about 12%. about 11 75%. about and antifungal agents. for example. paraben. chlorobutanol, 11 50%, about 11 25%, about 11%. about 10 75%. about phenol sorbtc acid, and the like. It can also be desirable to 10.50'!o. about 10.25;o, about 10%, about 9.75%, about include Isotonic agents, such as sugars, sodnim chloride, and 9.50'/o. about 9.25%, about 9i'o, about 8.75%, about 8.50%. the like Into thc compostuons. In addiuon, prolonged absorp- about 8.25%, abou( 8%, about 7.75%, about 7.50%. about tion of thc injcctablc phannaccuncal lirmt can bc brou ht 7.25%, about 7%. about 6.75%, about 6.50%, about 6.25%. about by the inclusion of agents which delay absorption such about 6%. about 5.75%, about 5.50%, about 5.25%. about as alumimtm monostearate and gelatin 5%, about 4.75%, about 4.50%, about 4 25%. about 4%, [0446J Methods ofpreparing these tiirmulations orcompo- about 3.75%, about 3 50%. about 3 25%. about 3%. about sitions include the step of bringing into association n com- 2.75%. about 2.50%, abou1 2,25%, about 2%, about 1.75%. pound de ac nb ed herein and/or the chemotherapeutic with the aboUt 1.50%, about 1.25;o, abou1 I io, aboUt 0.5%, about carncr;md, optionally. onc or more accessory utgredmnts. In 0.4%, about 0 3/o, about 0 2/o. about O.l /o. about 0 09%. general. (hc formulations are prcparixl by urulomtly and Inti- about 0 OS%, about 0 07%, about 0 06 /o, about 0 05%, about mately bnngutg into association a compound as provided 0.04%, about 0.03'!o, about 0.02%, about 0.01%, about herein v ith liquid carriers, or finely dii ided solid camera. or 0 00')ori, about 0 008')1 . about 0.007'%, about 0 (Xko'ri, about both. and then, if necessary. shaping the product. 0 005%, about 0 004'r(. about 0.003'%, about 0 (X)2%, about US 20]4/0275 [35 A1 Sep. 18, 2014 39

0.001i's. about 0.0009%. about 0.0008%. abour 0.0007%, about 0 35 g, about 04 g. about 0 45 g. about 0 5 g, about 0 55 about 0.0006%, about 0.0005%, about 0.0004/w about g, ubou10.6 g, about 0.65 g. about 0 7 g, abou10.75 g, about 0 0003 /w about 0 0002%. or about 0 0001% v /w. w/v, or v/v. 0.8 g, Bbou(0.85 g, abou(0.9 g, abou(0.95 g, about I g, about [0450] In some embodiments. thc concmtlralion of onc or I 5 8, abnut 2 g, about 2 5 g. about 3 8, about 3.5 8, about 1 8„ more of the compounds as provided herein is in the range about 4 5 8, about 5 8, about 5.5 g, about 6 g, about 6.5 8„ fmm approximately 0 0001'i to approximately 50%, about 7 g, about 7.5 g, about 8 g. about 8.5 g, about 9 g. about approximately 0.001'is to approximately 40%, approxi- 9.5, or about 10 mately 0.01% to approximately 30%. appniximarely 0.02% [0454] In some embodiments, the amount ofone or more of to approximately 29%, approximately 0.03% lo approxi- thc compounds as provided herein Is in lhc range of about malclv 28'!w approxunalcly 0.04% lo approximately 27%, 0.0001 to about 10 g. about 0.0005 to about 9 g, about 0.001 approximately 0.05'!o lo appmxunalcly 26%, Upproxunalcly to about 8g, about0005toabout 7g,about 0 0) to about 68„ 006'%o approximately 25%. approxiniatelv 0.07% to about 0.05 tn about 5 8, about 0.1 to about 4 g. about 0 5 to apprnximately 24%, appmxiniately 0 08% tn approximately about 4 g. or about I to about 3 g. 23;8, approximately 0 09% to approximately 22'is. approximately 0.1 "is to appmximately 21'!w approximately 0.2% to 6 I I. Fnrmulations for Oral Administration 20'!o, Ui approximately approximately 0.3% Upproxunalcly [0455] In some cmbodimcnts, provided hcrcin arc phannd- 19%, 0.4% lo approxi- approximately approximately 18%, CCtuiC&d ConlpoSIIIOUS f&ir Oral BdriliiliS(IBlioii coillBiiliilg d malclv 0.5% to approximately 17%, approximately 0.6% to cnmpnund as prnvided herein, and a plmrmaceutical excipi- apprnximately 16%, approximately 0.7% to approximately ent suitable for oral administration ln some enibodiments, 15%, appmximately 0 8% to approximately 14%, approxi- provided herein are phamtaceutical compositions for oral mately 0.9% to or 1% to approximately 12%, approximately administration containing: (i) an effective amount of a dis- v v/v. approximately 10% w/w, /v, or closed compouml, oplioimlly (ii) an cffeclivc mnount of onc [0451] In some embodiments. the concentmtion of one or or morc second agents: and (Iii) onc or morc phamtacculical morc of Ihe compounds as provided herein is ut lhc range cxcipicnts suitable for oral administration. In some embodi- from approxnnately 0.001% to approxunatcly 10'!o, approxi- ment~, the pharmaceutical composition further contains (iv) mately 0 01% tn approximately 5%. apprnxiniately 04)2% to an effective amount of a third agent. apprnximately4 5'%. approxmiately 0 03'!! to approximately [0456] In some cmbodimcnts, lhc phannaccuucal compo- 45 . Bppl'oximatsly' 04% trl Bpprnxiulalclv 3 5%, Bppi'oxi- siuon can bc a liquid phamtaceu1 ical composition suitable lor mately 0.05% to approximately 3%. approximately 0.06% to orul consumption. Phamtaceulical compos&nona suitable lor 2 5'is, 0.07% to approximately approximately approximately oral adnnnistration canbepresentedas discretedosage fornis, 28/w approximately 0.08% to Bpproximaicly I.S%, approxi- such as capsules, cachets. or tablets. or liquids nr aerosol malclv 0.09!o to approximately 1%, or approxtmalelv 0.1% sprays each containing a predetermined amount of an active tn appmximately 0.&)% w/w. w/v, or v/v ingredient as a powder or in granules. a solution, or a suspen- [0452[ Insomeembodiments,theamountnfnnenrnxireof Sioii Ill Bn BquCOUS Or Iloit-BqUCOUS liquid. Bn Oil-In-wau:I the compounds as provided herein is equal to or less than emulsion. or a water-ut-oil liquid emulsion. Such dosa c akiut 10, about 9 5 g, about 9.0 g, about 8.5, shorn 8 0 g, forms can bc prep ared by mty ofthc methods ofpharmacy, but 5 5 akiut 7.5 g, about 7.0 g, about 6.5 g, about 6.0, about g, all nlethods include the step of bung& ng the active ingredient akiut 5.0 g, about 4.5 g, about 4.0 g, about 3.5, about 3 0 g, into assnciation ivith the carrier. which constitutes nne or abou(2.5 g. about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 more ingredients. In general. the phamtaceutical composi- g. about 0.9 g, abou(0.8S g, abou(0.8 g, about 0.75, about tions are prepared by uniformly Bnd intimately admixing the 0 7 g. about 0 65 g. about 0.6 g, about 0 55 g, abnut 0 5 g, dctlvc Iilgi&xhcnl w lib liqUid cBIrlcrs or Iiiicl)'hvidixl solid about 0 45 g, about 0 4 g. about 0 35 g. abnut 0 3 a. about 0 25 carncrs or both, and then, if ncccssary, shaping thc product g. about 0.2, about 0.15 g, about 0.1 g. about 0.09 g. about Iillo lhc desired pioscnlalioit. For cxBnlplc, a tablet can bc 0.08 g, about 0 07 g, about 0.06 g, about 0.05 . about 0 04 g, prepared by cnmpression or molding. optionally with nne or akiut 0.03 g, about 0 02 g, about 0.01 g, about 0.009 g, about more accessory ingredients. ('ompressed tablets can be pre- 0.008 g, about 0.007, about 0.006 g, about 0.005 g. about pared by compressing in a suitable machine the active ingre- 0.004 g, about 0.003, about 0.002 g, about 0.001 g. about dient in a free-Oowin form such as powder or granules. 0 0009 8,. about 0 0008 g. about 0 0007 o, about 0 (X)06 g, opuonally mixed with mt cxcipicnt such as, bul not bruit cx) ui. about 0.0005 g, about 0 0004 8, about 0 0003 8, about 0.0002 a b utdcr. B lubricant. Bn inca diluent, and/or a surface acuvc or g. or akiut 0.0001 g. dispersing agent. Molded tablets cmt be made by molding in [04531 In some embodiments, the amount ofone or more of a suitable machine a mixnire of the powdered compound the compounds as provided herein is more than abour 0.0001 moistened with an inert liquid diluent g. about 0.0002 g, about 0.0003 g, about 0.0004 g, about [0457] The present disclosure liirthcr cncompasscs Iudty- 0.0005 g. about 0.0006 g. about 0.0007, about 0.0008 g, drous phannacculical compositions mid dosage I'orms com- abou(0.0009 g, about 0.001 g, about 0.0015 g. Shout 0.002 g, pnsing Bn Bclwc utgredicnl, sutcc water can lacililalc Ihc about 0.0025 g, about 0 003 8, abnut 0.0035 g. about 0 (X)4 g, degradatmn nf some compounds )&or example, water can be about 0.0045 g, about 0 005 8, ah nut 0.0055 g. about 0 (X)6 g, added (e.g, about 591 ) in the pharmaceutical arts as a nieans akiut 0.0065 g, about 0.007 g, about 0.0075, about 0.008 g, of simulating long-tenn storage in order to determine char- akiut 0.0085 g. about 0.009 g. about 0.0095 g. about 0.01 g, acteristics such as shelf-life or the stability of formulations abou(0 015 g, about 0 02 g. about 0 025 g, about 0 03 g, about Over lilac. Arlltydi Oii s phBItuaCO& lliCBI coinpo S1110IIS drid do S- 0.035 g, about 0.04 g, abou(0 045 g, abou(0 OS g, abou(0 055 agc fonna can bc prcparcd using anhydrous or low moisture g. about 0.06 g, about 0 06S g, about 0.07 g, Shout 0.075 g, containutg utgrcdicnls Bnd low moisture or low humidity about 0.08 g. about 0 (y85 g. about 0 09 o. about 0 0')5 g. about conditions i&or example, pharmaceutical compositions and 0 I g. about 0 15 g. about 0.2 g, about 0 25 g, abnut 0 3 g, dosage forms which cn n tain lactose can be nmde anhydrous if US 20]4/0275 [35 A1 Sep. 18, 2014 40

substantial contact iiith moisture and/or humidity durin potassium. sodium starch glycolate, potato or tapioca starch. UIBUUfacIUllng. packagulg, anipol stoldgc ls expected. Au other starches, prc-gelatinized starch. other starches, clays. anhydrous phannaccuucal composiuon can be prepared and other alguls. other celluloscs, gums or mixtures thereof. stored such tlmt its anhydrous nature is Inaintained Accord- [0462] Lubncants which cml bc used to form phannaccu- ingly, anhydrous phaunaceutical compositions can be pack- tical composiuons and dosage lonns ulcludc, but arc not s ed using materials known to prevent exposure to water such hmited I o. calcium s icerato, magnesnun s tea rate, mulcra1 oil. that they can be included in suitable formulary kits. Examples light nunemll oil, glycerin, sorbitol. mannitol, polyethylene of suitable packaging Include. but are not limited to. hemleti- glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, cally sealed I'oils, plastic or thc hkc, umt dose contdulcls, hydro enated ve etable oil fe.g., peanut oil. cottonseed oil. bhster packs. and stop packs sunflov er oiL sesame oil, olive oil. corn oil, and soybean oil). [0458] An acuvc Ingrcdicnt can bc combutcxi m an mtimatc zulc stcaratc, ethyl olcatc, cthylaurcatc. agar, or mixlures admixture with a pharmaceutical carrier according to conven- thereof. Addutolml lubncmus include, for cxiunplc, a syloid tional pharmaceutical compounding techniques. 'I he carrier sihca gcl. a coagulated aerosol ofsynthetic sihcd, or mixtures can take a wide variety of fomls depending on the form of thereof. A lubricant can optionally be added, m an amount of preparation desired for administration. In preparin the phar- less than about I weiPI percent of the pharnlaceutical coni- ulaccUIlcdl coulposluons lor Bn olal dosage folnl, Bu)'l thc positiou. usual pharmaccuucdl media can bc employed us carriers, [04651 When aqueous suspensions and/or elixirs are such as, Ibr example, water, glycols, oils, ulcohols. Ilavorulg desired tbr oral administration, the active ingredient therein agents, preservatives, coloring agents. and the like in the case can be combined lvith various sweetenin or flavoring agents. of oral liquid preparations [such as suspensions, solutions, colorm matter or dyes and, for example. emulsifying and/or and elixirs) or aerosols: or carriers such as starches, suglrs, suspending agents, togcthcr with such dilumus as water, etha- micro-crystalline cellulose. diluents. @anointing agents, nol, propylene glycol, glyccun and various combinalions lubricmlts, binders, and disuucgratulg agents can bc uscxf In thcrcoi. the case of oral sohd prcparauons, ul some mnbodimcnts [0464] The tablets can bc uncoated or coated by lolown without muploying the use of lactose. For cx unplc. suitublc tccluliqucs to delay disinte ration and absorption in Ihc gas- carriers include polvders, capsules. and tablets, with the solid trointestinal tract and thereby provide a sustained action over oral preparations In some embodiment ~ . tablets can be a lmlger period. I'or example. a time delay material such as coated by standard aqueous or nonaqueous teclmiques. glyceryl monostearate or glyceryl distearate can be [0459] Binders suitable for use in phamlaceutical compo- employed. Formulations for oral use can also be presented as sitions and dosage forms Include. but are not limited to, corn hard elatin capsules lvherein the active Ingredient is mixed starch. potato starch, or other starches, gclatm, natural and with mi inert sohd diluent, for cxmnplc, calcium carbonate. sv'uthctlc gUnls such Bs acacl'd, sodlUUI Bl UIBIC, alguuc Beld, calcium phosphate or kaolin. or as soft gclaun capsules other alginates, polvdered trlgacanth, guar gum, cellulose wherein the active in redient is mixed with water or an oil and its derivatives (e g, ethyl cellulose, cellulose acetate, medium, for example, peanut oil, hquid paraffin or olive oil carboxymethyl cellulose calcium. sodiuni carboxymethyl [0465] Surfacuult whwh can bc used Io form pharmaceuti- cellulose), polyvinyl pyrrolidone, methyl cellulose. pre-geLS- cal compositions and dosage forms include, but are not lini- tinized starch. hydroxypropyl methyl cellulose. microcrystnl- ited to, hydmphilic surfactants. Iipophilic surfactants, and huc ccllUlosc, Bnd nuxtUrcs lhcrcofi mixtures thereof. That is, a mixture ofhydrophilic surfactants [0460] Exmuplcs of suitable Iillcrs liir usc m thc phamui- can be employed. a mixture of lipophilic surfactants can be ceutical composiuons and dosage forms pmvldcd hcrmn employed, or a mixture ofat least one hydrophilic surfactant include. but are not limited to. talc, calcium carbonate fe g., and at least onc hpophihc surfacmult can bc cmploycd. grainiles or powder), microcrystalline cellulose, powdered [0466] A suitable hydrophilic surfactant can generally have cellulose. dextrates, kaolin. mannitol. silicic acid. sorbitol, an HLB value of at least abolut 10. while suitable lipoplfilic starch, pre-gelatinized starch. and mixtures thereof. surfactants can gcncrally lmi c an HLB value of or less Ihdn [0461] Disinte rants can be used in the phanuaceutical about 10. An empirical pariunctcr used Io chamclcnzc Ihc composiuons as provulcd hcrcul to provide Iablcts thai dis- relative hydrophilicity and hydrophobicity of non-ionic intcgratc when cxposcxf to an aqueous mlvirolunmlt. Too amphiphilic compounds is the hydrophihc-lipophihc balance much of a disintegrant cml produce tablets wluch can disul- 1" HLB*'alue). Surfactants lv ith lower HLB values are more tey ate in the bottle. Too little can be insufficient filr disinte- lipophilic or hydrophobic, and have greater solubihty in oils. gration to occur and can thus alter the mate and extent of v bile surfactants with higher HLB values are more hydro- release ofthe active ingredient(s) from the doss e form. Thus, pluhc, aml have greater solubility in aqueous soluuons. a sufficient amount ofdisintegrant that is neither too little nor Hydrophilic surfactants arc gmlcrally considcrcd to bc those too much Io dctrnucntally alter the rclcasc of Ihc acuvc ul rc- compounds having an I II,I3 value greater than about 10. as dientfs) can bc used Io fonu Ihc dosage lorms of thc com- well as anionic, cationic. or zwltteuonlc compounds fbr pounds prox idcd hcrcin. Thc amount ol'disintcgrunt used can v hich the HLB scale is not generally applicable. Similarly. vary based upon the type of formulation and mode ofadmin- lipophihc fi.e.. hydrophobic) surfactants are compounds hav- istration, and can be readily discernible to those of ordinary ing an HLB value equal to or less than about 10. However. skill in the art. About 0 5 to about 15 weicht percent of HLB value ol' surfactant is merely a rou Ji guide gcncmlly disintegrant, or about I to about 5 wei ht percent of disinte- used Io cnablc fiinmilatlon ol'uldustrial, phanuaccuucal and granu cml be used ul the phamlaccuucal composition. Disul- cosmetic emulsions tcgnmts that can bc used Io form pharmaccuucal mimposi- [0467] Hydmplulm surfmtants cmi be cithcr tome or non- tions mid dosage fonna ulcludc, but arc not hnuted 10, agar- Ionlc. Suitable ionic surfactants ulcludc, but arc not limitixl agar, alginic acid, calcium carbonate, niicrocrystalline to. alkylammonium salts: fusidic acid salts, fatty acid deriva- cellulose. croscarmellose sodium. cmspovidone, polacrilin tives of amino acids, oligopeptides, and polypeptides: glyc- US 20]4/0275 [35 A1 Sep. 18, 2014 41

eride derivatives ofamino acids, oligopeptides. and polypep- PECI-40 palm I ernel oil, PECi-50 hydro enated castor oil. tidcs, Icclthuts and hydrogcoa ted hx itluns, lysolccitlnns and PECI-40 castor oil, PEG-35 castor oil, PEG-60 castor oil. hydrogcuatcd lysolccithins, phospholipuls and denvauvcs PECI-40 hydrogcrmted castor oil, PECI-60 hydrogcnaicd cas- thereof: lysophosphohpids and derivatives therolf; carnitine tor ml, VI!G 60 corn oil, VI i(i 6 caprate/caprylate glycerides, fatty acid ester salts: salts of alkylsulfates; fatty acid salts, VI!G-3 caprate/caprylate glycerides. polyglyceryl-I 01aurate, sodium docusate; acylactylates: mono- and di-acetylated tar- PECI-30 cholesterol, PECI-25 phyto sterol, PECI-30 soya ste- taric acid eaters of mono- and di-glycerides: succinylated rol, PECI-20 trioleate, PECI-40 sorbitan oleate. PEG-80 sor- mono- and di- lycerides; citric acid eaters of mono- and bitan laurate. polysorbate 20, polysorbate 80. POE-9 lauryl ill-glvcclldcs; slid nllxturcs thcrcoi. cthcr, POE-23 Imiryl cthcr. POE-10 olcyl ether, POE-20 oleyl [0468] Within thc albrcmcnuoned roup, Ioiuc surfnctants cthcr, POE-20 stcaryl ether, tocophcryl PEG-100 succinaic. illcllulc. bv w Bv ol cxBnlpkx lect(hills, Ivsolcclthln, phiispho- VE(i-24 cholesterol, poly lyceryl-10 oleate, I'ween 40, lipids. Iysophospholipids and derivatives thereof: carnitine 'I'ween 60, sucrose monostearate. sucrose monolaurate, fatty acid ester salts: salts of alkylsulfates; fatty acid salts, sucrose monopalmitate, PECi 10-100 nonyl phenol series. sodium docusate; acylactylates: mono- and di-acetylated tar- PECI 15-100 octyl phenol series, and poloxamers. taric acid eaters of mono- and di-glycerides: succinylated [0472] Suitable lipopluhc surfactants ulcludc, by way of mono- and di-glyccndcs, citric acid caters ol mono- and example only: Ib t ty alcohols; glycerol Ih uy acid eaters, accty- ill-glvcclldcs; slid nllxturcs thcrcoi. lated glycerol fatty acid eaters, lower alcohol fatty acids [0469] Ionic surlbctants cmi bc ihe ionized fonna of leci- eaters; propylene glycol fatty acid eaters, sorbitan fatty acid thin, lysolecithin, phosphatidylcholine, phosphatidylethano- eaters: polyethylene lycol sorbitan fatty acid eaters; sterols lamine, phosphatidylglycerol. phosphatidic acid, phospllat- and sterol derivatives; polyoxyethylated sterols and sterol dylserine. lysophosphatidvlchohne, dcnvativcs, polyethylene glycol alkyl cthcrs, sugar caters. lysophosphatidylethanolamine. Iysophosphatidylglycerol, sugar cthers: lactic acid dcnvatives of mono- aud di-glyccr- lysophosphatidic acid, lysophosphatidylserine. PECrxphos- ulcs, hydrophobic umlscstcrilication products of a polyol phatidylctlmnokunulc, PI/P-phosphattdylctlmnolammc, lac- with at least one member ofglycerides. vegetable oils. hydm- tyhc caters ol letty acids. stcaroyl-2-lactylatc. stmroyl lucty- genated vegetable oils, fatty acids and sterols; oil-soluble late, succinylated monoglycerides, mono/diacetylated vitamins/vitamin derivatives; and mixtures thereof. Within tartaric acid eaters of mono/diglycerides, citric acid eaters of this mup. non-limiting examples of lipophilic surfactants monoidiglycendes, cholylsarcosine, caproate. caprylate, ulcludc glycerol fatty;mid cstars, propylene glycol letty acid caprate, laurate. myristate, palmitate, oleate, ricinoleate, caters, mid mixtures thereof, or arc hydrophobic transcstcri- linoleate, linolenate. steamte, lauryl sulfate. teracecyl sulfate, Iication products of a polyol with at least oue member of docusatc. Iauroyl canuunes, palnutoyl carmuncs. mynstoyl vegetable oils, hydmgenated vegetable oils. and triglycer- carmtincs. and salts and mixtures thcrcoli ides [04'70] Hydroptuhc nou-Ionic surfactunts can ulcludc. but [0473] In one embodiment, the pharmaceutical composi- are not limited to. alh3 lglucosides: alhwlmaltosides: alkwltb- tion can include a solubilizcr to ensure good solubihzation ioglucosides: lauryl macrogolglycerides: polyoxyalk3lene and/or dissolution of a compound as provided hcrcui mid to allwl ethers such as polyethylene glycol ailyl ethers; poly- nuninuze precipitation of the compound. 'I'his can be espe- oxyalkylene allylphenols such as polyethylene glycol allyl cially important for plmrmaceutical compositions for non- phenols; polyoxyalkylene alkyl phenol fatty acid eaters such oml use. e.g.. pharmaceutical compositions for injection. /0 as polycthylcnc glycol fatty acids monocstcrs und polycthyl- solubilizer can also be added to mcrease the solubility ofthe cne glycol fatty seals theaters, polyclhylcnc glycol glycerol hydrophilic dmg and/or other component~, such as surfac- fatty acid eaters: polyglycerol fatty acid eaters; polyoxyalkT- tants. or to maintain tlm pluinnaccuticsl composition as a lene sorbitan fatty acid eaters such as polyethylene glycol stublc or homogcncous solution or dispersion. sorbitan fatty acid eaters; hydrophilic trmisesteriTication [11474] I ixamples of suitable solubilizers include, but are products of a polyol with at least one member of lycerides, not limited to, the follolvin: alcohols and polyols. such as vegetable oils, hydrogenated vegetable oils, fatty acids. and ethanol. isopropanol, butanol, benzyl alcohol, ethylene gly- stcrols, polyoxycthylmle stcrols, dcnvauvcs,;uid;uialogucs col, pmpylcnc glycol, butancdiols and isomers Ihcrcof, lyc- thereof. polyoxycthylated vitamins and dcnvauves thereof, crol, pcntacrythritol, sorbitol, mtulnitol, transcutol, duncthyl polyoxyethylene-polyoxypropylene block copolymers; and isosorbule, polycthylcnc glycol, polypropylcnc glycol, poly- mixtures thereof: polyethylene glycol sorbitan fatty acid vinylalcohoi. hydroxypropyl methylcellulose and other cel- eaters and hydrophilic tmnsesterification products of a palyol lulose derivatives. cyclodextrins and cyclodextrin deriva- with at least one member oftriglycerides. vegetable oils. and tives: ethers of polyethylene glycols having an avemge hydrogenated vegetable oils. The polyol can be glycerol, molecular weight ofabout 200 to about (i000, such as tetrahy- cthylcne glycol, polycthylcne glycol, sorbitol. propylene ly- drofurfuryl alcohol PEG ether [glycofurol] or methoxy PEG. col, pentaerythritol, or a sacchandc. anudcs and other iutrogcn-containin compounds such as [04'71] Other hydroplulic-non-ionic surlactants nmludc, 2-pyrrolidone, 2-pipcridonc. B-caprolactam, N-alkylpyrroli- without limitation, VI I(1-10 laurate, Vl:(1-12 laurate, Vl!G-20 done, N-hydroxyalkylpymllidone, N-alkylpiperidone, lmirate, VIICI-32 launlte. Vli(1-32 dilaurate, VEI(i-12 oleate, N-llkylcapmlactam, diiuethylacetamide and polyvinylpyr- PEG-15 oleate, PECI-20 oleate. PECI-20 dioleate. PECi-32 rolidone; eaters such as ethyl propionate, tributylcitrate. oleate, PECI-200 oleate, PECI-400 oleate, PEG-15 steamte, acetyl triethylcitrate. acetyl tributyl citrate, triethylcitrate. PEG-32 distc irutc, PECI-40 stcaratc, PEG-100 a(curate, PEG- ethyl olcatc. ethyl caprylatc. ethyl butyratc, triaccun. pmpy- 20 dilmiratc. PECI-25 glyceryl triolcatc, PEG-32 duilcatc, lcnc glycol monoacctatc. propylcnc glycol diacctatc, E-ca- PEG-20 glyceryl lauratc. PEG-30 glyceryl lauratc, PEG-20 prolaclonc tllul Isonlcls lhclixif, o-vBlcrolBctoiu: Bnd Isonlcrs glyceryl stearate. VIIG-20 glyceryl oleate, Vli(1-30 glyceryl thereof, [I-butyrolactone and isomers thereof, and other solu- oleate. Vl:(I-30 glyceryl laurate, VE(i-40 glyceryl laurate, bilizers knov;n in the art. such as dimethyl acetamide. dini- US 20]4/0275 [35 A1 Sep. 18, 2014 42

ethyl isosorbide, N-methyl pyrroiidones, monooctanoin, but are not limited to, vitamin A, vitamin C, vitamin E, beta- diethylcnc glycxil monoethyl ether, and water. carotcnc, citric acid, acetic acid. dchydroaccbc acid, ascorbic [04'75] Mixtures of solubihzcl scan Blso bc Used. Exiinlplcs acid. sorbic acid, and phyuc acid. Other prcscrvauves include. bul nol lunilcd lo, Uaaccbn, lricthylcilralc, ethyl olc- include, but are not limited to, tocopherol. tocopherol acetate, ate. ethyl caprylate, diniethylacetainide. N-methylpyrroh- deteroxime mesylate, cetrimide, butylated hydroxyanisol done. N-hydroxyethylpyrrohdone, polyvinylpyrrolidone, (BHA). butylated hydroxytoluened (BHT), ethylenediamine. hydroxypropyl methylcellulose. hydroxypnipyl cyclodex- sodium lauryl sulfate (SLS), sodium lauryl ether sulfate trins. ethanol, polyethylene glycol 200-100. glycoflirol, tran- (SLES). sodium bisulhte, sodium metablsulfite. potassium sculol. propylene glycol, and dimethyl isosorbidc. In some sulfitc, poiassium metabisulliic, Glydmit Plus, Phcnonip. cmbodimcnts, solubihzcrs uicludc sorbitol, glycerol. triucc- mcthylparabcn, Gcrmafl 115. Gcrmabmi 11, Neolonc, tui, ethyl alcohol, PEG-400, glycofurol aml propylcnc glywil. Kathon, and iiuxyl In certain embodiments, the preservative [0476] 'I he amount ofsolubilizer that can be included is not is an anti-oxidant In other embodiments. the preservative is a particularly limited 'I he amount of a given solubilizer can be chciatul'gent. limited to a bioacceptable aniount, which can be readily [0479] Exemplary oils include, but arc not hmitcd io. determined by one of slofl in the art. In some circumstances, almond, apncol kcmcl. avocado, babassu, bergamot, black it can be advantageous to include amounts of solubilizers far current scixk borage. cade, camonulc, canola, caraway, cdr- in cxccss OI'bioacccptablc iunounts, for cxiunplc to maximize nmiba, castor, cinnamon, cocoa butter, coconut. cod liver, the conccntmtton oi'hc drug, wifli cxccss solubihzcr coffee, corn, cotton seed. emu, eucal)Titus, evening prinirose, removed prior to providing the pharniaceutical composition fish, flaxseed. gemsniol, gourd, grape seed. hazel nut. hyssop. to a subject using conventional techniques, such as distillation isopropyl myristate, jojoba, kulou nut, lavandin, lavender. or evaporation 'I hus. if present. the solubilizer can be m a lemon, litsca cubcba, macixlcmia nul, mallow, mango seed. weight ratio of about 10Yo. 25%, 50%. 100!w or up to about mcadowgiam seed, mink, nuuncg, olive, ormigc. oran c 20@% by weiptt. based on the combined weiptt of the dnig, roughy, palm, palm kcmcl, peach kernel, peanut, poppy seed. and other cxcipicnts. II dcsirixl, very smafl;unounls of sulu- punipkin seed, rapeseed, rice bran, rosemary. safllow:er, san- bilizcr cmi also bc used, such as about 5 io, 2%, 1% or cvcn dalv ood, sasquana, savoury, sea buckxhorn, sesame, shee less I)qucally, the solubilizer can be present in an aniount of butter. silicone. soybean, sunflower. tea tree, thistle, tsubaki. about 1% to about 100%. niore typically about 5% to about vetiver. walnut. and wheat germ oils. Exemplary oils also 25% by weight uicludc. but are mit hnulcd io, butyl stearaic, capryhc tn lyc- [0477] The pharmaceutical composition cmi further cndc, capric lriglyccndc, cyclomcthiconc, diethyl sebacdlc. include one or more phannaceutically acceptable additives dimctlnconc 560, isopropyl myristale, mineral oil, ociyldodc- and excipients. Such additives and excipients include. with- canol, oleyl alcohol. silicone oil. and combinations thereof out limilanon. dclackilicrs, anb-foaming agents, buffi:ruig [0480] In addition, an acid or a base can be incorporated agents, polymers. anlioxidmils, prcservatives, chelating into the pharmaceutical composition to facilitate processin . agents, vlscomodUlatorw toluciflet'1, fl;lvoi nits, colol'Bnls, to cnhancc stability, or for other reasons. Exiunplcs of phar- oils, odorants, opacifiers. suspending agents, binders, tiflers, nuiccUUcdllv'cceplBblc bBscs uu:litle Bnuno Bcalw Bnuno plasticizers, lubricants. and mixtures thereof. acid eaters, ammonium hydroxide. potassium hydroxide, [0478] ExempLary preservatlves can include antioxidants, sodium hydroxide. sodium hydmgen carbonate. alumimmi chelatin agents. antimicrobial preservatives. Bntihuigsl pre- hydroxide. calcium carbonate, magnesium hydmxide. ma- scrvatives, alcohol prcscrvativcs, acidic prcscrvativcs. Bnd ncslUnl BIUnllnUnl sillcaitc, svnthcllc 'IIUnlhlUnl silicate. By'n- other prcservatives. Exmnplary antioxidmils include. but arc thetlc hydrocalcite. magnesium aluminum hydroxide, diiso- not lunited to, alpha tocopherol. ascorbic ucid, Bcorbyl palnu- propylcthylaminc, clhmiolamine, cthylcncxitanunc. tate, butylated hydroXyanisOI, butylated hydroxytoluene, tnclhanolaminc, inelhylamine, tnisopropanolmninc, tnm- monothioglycerol. potassium nietabisulflte, pnipionic acid, ethylamine, tris(hydroxyiuethyl)-aminomethane f!'ITIS) and propyl gallate, sodium ascorbate, sodium bisulfite. sodium the like. Also suitable are bases that are salts of a pharmaceu- metabisultite. and sodium sulhte. Exemplary chelating agents tically acceptable acid, such as acetic acid, acrylic acid. adipic include cthylcncdiaminclclcdaccbc acid (EDTA), citnc ucid acid. alginic acid. alkanesulfonic acid, amino acids, ascorbic monohydralc. disodium ixlclalc, diponissnun cdcfalc. cdcbc acid. benzoic acid. boric acid. butyric acid, carbonic acid. acid. flunanc acid, malic acid, phosphoric ucid, sodium cdc- citnc acid, fatty acids, fonmc acid, I'umawc acid, glucoiuc tate, tartaric acid, and trisodiuni edetate I:xemplary antimi- dctiL hvdroquhlosiilfontc acul. lsodscol'blc Seal, lactic dctd, crobial preservatives include, but are not limited to. benza- nmleic acid, oxalic acid. para-bromophenylsulfonic acid, Ikonium chloride. benzethonium chloride. benzyl alcohol, pmpiomc acid, p-toluenesnlfiooic acid. salicylic acid, stearic bronopol, cetrimide, cetylpyridiniiun chloride. Cltiorhext- acid, succinic acid, tannic acid, tartaric acid, thioglycolic dinc. chlorobutanol, chlorocrcsol, cldoroxylcnol, crcsol, acid. toluenesulfonic acid, uric acid, and the lil e. Salts of ethyl alcohol. glyccnn, hexcbduic, umdurca, phenol, phc- polyprotic acids. such as sodiiun phosphate, disodium hydro- noxyclhanol. phcnylcthyl alcohol, phenylmcrcunc mlratc, gen phosphate. Bnd sodium ddiydrogcn phosphate can also bc the is a pmpylmie glycol. and thinierosal I ixemplary antifungal pre- used. %lien base salt, thc canon can be any convenient servatives include. but are not liniited to, butyl parabini, and pharmaceutically acceptable cation. such as ainmonium, methyl paraben, ethyl paraben, propyl paraben. benzoic acid, alkali metals, alkaline earth metals, and the hke I ixaniples hydroxybenzoic acid, potassium benzoate. potassium sor- can include, but not limited to, sodium. potassiuni, lithium, batc. sodium bcnzoatc, sodium propionaic. and sorbic acid. magnesituu. calcium and ammonium. Exemplary alcohol prescrvauvcs include, but arc not Innitcd [0481] Suitable seals arc phannaccutically acccptablc to. clhmiol. polycthylmie glycol, phenol, phmiohc com- orgaruc or inorganic acids. Examples of suitable inorgamc pounds, bisphenol, chlorobutanol. hydroxybenzoate. and acids include hydrochloric acid. hydrobroniic acid, hydriodic phenylethyl alcohol Iixemplary acidic preservatives include, acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, US 20]4/0275]35 A1 Sep. 18, 2014 43

and the like. Examples ofsuitable organic acids include acetic able compositions can contain from about 0.1 to about 5% acid. acrylm ucid, adipic acid, alginic acid. Blkancsulfoiuc w/w of d colllpoUild iis disclosed llcrciil. acids. mnino acids, ascorbic acid, bmizuic acul, boric acid, butyric acid. carbonic acid, citric acid, fatty acids, forniic 6.1.3. Formulations for Topical Administration acid. fiuuaric acid. gluconic acid. hydroquinosulfonic acid, [0488] In some embodiments, provided herein are phamia- isoascorbic acid. lactic acid. maleic acid. methanesulfonic ccutical composilions for topical (c.g., tnutsdcrmal) Bdmin- acid, oxalic acid, para-bromophenylsulfonic acid. propionic IS]rd]toit Coiluiillillg B Colllpolilld as providcxl IICICIII. dlld d suc- acid, p-toluenesulfonic acid. salicylic acid. stearic acid, pliarmaceuticai excipient suitable for topical administnstion cuuc acid, tannic acid, tartaric acid, Iluoglycolic acid. lulu- In some embodiments, provided herein are pharmaceutical cnesulfonic acid, uuc acid and thc like. compositions t'or topical aihninistration containing: (i) an effective amount of a disclosed compound, optionally (ii) an 6.1.2. Formulations for Parenteral Administration effective amount of one or more second agents; and (iii) one [0482] In some embodiments,providedhereinarephamia- ormorcpharmaceu]ical cxcipicnts suitublc for topicaladmin- ceulical composiuons for parcnlcral adnunislraIion conlaui- istration. In some cmbodunmits, thc pharmaceuucal compo- ing a compound as provides] hcreui, Bnd a pluinnaccutical sition further contains (iv) an effective amount of a third excipient suitable for parenteral adniinistration ln some 'lgCflt. embodiments, provided herein are pharinaceutical coniposi- [0489] Pharmaceutical compositions pmvided herein can fornnilated semi-solid. tions for parenteral administmstion containing: (i) an effective be into preparations in solid, or liquid t'or amount of a disclosed compound: optionally (ii) an effective forms suitable local or topical administmstion. such as amount of one or more second agents: and (iii) one or more gcls, wa]cr soluble ]allies, creams, lotions, suspensions. phannaccuticul cxcipicnts suitable liir parcntcral adimnistra- foums, powders. slurncs. oinuncnts, solutions, oils, pastes. tion. In some embodnucuts. Ihc pharmaceuImal compusition suppositories, sprays. ennilsions. saline solutions, dimethyl- further contains (iv) an effective aniount of a third agent. sulfoxide (])MSO)-based solutions In general, carriers ivith higher densities are capable of providing an area with a pro- [0483J 'I he forms in wluch the disclosed pharmaceutical longed exposure to the active ingredients In contrast, a solu- compositions can be incorporated foradniinistration by mjection formulation can provide more itmnediate exposure ofthe tion include aqueous or oil suspensions. or emulsions, with dctivc iilgicdicilt 10 tile clloscll Brea. sesame oil, corn oil. cottonseed oil, or peanut oil, as weil as [I]490J 1 he pharmaceutical compositions also can coni- clixirs, mmuiitol, dextrose, or a stcnlc uquwius solution, and similar pharmaceutical vcluclcs. prise suitable solid or gel phase carriers or excipients. which are compounds that allow increased penetration of, or assist [0484] AqliCOIIS 50]UIioils ill SdlillC BIC also COIIVClltioiidlly in the deli~cry of, therapeutic molecules across the stratum used for injection ]:thanol, glycerol, liquid propylene glycol. corncum pcnncabihty bamcr of thc sion. There are many of polyethylene and the like (and suitable mixtures glycol, these pcnclralion-enhancing molcmilcs known lo Ihosc thereot). cyclodextrin derivatives, and vegetable oils can also trained m the art of topical formulation Iixamples of such be employed. carriers and excipients include. but are not limited to, humec- [0485] AqliCOIIS 50]UIioils ill SdlillC BIC also COIIVClltioiidlly tants (e.g., urea), glycols (e.g., propylene lycol), alcohols used for in] ixuon Etlrdnol, glycerol, propylene glycol. liquid (e ., ethanol). fatty acids (e, oleic acid). surfactants (e... polyethylene glycol, and the like (and suitable mixtures isopropyl myristate and sodium lauryl sulfate). pyrrolidones. thereot). cyclodextrin derivatives, and vegetable oils can also glycclol iiioiioiBUidtc. sU]foxidcs. Icrpciics (c g., Illcii]1101). be employed The proper fluidity can be maintained, for anuncs, amidcs, alkancs. alkanols. water. calcium carbonate. example, by the use of a coating. such as lecithin, for the calcium phosphate. various sugaux starche~. cellulose deriva- mamtmiance of thc required particle size in Ihc case ol'dis- tives, gelatin, and polymers such as polyethylene glycols pcrsioii and by the use of surfactants. The prcvcnuon of thc [0491] Another exemplary formulation for use in the dis- action of microorganisms can be brough] abou] by various closed methods employs transdcnnal delivery devices antibacterial and antifungal agents. for example, parabens, ('*patches**). Such umisdcnnal pa]ches can bc used to provide chlorobutanol, phenol, sorbic acid, thimemsal. and the like continuous or discontinuous infiision of a compound as pro- [0486] Sterile injectable solutions are prepared by incorpo- vided herein in cmitrolled amounts, either with or ivithout ratmg a compound as provided hcrcui ui thc required amount another agent. in Ihc appropnutc solvent with various other m rcdmn]s as [0492] The construction and use oftransdcunal patches lor above, as followed filtered ster- enuinerated appropriate, by thc delivery ol'pharmaceutical agni ts Is w all known in Ihc alt. ilization. (ienemlly, dispersions are prepared by incorporat- See, e.g., U 8 Pat. Nos 5,023,252, 4.992,445 and 5,001,139 ing the various sterilized active ingredient ~ into a stenle fuel] patches can be constructed for coiitinuous. pulsatile. or vehicle xi hich contains the basic dispersion medium and the on demand delivery of pharmaceutical agents. appropriate other ingredients from those enumerated above. [0493] Suitable dcviccs for use ui dclivcung intradermal In Ihc case of s]crilc powders liir Ihe prep;ud]ion of sIculc phumiaccutically acccptablc compositious dcscrtbcx] hcrcin in]cxuiblc soluuons, ccrtaui methods ol prcparauon arc include short needle devices such as those described in U 8 vacuum-drying and freeze-drying techniques v hich yield u Pat Nos. 4,NN6 499 5 190 521 5 32N 483 5 527 288:4 270 powder ofthe active ingredient plus any additional ingredient 537, 5,015.235; 5,141.496: and 3.417,662. Intradermal com- fmm a previously stenle-filtered solution thereof. positions can be administered by devices which limit the [0487] The in]ixtablc lbmiulations can bc stcnhzed. Ihr cffcctivc penetration length of a nccdlc into thc skin, such as cxmuplc, by filtrution tluough B bacterial-rc]aming lilter, or those dcscnbcd in Pe'T publication WO 99/34850 Bnd fimc- by incorporating s ten 1 izuig Bgcnm ui Ihc liinn of s ten le solid tional cquivalen]s thereof. Jc] mjection devices which deliver compositions which can be dissolved or dispersed in stenle liquid vaccines to the dermis via a liquid ]et in]actor and/or via water or other sterile injectable mediuni prior to use. Inject- a needle v'hich pierces the stratum corneum and pmduces a US 20]4/0275 [35 A1 Sep. 18, 2014 44

jet wluch reaches the dermis are suitable. Jet injection dev tees ders The pharmaceutical composition can contain an etfec- are dcscnbcd. I'or cxtunplc, ut U.S. Pat. Nos. 5,480.381, ttvc tunount of a compound as prov(d(xl hcrcut ands phannd- 5.599,302: 5.334,144, 5,993.412, 5,649,912: 5,569).189 ccut(cal cxciptcnt su(table for ocular admintstrauon. 5 704 911 5 383 851 5 893 397 5.466.220: 5 339 163 Pharmaceutical compositions suitable for ocular administra- 5.312,335: 5.503.627: 5,064,413; 5.520.639: 4 596.556, tion can be presented as discrete dosage forms, such as dmps 4.790,824: 4.941.880: 4,940,460: and PCT publications WO or sprays each containing a predetermined amount of an 97/37705 and WO 97/13537. Ballistic powder/particle dehv- acttve ingredient a solution. or a suspension in an aqueous or tionallery devices which use compressed gas to Bcceiemte vaccine non-aqueous liquid, an oil-in-water emulsion, or a water-inin powder fomt tluough thc outcr layers oi'hc sian to thc otl hqutd cnnds(on. Other adnuntstration forms include dorm(s arc su(table. Alternatively or addtttotudly, conven- Intraocular inlcct(on. intrav((real Injection, topicallv, or syringes can be used in the classical ntantoux method of through the use Of a dntg elut(ng device, microcapsule, intradermal administrat(on in(plant, or microduidic device. In some cases, the con(- [0494] Topically-mhninwuablc formula(tons csut, Ior pounds as provided herein are administered with a carrier or example, comprise from about 1% to about 10'%w/(v) of a exciptent that increases the intraocular penetrance of the compound provided herein relative to the total weight of the compound such as an oil and water emulsion wtth colloid formulation, although the concentration of the compound purttclcs lraving mt o(ly core surrounded by mt uttcrfac(al provided herein in the formulation can be as hi h as the Iilm. It Is contcmplauxl that all local routes to thc cyc 0 m bc solubility limit of the compound in the solvent. ht sotne used hlchldhtg top(cal. SubcouIUuctlval. perlocUIBf. Iet('obul- cmbodimcnts, top(cally-admimstrablc formulations can. Ibr bar, subtenon, intracameral. intrav(treal, intraocular, subreti- cxmnplc, txtmpnsc from about 1% to about 9% (v,/w) Of a nal,juxtascleral and suprachoroidal adm(nistration Systemic compound prov(ded herem, such as fmm about 1% to about or parenteral administration can be feasible including, but not 8% ((v(w ), further such as fm(n about 1% to about 7% (w/w), limtted to intravenous, subcutaneous, and oml delivery. An further such as from about 1% to about 6% (w/w), further cxcmplary method of admuustration wdl bc Intrav(trcal or such as from about 1% to about 5% (w/w), further such as subtcnon injection oi soluttons or suspensions, or uttravitreal from about I'!6 to about 4% (w/w), further such as from about or subtenon placement of bioerodible or non-bioerodible 1%a to about 3%B (U/w ), and gtrthcr such as Ibom about 1% (0 dev(ces, or by topical Ocular administmtion of solutions 0('uspensmns, about 2% (w/w) of a compound provided herein. Fonmda- or posterior juxtascleral administration of a gel tions for topical administration can further comprise one or or cream fornutlation. more of the additional pharruaceutically acceptable exmp(- [0498] Eye drops can be prepared by dissolving the active ents described heretn. ingredient in a sterile aqueous solutton such as physiological salute, buifcring solut(on. etc.. or by combuung powder com- 6.1.4. Formulations for Inhalation Administration post(iona to be dtssolvcd before usc. Other vcluclcs can bc chosen, as is known in the art, including, but not limited to [0495] In some embodiments.provtdcdhcrcut are phamu(- balance salt solution, saline solut(on. water soluble ceut(cal compos(nona for uthalauon adnunistration contaut- poly- ethers such as polyethyene glycol. polyvinyls. Such as poly- ing a compound as provided herein. and a pharmaceutical vinyl alcohol and povidone. cellulose derivatives such as excipient su(table for topical administration. In some embod(- ments, provided herein are pharmaceutical compositions for methylcellulose and hydroxypropyl methylcellulose, petro- leum dcrivativcs such as mineral od and white pc(rois(urn. inhalation administration containing: (i) an effective amount dnnnal fdts such Bs ldltohn, poly'Bless of Beryl(0 acid sUch Bs of a disclosed compound, optionally (ii) an effective amount carboxypolymethylene gel, ve etable fats such as peanut oil of onc or more s(mond agents, and (iti) onc or morc phamu(- and polysaccharides such as dextrans, and ceut(cal cxc(ptcnts su(table Ior uthalatton adnumstration. In glycosaruinogly- cans such as sodium some entbodiments, some embodiments. the phar(naceutical con(position htrther hyalumnate In additives ordinarily used in the eye drops can be added. Such contains (iv) an effective antount of a third agent. additives include isotonizing agents (e.g, sodium cldoride. [0496J Pharmaceut(cal con(positions for inhalation or ctc ). buffbr agent (e.g.. boric acid, sod(um monohydrogcn solutions in insuftiation include and suspensions phamtaceu- phosphate. sodium dthydrogcn phosphate, etc.), prcscrvd- tically acceptable. aqueous or organic solvents. or mixtures ttvcs (C.g.. bcnzalkonium cldoridc. bcnzcthonium chlondc, thereof, and powders The liquid or sohd plu(nnaccutical chlorobutanol, etc ), thickeners (e saccharide such as lac- compos(uons can mtntatn su(table phdmtaccuttcally accept- g, tose, mannitol, maltose, etcd e g.. hyaluronic ac(d or its salt able cxcip(cuts as dcscribcd herein. In some embodunmtts, such as sodium hyaluronate. potassium hyaluronate. etcd the pharmaceutical are administered the oml con(positions by e ., Untcopolysaccharide such as chondroittn sulfate, etcd or nasal respiratory route for local or systemic effect Phar- c g., sodium polyacrylatc. cdrboxyvinyl polymer, crosslink(xl sol- maceutical compositions in phannaceutically acceptable polyacrylatc. polyvutyl alcohol, polywnyl pyrrolidonc. vents can be nebulized use of inert gases. Nebulized solu- by methyl ccllulosc, hydroxy propyl mcthylccllulosc, hydroxy- ttons can bc u&a Icd dtrcc(1y from thc nebulizing dcv Ice or thc ethyl cellulose, carboxy methyl cellulose, hydroxy propyl cel- ncbuhz(ng devtcc can bc auachcd to a face mask tcnu or lulose or other agents kno(vn to those skilled in the art) intcrm(ttcnt postttvc prcssure brea(lung maclunc. Solution, suspension. or powder pharmaceutical con(positions can be [11499J In some cases, the colloid parucles mclude at least administered. e g, orally or nasally, from devices that deliver one cattonic agent and at least one non-ionic su fee tant such as the formuLation in an appropriate manner. a poloxamer. tyloxapol, a polysorbate. a polyoxyethylene castor o(I dcrivs ( tvc, a sorb( tan ester. or a po1yoxy1 a(cerate. In 6.1.5 Formulattons litr Ocular A(hnimstrauon Boule crises, thc ca(toute agent ls Bn alkvlanunc, d Icrtldry alkyl aminc, a quartcrnary Iumnonium compound, a cauomc [0497J In some embodiments. the disclosure provides a lipid, an amino alcohol, a biguanidine salt. a cationic con(- pharmaceutical composit(on for treating, ophthahnic d(sor- pound or a mixture thereof In some cases, the cationic agent US 20]4/0275]35 A1 Sep. 18, 2014 45

is a biguanidine salt such as chlorhexidine. polyaminopropyl [0502] All controlled release plnnnaceutical products have biguaniduic, phcnformin, Blkylbiguamdnic. or a mixture a comnion goal ofimpmvin dnig, therapy over that achieved thC&COf. Cd Sos. Ill sortie tile 9&1 B)C&llarv Bllllllolilillll Colllpoullil by their non controlled counterparts. In some embodiments. is a benzalkonium halide. Iauralkoniuin halide, cetrinude, thc usc ol a controlled rclcasc preparation ui mixhcal treat- hexadecyltrimethylanimonium halide, tetradecyltrimethy- ment is characterized by a minimum ofdrug substance bein lanunonium halide. dodecyltrnnethylammonium halide. cet- 1 lllp1ov &xi to cure OI colitiol &lie ill Bed so, illso&0& r, or co lid& tin&i rimonium halide, benzethonium halide. behenalkonium in a minimum amount of time Advantages of controlled halide, cetalkonium hahde, cetethyldimonium hahde, rclcasc formulations uicludc cxtcndcd Bcuvity of thc dnig. halulc, halide, cldorallyl cetylpyndinium benzododecuuum reduced dosage frequency. and increased subject conipliance methenamine halide, mynstylalkonium halide, stcaralko- In add&non. controlled rclense fomiulations can bc us&BI to niuin halide or a mixture of two or more thereof ln some atfect the time ofonset 0 faction or other characteristics. such cases. cationic agent is a benzalkoniuni chloride, lauralko- levels tlnis nium chloride, benzododecinium bromide. benzethenium as blood of the drug. andean affect the occurrence cldoride, hexadecyltrimethylammonium bromide. tetrade- of side (e.g, adverse) effects. cyltrimethylanunonium bromide. dodecyltrimethylanuno- [t)5()3J In smne embodimen&1, controlled release formula- nium bronudc or a mixture of two or morc thcreol: In some tions are designed to initially release an amount of a com- cases. thc 0&1 phase is mineral oil and hght muicml oil, pound as provided herein tint promptly produces the desired medium chain triglycerides (M("I ), cocomit oih hydroge- therapeutic effect, and gradually and continually release other nated oil& comprising hydrogenated cottonseed oil. hydroge- amounts ofthc compound to maintain this Icvcl ol'thcrapeuuc nated palm oil, hydrogenate castor oil or hydnigenated soy- or prophylactic clli:ct over an extended pcnod ol tune. In bean oi h po lyoxy ethylene hydrogenated castor oil derivatives order to maintain this constant level of the compound in the comprising poluoxyl-40 hydrogenated castor oiL polyoxyl- body, the compound should be released from the dosage forni 60 hydrogniated castor oil or polyoxyl-100 hydrogenutcd at a rate that Vvill repLace the amount of drug being metabo- castor 011. lized and excreted fmm the body. Controlled release of an active agent can be stimulated by various conditions includ- 6.1.6. Fonnulauons Ibr Controlled Release uig, but not limited to. pFL tempcraturc, enzymes, water, or Adniinistration other physiological conditions or compounds [0500] In some embodiments,providedhereinarephamia- [t)5()4J In certain embodiments. the pharmaceutical con&- ceutical wimpositions for &Bin&rolled rclcasc B&hnunstrution position can be administered using intravenous uifusion. an Colltallllllg a Colllpo illld B S pl Ovid& il lli i C ill, slid a plulilllBCC&l- implantable osmotic pump, a transdermal patch. Iiposomes. tical cxcipinit suitable for controlled rcleasc adnunistration. orother modes ofadministration. Inoneembodiment, a pump In some embodiments, provided herein are pharmaceutical can bc us&xi (scan Scfton. CRC Crit. Re/Riomed. Eag. 14.201 compositions fiir controlled release adniinistration contain- (1987): 13001&wald et al., Svrgen 88.507 (1980), Saudck et in: (i) an effective amount ofa disclosed compound; option- al., M Ettg/. J. Mad. 321.574 (1989)) In another cmbodimenn ally (i i) an effective amount ofone or more second agents, and polymeric materials can be used In yet another embodiment, (ni) onc or morc phannaccutical cxcipicnts suitable for con- a controlled release system can be placed in a subject at an trolled release adminntration. In some cmbodunnits, thc appropnate site determined by a practitioner of skill, i.e., thus phannaccutical composition liirthcr coniaun. (iv) an cffcc- requinn only a fraction ofthe systemic dose (see, e g., Ciood- tive amount of a third agent son, it/ed/cd/ Applications 0/ Controlled Re/Crise. 115-138 [0501] Acuvc agents such as thc compounds provided (vol 2. 1984). Other controlled rclcasc systcnn are discuss&BI hcrcui c;m be a dnunntered by controlled rclca ac mesin or by ui thc rcv&csv by Lunger. Science 249 1527-1533 (1990). Thc delivery devices that are well known to those ofordinary skill one or more active a ents can be dispersed in a solid inner in the art lixamples include, but are not liniited to, those nntrix, e g., polymethylmethacrylate, polybutylinethacry- described in U.S. Pat. Nos 3,845.770; 3,91ti,899; 3,536,809, Late, plasticized or unplasticized polyvinylchloride. plasti- 3.598,123: and 4,008,719; 5.674.533: 5,059.595 5.591,767, cized nylon, plasticized polyethyleneterephthalate, natural 5.120,548: 5.073,543, 5,639.476, 5,354,5561 5,639).480 rubber, polyisoprcnc. polyisobutylcnc, polybutadienc, poly- 5.733,566: 5.739,108, 5,891.474, 5,9223561 5,972.891, cthylcnc, cthylenc-vmylacetate copolymcrs, ~ ihconc rub- 5.980,9451 5.993,855, 6,045.830, 6,087324: 6,113.943, bers. polydimcthylsiloxanes, ail&wine carbonate copolymcrs. 6.197,350: 6.248.363: 6,264,970; 6.267.981: 6O76.461, hydrophilic polymers such as hydrogels of eaters of acrylic 6419961: 6589548; 6613358; 6699500 each ofwhich is and methacrylic acid. collagen. cross-linked polyvinylalco- incorporated herein by reference. Such dosage fonna can be hol and cross-linked partially hydrolyzed polyvinyl acetate. used to pmvide slow or controlled release of one or more that is surrounded by an outer polymeric membrane, e... active agents using, for example, hydropropylmcthyl cellu- polvctll)'leiic, polv'propv'lclic, ctliv'lcllc/propvh:iic copolv- lose, other polymer matrices. gcls, pcmicablc membranes, mcrs, ethylene/ethyl acrylate copolymcrs, ethylene/vutylac- osmotic systems, multilayer coatings. microparticlcs. Iipo- ctatc copolymers, silicone rubbers, polydimethyl siloxancs. somes, microspheres, ore combination thereofto provide the neoprene nibber, chlorinated polyethylene, polyvinylchlo- desired release profile in varying proportions Suitable con- ride, vinylchloride copolymers with vinyl acetate, vinylidene trolled release formulations known to those of ordinary slull cldonde, ethylene and propylene. ionomer polyethylene in the ath including those described herein. can be readily terephthalate. butyl rubber epichlorohydrin nibbers, ethyl- sclcctcd I'or usc with the active agcnn provided herein. Tlnis, ene/vinyl alcohol copolymer, ethylene/vuiyl acetate/vuiyl the pharmaceutical compositions provided encompass single alcohol tcrpolymcr, and ethylene/vuiyloxyethanol copoly- unit dosage forms suitable Ihr oral admim strauon such as, but mer, that is insoluble ui body Iluids Thc onc or morc active not limited to, tablet&. capsules, gelcaps. and caplets that are agents then diffuse througit the outer polymeric niembrane in adapted for controlled release a release rate controlling step. '11)e percentage Of active agent US 20]4/0275 [35 A1 Sep. 18, 2014 46 in such parenteral compositions is hilly dependent on the include a "drug holiday.*'.g.. the dni can be administered spccilic nature Ihcrcol, as well as Ihc needs ol Ihc sub)cct. for two wccks on. Onc wcck olk or &luce weeks on, one week olT, or four weeks on. Onc wack olT, ctc, or m&nunuously, (02. Dosages without a dnig holiday 'I'he compounds can be adniinistered orally, intravenously. intraperitoneally, topically, transder- [0505] A compound descnbed barmn can be dehvcrcd in separa- mally. intramuscularly. subcutaneously, intmlnasally, sublin- the form Ofpharmaceutically acceptable compositions which gually. or by any other route. comprise a thenlpeutically effective amount of one or niore compounds descnbed herein and/or one or more additiotial [0509] In some embodimmi&s. a compound as provxhxl therapeutic agents such as a chemotherapeutic. fonuulated hcrmn is adnunis&ared ui multiple doses. Dosing can bc abou& togcthcr with onc or morc pharmaccutmdlly acccptublc once, hvice, three times, t'our ti&nes. five times, six times, or cxcipicnts. In some &ns&anccs, Ihc compound dcsci&bell hcrmn more than six times per day. Dosing can be about once a month, about once every tv'o &i eeks, about once a week, or and Ihc addi& tonal therapeutic a gcn& arc ddnumsIcred u& tete pharmaceutical compositions and can (e 8,. because of about once every other day. In another embodiment, a com- different physical and/or chen&ical characteristics) be admin- pound Bs provided hcrcui and another agcn& are txhnuustcrixl istered by difTerent routes (e.g., one therapeutic is adminis- togcthcr from abou&once pcr day to about 6 &uncs per day. In tered orally, wlule the other is administered intravenously) In another cmbodimcn&. thc adnunistrauon of a compound as other instances, thc compound described hcrmn and Ihc addi- pmvided herein and an agent continues for less than about 7 tional Ihcrapcu&ic agent can be admin&ster&BI scp&arafciy. but days. In yet another e&ubodiment. the administration continues for more than about Ii about 10 about 14 1 ia Ihc same ro u& c (c g., bo&h orally or both uil rave&a&u sly). In days, days. days. still other instances. the con£ described herein and the about 28 days. about two months, about six months, or alxlut additional therapeutic agent can be adininistered in the same Onc vedi; Ill so&lie cases. coil&i&lao&is dosiilg is acliicvcd diid phanuaceutical composition. 1111&i&&tait&Cd iis 10&lg Bs i&CCCSSarv. [0506] The sclcctcd dosage lcvcl will depend upon a vancty [0510J Administration Of the pharmaceutical con&positions of lac tora includin, for example, Ihc dcl&vity ol the p nt&euler as pmvided herein can continue as long as necessary. In some compound employed, the route of administnltion, the time of embodiments. an agent as provided herein is administered for administration, the rate of excretion or inetabolism of the more than about I, about 2. about 3, about 4. about 5, about 6. particular compound being employed, the rate and extent of about 7. abou& 14, about 21. or about 28 days. In some absorption, the duration of the treatment, other dnigs. com- cmboduncnts, an agent as providixl hcrmn is admi&us&cred lor pounds and/or ma&cnals used in m&mbuiation with Ihc par- less than about 28, about 21. about 14. about 7, about 6, about ticular compound employed, Ihc agc, sex, v cighl, mmdition, 5, about 4, about 3, about 2. or about I day. In some embodi- general health mid poor medical lustory of the pat&cut being ments. an agent as provided herein is administered for alxlut treated, and hke factors well known in the medical arts 1. about 2. about 3. about 4. about 5. about 6, about 7, about [0507] In general. a suitable daily dose of a compound 14. about 21. or about 28 days. In some embodiments. an dcscnbcd hcrcui and/or a chemothcrdpcutic w&11 be Ilmt agmi& as provided hcrcin is aihninis&ared chronically on dn amount of Ihc m&mpound whiclb ui some cmbodimcnts, can ongoing basis, e.g., for Ihc treauncn& ol cluonic clfccts. be Ihc lowest dose cffi:c&ivc to produce a Ihcrapculic cffccl. [0511J Since the co&upounds described herein can be Such an effective dose will generally depend upon the factors administered in combination with other treatments (such as described above (ienerally. doses of the compounds additional chemotherapeutics. radiation or surgery), the described herein for 0 patient, v hen used for the indicated doses of each agent or therapy can bc lower than thc corre- ef'acts, will range from about 0.0001 mg to about 100 m per sponding dose for single-agent therapy 11&e dose for suiglc- day, or abou& 0 001 mg to abou& 100 mg pcr day, or about 0 01 agmi& therapy can range from, I'or example. Bbou& 0.0001 Io mg Io about 100 m pcr day, orabou&0.1 mg to about 100 mg about 200 mg, or about 0.001 to about 100 mg. Or about 0.01 pcr day, or about 0.0001 mg Io abou&500 mg per day, or about to about 1(X) mg, or about 0.1 to about 100 mg, or about I to 0 001 mg to about 500 mg per day, or about 0 01 mg to 10(X) about SO mg per kilogram of body ii eight per day. mg, or about 0 01 mg to about 500 nig per day, or alxlut 0.1 mg [0512] %1&cn a compound prox idcd hcrmn, m txhnuustcrixl to about 500 or about I to 50 day. or mg per day, mg nig per ln 11 phaillldCCOI&CBI Coil&posit&011 Iha& 0011&pi&SCS 01&C 01 ino&C abolut 5 mg to 40 m . An exemplary dosage is about 10 to 30 agents, and the agent has a shorter half-life than the con&- mg pcr day. In some cmbodimcnts, for B 70 kg human. a pound provided herein unit dose forms of the agent and the suitable dose would bc abou& 0.05 to about 7 g/ibiy. such as compound provided herein can be adjusted accordingly. abou& 0.05 to about 2.5 g/day. Actual dosage levels Of Ihc active in the plmrmaceutical ingredients compositions 6 3 Kits described herein can be varied so as to obtain an amount ofthe active ingredient which is elTective to aclfieve the desired [0513] In some emboduncn&s. provnlcd herc&n are kits. Thc therapeutic response for a particular patient. composition, ki&s can include a compound or phannaccuticdl composinon and mode of adnunmtrauon, withoui bcuig toxic to thc as dcscribixl herein, ui suitable packaguig. and wnt&cn mate- pelican In some ins&anccs. dosage levels below Ihc lower rial that can include i nitnictions filr use. discussion ofclinical lunit of tlm aforcsanl range can bc more llrdn adcxtuafc. while studies, listing of side effectm and the like. Such kits can also in 0&her cases still larger doses can be empklved v ithout include information, such as scientilic literature references. causing any harmful side effect, e 8, by dividing such larger pacl i e insert materials, clinical trial results, and/or summa- doses into several small doses lilr aihninistmltion throughout ncs Of Ihcsc and thc like, whwh ind&cd&c or cs&abl&sh Ihc the day. activ&ties mid/or advan&ages ol'Ihc phannaccutical composi- [0508] In some cmbodimcn&s, the con£s can bc tion, and/Or which dcscnbc dosing, Bdnuiustranon, side administered daily, every other day, three tin&ca a week. twice efi'ects, dnig interactions, or other infilrmation useful to the a week, weekly. or bi-weekly 'I'he dosing schedule can health care provider. Such infilrmation can be based on the US 20]4/0275 [35 A1 Sep. 18, 2014 47

results of various studies. for example, studies usin experi- cottonseed oil. peanut oil, sesame oil, ethyl oleate, isopropyl mental anuns Is uiv o1v ing in vsvo models and st u dws bnsad on mynstatc, and bcnzyi beni nate. liuiiiall ClllllCJI Iildls. [0518J I he present disclosure further encompasses anhy- [0514] In some embodnucnts. a memory aid is provided drous pharmaceutical compositions and dosage forms com- with the kit. e.g., in the form of numbers next to the tablets or prising an active ingredient. since isater can facilitate the capsules v hereby the numbers correspond with the days of degradation of some compounds For example, v ater can be the regimen which the tablets or capsules so specified should added (c g.. about 5 /o) ui thc phannaccuuca1 arts as a means be ingested. Another example of such a memory aid is a of simulating long-Icmi storage in order lo dclcrnnnc char- calendar pruitcd on the card, c.g., as follows *'First Wcck, acteristics such as shelt(life or the stability of formulations Monday. Tuesday, ctc.... Sixond Week, Monday, Tues- over tinie Anhydrous pharmaceutical compositions and dos- day,... ctc." Other varia (tons ofmemory axis will bc reudily age fonna can be prepared using anhydrous or low moisture apparent. A "daily dose" can be a single tablet or capsule or containing ingredients and low moisture or low humidity several tablets or capsules to be taken on a given day conditions. For example, phamiaceutical compositions and [0515J 'I he kit can further contain another agent. In some dosage forms wluch contain lactose cau bc made anhydrous if embodiments, the compound as provided herein and the agent substimtial contact vnth moisture and/or Ininndity dunng are provided as separate pharmaceutical compositions in nmnufacturing, packaging, and/or storage is expected An scytaratc containers within the kit. In some mnbodunmits, thc anhydrous pharmaceutical composition can be prepared and coillpoulld ils pl'ovidcd llcrcill SIld Ilic d cllt die plovldcd iis iI stored such that its anhydrous nature is maintained. Accord- single pharmaceutical composition within a container in the ingly. anhydrous phamiaceutical compositions can be pack- kit Suitable packaging and additional articles for use (e g., aged using materials known to prevent exposure to water such measuring cup for liquid preparations, foil wrapping to nuni- that Ilmy ca+bc inc lu desi in suitable I'onnulary kits Examples mi ze exposure to air. and the hke) are known in the art and can ofsuitable peel aging include, but arc uot 1inutcd Io, hcrmcti- be included in the kit. In other embodiments. kits can further cally sealed foils, plastic or the like, unit dose containers, comprise devices that arc used to tulnuni ster Ihc active agmit s. hister packs, and strip packs. Exmnples of such devices uicludc, but arc not lumtcd Io, I'I( syrin es. dnp bags. patches, and inhalers Kits descnbed 7. 11IIIRAPIIU Mli II IODS herein can be pmvided, marketed and/or proinoted to health [0519] Phosphomositidc3-kinascs(PI3Ks)arcmembcrsof pmviders, including physicians, nurses, pharmacists. formu- a couscrvcsf family of lipid kmascs that rcgulatc numerous lary ofhcials. and the like. Kits can also. in some embodi- cell functions. including prolifi:ration, diffcrmitmuon, cell ments, be marketed directly to the consumer. survival and metabolism. Several classes of PI3Ks exist in [0516] An example of such a kit is a so-called blister pack. nmnimalian cells, including Class IA subgroup (e g., PI3K-O, Blister packs arc well known ui thc packaging uidustry and [1. 6), wlfich are generally activated by receptor tyrosine are being widely used I'or thc packaguig ol'luinnaccutical kinases (RTKs): Class IB (e g., PI3 K-I ), which is activated by unit doss e forms (tablets, capsules. and the like). Blister G-pro(cut couplixl rcccyt tora (GPCRs), among others. PI3Ks packs generally consist of a sheet of relatively stiff niatenal cxcrt their biologicdl activiucs via a **P13Kmcdiatcd si nial- covered with a foil of a preferably transparent plastic mate- uig patli way" that includes sci eral components that directly rial. During the packaging proces~, recesses are fiirmed in the and/or indirectly transduce a signal tnggered by a PI3K, plastic foil. The recesses have the size and shape ofthe tablets including the generation of second messenger phophotidyli- or capsules Io bc packixh Next. Ihe tablets or capsules arc nositol, 3CL5-triphosphate (PIP3) at the plasma membrane. placed in Ihc rcccsscs and Ihc shcct ofrclativcly stiffmatens 1 activation of heterotrimeric Ci protein signahng, and genera- is sealed against the plastic foil at the face ofthe foil which is tion of further simond messengers such as cAMP, DAG, and opposite from the direction in which the recesses v ere IP3, all of wluch leads to an cxtmisive cascade ol'ro(cia formed. As a result. the tablets or capsules are sealed in the kinasc activation (rcvicwcd in Vanlmescbroixk, B. ct al. recesses betv een the plastic foil and the sheet. The stren th of (2001) ~nmi Rev Bioi hem 70 535-602) I'or example, the sheet is such that the tablets or capsules can be removed I'13K-6 is activated by cellular receptors through mteraction from the blister pack by manually applyuig pressure on thc between the PI3K regulatory subunit (p85) SH2 domains. or rcmcsscs whereby au opcnuig is lormcd ui Ihc shcct ut thc through direct interaction with RAS. PIP3 produced by PI3K place ofthe recess 'I he tablet or capsule can then be removed dctlviitcs clfcctoi patiiway's ilowiislri alii Illrougll llltciacllo11 via said opening with plcxtnn homology (PH) domaui contauiing enzymes [0517J Kits can further comprise pharmaceutically accept- (c g., PDK-I and AKT [PKB]). (Fuug-Lcuug W P. (2011) able vehicles that can be used to administer one or more active (:el/5/gaul. 23(4):603/0) Unlike PI3K-ik PI3K-7 is not asso- a ents. For example. if an active agent is provided in a solid ciated with a regulatory subunit ofthe pg5 family, but rather form that must bc rcconstitu I cd liir parcn1 era 1 adnuni sIra I ion, v ith a re ulatory subunit in the pl 01 family. PI3K-y is asso- the lot can comprise a scaled container of a suitable vcluclc in ciated v ith CrPCRs. and is responsible for the very rapid w luch the active agent cmi bc dissolved Io form a particulutc- uiduction of PIP3. PI3K-y cmi bc also acuvatcd by RAS. free sterile solution that is suitable tiir parenteral administra- [0520J In some embodiments, provided herein are inethods tion lixamples of plmrmaceutically acceptable vehicles ofnmdulating a PI3K kinase activity (e 5, selectively modu- include, but are not limited to: Water for hi]ection USP, Lsting) by contacting the kinase with an effective amount of a aqueous vehicles such as, but not limited to. Sodium Chloride compound. or a pharmaceutic ally acceptable form (e g., phar- Infection, Ringer's Iutccuou. Dextrose Intccuon, Dextrose maccutically acccyitablc salts, hydra(ca, solve(ca, isomers. and Sodium Chlondc lot ix tron. Snd Laciatcd Ruiger's Infec- prodrugs, mtd isoiopmdlly labclcd dcrii Jtives) Ihcrcof; or tion. w a Icr miscible vcluc les such as, bu1 not limited Io. ethyl phumiaccu (ical compositions as provided herein. Modulation alcohol. polyethylene glycol. and polypropylene glycol, and can be inhibition (eg . reduction) or activation (e g, enhance- non-aqutxsus vehicles such as, but not liniited to, corn oil, ment) of kinase activity In some embodiments, provided US 20]4/0275]35 A] Sep. 18, 2014 48

herein are methods ofinhibiting kinase activity by contactin genetic models. PIJK-&5 is an in&po&tant mediator of B-cell the kmasc w&th an cffi:ct&ue amount of a compound as pro- rcccy&tor (BCR) srgnalu&g, m&d &s ups&rema ofAKT, calcium

& &dcd hcrcin u& solution. In some embod&ments. provided flux, PLCy, MAP kiimsc. P70S6k, and FOXO3a act&vauon. herein are methods of inhibiting the kinase activity by con- V 13 K-&5 &s also important in I I 4R, S I V, and ('X('R5 signaling„ tacting a cell, t&ssue. organ that express the kinase of interest and has been shou n to modulate responses to toll-like recep- with a compound pmvided herein. In some embodiments, tors 4 and 9 Inhibitors of PIJK-8 have shov n the importance provided herein are methods ofinhibitin I inase acrivity in a of PLSK-8 in B-cell development (Marginal zone and Bl subject by administenng into the subject an effective amount cells), B-cell activation. chemotaxis, m&gration and homing ofa compound as provided hcrcu&. In some mnbodnncnts. thc to lympho&d t&ssuc. and in thc control of &nununoglobulin k&nasc acti& ity &s &nlub&tcd (c.g., rcduccd) by more tluu& about class switclung leading to thc producuon oflgE Clayton E et 25%, 30'%. 40%, 50%, 60%, 70%, 80%. or 90'%hen con- al. (2(X)2) J/ ipMed 196(6) 753-63:13ilancioA, et el (2006) tacted with a compound provided herein as compared to the 8/ood 107(2) 642-50; Okkenhaug K et al. (2(N)2) Br/ence kinase activity without such contact. In some embodiments, 297(5583):1031-4: Al-Alwan M M et al (2007) J Irrnnuno/. provided herein are methods of inhibiting PI3 kinnse activity 178(4):2328-35: Zlmng T T, et al (2008) J..i//ergv ('/m linnm- in a subject (including mammals such as humans) by contact- no/. 2008: 122(4j&811-819.e2; Srinivasan L, et al (2009) Cell ing sa&d subject with an amount of a compound as providrxi 139(3):S73-86) hcrcu& suflicmnt to &nlub&t or rcducc thc acnv&ty ol thc PI3 [t)525[ In 'I&cells, PI3K-b has been demonstrated to hme a kinase in said subject. role in 'I&cell receptor and cytokine signaling, and is upstrean& [0521[ In some embodiments, the kinase is a lipid kmase or of AKT. PLC/. and GSK3b. In PI3K-o deletion or kinase- a protein kinase In some embodiments, the kinase i ~ selected dead in&ock-in mice, or in inhibitor studies, T-cell defects from a P13 kinase including different isoforms such as PI3 u&eluding prohfcration. acti&ation, and d&ffi:rcnuation have kinase eb PI3 kinase [3. P13 kinase y, PI3 kinase 8; DNA-PK, brmn obscrvcd. Icadu&g to reduced T helper cell 2 (TH2) mTor, Abl. VEGFR, Ephrin receptor B4 (EVEB4). TEK rcsponsc. memory T-cell spccilic defi:cts (DTH rcduct&on). receptor tyrosinc ku&a ac (TIE2), FMS-related tyros&nc kuursc defects in antigen dependent cellular traflicking. and defects 3 (FLT-3), Platelet dcrivcd growth factor receptor (PDGFR), &I& chen&otaxis/n&ip'at&ol& to cheluoku&es (e.g. SIV. ( (IR7, RE'I', .Ai'MLAI'8: hgmg-I: I lck; Src; I ipidern&al growth fac- CD62L). (Gargon F. et al. (2008) B/ood 111(3):1464-71: tor receptor (I:(il'R); KI'I; Inulsin Receptor (IR): and l(iFI( Okkenlmu Ketal. (2006).,/bnmuno/. 177(8)5122-8; Soond [0522[ As used herem. a "VI3K-mediated disorder" refers D R, ct el. (2010) Blood 115 (11):2203-13, Re&l'. (2004). J. to a disease or condition involving aberrant PI3K-mediated 1&rnrnmo/. 2004, 173(4):2236-40: J& H. ct al. (2007) B/ood signalin pathway. In one embodiment, provided herein is a 110(8):2940-7, Webb L M, et al. (2005) J Immnno/. 175(5). method ol'treatu&g a P13K media&cd disorder m a subject, thc 27N3-7; l,iu Ij. et al (2010) .I /mr&rum&/ 184(6):3098-105; method compris&ng mhnu»stcnng a thcrapcut&cally cfli:ct&vc I laylock-Jacobs 8, et el. (2011)./driroimmnn 2011; 36(3-4) amount of a compound or a pharmaceutical compositiim as 278-87: Jarmin S J, et al. (2008) J C/in lrruesr 118(3): 1154- pmvided herem. In son&e embodiments. provided herein is a 64) method oftreatmg a VI3 K-&5 or Vl 3 K 7 mediated disorder &n a [0526] In neutrophils. PI3K-b along w&th PI3K-y, and subject, the method comprising administerin a thernpeut&- VI3KBL contribute to the responses to immune complexes, cally effective amount of a compound or a pharmaceutical I&('ygll signaling. including migration and neutrophil mspi- con&posit&on as p&'ovulcil hcrcu&. In son&c cn&bod»lu:nts. pro- ratory burst. Human neutroplflls under o rap&d induction of & &dcd herein is a method for u&lubiting at least onc of PI3K-6 PIP3 in response to fom&yl peptide receptor (FMLP) or and V13K-/. the method comprising contacting a cell express- complement component C5a (CJa) in a PI3K-y dependent ing VI3K in v&tro or in vive with an effective amount of the mtuu&cr, followed by a longer PIP3 producuon pcnod that &s compound or composition provided herein F13 Ks have been PIJK-t& dependent, m&d is essential I'or resp&ratory burst. Thc associated with a wide mange of condition~. includin inunu- response to immune complexes is contributed by VI3K-/&, nity, cancer and thin&nbosis (reviewed in Vanhaesebroeck, B. VI3K-y, and VI3KB L and is an important mediator of tissue ct al. (2010) Current Topics in AI/crobio/og& imd Immnno/- damage in nx&dels of autoimmune disease (Randis 'I' et al ogy, DOI 10 1007/82 2010 6S). For example. Class I (2008)Enr J. Inm&uno/. 38(5):1215-24; Pinho V, (2007) J P13Ks, particularly PI3K-y m&d PI3K-6 &soforms, arc lu hly Immm&o/. 179(11):7891-8; Sadhu C. et al. (2003) Jlrrnnuno/. expressed in leukocytes and have been associated with adap- 170(5):2647-54: Condliifc A M ct al. (2005) Blood 106(4). tiveandinnateimmun&ty;thus, these V13Ksarebelievedtobe 1432-40). It has been reported that u& certain autoinumu&c important mediators in &nflammatory disorders and hernato- diseases, perfrential activation of VI3K[3 may be involved lo ic mali'&uncles (rev&ewed &n Harris. S I et el. (2009) Carr (Kulkarni et al. /mm&rrrr&ir&gy& (2011) 4(168) ns23 l-i I) It 0/&/n Invert/g Drugs 10(11) 1151-62), Ronuncl C. ct al. was also reported that VI3K[3-deflcient mice were highly (2007) &Var Rev Immimo/ 7(3).191-201, Dur u&d C A ct al. protected in an Fc/R-dependent model of autoantibody-in- (2009) J Irmnnno/. 183(9) 5673-84. Dil N, Murshall A J. duced skin blistering and partially protected in an FcyR- (2009) r(fr&/. /mmnno/ 46(10) 1970-8: Al-Alwan M M et al dcpcndcnt model of inflmnmatory artlu&us, whereas com- (2007),//mnumo/ 17N(4):2328-35: Zhang,'I'1; et al (200N),/ b&ncd dclicicncy of PI3K[3 m&d P13Kb resulted u& near B//ergu C// n Iminuno/. 2008; 122(4):811-819.e2: Srinivasan complete protection in inflammarory sr&brit&s (Id ). L, et al. (2009) Ce// 139(3) 573-86). [0527] In macrophages collected from patients with [0523] Numerous publ&cat&ons support roles of PI3K-b, cluonic obstructive pulmonary ihsease (COPD), glucocorti- P13K-;. m&d P13K-[& u& thc d&ffcrcnriauon, maintcnancc, and coid responsiveness can bc restored by treatment of thc cells activauon of inm&une and malig&mnt cells, as doser&bui &n with inhib&tora ol'I3K-b. Macrophagcs also rely on P13K-6 more detail below and P13K- / R&r rcspunscs to immune complcxcs tluough thc [0524[ 'I he importance of VI3K-/& in the development and artln&s reaction (1&CgR and ('Sa signaling) (Randis 'I'. et al function of 13-cells is supported from inhibitor studies and (2008) /:'&rr,/ /mmano/. 38(5):1215-24: Ma&wick .I A et al US 20]4/0275 [35 A1 Sep. 18, 2014

(2009).4m JRespir Crit. Care led. 179(7):542-8; Konrad S, these diseases. A role for PI3K in lupus is also predicted by ct al. (2008) J Bio/. Chem. 283(48):33296-303). two genetic models oflupus. Thc dclction ol'phosphatasc and [0528] In mast cells, stem cell factor (S('F) and IL3-de- tcnsln homolog (PTEN) leads to a lupus-like phenotype, as pendent prolifi rauon, dilfcrcnua (ion and function;u c PI 3K-6 does a transgenic activation of ('ass IA VINKs. which dcpcndcnt, as is chmnotaxls. Thc aller ctVINE crosslulkulg of includes V 13K-iy. Ihe deletion of V13 K 7 m the transgenically FCgRI resulting ul cytoklnc release and dcgramilauon of thc activated class IA lupus model is protective, and treatment mast cells ls severely inhibited by treatment with 913K-iy v ith a PI3K-y selective inhibitor in the murine MLR/lpr inhibitor, suggesting a role for PINK-8 in allergic disease model oflupus improves symptoms (Barber, D F et al. (2006) (Ali K et al. (2004) iVuin re 431 (7 01 I ): 1007-11; Lee K S. et el. J /mmnaoi. 176(1): 589-93). (2006) FASEB J 20(3) '455-65: Kim M S. et al. (2008) Trends [0534] In allergic discase, PI3K-6 has bccn shown by Inrmnnol. 29(10).493-SOI). gcnctic models and by udubitor trcauncnt to bc csscnunl lor [0529] Natural killer (NK) cells are dependent on both nmst-ceil activation in a passive cutaneous anaphalaxis assay P13K-6 and PI3K-1 for efficient migration towards chemok- (Ah K et al. (2008),//mmnnrr/ I NO(4) 2538-44; Ali K. (2004) ines ulcluding CXCLIO, CCL3. SIP and CXCL12, or ul IVarnre 431(7011):1007-11). In a pulmonary measure of response to LPS ul thc pcritoncum (Guo H, ct al. (2008) 7Exp response to inunune complexes (Arthus reaction) a PI3K-6 Mad 205(10) 24193S, Tassi I. cl al. (2007)/iinmmiiy 27(2) knockout ls rcsistanu showing a defect ul macrophagc acti- 214-27: Saudemont A. (2(X)9) I'roc /Vail Ared,yci I (S'A 106 vation aml C5a production. Knockout studies and studies (14) 57')5-800; Kim N, et al. (2007) Bluer/110(9) 3202-8) with uilnbitors for both PI3K-6 and PI3K-, support n role lor [0530J 'I he mles of VI3K-ik VI3K-y. and VI3K-[I in the both of these enzymes in the ovalbumin induced allergic differentiation, maintenance, and activation of inunune cells airv ay inflammation and hyper-responsiveness nlodel (i,ee K support a role for these enzynles in inflammatory disorders S et al. (2006) FASEB J. 20(3):455-65). Reductions of infi- ranging from autoinunune diseases (e.g., rheumatoid arthri- ltratio of eosinopluls. neutroplfils, and lymphocytes as lvell tis, multiple sclemsis) to allergic inflanunatory disorders, as TH2 cytokulcs (IL4, IL5. and IL13) werc semi with boll such ns as(luna, mid inflanunatory rcsptmtory diseuse such as PI3K-6 spixific aml dual PI3K-6 and PI3K-, inhibitors in thc COPD. Extcnsivc evidmlcc is available ul cxpcrimcntal iuu- Ova ulduced astluua model (Lec K S ct el (2006) JAllergl mal models. or can be evaluated using art-recognized aninlal C/m immnnn/ 118(2):403-9) models. In an embodinlent, described herein is a metluld of [(1535J VI3K-iyandpi3K-sinhibitioncanbeusedintreating treatillg lnfl'lmluatory ifisol'riel's rallglllg frolu;urtoinlluulle ('OVD. In the smoked mouse model of ('OVD, the VIJK-6 diseases (e ., rheumatoid arthritis, multiple sclerosis) to knockout does not develop smoke induced glucocorticoid allergic inflammatory disorders. such as astluna nnd COPD resistance, ~bile lv i id-type and Pl 3K-1 knockout mice do. An using a compound dcscubcd hercul. ulhalcd formulation of dual PI3K-b and P13K-1 ullubitor [0531] For example. inhibitors of PI3K-6 and/or -/ have blocked inflanuuation in a LPS or smoke COPD models as been shown to have anti-inflammatory activity in several measured by neutmphilia and glucocorticoid resistance autounmunc mllmal models for rheumatoid artlmus (Will- (Doukas .I, et al (2009),/ I'hnrmucul /371 7 her. 328(3)'758- iams. O. ct al. (2010) Chem Biol. 17(2).i 23-34. WO 2009/ 65) ONN')86: W02(X)9/ONNNNO; WO 2011/(X)8302) V13K-6 ls [0536] Class I PI3Ks, particularly PI3K-o and PI3K-y iso- expressed in the RA synovial tissue (especially in the syn- forms, are also associated with cancers (reviev ed, e.g.. in ovial lining which contains fibroblast-lil e synoviocytes Vogt. P K et al. (2010) Curr Top Micmbiol Inununol. 347 79- (FLS), and selective P13K-o inlubitors have been shown to be 104, Fresno Vara, I A ct al. (2004) Cancer Treat Rail 30(2). effective in inhibiting synoviocyte grolvth and survival (Bar- 193-204, Zhao, L mid Vogt, P K. (2008) Oncogcnc 27(41). tok ct al. (2010) .Imhriiis Rheina 62 Suppl 10.362). Scvcral 54N6-96) Inhibitors of PINK. e.g, PINK-6 and/or -1, have P13K-8 and -y ulhibltors have been shown ul amclulratc been shown to have anti-cancer activity (e g.. ('Ourtney, K I) arthritic symptoms (e g, sw:elling of joint ~ . reductum of et al (2010) J Clia (/rico/. 28(6):1075-1083): Markman. B et serum-induced collagen levels, reduction ofjoint patlullogy al. (2010) Atut Oncol. 21(4):(i83-91: Kon . D and Yamori. T andior inflammation), in art-recognized inodels filr RA. such (2009) Curr Med. Chem. 16(22):2839-54; Jlmeno, A et al. as collagen-induced arthritis and adjuvant induced arthritis (2009) J Clul Oncol. 27.156s (suppl, abstr 3542). Flinn, I W (WO 2009/08898(b WO2009/088880; WO 2011/008302). ct al. (2009) J Clin Once/. 27:156s (suppl, abstr 3543). Sha- [05321 The role ofPI3K-o has also been shown inmodels of piro, (r et ai. (200')).I ('lin Oncol. 27 146s (supph abstr3500); T-cell dependent response. including the DTH model. In the Wagner, A .I et al (2001) ),/ C/i n Onr o/ 27:146 s (supph abstr murine experimental autoimmune encephalomyelitis (EAE) 3501):Vogt. PKetal. (2006)Virolo y 344(1):131-8:Ward, S model of muluplc sclerosi ~ . the P13K-y/6-double mutmlt et nl. (2003) (yhem. Bin!. 10(3);207-131 WO 2011/041399: mice are resistant. PI3K-6 inhibitors lieve also bccn shown to US 2010/0029693: US 2010/030509(a US 2010/0305084). block I IAI 1 disease induction and developnlent of'I'I 1-17 cells In an cmbodimcnt, descubcd herein ls a method of treating both in vitro and in viva (I iaylock-.iacobs, 8 et al. (2011),/ ciulccl; Anroimiannit& 36(3-4):278-87). [0537] Types ol'cancer 01st cmlbe treated with au ullubitor [0533J Systemic lupus erythematosus (Si,l 1) is a complex of VISK (particularly. F13 K-15 anChor -7) include. e.a . Ieuke- disease that at different stages requires menxlry T-cells, nuth chronic lymphocytic leukemia, acute myeloid leukenlia, B-cell polyclonal expansion and differentiation into plnstna cluonic myeloid leukemia (e.g.. Salmena. L et al. (2008) Cell cells, and the innate inumlne response to endo enous damage 133 403-414; Clmpuis. N et al. (2010) Clin Cancer Res. associated molecular pattern mohxules (DAMPS), and thc 16(22):S424-35: Khwqta. A (2010) Carr Top Microbiol intlammatory responses to inuuune complexes tluou h thc liininmol. 347:169-88), lymphoma. e.g., nou-Hodgkul* s lym- complcmcnt system ns well as the F&. rcccptors. Thc rulc of phoma (c g., Salmcn l. L ct al. (2008) Ce/I 133:403-414) I lung F13 K-6 and VI3K-y together in these pathways and cell types cancer, e g, nml-small cell lun cancer, small cell luna cancer su gest that blockade with an inhibitor w auld be effective in (e g., I lerreia, V A et al. (2011) Aniirmir er Rer. 31(3) 849- US 20]4/0275]35 A] Sep. 18, 2014 50

54); meLanoma (e.g.. Halusl a, F et al. (2007) Se iia Oucul. is the PI3K isoform tlmt is most commonly activated in 34(6):546-54); prostate cancer (c.g.. Sarkcr, D ct al. (2009) tumors whcrc the PTEN tumor suppressor is mutatixl (Ward C/i a Cancer Res. 15(15) 4799-805), glioblustoma (c g., S, ct al. (2003) Chem. Biol. 10(3) 207-13). Iu tlus subset of ('hen..l Set al. (2008) Mol ( sneer'I'her 7 N41-850): endome- tumors, treatment with the PI3 K-ij inhibitor either alone or in trial cancer (e.g . Ijansal. N et al (2009) Cancer ('ontrol colnbination with a cytotoxic a elit cali be effective 16(1):8-13), pancreatic cancer (e.g., Funikaws. T (2008) J [0542] Another mechanism for PI3K-6 inhibitors to have (Iusirue»ierul. 43(12) 905-11); renal cell carcinoma (e an uffcct in solid tiunors involves the tumor cells's(erection Porta. C and Figlin, R A (2009) J Urui, 182(6):2569-77), with tlmir micro-cnvironmcnt. PI3K-b, PI3K-y, and PI3K-[i col orectal cancer (c.g., Sa if, M W and Chu, E (2010) C carer arc cxprcsscd in thc uunmnc cells 1hat inliltratc tumors, J. 16(3).196-201), breast cancer (c, Torbeu, N E et al. including tunxir infiltrating, lymphocytes. macrophages. and (2008) Biuihem,/ 415 97-100); thyroid cancer (eg. 13rze- neutrophils PI3K-ij inhibitors can modify the function of zianska, I 1 and Vastuszak-l,ewandoska, D (2011) /trout Biu- these tumor-associated inunune cells and how they respond to sri. 16;422-39), and ovarian cancer (e.g., Mazzoletti. M and signals from the stronm, the tumor, and each other. and in this Broggini. M (2010) Carr hfed. Chem. 17(36):4433-47). way aflhct tumor cells and metastasis (Hoclleuucgcl, J, ct al. [0538] Numerous pubhcations supports role ofPI3K-band 52"s Aiuiual ASH Meeting and Exposiuon, 2010 Dcc. 4-7. P13K-; ui trcaun hmnatological cancers. PI3K-6 and PI3K-7 Orlando, Fla.). are lnghly exprcsscd in thc hcmc cumparunmit, and some [0543] PI3K-6 is also expressed in endothelial cells. It has solnl tumors, including prostate, breast and glioblas1omas been shov:n that tumors in mice treated with P13 K-6 selective (( hen.l S.et el (200N) Misl('uucer 7her 7(4)'N41-50; lkedu inhibitors are killed more readily by radiation therapy. In tlus I l. et al. (2010) Bluud 116(9):1460/8) same study. capillary ac(work fomiatiou is impaired by thc [0539J In hematological cancers including acute niyeloid P13K inlnbitor, and itis postulated that this defi:ct contnbutes leukemia(AML).multiplemyeloma(MM),nndcluonic lym- to the greater killing ivith radiation P13K-6 inhibitors can phocytic leukemia (CLL). overexpression and constitutive afi'ect the v;ay in which tumors interact with their microenvi- activauon of PI3K-6 supports thc model that P13K-6 inlubi- ronment. including stromal cells, inmiune cells, and endot- tion would bc therapeutic Billottci C, ci al. (2006) Ortcugctte helial cells and be therapeutic either on its ov n or in conjunc- 25(50)'6648-59: I jillottet (2 et al. (2009) ('uucer Rei. 69(3) tion v ith another therapy (Meadows, S A. et al. Paper 52"* 1027-36; Meadows, 8 A, Annual ASI I Meeting and prcscutcd at: 52" Atutual ASH Meeting mid Exposiuon. lixposition: 2010 Dec 4-7; Orlando, lilsu Ikeda 11. et al 2010 Dcc. 4-7, Orlando. Flax Geng L, ct al (2004) Caiicer (2010) Blued 116(9):1460-8: Herman S E et al. (2010) Blood Res 64(14):4893-9). 11(i(12):2078-88; Herman S E et al. (2011). Blood 117(16) [0544] In other embodiments, inhibition of PI3K (sucll 4323-7. In an embodiment, dcscubcd hcrmn is a method of P13K-6 and/or -,) can be used to treat a neumpsychiatric treating hematological cancers includm, but not hmitcd to dlsordi:r, c.g., all ililtolllllliuilc braill ilisordcr. Illfcctlous slid acute myeloid leukemia (AMI.). multiple myeloma (MM), unnnmc factors have benz unplmuted in thc pathogcnesis of and clinmic lymphocytic leukemia (Gl,l.) scvcra1 ncuropsycluatric disorders, including, but not limit ixl [0540J A PI3K-ib inhibitor (( A1,-101) has been evaluated to. Sydenham's chorea (8(:) ((iarvey, M. A et al (2005) ./. in a phase I tnal in patients with haematolo ical mali nan- i:hiid Beiirol. 20 424-429), I'ourette's syndrome (TS), obses- cies, and showed activity in CLL in patients with poorpro- sive compuLsive disorder (OCD) (Asbalm F. R et al. (1998) nostic characteristics. In CI.L, inhibition of PI3K-6 not only Am. J. Psi c/uutri 155:1122-1124), attention deficit/by pemsc- affects uimor cells directly, but it also aliixts the ubihty ofthc tivity disorder (ADiHD) (Hirschtnu, M. E. et el (2008) Child tumor cells to interact with their microcnviromncnt. Tlus ¹urupsi chul. 1.1-16; Peterson. B. S. ct el. (2000) Arch. Crea. microenvironment includes contact with and factors front Psychuitri: 57:364-372), anorexia nervosa (Sokol, M. S. stromal cells, ltcell s. nurse like cells, as well as other tunxir (2000) .I Child Ado/est I(svuht&phurmuuul 10'133-115; cells. CAL-101 suppresses the expression of stromal and Sokol, M 8 et el (2002).ltu,/. I's)vhiutri 159:1430-1132), T-cell derived factors including CCI 3. CCL4, and CXCL13, depression (Leslie. D. L, et al. (2008) J. Am Acud, Chdd as well as the CLL tumor cells* ability to respond to these Adu/esc Psychiutn; 47:I i(i(i-1172). and autism spectrum factors. CAL-101 treatment in CLL paucnts induces rapid disorders (ASD) (Hollander, E. eral. (1999) Am. J Psychi utri lymph node reduction mid redistribution of 1ymphocy1es uito 156 317-320, Margutti. P. ct al. (2006) Curr. Neuruvusc. Res. the circulation. and affects tonic survival signals through the 3.149-157). A subset oi'childhood obsessive compulsive dis- 13CR, leading to reduced cell viability. and an increase in orders and tic disorders has been grouped as Pediatric apoptosis. Single agent CAL-101 treatment was also active in Autoimnnine Neumpsychiatric Disorders Associated ivith mantle cell lymphoma and refractory non Hodgkin*s lym- Streptococci (PANDAS). PANDAS disorders provide an phoma (Fumian, R R, et al. 52sa Annual ASH Meeting and example of disorders where the onset and exacerbation of Exposition: 2010 Dcc. 4-7, Orlando, Fla., Hocllcnric cl. J. ct ncuropsycluatnc symptoms is preccdcd by a streptococcal al. 52"'nnual ASH Mccting and Exposiuon; 2010 Dec 4-7, ufii:ction (Kurlan, R.. Kaplan, E. L. (2004) Pediatrics 113. 52"a Orlando, I'la, Webb, I I K, et al Annual ASI I Meeting 883-886, Garvey, M. A. eral. (1998) J Clio..Veurul. 13.413- and Iixposition; 2010 Dec. 4-7; Orlando. Isles Meadow~, et 423). Many of the PANDAS disorders share a common al. 52"" Atutual ASH Meeting and Exposition: 2010 Dec 4-7, mechamsm of action resulting from antibody responses Orlando, Flax Kahl, B, et al. 52" Annual ASH Meeting and against streptococcal associated epitopes, such as (ilcNAc. Exposition: 2010 Dec. 4-7; Orlando. Flax Lniututti B 1. et al. v hich produces neurological effects (Kirvan. C. A. et al. (2011) Blood 117(2). 591-4). (2006) J hveuruimmtmu/. 179:173-179). Autoanubodms rcc- [0541] PI3K-o inhibitors have shown activity against ognizmg central ncmous system (CNS) cpitopcs arc also P13K-6 positive ghomas in vitro (Kaslnsluiui A, et al. Poster found us sera ofmost PANDAS subtccts (Yaddanapudt, K. et presented at: I'he Ameucan Association of ('sneer Research al. (2010) Mul I'.s) thi utOi 15:712-726) 'I bus. several neu- 102""Annual Meetmg, 2011 Apr. 2-6; Orlando, itis.) PI )K-tj ropsychiatric disorders have been associated with immune US 20]4/0275]35 A1 Sep. 18, 2014 51

and autoimmune components, making them suitable for carcinoma in duct tissue in a mammary land, medullary therapies that include PI3K-b mid/or -I ulhhbition. carcmmnas, cnlloid carcinnmas. tubular carculonias. and [05451 In ccrtaul embodiments, a method ol trcalulg (c g., inflmnmatory breast cancer, ovanan cancer, including epithe- rcxiuchhhg or iunclhorathng onc or more sympunns Of) a ncu- lial Ovillldll Itlhnols SUCh BS adCIIOCBICltlollld ltl thC Ovary dill rnpsychiatric disorder, (e.g . an autninimune brain disorder), dll adCIIOC IICihloln I (hilt has llllglahCd froihl lllc Ovdry ill(0 lhC using a VI3K-iy and/nr -7 inhibitnr is described, alone or in abdomulal cavity: utcrinc cmlccr: cervical cancer such as combination themspy, For example. one or more P13K-8 and/ adenncarcinnma in the cervix epithehal including squamnus or -7 inlubitors described herein can be used alone or in cell carchnnma andadenocarcinnmas; prostate cancer, such as combuhation with any suitable thcrapeutm ugent;uld/or a prostate cancer selected from the following, an adenocarci- modahties, e.g., dietary supplement. Iihr trcuunenl ol neurop- noma or an adenocarinoma that lhas migrated to the bone: sychiatrw. disorders. Exemplary ncuropsycluatnc disorders puncrcatic cancer such as cpitheliod carcinoma in thc pmlcrc- that can be treated with the VI3K-IX and/or -7 inhibitors atic duct Iissuc and im adcnocarculoma hn a pmlcrcauc duct. described herein include, but are not limited to, PANDAS bladder cancer such as a transit i one I cell care uloma in uriimry disorders. Sydenham*s chorea, Tourette's syndrome. Obses- bladder, urothelial carcinomas (transitional cell carcinomas), sive compulsive disorder. attention deficit/hyperactivity dis- tumors in the urothelial cells that bne the bladder, squamnus order, anorexia nervosa, depression, imd autism spectrum cell carcinomas, adenocarcinomas. Bnd small cell cancers: disorders. Pcrvashvc Devclopmcntal Disorder (PDD) is an leul emia such as acute myeloid leukemia (AML). acute lym- cxcnlplarv'lass ol BUllslll spcctrUIII dlsoldcls Ilult lllclUdcs phocytic leul ernie. cluonic lymplmcytic leukemia, chronic Autistic Disorder. Asperger's Disorder, ('hildhond Disinte- mycloid leukemia, luury cell leukemia, myclodysplashu. grative Disorder (('DD). 1(ett's Disorder and VDI)-Not Oth- mycloprolifcrativc disorders, NK cell leukemia (c g., blasuc erwise Specihed (PDD-NOS) Animal models for evaluatin plasnmcytnid dendritic cell neoplasm), acute myelogennus the activity ofthe PI3K-o and/or -7 inhibitor are known in the leukenna (AMI,), chronic myelogenous leukemia (('MI ), art. For cxiunplc, a mouse model of PANDAS disorders is mastocytosis. cluonic lymphocytic leukemia (CI.L), multiple dcscnbcd uh, c... Yaddanapudi, K. ct al. (2010) supm, and myeloma (MM). and myelodysplastic syndrome (MDS): HolTinml. K. I. chal (2004) J. Xcurosc/. 24.1780-1791. bone cancer: lung cancer such as ixm-small cell lung cancer [0546[ In some embodiments, provided herein are methods (NSCLC), whiCh is dii idcd into squamous cell carcuxhmas, of using the compound~. or a pharmaceutically acceptable ddCIIOCBI C lllohnaS. Slid largC CCII I llul I ffbrCllllateil CBICIIIOIUJ s, fihrm (e g., pharmaceutically acceptable salts, hydrates. sol- and small cell lung cancer; skin cancer such as basal cell vates, isomers, prodru s, and isotopically labeled derivatives) carcmmna. melanoma. squamous cell carcinoma and actinic thereof, or pharmaceutical compositions as provided herein keratosis. which is a skin condition that sometimes develops to treat disease txhnditions, inc lu din, bui not lum had 10. dhs- into squamous cell carcinoma: eye rethnoblastoma; cutaneous CBSCS BSSOClil(Cd With IIIBlfilhlCtholllllg Ol Olio OI Iilol c typiu Of or Intraocular (eye) melanoma, primary liver cancer (cancer VI3kinase A detaileddescriptionnfcnnditinns and disorders that begins in the liver): todney cancer, thyroid cancer such as mediated by pi I flb kinase activity is set forth in Sadu et al., puphllury. folhcular. medullary and mlaplastici lymphoma 3''0 OI,'8134/I, which is incorporated herein by reference in such as diffuse large 13-cell lymphoma, 13-cell inlmunoblastic its entirety for all purposes. lymphoma, NK cell lymphoma (e 8, blastic plasinacytoid non-cleaved [05471 In some embodiments, the disclosure reLstes to a dendritic cell neoplasm), and small cell lym- method of treating a hyperprolifemstive disorder in a subject phoma: Kaposi's Sarcoma; viral-induced cancers includin hepatitis B viols (HBV), hepatitis C virus (HCV), and hepa- the(comprises administcnng to saul sublccl u therapcuticully

toccllular carmnoma. humml lymphotropic virus-type I CITCC(IVC illnollllt Ol B CotllpoUnd, Or B phillnldCclltlCJ11)'cceptable T-cell form (e 8, pharniaceutically acceptable salts, (HTLV-I) mid adult leukemia/lymphoma, and human hydrates. solvates, isomers, prodrugs, and isotopically papillmna viols (I IVV) and cervical cancer: central nervnus 'ls labeled derivatives) thereof, or pharmaceutical compositions SVStCIU CBIICCIS ((INS) SIICII prilhhahy bl'Bill tlilunl', ivhICII as provided herein. In some embodiments. said method includes gliomas (astrocyxohna, anapLhstic astrocytoma, or relates to the treatment of cancer such as acute myeloid leu- glhoblastoma multifomte), Oligodendroglioma, Ependy- kcnud. (hymus, brmn, lung, squamous cell, skin. eyc. rctino- mom i, Meningioma. Lymphoma. Schv annoma. and blastonui, ultraocular melanoma. oral cavity and oropllaryn- Mcdulloblastoma; pcnphcral hhclh ous system (PNS) cancers geal. bladder, gastric, stomach, pancreatic, bladder. breast, such as acoustic neuromas mid mali nmlt penplmral ncrvc I') cervical. head. neck, renal, kidney, liver. ovarian, prostate, sheath tunmr (MENS including neumhbronlas and sclwv- colorectal, esophageal, testicular, gynecological, thyroid, allllotnas, malignalht fibmus cytoma, Inalignant fibrous his- tiocytoma. mali nant meningioma, nhalhp&ant mesothelioma. ( 'NS. PNS. AIDS-related (e g.. Lymphoma and Kaposi's Sar- coma) or viral-induced cancer. In some embodimentg said and malighhant mixed Mulleriml tumor: oml cavity and method rcla tea to thc treatment of a non-c mcerous hyperpro- oropllaryn eal cancer such as, hypopharyngeal cancer, laryn- geal 1 0Jllccn Ilasopharvngcal cathect, Btld orophaDllgcJI cdll- lifi:raus c disorder such as ben i gobyperpla sha ofthe skm (c g., ccr. stomach ciulcer such as lymphomas. gastnc stromal psol'I,'isis), rcstcilosls. Cr pi'ostate (e.g . beillgil pl'ns1utlc tumors, and carcinnid tumnrs; testicular cancer such as Ih)qhertrophy (13VI I)) Semi cell tumors ((I('. I'). which include seminomas and nonsemi- [0548J Patients that can be treated ivith compounds. or a nonlas, and gonadal stromal tumors, wluch include I phanuaceutically acceptable foun phamtaceutically eydig (e, cell tumors and Sertoli cell tumors; thymus cancer such as to acceptable salts, hydrates, solvates, isomer~. prodni 0 and thymomas, thymic carcinomas, Hodgkin disease, non- isotopically labclcd dcnvativcs) thcreul', or plmnnaccutical Hodgkul lymphomas cdrcmoids or cdrcinoid tumors, rcclal composiuons as prowded hereul. according uh flle mcthods as iulllccl, dlul colon cilllccl. provided hcreul include, for cxiunplc, but not lhhnituI to, patients that have been diagnosed as hal ing psoriasis; rest- [0549[ In one embodiinent, provided herein is a nlethod of enosis: atherosclerosis: 13VI k breast cancer such as a ductal treating an inflammatinn disorder, including autouninune dis- US 2014/0275 [35 A1 Sep. 18, 2014 52

eases in a subiect. The method comprises administerin to sclerosis, morphea, myeasthenia gravis, myocardial smd subiccl a thcrapcutically OIPcctive amount of a com- ischemia, nephrotic syndrome. pemphigus vulgaris, perni- pound, or a phannaceuucally accc3htablc lorm (C.g.. phamuh- cious meaemia. peptic ulcers, polymyositis. primary biliary ceuticafly acceptable salts. hydrates. solvates, isomers. pro- cirrhosis, ncuroinflanmuhtion associated with braul disorders dnigs. and isotopically labeled derivatives) thereof, or (c g., Parkinson*s discase, Hunlulgton's disease, and Alzhc- phanuaceutical compositions as provided herein. Examples llucr 1 dhsCBSC), proSlhltllls. Clhrolllc lllflslulhlatloll BSSOCIBU:0 of autoinunune diseases includes but is not limited to acute with cranial radiation injury, pelvic mflammatory disease, disseminated encephalomyelitis (shhDEM), ahddison*s dis- polymyalgia rheumatic, reperfusion injury. regional enteritis, case, antiphospholiphd antibody symlromc (APS). apluslhc rhemnatic fever, systemic lupus erythematosus, scleroderma. anemia, mitoimmunc hc)ha(Itis, automununc skm discase, scierodoma. sarcoidosis. spondyloarthopathhes. Sjogren's coeliac disease. ('mhn*s disease, Diabetes inellitus (type I), syndrome, thyroidilis, transplmualion rqcuhhon, lcndomus. (ioodpasture's syndmme. (inlves'isease, (iuillain-13arre trauma or uljury (O.g.. frostbite. chemical irritants, loxins, syndrome ((IB S). Hashimoto* s disease. lupus erythematosus, scarring, bunls, physical ulpiry), vasculilis. vitiligo and multiple sclerosis, myastheiua gravis, opsoclonus myoclonus Wegener's granulomatosis In certain embodinhents, the syndrome (OMS). optic neuntis, Ord*s thyroiditis. oemphi- inflammatory disorder is selected from arthritis (e n.. rheu- gus, polyarthritis, prunary bhlmry cirrhosis, psonusis. rheumatoid artluitis). inflammatory bohwel disease, inflammatory matoid arthritis, Rcilcr's syndrome. Takayasu's urlcrilis, lmn- bov el syndrome. asthma. psoriasis, endometriosis. intersti- pnral arteritis (also known as "giant cell arteritis"). v arnl tial cystitis and prostatistis. In certain embodiments. the autoimnnule hemolytic anemia, Wegener's gramilomatosis, ulflamnuilory condiiion is an acute ulflanmlnlory comlilhon alopecia universalis (e g . intianunatory alopecia), ('hagas (c g., Rhr cxamplc, mflanunalion resulting Ibom infi:cuon). In disease, cluonic fatigue syndrome, dysautonomia, certain embodiments, the intlammatory condition is a chronic endometriosis, hidmldenitis suppurative. interstitial cystitis, inflammatory conditinn (e g., conditions resulting fronh ucUIolllv'Otollla, sarcoldosls, sclcrodcrlua, Ulcelilllve colitis, astlunm arthritis and infimmnatory bov el disease) The com- 1 uiligo, and vulvodyrua. Other disorders include bone-rc- pounds can also be useful in treating inflanunation associated sorptinn disorders and thrombosis. v ith trauma and non-inflanunatory myalgia. [0550J Intlammation takes on manyforms andincludes.but [05521 Inununc disorders. such as auto-inununc disorders. is not limited to, acute. adhesive. atmphic, catarrhal, chrmlic, include, but are not limited to, arthritis (including rheumatoid cirrhotic. diffuse, disseminated, exudative, fibrinous, fibros- arthritis, spmldyloarthopathies, gouty arthritis, degenerative in, focal. granulomatous. hyperplastic. hypertrophic, inter- joint diseases such as osteoarthritis, systemic lupus erythe- stitial, metastatic. necrotic. Obliterative. parenchymatous, matosus, Sjo ren*s syndrome, ankylosing spondyhtis, Iuldif- plastm. producuvc, prolifi:rous, pseudomcmbrunous, puru- ferentiated spondylitis, Behcet's disease. haemolytic autoim- lent. sclcrosing, seroplaslhc, serous, simple, specific, sub- mune anacmias, multiple sclerosis. Iunyolrophhc lateral acute. suppurative. toxic, tnlumatic. Bhhd'or ukerative inflanl- sclerosis, amylosis, acute pmnful shoulder, psonalic, and iu'Itloll IUvcllllc arlhillls), BslhlnB, iuhcrosch:rosls, oslcopolosls. [0551J Exemplary intlamnhatory conditions include. but bmilclutis. tendonitis, bnrsitis, skin condition (e.g . psonasis, are not limited to, intlammation associated with acne. anenlin eczenm, burns, dermatitis. pniritus (itch)), enuresis. eosino- (e.g.. aplastic anemia. haemolytic autoimmune annemia), philic disease. gastrointestinal disorder (e g., selected from astlmla, arteritis (e.g., polyarteritis, temporal arteritis. periar- peptic ulcers. regional enteritis, divehticuhtis, gastrointestinal tcmlis nodosa, Takayssu's artcnlhs), artlmus (c.g., crystallulc blcixiing, cusinopihflic gaslroinlestulnl disorders (c.g., eosi- arfluitis. oslixharlluitis, psomauc artluhths, gout flarc, gouty ilophlllc csophiigllhs. coshllophlllc gBsllltls, cosillophlllc gss- arfluitis. rcaclivc arthritis, rheumatoid uriluhtis and Rcitcr's tromucntis, cxishnoplulic cohlis), gaslnUB, diarrhea, gaslroc- arthritis), anh3 losing spondylitis, anhylosis, amyntropbic lat- sophageal reflux disease ((IORI), or its synonynh (IERD), eral sclernsis. autoimnlune diseases, allergies or allergic reac- inflammatory bolvel disease (1131)) (e g, ('rohn's disease, tions. atherosclerosis, bmnchitis. bursitis. chronic prostatitis, ulcerative colitis. collagenous colitis, lymphocytic colitis. conjunctivitis. Chagas disease, chronic obstructive pulmo- ischaemic colitis. diversion colitis, Behcet*s syndrome, inde- nary discase, ccrmatomyosius, divcruculitis. diabctcs (c g., tcnninatc colitis) and udlanunatory bowel syndrome (IBS)). type I diabetes mcllitus, type 2 diabcies mellilus), a skin relapsing polychoiulruis (c.g.. alropluc polychondnus and condition (c g., psonasis, eczema, burns, dermatitis, pruritus systcnuc polychondronuhlacia). and disorders ameliorated by (itch)), endometriosis, (iuillain-13arre syndrome. infection, a gastmprokinetic agent (e.g., ileus. postoperative ileus and isclmemic heart disease, Kawasaki disease, glomerulonephn- ileus during sepsis: gastmesophageal reflux disease ((IORI), tis, gingivitis. hypersensitivity. headaches (e.g.. migmine or its synonym CIERD) I sosinophilic esophagit is, gastropare- headaches, tension headaches). ileus (e g.. postoperative hleus sis such as diabetic gastroparesis: food hntolerances and food and ileus durulg sepsis), iihopalhic fluombocylopcnic pur- allcrghcs iuld other I'unctioiral bow cl disorders, such as non- pura. interstitial cystitis (pmnliil bladder syndrome). gas- ulccrathvc dyspc)hsha (NHD) mid non-cardiac chest pain trointestinal disorder (c.g., selcclcd from peptic ulcers, (NCCP, ulcludhng cosho-CIhohhdnhhs)). In ccrlaul embodi- regional ententis. diverticulitis, gastrointestinal bleeding, ment~, a method of treating inflammatory or autoimnhune eosinnphilic gastrointestinal disorders (e.n, eosmophilic diseases is pmvided comprisin administering to a subject esophagitis, eosinophilic gastntis, eosinophilic gastroenten- (e ., a manunal) a therapeutically efl'ective amount ofa com- tis, eosinophihc colitis), gastritis, diarrhea. astmesophageal pound, or a pharmaceutically acceptable form (e.g., phamla- rcflux discase (OORD, or hls synonym GERD). inflanmuhtory ccutically acccplablc salts, hydrates, sob ates, isomers, pro- bowel discase (IBD) (c.g., Crolm'1 discase, ulcerauve cohus, drugs. and isolopically labeled dcnvsuvcs) thereof; or collagcnous militia, lymphocytic cohus, ischamnic cohlis, ph'amlaccUllcBI coulposhllolls Bs providixl llcrclll, lhal sclcc- diver ion colitis. 13ehcet's syndmine. indeterminate cobtis) tively inhibit PI3K-(I and'nr PI3K-I as compared to all other and inflammatory bowel syndrome (1135)), lupu~. multiple type I PI3 kinases US 20]4/0275 [35 A1 Sep. 18, 2014 53

[0553] Such selective inhibition of PI3K-6 and/or PI3Kff treat ohstnictive pulmonary disease Cluonic obstnictii e pul- can bc advantageous lbr trcaung mty of thc diseases or ixm- monary disease (COPI)) is an umbrella term for a youp of ditions dcscribcd hcrmn. For cxiunplc, sclectivc udubition of respimtory tract diseases that are chamlcterized by airflow P13V.-O can inhibit intlammatory msponses associated v ith obstruction or lmntation. Condiuous included ut tins inflammatory diseases, autointmune disease, or diseases umbrella tenn include. but are not lun&ted to. chronic bmn- related to an undesimlble inunune response including. but not clutis, cmphyscmd, and bronclucctas&s. limited to astlmm. emphysema, allergy. dermatitis. rheuma- [(1557J In another einbodiment, the or a phar- toid attlu itis, psoriasis, lupus erythematosus. anaphylaxsig or compounds, graft icrsus host ibscasc. Sclixuvc udubbion ol'PI3K-6 can nmceuticaily acceptable form (e.g, pharmaceutically acceptable salts. hydrates. solvates. isomers, and isotopi- further provide for a rcxtuction in thc utflimunatory or undc- prodrugs, sinlble imnnute response without a concomittant reduction in cally labeled derivatives) thereof. or pharmaceutical as provided hcrcin arc used lor thc treatment of the ability to reduce a bacterial, viral, an&For bingal infection compositions Selective inhibition ofboth PI3K-8 and PI 3K-; can be advan- asthma. Also, thc compounds or phannaccuucal compositions described herein can be used for the treatment endot- tageous for inhibiting the inflammatory response in the sub- of oxemia and sepsis In one embodiment. the compounds or ject to a greater deyee than that would be provided for by plmrmaceuticai compositions described herein are used to filr inhibitors that select&vcly inlubit P13K-b or PI3Kff alone In the treatment of rheumatoid arthritis (ICA). In yet another onc aspect, one or morc o I &bc sub I methods;u c elTi ct&vc in jcc embodiment. the compounds or pharmaceutical composi- reducing antigen specific antibody production in vivo by tions dcscnbcd hcrcut is used I'or thc trcatmcnt contact or about 2-filld. 3-fold, 4-fold. 5-fold, 7 5-filld, 10-fold, 25-fold, of 50-filld. 100-fold, 250-fold, 500-fold. 750-fold, or about atopic dcnuatitis. Contact dcnuatitis includes &rntant dcnnd- titis, phototoxic dermatitis, allergic dermatitis, photoallergic 1000-fold or more. In another aspect, one or more of the subject methods are effective in reducing antigen specific dernmt&tis. contact urticaria, systemic contact-type dermatitis and the like. Irritant dermatitis can occur ivhen too n&uch of a IgG3 and/or IgGM production in vivo by about 2-11&ld, 3-fi&ld, is when is sensitive to 4-fi&ld. 5-fold, 7.5-fold, 10-Ibid. 25-fold, Sfl-fi&ld, 100-fi&ld, subst mce used on the skin of the skin 250-fold, 500-fold, 750-fold, or about 1000-fold or more. certain substance. Atopic dermatitis, sometimes called cczcmd, ts a kutd of dcnuatitis, an atopic sku& d&swisc. [05541 In one aspect, one of more of the subject metlmds are effective in ameborating symptoms associated with rheu- [0558] In some cmbodimcnts, tbc disclosure provulcs a matoid arthritis includu&g, but not 1 united to B reduction in thc method of treating diseases related to vasculogenesis or

S&& Clliitg Of In&11&S, B reductio&1 lu Si &111&1 Bll&1 Collt&gC&1 li vi la, angiogenesis in a subject that composes adntinistering to said and/or a reduction ut )oint pa&bolo y such as bone resorption, subject a therapeutically effective amount of a compound. or cartilage damage, pannus, and/or inflammation In another a phamtaceutically acceptable form (e ., phamtaceutically aspect, the subject methods are effective in reducing ankle acceptable salts, hydrates, solvates, isomers, prodrugs. and inflanunation by at least about 2%, 5%, 10%. 15/o, 20%, &sotopically labeled deme&iles) thercol; or phamtaccut&cal 25;v, 30/'v, 50'/6, 60yw or about 75% to 90%. In another compositions as provided hcrcin. In some cmboduncnts, said aspect, the subject methods arc efiimuvc in reducing knee method is for treating a disease selected front tun&or angio- inflammauon by at least about 2%, 5%, 10%, 15%, 20%, genesis, chrm&ic inflammatory disease such as rheumatoid 25%, 30'/w 50%, 60'!w or about 75% to 90% or more. In still arthntis and cluonic inflmmnatory demyebnating polyneur- another aspect. the subject methods are effective in reducing opathy, atherosclerosis, inflammatory bowel disease. skin serum anti-type Il collagen levels by at least about H)%, 12%, diseases such as psoriasis, eczema, and scleroderma. diabe- 15;o, 20/8, 24%. 25%, 30%. 35%. 50/w 60/o. 75%, 80%, tes, diabetic rcnnopathy, rctulopatby of prcmatunty, a c-rc- 86;o, 87%, or about 90% or more. In another aspect, the latcil uliicidBI di:gcucratlou, hi:lust&gin&us, glloiu'd, Iucla- subyct methods arc cflcctivc ul rcduc&ng ankle lustopathol- nonta, Kaposi's sarcoma and ovarian. breast. lung„ ogy scores by about 5%, 10%, 15%. 20/8, 25%, 30/w 40%, pancreatic, prostate, colon and epidermoid cancer 50%, 60/w 75!w 80 /w 90% morc. In sull another or aspect, [0559] In addition. the compounds described herein can be the subject methods are effective in reducing knee histopa- used for the treatment of arteriosclemsis. Including athero- thology scores by about 5%, 10'%, 15%, 20%, 25%, 30%, scbzosls. Attcriosclcti&sls Is B get&eral tenn dcscnbiilg ativ 40"v, 50%v, 60'/v 75%. 80%, 90% or more. hurdcnutg of medium or large artcnes. Athcrosclcrosis &s a [0555] In some mnboduncnts, provided hcrcm;uc methods hurdcnutg of an sr&cry specifically duc to au athcromatous for trcatutg disorders or condit&ons in wluch the 6 isofonn of plat]ue. P13V. is implicated to a greater extent than other PI3K iso- filrms such as PI3K-o and/or -[] Selective inhibition of [0560] In some embodiments, provided herein is a method F13 V.-O and/or PI3Kff can provide ad& antages overusing less oftreatingacardiovasculardisease ina subject thatcomprises selective compounds winch inhibit PISK-o and/or -[I. such as administering to said subject a therapeutically etTective an improved side effects profile or lessened reduction in the dtuouilt of B coiupouud Bs proi &fed bc&el&I, or B phatluaccu- ability to reduce a bacterial, viral, aml'or fungal u&lbction. tically IICCCT&table form (c.g., phannaccutically acccpiablc salts, hydrates, solvates, isomers, prodrugs, and isotopically [0556J In other embodiments. pmvided herein are methods labeled derivatives) thereof. Iixamples ofcardiovascuhlr con- ofusing a compound, or a pharmaceutically acceptable fornt ditions include, but are not limited to. atherosclemsis, rest- (e.g.. phannaceutically acceptable salts, hydrates. solvates, enosis, vascular occlusion and carotid obstructive disease. isomers, prodrugs. and isotopically labeled derivatives) thereof, or phannaccuticdl compositions as provided hcrcin, [0561] In some embodiments. tbc disclosure rclatcs io a to treat respiratory discascs includutg, but not luuitcd to dis- method ol trcatutg diabctca ma subtcct that compn sea mbnin- cascs alfectutg the lobes of lung, plcuml cavity, brotmhial &stcnng to s ud sub)act a therapeutically cffi ct&vc amount of a tubes. trachea, upper respiratory tract. or the nerves and compound as provided herein. or a pharmaceutically accept- muscle filr breathing I'or exan&pie, ntethods are pmvided to able foun (e.g, plmm&aceutically acceptable salts, hydrates,

US 20]4/0275 [35 A1 Sep. 18, 2014

54 platelet-

solvates, isomers, pmdnigs, and isotopically labeled deriva- pharmaceutical compositions as provided herein. Ibr the tives) thereof, or phannaccutical compositions as provided treatment ofdisorders invo1 vulg platelet aggregation or hCrClll. lct adhesion, incluihng. but not lnnited to Idiopatlnc throm- [0562] In addiuon. thc compounds, or a phannuccuticully bocytopenic purpura, 13ernard-Soulier syndronle. (iLln- acccptablc form (C.g., phannaccuticully acceptable salts, nuann's thmmbasthenia, Scott's syndrome. von 30illebnlnd hydrates, solvatcs, Isomers, prodrugs, and isolopicully disease, Hennansky-Pudlakdern Syndrome, and Ciray platelet labeled denvatives) thereof. Or phanuaceutical compositions syndrome. as pmvided herein, can be used to treat acne In certain [0568] In some embodiments. compounds, or a phamla- embodiments, the inflammatory condition and/or inunune ccut l cally acceptable foml (e.g .. phannac cut l cally acceptable disorder is a skin condition. In come embodiments, the skin salts, hydrates, solvatcs, isomers, prodrugs, and lsotopically condition is pruntus (Itch). psonasis, cczcnui, burns or dcr- labchx! dcnvatlvcs) thereof, or phannaccuucal compositions mauus. In ccrtmn embodiments. thc skin conditum is psoria- as provided herein. are provided for treating a disease which sis. In ccrtaul cmbodunmlts, thc skul condluon is prurius. is skeletal muscle atmphy, skeletalstiles) or muscle hypertrophy In [0563] In ccrtaul embodiments, the inflmmnaulry disorder some embodiments, provided herein are compounds. or a and/or thc immune disorder i ~ a gastrointestinal disorder. In phannaceutically acceptable form (e.g., phamlaceutically some cmbodimmlts, the gastrointcstiiml disorder is selected acceptable salts, hydrates, solvates, isomers, prodrugs. and fmm gastrointestinal disorder (e g., selected fmm peptic lsotopically labeled thercol; or phamlaccutlcal ulcers. regional enteritis. diverticulitis, gastrointestinal bleed- compositions as prui Idcd hcrmn, for the treatment ol'isor- in, eosinophilic gastrointestinal disorders (e... eosinophilic ders that include. but are not limited to, cancers as discussed esopbagitis, eosinophilic gastntis, eosinophilic gastroenten- herein, transplantation-related disorders (e.g . lowering rejec- tis. eosinophillc cohtts), gastntls, diarrhea, gastroesoplmgcal tion rates, graft-versus-host disease, etc ), muscular sclemsis rcflux discase (CiORD, or its synonym GERD). inflanmuitory (MS). allergic disorders (e, arthritis, allergic encephalomy- bowel discase (IBD) (c.g., Crolm's discase, ulcerauve cohus, elitis) and other immunosuppressive-related disorders, meta- collagenous colitis, lymphocytic colitis, ischaemic cohtls, bolic disorders (c.g., diabctcs). reducing intimal thickciung diver ion colitis. 13ehcet's syndmine. indeterminate cohtls) following vascular ullury. and mislolded protein disorders and inflanunatory bowel syndrome (IBS)). In certain embodi- (e g., Alzheimer*s Disease, (iaucher's Disease, Parkinson' ments, the astrointestinal disorder is infliunmatory bowel Disease, I luntington's Disease. cystic fibrosis. macular discase (IBD). degeneration, retinitis pigmentosa. and pnon disorders) (as [0564] Further, the compounds. or a phamlaceuticafly mTOR inhibition can alleviate the effects of mlsfolded pro- acceptable form (e.g.. phamlaceutically acceptable salts, tein ag re ates). The disorders also include hamartoma syn- hydrates, solvatcs, Isomers, prodrugs, and isolopicully ilrolucs. all ch Bs lubclous sclcl 0sls slid Cow dell Discase (disc labeled dcm stiles) thcrco I; or phamla ceu ll ca I compositions tCnllixl COWRCII SvlullolnC Blul lnultlplC haillaltonla SYII- as pmvided herein, can be used for the treatment of glonleru- drome) lonephritis Glomerulonephritis is a primary or secondary [0569] Additionally. the compounds. ore pharmaccutically autoimnnule renal disease characterized by intlanuuation of acceptable form (e g., phamlaceutically acceptable salts, the lomenili. It can be asymptomatic. or present with hema- hydnltes, solvates, isomer, prodrugs. and isotopically turia and/or pmteinuria. There are many retxlgnized types, Labeled derivatives) thereof, or pharmaceutical compositions divided ul acute, subacute or chrome glomcruloncpihntis. as provided herein, can be used for the treatment of bursitis. Causes arc mfi ctious (bacterial, viral or purasitic patho cns), lupus, Scute disscmina I cd cuec)thai omycll tw (AD EM), Addi- autoinlmuile or paraneoplastic son*s discase, antiphosphollpid antibody syndrome (APS). [0565] In some embodiments, provided hcrcul arc com- amyloidosls (ulcludulg systemic and localized amyloidosis. pounds, ore pharmaceutical ly acceptable lilnn (c, phamui- ,'Illd pilnlaiy Bllil SCCOlldaiy Bllll'klltlosiB),,'lpiaStlC,'lnellu;I, ceutically acceptable salts. hydrates. solvates, isomers. pro- mitoinunune hepatitis. coeliac disease, crohn's disease, dia- dnigs. and isotopically labeled derivatives) thereof, or betes mellitus (type I). eosinophilic gastroenteridec. good- pharmaceutical compositions as provided herein. for the pasture* s syndrome, ~aves* disease, gulllain-barre syndrome treatment of multiorgan failure. Also provided herein are (GBS). hashunoto's discase, ulflanunatory bowel ihscasc, compounds. or a phannaceutically acceptable foml (e lupus crythcmatosus (includulg cutantxius lupus erythcmato- phannaccutically acceptable salts, hydrates, solvatcs. Iso- sus and systenuc lupus crythematosus), myasthenia gravis. mers. prodnigs, and wotopically labclcd dcrivafivcs) thcrcof, opsoclmius myoclonus syndmme (OMS), optic neuritis, or pharmaceutical compositions as pmvided herein. for the ord's thyroiditis, ostheoarthritis, uveoretinitis. pemphigus, treatment of liver diseases (including diabetes), gall bladder polyarthritis, primary biliary cirrlxlsis. reiter*s syndrome. disease (including gallstones), pancreatitis or kidney disease takayasu's arteritis. temporal arteritis, warm autoinunune (including proliferatlve glomerulonepluitis and diabetes-in- IICluolvtlC iulCBBB, v CgCIICI S gldlluloillatoSIS, alopix'.Id lllll- duced renal disease) or pain in a subject. vcrsahs, chagas'iscase. cluonic fatigue syndrome, dysau- [0566] In some embodiments, provided herein are com- tononna, cndometnosis. hidrademtis suppurauva, intcrsuual pounds, or a pharmaceutical ly acceptable foml (e g.. phamia- cystitis, neuromyotonia, sarcoidosis. scleroderma, ulcerative ceuticafly acceptable salts, hydrates. solvates. isomers, pro- colitis, vitiligo. wilvodynia. appendicitis, arteritis. arthritis, drugs. mid isotoplcdlly labchxl dcrivutivcs) thereof, or blepharitis. bronchiolitis, bronclfltis, cervicitis, cholangitis. phannaccutical compositions as providcxi hcrcul, fhr thc pre- cholecystitis, chorioanulionitis, colitis, conjunctivitis. cvsti- vention of blastocyte implantation in a subject. tis. dacryoadcrutis. dcnnatomyositls, cndocardius. [0562] In some embodiments, provided hcrcul arc com- cndomctritls, enteritis. entcrocolitls, cpicondyllus, cpid- pounds, ore pharmaceutical ly acceptable lilnn (c, phamui- nlynuns, fascilns, librositis. gastritis, gastrocntcritis, gulglvi- ceutically acceptable salts. hydrates. solvates, isomers. pro- tis. hepatitis. hidradenitis, ileitis. Iritis, laryngitis, mastitis, dnigs. and isotopically labeled derivatives) thereof, or meningitis, myelitis. myocarditis. myositis. nephritis, US 20]4/0275 [35 A1 Sep. 18, 2014 55

ompl&nlitis, oophontis, orchit&s, osteitis. otitis, pancreat&t&s, ous lupus erythematosus ("CLE") or systemic lupus erythe- parontis, pcncard&t&s, pcnton&ns, pharyng&us, plcunt&s. phlc- nmtosus ("Sl,l C)): or Sjo ren's syndrome b&ns. pnc&unon&tis. procure&s, prostatitis, pycloncplmns, rhnn- tis. salpin itis. sinusit&s, stomatitis, synovitis, tendonitis. ton- [0577] Ethcacy of a compound provided herein intreatin . and/or mana the disease or disorder can be sillitis. uveit&s (e g., ocular uveitis), vaginitis, vasculitis, or preventing ing vulvitis. tested usia various animal models known in the art. For [05'70] In another aspixn provxlcd hcrmn are methods of ex&le. cli&cacv'n &Icath&g, prcvcnnng dnd/or n&snag&ng ova d&erupting the funcuon ofa leukocy1c or d&sniptu&g a Iiu&c &ion astluna can be assessed using treatinduced &ng, astluna model of an osteoclast. 'I he method includes contacting the leuko- dcscribcd. for cxamplc. &n Lec ct al. (2006) JAllerg& Cliu cyte or the osteoclast w&th a function disrupting, amount of a Immund/ I I 8 (2): 403-9; efflcacy m preventing and/or compound as provided herein. nnlnagh&g a&thr&1&s (c.g., I'hcun&ato&d or p sot&at&c a&thol&s) can [05'71] In another aspect, &ncthods arc provided fhr tree 1u&g be assessed using autoimmune animal models described, fbr ophtlrdlmic d&scasc by adm&ni ~ tcnng one or morc oi thc sub- example, in Williams et al. (2010) Chem Biol, 17(2):123-34. ject compounds or pharmaceutical compositions to the eye of WO 2009/ONN986, &&YO2009,'088880. and WO 2011/008302; a subject. etTicncy in treating, preventing aniUor managing psoriasis can [05'72] In ccrtau& cmbod&ments, provided hcrcu& arc meth- be assessed usia transgenic or knockout mouse model with ods of treanng. preventing and/or mansginu a disease or a tar eted mutations in epidermis, vasculature or inunune cells. disorder using a compound, or a pharmaceutically acceptable mouse model resultin from spontaneous mutations, and form (e.g., pham&aceutically acceptable salts. hydrates, sol- unnnmodeiic&cnt muusc model with xcnotransplantauon of vates, isomers, prodru s, and &sotopically labeled derivatives) human skin or &numu&c cells, all of wluch are descnbixk lor thereof, or phannaccut&cdl compositions as prov&dcd herc&n, example, in13oehncke et al. (2007) (7iuiis iu Deruui/u/dg&; w hcrcin the d&scuse or d&sordcr is. Crolm*s discase: cutammus 25 596-605: etTicacy in treating,. preventing and/or managing lupus; mulnplc sclcros&s, rhcumato&d arthri1is. and sys1mn&c fibrosis or hbrotic condition can be assessed using the unilat- lupus ei)shen&a&usus. eral ureteral obstruction model ofrenal fibrosis (see Chevalier [05'73] In other cmbod&ments, prov&ded herein;uc methods et al.. Kidue& Iuicrnuiic»u/ (2009) 75.1145-1152), the bleo- oftreating. prevent&ng and/or managing a disease or a d&sor- myc&n induced model of pulmonary Iibrosm (scc Moore and Hogaboam. Am. J. Ph& siol. I.uug Cell. Mol. Physio/. (2008) der using a compound, or a ph arm ac euti cally acceptable forn& (e .. pharmaceutically acceptable salts, hydrates, solvates, 294 1,152-1,160), a variety of liver/biliary tibmsis models isomers, prodrugs. and isotopically labeled derivatives) (see Cinmng et al. Cliu /.iver Dis (200N) 12:333-347 and thereof, or pharmaceutical compositions as provided herein, Omenetti. S. et al. (2007) Luhoru&ur& Iuves&iguiiuu 87:499- whcI'cn& thc d&scuse or d&so&dc& &s. dnkvlosn&g spo&xlyht&s, 514 (biliary duct-ligated model)), or a number ofmyelofibro- chrome obstnictivc pulmonary discdscl myasthcrua grav&s, sis mouse models (seeMaricchio, L et al. (2009) Esperr Rev. ocular uveitis, psoriasis: and psoriatic arthritis llemuiol. 2(3): 315-334). ctiicacy in treat&ng, prevcntu&g andi [05'74] In other cmbod&ments, prov&ded herein;uc methods or m snag u&g scleroderma cm& bc a as ca sexi using mouse model Inca) bleon&ycu& ("III.M") of 1rcaung. prcvcnung and/or ma&mgu&g a d&sease or a d&sor- induced by repeated injections of described, for example. in Yammnoto et al (1999) .I luvesi der using a compound, or a ph arm ac euti cally acceptable forn& (e .. pharmaceutically acceptable salts, hydrates, solvates, Dermurol 112: 456-462: ethcacy in treating, preventing andi isomers, prodrugs. and isotopically labeled derivatives) or managing d erma to myositis can be assessed us &ng myositis thereof, or pharmaceutical compositions as provided herein, mouse model induced by inununization with rabbit myosin wherein the disease or disorder is; adult onset Still* s disease, dcscribcd. Ior example, in Phyamig& ct al. (20E09) Arthritis intlammatory slop&via, amyloidosis, imuphosphohp&d syn- Rheim&diism. 60(10). 3118-3127: cflicdcy u& trcaung, pre- . ('l,l: dron&c: au&conn&unc hcpal&nsl au&o&nnnnnc skn& d&scuse, venting and/or managing lupus (e g or Sl.li) can be 13ehcet's disease: chronic inflammatory demyelinating poly- assessed using various animal models described, for example, neuropathy: eosinophilic gastroenteriti; inflanImatory myo- in Ohoreishi et al. (2009) Lupus, 19. 1029-1035, Ohl et al. pathies, pemphigus, polymyalgia rheumatica; relapsing poly- (2011) Journal ofBiomcdicme aud Bio&er huologv. Article ID clmndritis: Sjorgen* s syndrome; temporal arthritis: ulcemtive 432 S95 (14 pages), Xia et al. (2011) Rheumuiologv, 50 2187- colitis; vasculis; v&til&go. and Wegner's granulomatosis. 2196, Pau ct al. (2012) PLCS O&XIE. 7(S).c36761 (15 pages). Mustafa ct al. 290.156-168, Iclukawa et [0575] In other embodiments. provided herein are methods (2011) Iosirolom; al. (2012)drihriiisuudgheumuiisu&, 493-503,0uyang oftreating. preventing and/or managin a disease or a d&sor- 62(2) et al. (2012)I Mul Med. 1&OI 10.1007/s(X)109-012-0866-3 der using a compound, or a pham&ac fomt cut i cally acceptable Rankin et al. Journal Immmiulogv, (c.g.. pharmaccuucdlly acccptablc salts, hydra&ca. solvatcs, (10 pages). (2012) of 1656-1667: and/or isomers. prodru nnd isotop&cally labeled deuvnt&vcs) 188 and ethcacy in treating, prevent&ng s, ogren's thereof, or pharmaceutical con&positions as provided herein, mana in Sj syndrome can be assessed using various mouse models dcsci&bcxl, for example. &n Ch&onm ct al. wherein Ihe disease or disorder is gout flare; sacoidos&s; and systemic sclerosis. (2009) Jourui&l ol Autoi unu&miii; 33. 190-196. [0576J In certain embodiments. pmvided herein are meth- [11578J In one embodiinent, provided herein is a nðod of ods of treanng. preventing and/or mansginu a disease or a treating,preventinganiUormanagingasthma Asusedherein, disorder using a compound, or a pham&aceutically acceptable "asthma" encompasses airway constriction regardless of the form (e.g., pham&aceutically acceptable salts. hydrates, sol- cause. Conunon triggers of astluna include. but are not lim- I ates, Isomers, pro drugs. and &a otop&cally lube led deuvnt&vcs) &tcd to. exposure to an em iro&unm&tal sumulants (c.g., aller- thereof, or phannaccut&cdl compositions as prov&dcd herc&n, gcns), cold a&r, warm mr. perfume. mo&sl a&r, excrcisc or whcrc&n Ihc discase or ihsordcr &s: asthma; arrl&nfts (c g., cxcrt&on, and arnot&onal stress. Also prov&dcd herein is a rheumatoid arthritis and psoriatic arthritis); psoriasis: sclero- method nftreating, preventing and'or managing one or n&ore derina: myos&tis (e.g, dermatoinyositis): lupus (e.g . cutane- symptmns associated with asthma I:xamples of the symp- US 20]4/0275 [35 A1 Sep. 18, 2014 56 toms include, but are not limited to, severe coupling. Binvay systemic sclerosis sine scleroderma), nephrogenlc systemic constrictinn and mucus production librosis. cystic fibrosis, cluonic graft vs host discase, or ath- crosclcm sls. [0579[ In one embodiment. provided herein is n method of trenllng, prcvcnung mid/or managing arllultls. As used [0584] In cert&un embodiments. Ihc librotic cond&non is a fibrotic condition the a tibrotic condition the liver, hcrcul, ill'linus cnconlpasscs Bll lvpcs and n&BB&fcs&B&ious of lung, of tiss. a fibrntic condition of the heart nr vasculature. a tibmtic of arthritis. I ixamples include. but are not limited to. crystal- condition the a fibrotic condition the skin. a line arthritis, osteoarthritis, psoriatic arthriti ~, gouty arthntls, nf kidney. of reactive arthriti~. rheumatoid arrhritis and Ifeiter's arthntis In fibrotic condition of the gastrointestinal tract. a hbrotic con- one embodiment, the disease or disorder is rhemnatoid arthri- dition ofthe bone marmw or a hematopoietic tissue, a fibrotic condition Of the no&vous system, a fibrotic condition of Ihc In another embodiment, the disease or disorder is ps onatic arllultis. Also prov&dcxf hcrmn is a method of Irculing, pre- cyc, or a combination thcrcof; s cnun Bnd/or nldnagulg Onc or nlolc ssnlptonls Bssoc&J&cd [0585] In Other cmbodunmu, Ihc librot&c condilion BIPccls a with arthritis I:xamples ofthe symptonls include. but are not tissue chose&1 trom one or nxlre of inuscle, tendon, cartilage, limited to, joint pain. which progresses into joint deforma- skin (e.g., skin epiderinis nr endodermis). cardiac tissue, vas- tion, or damages in body or ans such as in blood vessels, cular tissue (e.g., artery. vein). pancreatic tissue, luna tissue, hearb lungs. skin, and muscles. liver tissue. kidney tissue, uterine tissue. ovarian tissue, neu- ral tissue, testicular tissue, peritoneal tissue. colon. small [05801 In one embodiment. provided herein is n method of uucsliuc, biliary tract, gul. bouc marrow, hcmatopo&otic us- trenllng, preveul&ng mid/or managulg psoriasis. As used sim. Or cyc (c.g.. reunal) tissue. hcrcul, psoriasis In& on&passes dll tvpcs dud n&BB&fcs&B&ious ofpsnriasis. I ixamples include, but are not limited to, plaque [0586] In some cmbodimcnls, thc fibrotlc txlndition is a psoriasis (e.g., chronic plaque psoriasis, nxldemste plaque librolic comlilion of Ihc cyc. In some cmbodimenls, Ihc psoriasis mid severe plaque psoriasis). Uttate psonasis, fibrotic condition is glaucnma, macular degeneration (e.g, inverse psoriasis, pustular psoriasis, pemphigus In&igans, age-related macular degeneration). macular eden&a (e g, dia- erytluodennic psoriasis, psoriasis associated with inflnmma- betic macular edema). retinopathy (e, diabetic retinopa- tory bowel disease (IBD), and psoriasis assoc&u lcd with rheu- thy), or dry eye disease. matoid arthritis (ILA). Also provided hcrcin is a me&laid of BI [0587] In cert&un embodiments. Ihc librotic cond&non is a treatinu, preventing and/or managing one m &nore symptoms librolic condition of Ihc lung. hl ccrtaul cmboduncnts, Ihc associated ivith psonas is I:xanlples ofthe syinptoms include, fibrotic cmlditinn of the lung is chosen from one or &nore of but are not limited to: red patches of skin covered with silvery puln&ona&) fibmsis. idiopathic pulmonary fibmsis (lpl'), scales; small scaling spots: dry, cracked skin that mny bleed, usual interstitial pneumonitis (IJIP). interstitial lung disease. itclfing; burning, soreness: thickened. pitted or rid ed nails, cryptogenic fibrosing alveolitis (CFA), bronchiectasis. and and swollen mid stiff loin&a. sclcrodcmla lung disease. In one cmbodimcnL Ihc librosis of &s to a a u&suit, a [0581] In onc mnbodimmu, provnlcd hcrcm is a method of thc lung simondary discase. toxin, au mixhcal treatinu, preventing and/or managing fibmsis and fibultic treatment, ore combmalion thereof For example, the librosls condition. As used herein, "fibmsis" or "hbrotic condition ofthe lung can be associated with (e.g, seconihry to) nne or encompasses all types and manifhstations of fibrosis or more of: a disease proce~s such as asbestosis and silicosis: an fibrotic condition Examples include. but are not limited to, occupational hazard; an environmental pollutant, cigarette lormallon or deposition of issue fibros&si rixluculg thc size, smoking: an autoinunune connective tissue disorders (e... rheumatoid artlu&tis, sclcrodenna and systemic crylhc- cellulauty (c g., fibroblast or &nunune cell numbers), compo- lupus a as sarcoi- siuon, or ccllulur content, of a librol&c lcsum, reducing thc matosus (SLE)), conlmctlve ussuc dwordcr such collagen or hydroxypmline content, of a hbrotic lesion, dosls, an ulfccl&ous discase. c.g., ultecl&on, purl&cularly linl- reducing expression or activity of a fibrogenic protein; reduc- chronic in fectinn; a medical treatment. including but not in fibrosis associated with an inffiunmatory response, ited tn, radiation therapy, and drug themspy, e.g, chemo- Ivith decreasing v eight loss associated with hbrosis: or increasin therapy (e.g., treatment as bleomycin, methotrexate. amiodarone, busulfan. and/or nitrofurantoin). In one embodi- SU& v&V . ment, the librolic condition ofthe fun trcatcdwiththcmcth- [0582] In certain mnbodimcnls, the tibrolic cond&tlon is Odsrhosisof thc invention ls associated with (c.g., secondary lo) J priinary fibrosis In one embodiment, the fibrotic condition is ctlnccl ucilnucnL e.g.. Ircauucnl of a cancer (O.g., sqUBB&oos idiopathic. In other embodiments. the fibnltic cnndition is cell carcinoma, testicular cancer. I lodgkin's disease ivith associated with (e.g., is secondary to) a disease (e.g. Bn bleonlycin) In nne embodiment, the fibrotic conditinn ofthe infectious disease. an inflammatory disease, nn autoinunune lung is associated with an autoinunune connective tissue dis- disease, a malignant or cancerous disease. and/or a connec- order (e.g.. sclemderma or lupus, e.g., SLE). tive discase), a toxin: an insult (c g., an mls lromncnla1 Ilazard [0588] In cert&un embodiments. Ihc librotic cond&non is a (c.g.. asbestos, coal dusL polycycl&c aromalm hydrocarbons), librolic condition of ihc liicr. In certain cmboduncnts, Ihc ci arette smoking, a wound), a nledical treatment (e.g, sur- fibrotic cmlditinn of the liver is chosen from one or &nore of gical incision, chemotherapy nr radiation). or a cnmbination liver disease, steatosis B., nonalcoholic steatohepatitis thereof fatty (e (NASH). cholestatic liver disease (e.g . primary biliary cir- [0583[ In some embodiments. the fibrotic condition is 'Issu- s (PBC) ). cirrhosis. alcohol induced liver fibrosis. bi 1 iary e&a&cd with Bn Bulou&UUUnc discase sclcc&ixl floni sclcro- duct inlury, b&fiery librosis, or cholangiopatlucs In other ilcrnla or hlpUS. c.. syslcnuc ltlpUs cry&ion&B&osUs. In sonic cmboduucnts, hepatic or hvar fibrosis includes, bul &s nul cmbodimcnts, the fibrouc condition &s syslmnic. In some hmitcd lo. hcpal&c fibrosis associated with alcohohsm, viral embodiments, the hbrotic condition is systemic sclerosis infection, e.g., hepatitis (e.g, hepatitis (', l3 or D), autninl- (e .. limited systemic sclerosis. diffuse systemic sclerosis. or nnine hepatitis. non-alcoholic fatty iver disease (NAIII,D), US 20]4/0275 [35 A1 Sep. 18, 2014 57

progressive massive fibrosis. exposure to toxins or irritants bone marro~ is an intrinsic feature of a cttlonic myeloprolif- (C.g.. alcohol, phannacculical dru 9 mid cnvlromncntal tox- crativc ncslplasm of thc bone marrow, such as prunary ln9). myclolibrusis (also rcferrcd to hcrmn as aguogm»c mycloid [0589] In certain emboduucnls, the librolm condition is a metaplasia or chronic idiopathic myelohbrosis) In other librolic condition ol'he heart. In ccnaui mnbodunenls. thc embodinlents, the bone marrov hbrosis is associated ivith librotic condition of Ihc bean is myocarihal Iibrosls (c g., (e ., is secondary to) a malignant condition or a condition myocardial hbrosis associated with radiation myocarditis, 0 caused by a clonal proliferative disease In other embodi- sur ical procedure complication (e.g. myocardial post-op- ments. the bone marrow fibrosis is associated with a hemato- erative tibrosis), infectious diseases (e.g.. Cha ss disease, logic dlsoldcl (c.g., a llcnlalologu: dlsol'dcl'lloscll Iroul otic bacterial, trichinosis or fungal myocarditis)): granuiomatous, or morc Of polycylhcnua vera, essmitlal tluombocythcmlu. metabolic storage disorders (c.g., carihomyopalhy. hcmo- myelodysplasil, hairy cell leukemia, lymphoma (e.g, chromalosis): developmental disorders (e.g. mxlocardial I lodgkin or non-I lodgkin lymphoma). multiple myeloma or libroelaslosls); arlcnosclcrotic, or exposure lo loxms Or irn- cluonic myelo eneous leukemia (CML)). In yet other tants (e g., dnig induced cardioinyopathy. drug induced car- embodiments. the bone marmv hbrosis is associated with diotoxicity, alcoholic cardiomyopathy, cobalt poisoning or (e ., secondary to) a non-hematolo ic disorder (e.g.. a non- exposure). In certain embodiments. the myocardial fibrosis Is hcmatologic disorder chosen from solid tumor metastasis Io associated with an inflanmiatory disorder of cardiac tissue bouc marrow, an autoimmune disorder (C.g., systcnuc lupus (e.g.. myocardial sarcoidosis). In some embodiments. the erythematosus. scleioderm. mixed connective tissue disor- librolic condition is a librolic condition associated with a der, orpolymyositis), an infection (e g . tuberculosis). or sec- myocardial ullhrctlon. In some cmbodmicnls. Ihc librollc ondary hyperparathyroidism associated with vitamui I) def- condition is a fibrotic condition associated with congestive icienc. In some embodiments, the fibrotic condition is heart failure idiopathic or dnig-induced myelofibrosis. In some embodi- [0590] In certain emboduucnls, the librolm condition is a ments. the librolic condition of thc bone marrow or hcmalo- fibmtic condition of the kidney ln certain erubodiments. the poictic tissue is associatnl with systemic lupus erylhcmalo- fibmtic condition ofthe kidney is chosen from one or more of sus or scleroderma. renal hbrosis (e, cttionic tudney fibrosis). Bepllroputhies [0594] In one embodiment, provided herein ls a method of associated with injury/fibrosis (e.g.. chronic nepllroputhies treating, preventing and/or managing scleroderma. Sclero- associated with diabetes (c.g . dlabcuc nepluopaflly)), lupus, ilCrlllil Is B gl Clip 01 il19ei19CS thai lllvolvc hardCllulg alii llglll- sclcrodcmia of the kiihiey, glomcnilar ncpttnlts, focal seg- cnuig Of Ihc stun and/or other connective ussucs. Sclcro- mental glomcrulur sclerosis, Igar ncpluopalhyrciml Iibrosls dcrma muy bc tocattzcst (e.g.. affecting only thc skin) or associated with human chronic kidney disease (CKI)), systennc (e g., affecting, other systems such as. e g, blood chronic progressive nephropathy (( PN), tubulointerstltlal vessels and/or internal organs). Common symptoms of scle- fibrosis, uretemsl obstnictlon. chronic uremia. cluonic inter- roderma include Raynaud's phenomenon, gastroesophageal stitial nepttritts, radiation nephropathy. glomerulosclerosls, refhix disease. and skin changes (e.g., swollen fingers and progrcssivc glomcruloncpluusis (PGN), cndofhclial/lluom- hunds, or thickened patches of skin). In some emboduucnls. botic microangiopalhy uilury, kilV-associated nepluopathy, lllc sclcludcllna Is locidlLcd, c.g., lnorpllca 01'llcal sclcro- or librosis associated with exposure lo a toxul. an lrnnuit. or dcrma. In some cmbodimcnts, thc mlndilion m a systemic a chemotherapeutic agent In one einbodiinent, the fibnltic sclerosis, e.g, limited systemic sclerosis, diffuse systemic condition ofthe kidney Is scleroderma ofthe kidney ln some sclerosis, or systemic sclerosis sine scleroderma. embodiments, the fibrotic condition of the kidney is trans- [0595] Localized sclerodemia (localized cutaneous fibr- plant nepluopathy, diabetic nepluopathy, lupus nephritis, or osi) uicludcs morphea and luicar sclcrodcrma. IVIorphca is focal scgmcntul glomcrulosclcrosis (FSGS). typically characlenzcd by oval-shaped thickened patches of [05911 In certain embodiments, the fibrotic condition is a skin that are white in the middle, with a purple border I.inear fibrotic condition of the skin. In certain embodiments, the scleroderma is nmre common in children Syniptoms oflinear librotic muidition ol'hc skin is chosen from onc Or more of scleroderma may appear mostly on one side of the body In skin librosis (c g., hypertrophic scarnng, keloid). sclero- linear sclerodemla. bands or streaks of hardened skin may derma, nephrogcnic systemic librosis (c.g., resulling uftcr develop on one or both anna or legs or on the forehead. En exposure to gadolinium (which is frequently used as a con- I Clip dC SBbl 0 (flolllBI llllCBI SC1Crodi rllla OI lllolplli d Cll COUp trast substance for MRIs) In patients with severe kidney fail- ilc sable) Is 9 Ivpc 01 limdhLcd sck:I'odcrllla ty'plcdllv clullac- ure), and keloid terized by linear lesions of the scalp or face [05921 In certain embodiments, the fibrotic condition is a [0596] Systemic scleroderma (systemic sclerosis) fibrotic condition of the gastrointestinal tract. In certain includes. e.g.. limited systemic sclerosis (also knov n as lim- cmbodimcnts, the librotic condluon is clxlsen from onc or ited curdncous systemic sclerosis, or CREST syndrome), dil- morc ol: librosis associalrxl with sclerodermu. radiulion fllsc svslcnllc sclerosis (illso kllown d9 ihflUsc cU(ancoUB svs- induced gut hbrosis: hbrosis associated with a foregut inflani- tcmic sclerosis), and systmmc sclerosis suic sclcrodcrmu. matory disorder such as ltarrett's esophagus and chronic ('t(I)S I'tands for the follolving complications that may gastritis, and/or fibrosis associated with a lundgut inflamma- accmnpany limited scleroderma: calcinosis (e g., of the dig- tory disorder. such as inflammatory bowel disease (IBD), its), Raynaud's phenomenon, esophageal dysfunction. scle- ulcerative colitis and Crohn * a disease. In some embodiments, rodactyl), and telangiectasias. Typically. limited scleroderma the librolic condition ol'hc gaslroinleshnul tract is Iibrosls lnvolvi:9 cUIancoUs nlallllcsusllons thai lllBlnly allcct Ihc associated with scleroderma. hunds, anus. mid face. Linutcd and dilfusc subtypcs arc dis- [0593] In certain emboduucnls, the librolm condition is a tinguishrx! based on Ihc cxtcnt of stun uivolvmncnt, wlfll fibmtic condition of the hone marmw or a hematopoletic spanng of the proximal limbs and trunk in limited disease tissue In certain embodiments, the fibrotic condition of the See, e g., 1)eutou, (L P et at (2006),,'Varure ('/inir u//'rar rica US 20]4/0275 [35 A1 Sep. 18, 2014 58

Rite«t«a/c/o~; 2(3):134-143. The limited subtype also typically (e... as a topical cream, eyedmp, nose drop or nasal cally im olves a long previous lustory ufRuynuud's phcnom- spray). In some such embodiments. the compound ls a PI3K cnon. whereas in thc dilfusc sublypc, onset ol'aynaud's delta inhibuor (e.g.. a PI3K inlubttor tlrst demonstrates phenomenon can be simultaneous with other manifestations greater inhibition of P13K delta than ofother P13 K isofornls) or mi ht occur later Both limited and diffuse subtypes may In some embodiments, the F13 K delta inhibitor prevents mast involve internal organs. Typical visceral manifestations of cell de ranulation. limited systemic sclerosis include isolated pulmonary hyper- [0600] As used herein, "skin condition" includes any tension, severe bov el involvement, and pulmonary fibrosis. inflmnmatory condition of the skin (e.g., eczema or dermati- Typical visceral manlfbstations of dilluse systemic sclerosis tis. c.g, contact dermatitis. atopic deunauus, dermatlus hcr- includcrcnal costs, lung librosls, amlcardiacdiscusc. Diffuse pctifflrmis, scborrhcw. dcnnatitis, nummular dermatitis, sta- systemic sclerosis typically progresses rapidly and affects B sw dermatitis, pcrioral dcunatitis), as well as accompanying lar e area of the skin and one or more internal organs (e g., symptmns (e.g, skin mash, itchiness (pnlritts), swelling kidneys, esophagus, heart. or lungs). Systemic sclerosis sine (edenla), hay fever, anaphalaxis) I'requently, such skin con- sclerodenua is a rare disorder in which patients develop vas- ditions are caused by an allergen. As used herein. a "skin cular and fibrotic damage to internal organs in the absence of condition" also includes. e.g., skin rashes (e g., allergic cU(ancous sck:rusts. rashes, c.g., rashes rcsultul from cxposurc to allcrgens such [0597J In one embodinlent, provided herein is a method of as poison ivy, poison oah, or poison sumac. or rashes causixl trCBtitla, pl'CVClltlllg Slid/Ol'u,'illa ttl llrfl'lluluatoty ulVOpa- by other discascs or conditions), insect bites, muxlr burns, thi es. As used herein, "inflanunatory myopathies" encompass sunburn, minor cuts, and scrapes. In some embodiments. the all types and manifestations of inflammatory myopathies. symptmn associated with intlammatory myopathy. or the skin Exmnples ulcludc, but arc not luniied to, muscle wcahncss condition or symptom associated with the skin condition. is a (c.g.. pioxuual unlsclc weakness), skul rash, I'ltl Uc after skin rash or itchiness (pruritis) caused by a skin rash. walking or staudtn, tupptng or fallulg, dyspha ia, dyspho- [0601] The skin condition(e g.. the skin rash) may be spon- nia, difficulty breathing. nluscle pain. tender tnuscles. v eight tanruus, or it may bc induced, eg . by exposure to an allergen losg lmv-grade fever, inflamed lungs. light sensitivity, cal- (c g., poison ivy. poison oak, or poison sumac), drugs, loud. cium deposits (calcinosis) under the skin or in the muscle, as insect hite, inhalants. emotional stress, exposure to heat, well as biological concomitants ofinflanunatory myoputhies exposure to cold, or exercise. In some embodiments the skin um- as dtsclosixl hcrmn or as known in the Brt. Biological condition is a skin rash (e g . a pnlntic mash. e g, utricaria). In conutants of inflmmnatory myopatlucs (e.g., dcrnutfomyosi- some embodiments. the skin condition is Bn insect bite. In tls) lllclUdc, c g., BI(el'cd (c.g., Oleic'Bsixl) levels uf cvtoklucs some embodiments, the skin condition is associated with (e .. 'Iype I interferons (e g, 111N-u and/or 111N-[1), interleu- another discase (c.g.. ml ulflanunatory myopathy, c.g., dcr- kins (e g., 11,-6, II -10, II -15, II -17 and 11,-18). and TNluu), nultoulvosltls). TOF-J), B-cell activating factor (BAFF). overexpression of [0602] In some cmboduncnts, the subtcct (c.g.. thc sub)act IFN induci hie genes (e.g . Type I IFN inducible enes). Other in need of treatment for an intlammatory myopathy anrgor a biological conconutants of infliunmatory myopatlucs can skin condition) exhibits an elevated level or elevated activity include. e.g.. an utcrcascxl erythrocyte scdnuental«ln rate ofIF¹x, TNF-CU IL-6. IL-8. IL-I, or a combination thereof. (ESR) mid/or elevated Icvcl of crcaune kin«ac. Further bio- In certain embodiments, the subject exhibits an elevated level logical concomttants of mflammatory myopatlues can ofIF¹x. In some embodiments, treating (e.g.. decreasing or include autoantibodieg e.g . anti-synthetase autoantibodies ulhlbitlng) thc inflmnmatory myopathy, or thc skul cond thon, (e.g.. anti-lol antibodies). anti-signal reco~«utica particle compuscs inhibiting (e.g.. dccrc ising a Icvcl ol; or dccruising antibodies (anti-SRP). anti-Mi-2 antibodie~, anti-p155 mlti- a biological activity of) one or more of 111N-u, I'! -u. II -6, bodtcs. anti-PM/Sct antibodies, and mitt-RNP antibodies. fl,-g, or II -I in the subject or in a sample derived from the [0598J 'I he inflammatory nlyopathy can be an acute inflanl- subject. In some embodiments, the method decreases a level matory myopathy or a chronic inflammatory myopathy. In of IFN-u. TNF-u. IL-6. IL-8. or IL-I in the subject or in a some embodiments, the intlanuuatory myopathy i ~ a chronic sample derived from the subject. In some embodiment~. the inflanuuatory myopathy (e.g.. demlatomyositis, polymyosi- method dccrcascs a level of IFN-u in thc sub)Oct or ul B tis, or inclusion body myositis). In some embodiments. the sample dcnved from thc subffct. In some mnboduncnis, thc inflammatory myopathy is caused by an aflcrgtc rc wtion, level of lf N-u, 'I'Nli-ix. 11 -6, 11.-8. or 11,-1 ts the level another discase (c.g., cancer or B connective tissue discase), assessed in a sample of whole blood or PI3M('s In some exposure to a toxic substance, a medicine. or an infectious embodiments. the level of IFN u, TNF iu IL 6,1L 8, orlI -I agent (e 8, . a virus). In some enlbodiments, the inflammatory is the level assessed in a sample obtained by a skin biopsy or myopathy is associated with lupus, rheunlatoid arthritis. or a nulscle biopsy. In some embodiments, the sample is systemic sclerosis. In some embodiments. the inflammatory obtaulcd by B skin biopsy. myopathy is idiopathic In some embodiments. the inflam- [0603] In onc cmbodimult, provtdcxt hcreul ts a method of malory w selected from dcnnato- myopathy pulymyositis, treating, prcvcnting mid/or managulg myositi ~ . As usixl myositis, ulcluslon body myosius, mid mlmunc-mcdiutcd herein, "myositis" encompasses all types and nlantfestations In necmtizing myopathy some enlbodiments. the inflamma- ofnlyositis I ixamples include, but are not limited to. tnyositis tory myopathy is dermatomyositis ossificans. Iibromyositis, idiopathic inflanmlatory myopa- [0599] In another embodiment, provided herein is B method thles. dermatomyositis. juvenile dermatomyositis. polymyo- oftreating, preventing and/or m uluging a skm condition (c g., sltis, ulcluslon body myositis and pyomyositls. In onc a dermatitis) In some cmbodimcnts, thc methods provided cmboduucnt, the discase or disorder ts dcrmatomyosins. Also hcrcul can rcdUco svnlptouls B s sue 1 at ixl tvlfh B skul condition provided hcrcin is a method of treating, prcvcnung andtor (e .. itchiness and/or inflammation) In smue such embodi- uluflBgllig onc ot'uol'c'vulplollls associated ivlth lily'osiris ments. the compound provided herein is administered topi- I:xanlples of the symptoms include, but are not lmlited to US 20]4/0275]35 A1 Sep. 18, 2014

muscle weakness, trouble lifting annal trouble swallowing or ccut i cally acceptable fomt (e.g .. phannac cut i cally acceptable brea&hmg; muscle paul, muscle &cndcnlcss; langue; fever, salts, hydrates, solvatcs, isomers, prodrugs, and &so&opically lung problmns, gas&roultcstinal ulccrsi ultcs&inal pcrfiira- labchx! derivatives) tlmrcof. In onc aspec&, such therapy tions: calcinosis under the skin; soreness: arthritis; v mght includes, but is not limited to. the combination of the subject loss: and rashes. compound with chemotherapeutic agents. thenspeutic anti- [06041 In one embodiment. provided herein is B method of bodies. and/or radiation treatment, to provide a synergistic or treating, preventing and/or managing lupus. As used herein, additive therapeutic eifect. "lupus*'efers to all types and manifestations of lupus. [0608] By "in combination with;* it is not intended to imply Exmnples ulcludc, bu& arc no& limi&cd &o, sysfcnuc lupus that the other therapy and the PI3 K modulator must be admin- crv&heals&Usus; IUpUs neph&&1&s, cUlancoUS n&Bnifcs&B&ious &stcrcd at the same tune and/Or formula&ixl Ihr dcl&very .. seen in (e manifestations cutaneous lupus erythematosus, togo&hi:I, BlthoUgh these nlc&hogs ol dchvc&y dlc wl&hnl &hc e g., a skin lesion or rash): CNS lupus; cardiovascular, pul- scope of this disclosure 'I'he compound provided herein can muscu- monary, hepatic. hematologicaL gastrointestinal and be adnnnistered concurrently v ith, prior to (e g., 5 minutes, loskeletal manifestations: neonatal lupus erythematosus, 15 nnnutes, 30 minutes, 45 minutes. I hour, 2 hours. 4 hours, cluldhood systemic lupus erythematosus: dru -induced lupus 6 hours. 12 hours, 24 hours, 48 lxiurs. 72 hours, 96 hours, I erythema&osus; ant&-phospholip&d symlromc, and comple- v eek. 2 weeks. 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks. ment dclicimlcy syndromcs resulting in lupus mamlcstn&iona. 12 wccks, or 16 Cocks bcforc). or subscquml»o (c.g., 5 is In one embodiment. the lupus systemic lupus erythemato- nunu&cs, 15 minutes, 30 mulu&cs, 45 nunu&cs, I hour, 2 hours. sus (SI,I:). cutaneous lupus erytheniatosus (CI Ii), drug-in- 4 hours, 6 hours, 12 houri, 24 hours, 48 hours, 72 hours, 96 In embodin&ent, duced lupus. or neonatal lupus another the houri, I week, 2 weeks. 3 weeks. 4 weeks. 5 weeks, 6 weeks, lupus is a CLE. e.g., acute cutaneous lupus erythemutosus 8 weeks, 12 weeks, or 16 weeks after). one or niore other (ACLE). subacute cutaneous lupus er)xhematosus (SCLE), therapies (e... one or more other additional agents). In gen- hi&cia&i&tent cU&ancous IUpils clythcnldlosus (dist& known iis eral. each therapeutic agent will be administered at a dose lupus crydlematosus tumidus (LET)), or cluomc cutammus and/or on a time schcdulc de&enn&ned for &lrdt paruculdr In ('I.E is lupus. some embodiments, the intermittent chronic agml&. Tllc other &hcrapcu&ic agml& can bc adminis&crcd w»h discloid lupus erythematosus (Cl)l,l 1) or lupus erythemato- the compound provided herein in a single composition or sus pmfundus (I.lip) (also known as lupus erythen&atosus separately in a different composition 'I'riple therapy is also paluliculitis). Types, symptoms. and pathogenesis ofCLE are contemplated herein. described. for example, in Wenzel et al. (2010), lupus. 19, 1020-1028 [t)609J In general. it is expected that additional thenlpeutic agents employed in combination be utilized at levels that do [0605J In one embodinient, provided herein is a method of not exceed the levels at which are utilized In treating, preventing and/or managing Sjbigren*s syndrome. they individually. some embodiments. the lci cia utilized ul combulation will bc As used herein. "Sjo ren*s syndrome** refers to ail types and lower &hdn &hose U&&i&Lcd manifestations of Sjo ren's syndrome. Examples include. but individually are not Inn&ted to, pnmary mid semindary S)ii rcn's syn- [0610] In onc aspect. a compound as provulcd hcreul, or a ilroale. Also prov&devi helen& Is d ale&hod 01 0 ixnnlg, prcvcn&- phumlaccu»cally accep&able form (c.. phannaccutically ing and&or managing one or niore symptoins associated v ith acceptable salts, hydratev, solvates. isomers, prodrugs. and Sjbgren'1 syndrome Iixamples ofthe symptoms include. but isotopically labeled derivatives) thereof. orphannaceutical are not limited to dry eyes: dry mouth; joint pain; swelhng, compositions as provided herein. can present synergistic or stiffness: sv ollen salivary glands: skin rashes: dry skin: vagi- additive CIF&cacy lvhen administered in combination with nal dryness: persistent dry cough: and proion ed fatigue agml&s &hat inlubit IgE production or activ»y. Such combmd- [0606J In some embodiments. a syinptom associated v ith tion can reduce &hc undesired elfcct of lugh lcvcl of I E the disease or disorder provided herein is reduced by at least associated with thc usc of onc or morc P13K-8 &nh&bi&ors, if 'I'his 10; 6, at least 20'/6. at least 30'/w at least 40%, at least 50%. at such effect occurs. can be particularly useful in treatment least 60'/6. at least 70'/6. at least 80'/0 at least 90%, or at least of mitoinm&une and inflammatory disorders (AI II)) such as 95; 6 relative to a control level. The control level includes any rhemnatoid artluitis. Additionally. the administration of appropna&c con&rol as known ul &hc art. For ex;unplc. thc P13K-8 or PI3K-8/7 inhibitors as provided herein in combi- control level cml bc the prc-&res&mcn& Icvcl in lhc s unplc or nu&ion with udubiiors of mTOR can also cxlubit synergy subject trea&CI. or it can be the level in a control population through cnhmlcixl inhibition 01 the PI3K pa&hway. (e .. the level in sub)acts who do not have the disease or [t)611J In a separate but related aspect, pmvided herein is a disorder or the level in samples derived Ibom subjects who do combination treatment of a disease associated with PI)K-8 not have the disease or disorder). In some embodiments, the comprising administering to a P13K-8 Inhibitor and an agent decrease is statistically signihcant. for example. as assessed that Inhibits IgE production or activity Other exemplary using ml appropma&e parmnc&ric or non-parametric stntis&ical Pl)K-8 n&h&bi&ors arc applicable for &lus combine»on and companson. they arc dcscribcd, c.g., U.S. Pat. No. 6,800,620. Such combination trcauncnt is particularly uscliil for &rcaung autoun- 8. COMBINATION THERAPY nn&ne and inflammatory diseases (AIII)) including, but not [0607] In some embodiments. the compound provided linuted to rheumatoid arthritis herein is aihninistered in combination with one or more other [0612] Agents that inhibit IgE pmduction are known in the therapies. In onc mnboduncnt, provided hcrcin are methods ar& and they include. but arc no& limi&id to. one or morc of for comburdtion therap&cs in winch an agml& known &o modu- TEI-9874, 2-(4-(6-cyclohcxyloxy-2-naphtyloxy)phenylac- late other pathways, or o&hcr componcnls of Ihc same pa&h- c&amide)benzoic acid. rapmnycul, rapamyc&n analogs (&.c.. way, or even overlapping sets of target enzymes are used in nlpalogs), 'I'ORCI inhibitors. 'IOI&('2 inhibitors. and any combination with a compound provided herein, or a phanna- other compounds that inhibit m I'ORE I and m'I'OR('2 US 20]4/0275 [35 A1 Sep. 18, 2014 (]0

Agents that inhibit IgE activity include, for example, anti-IgE tnetylenephosphoramide, triethylenethiophosphaoramide

ant&bod&ca such as for example Omalizumub and TNX-901. and tnmethylolomelamine: 13 I'K inhibitors such as ibrutinib [0613] For trcauncnt of auto&uumuic diseases, a compound (PCI-32765) and AVL-2921 HDAC inhibitors such as vori- as provided here&n, or a pharmaccuucally acceptable fi&mi nostaL ronudcpsin, panobinoslat, valproic acid, bcluioslah

(e .. pharmaceutically acceptable salts, hydrates, solvates, mocetinostat. abrexinostat, entinostat. SB939, resminostat. isomers. pmdrugs, and isotopically labeled derivatives) givuiostat, CUDC-101. AR-42, CHR-2845, CkiR-3996, thereof, or pharmaceutical compositions as provided herein, 4S('-202, ('(i200745, A('Y-1215 and kevetrin: .IAK/STAT can be used in combination with commonly prescribed dnigs uihibitors such as lcslaurtuiib. &ofacitu»b, ruxolilunb. pacri- aumisc inclu dmg, but not luni text to Eubrcligv Rmumddc ii., Hunurdiss tinib, CY'1387, baricitinib. fostamatinib. (il,p(i0636, Ai oncx'8. and Rcb&fiig. For trcauncnt ofrcspirulory diseases, TCi101348, INCB16562 and AZDI480, n&lrogcn mustards the subject compounds or phannaccuucal compos&tions can such as bedamustine, chlorambucil. chlornaphazine, cholo- I be administered&in combination ivith cominonly prescnbed phosphamide. estramustine, ifosfamide, mechlorethamine. but not limited to Xolairft, Advairg, Smgu-

dnlgs including, mechlorethamine oxide hydmchloride, melphalan, noveni-

lairg&, and Spiriva a'0614] bichin, phenesterine, prednimustine, trofosfamide, umscil The compounds as provided herein. or a phnmla- nnlstard; nitmsureas such as carmustine. chlorozotocin, tbte- ceutically acceptable form (e.g . pharmaceutically acceptable mustine. Iomustine. ninnlstine, ranimustine, antibiotics such salts. hydrates, solvalcs, isomers. pmdru s, and isolopicully as aclacinomysins. actinomycm, authramycin, azaserine. labeled dcm at&v ca) thcrco I; or pha ca I compositions blcomycins, caclinomycui, calmhcamicin, camb&c&n, cami- as provided herein, can be formulated or administered in nomycui. carzinoplulin. Cdsodex™, chromomycuis, dacti- conjunction with other agents that act to relieve the symptoms noniycin, daunorubicin. detorubicin, 6-diaz0-5-oxo-l.-nor- of inflammatory conditions such as encephalomyehtis, leucme, doxorubicin. epirubicin, esonlbicin. idarubicin, astlmia, and the other diseases described herein. These agents nmrcellomycin, mitomycins. mycophenolic acid. noualmny- include non-steroidal anti-inflammatory dru s (NSAIDs), cul. Ollvonlvc&1&s, pcplonls'el&1, potflroinvchl. purollly'cul. c.g., acctylsahcylic acid, ibuprofen, naproxcn. uidomethacin, quelamycin. rodonlbicin. streptonigrin, streptozocln, tuber- metho- nabumelonc, lolmctin, etc. Corucostcro&ds are used to reduce cidin, ubcnimcx. zinostatin, zorubicin, anti-mctabol&lcs such inflammationandsuppressactivityoftheiinmunesvstmn An as mclhotrcxatc and 5-fluorouracil (S-FU), foie ac&d ana- exemplary drug of this type is Prednisone. Chloroquine logues such as de nopt erin, methotrexate, p ms letrexate, pte m- (Aralen) or hydroxychloroquine (Phsquenil) can also be used pteri, trimetrexate; purine analo s such as fludarabine, 6-mer- in some inihviduals i& ith lupus. They can be prescribed for captopurine, thiamiprine. thioguanine; pyrimidine analogs skin and joint symptoms of lupus. Azssthioprine (Imuran) and such as ancitabine. azacitidine, 6-szauridine. caunof'ur, cyz- cyclophospham&dc (Cytoxan) suppress uillanunation and arabine. dideoxyuridine, doxifluridine, enocltabine. floxuri- tend to suppress the &nunuuc system. Oiler agents. cg., dinc, androgcns such as caluslcronc, dromostauolonc propi- trexatee and cyclosporin are used to control the symptoms of oiiutc, cpilioslanol, mcpitiostanc. Icstolaclonc, anl&-adrcndls to lupus. Anticoagulants are employed prevent blood froni silcl& tls iunulogh&lclhunnlc. 1111&oldnc, tnlosldnc: lollc acnl clotting rapidly 1'hey range from aspirin at very low dose replenisher such as frolinic acid: aceglatone; aldophospha- which prevents platelets fmm sticking, to heparin/coumadin. nude glycoside; aminolevulinic acid; amsacrine: bestrabucik Other compounds used in the treatment of lupus include bismitrene: edatraxatet defofamine, demecolcine: diazi- bclnuumab (Beulystag). quone: elfomithine: elliptinimn acetate: etoglucid, gallium [0615] In miolhcr aspect, prov&dcd barmn &s a phannaccu- nitrate, hydroxyurca, lcntuiani ion&dam&ac, nnloguazone.

tical composition Ihr uih&biting abnormul cell grov,th in a iultoxan&101&m I&lop&du&&101. Ol id crux m pcilto s td lul, phcnanlcl, subject which comprises an amount of a coinpound as pro- pirarub&cin, podophyllulic acid; 2-ethylhydrazidc, procarbd- vided herein. or a pharniaceutically acceptable forni (e g., inne, PSK.R™ mszoxane; sizofiran; spirogermanium; tenu- phannaceutically acceptable salt~. hydmstes, solvates, iso- azonic acid: triaziquone: 2.212"-trichlorotriethyla-niine; ure- mers. prodnlgs. Snd isotopically labeled derivatives) thereof, than: vuidesine: dacarbazine; mannomustine: mitobronitoh in combination with an amount of an anti-cancer agent (e mltolactol; pipobroman; acytosine; arabinoside ("Ara-C**): a chcmolhcrapcuuc agent). Mmiy chemofllerapcutics arc cyclophosphamidc; tluotcya: laxmlcs, c.g., pachlaxel presently known in thc art and can be used in combuialion (TAXOL™, Bnslol-Mycrs Squibb Ontu&logy, Princeton. with the compounds as provided herein. N.J.) and docctaxcl (TAXOTEREtv, Rhouc-Poulcnc Rorer. [0616[ In some embodiments, the chemotherapeutic is Antimy, I&rance) and AI3RAXANIili: (paclitaxel protein- selected from mitotic inhibitors. alkyhsting agents, anti-me- bound particles); retinoic acid; esperamicins: capecitabine; tabolites. intercalating antibiotics. growth factor inhibitors, and pharmaceutically acceptable forms (e.g., phamiaceuti- cell cycle inhibitors, enzymes, topoisomemsse inhibitors. bio- cally acceptable salts. hydrates, solvates, isomers. prodrugs. log&Cdl ICSponSC 11&odlflers. d&111-110111101&CS. Iulgn&gCOCS&S and iso&op&cally labeled dcnvatives) of any ol'thc above. Also inhibitors, and unti-androgmls. Non-lumung ex;unplcs arc ulcludcd as suitable chemotherapeutic cell o&nditioncrs arc chemolhcrapcuuc agmlls, cytotoxic agcnls, and non-pep&ale anti-lx&nuonal agents that act lo rcgulalc or inlubit honnonc small molecules such as (ileevectg (Imatinib Mesylate), Vel- action ml tunmrs such as anti-estrogens including fbr cadelr (bortezomib). Casodex (bicalutamide), Iressagh and example tamoxifen (Nolvadexua) raloxifene, aromatase Adriamycin as well as a host of chemothempeutic agents. inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene. Non-limiting examples of chemotherapeutic agents include keoxifene, LY 117018, onapristone. Snd toremifene (Far- alkylaung agents such as lhiotcpa and cyclosphosphamulc cston): and anti-androgcns such as lb&tarn&dc, mlutanmlc, (CYTOXAI&pn), alkyl sufi'one tea such as bu su 1 1'h unprosul- bicalutamidc, lcupruhdc, and goscrclin, chlortunbucil, cm- fan a&xi piposullhu, aziridulcs such as bmizodopa. carbo- citubinc: 6-thioguaninc: mcrcaptopunuc, methotrexate. quone. meturedopa. and uredopa: ethylenimines and methy- platinum analogs such as cisplatin and carboplatin; vinblas- lamelamines including altretainine. triethylenemelanune, tine, platinum; etoposide (VP-16), ifosfamide; mitomycin (1 US 2014/0275135 A1 Sep. 18, 2014

mitoxantrone; vincristine: vinorelbine: navelbine, NCT0110Ci508; PF-04449913 described, e.g., in National nnvantrone; teniposide: daunoniycin; aininopterin: xeloda, Institute of I lealth ( finical 'I'rial Identifier No ibandronate; camptothecin-11 (C'PT-11); topoisomerase NCT00953758; Hedgeho pathway antagonists provided in inhibitor RFS 2000, difluoromcthylormflnnc (DMFO). U.S. Patent Application Pubhcation No. 2010i0286114, Where dcsircd, thc compounds or phannaccutical mimposi- SMOi2-17 desvnbed, c.g., U.S. Patent Application Publica- tion as provided herein can bc used in combination with tion No. 2010/0093625, SANT-1 and SANT-2 described. commonly prescnbed anti cancer drugs such as I lerceptmg, e g., in RomingerC M et el.,/. l'izarnincol leip 7her 2009; Avastin8, Iirbituxeh Rituxan)e I'axolek Arimidexkb Taxo- 329(3)5)95-1005; I-piperazinyl-4-arylphthalazmes or ana- tereig( ABVD, AVICINE, Abagovomab. Acridine cnrboxam- logues thereof, described in Lucas B. S. et al, Bvoovg. Mev/. ide. Adecatumumab, 17-N-Allylamino-17-demethox- C.iiem. Ler/. 2010: 20(12):3618-22. ygcldanmnycin, Alplraradui, Alvocidib, 3-Anunopynduic-2- [0618) Other chemothcrapcutic agents include, but are not carboxaldchydc thioscmicarbazonc, Amona fide, limited to. anti-i:strogcns tamoxifcn, raloxifcne, and Antluaccncdione, Anu-CD22 unmunotoxins. Antuicoplas- (e.g. megestrol), I,I IRI I agonists (e . goscrclin and leupmlide), tic. Antitumorigenic herbs, Apaziquone, Atiprinuid. Azathio- anti-androgens (e g. flutamide and bicalutamide). photody- prine. 13elotecan, 13endannistine, 13I13)V 2992. 13iricodar, namic therapies vertnporfin (13RD-MA). phthalocya- Brostallicin. Bryostatin, Butlfionine sulfoximine. CBV (che- (e.g nine. photosensitizer Pc4, and demethoxy-hypocrellin A motherapy), Calyculin, Crizotinib, cell-cycle nonspecihc (2BA-2-DMHA)), nitmgen mustards cyclophospha- antineopfnstic Dichloroacetic acid. Discodemiohde, (e.g, agents, nudc, ifoslhmide. irofosfamidc, chlorambucil, cstrmnusunc. Elsanutrucin. Enocitnbuic, Epothilonc, Enbulin. Evcrohmus, and mclphalan), nitrosourcas carmustine (BCNU) and Exatccan. Exisuluul, Ferruginol, Forodcsuic, Fosfestrol, ICE (e.g lomustine (('('NU)), alhylsulphonates (eg busulfan and chemotherapy regimen. I I(101. Iniexon, Imiquimnd, Indolo- treosulfan). triazenes (e.g. dacarbazine. temozolomide), carbazole. Irofulven. I.aniquidar, I.arotaxel, I,enalidonude, platinum containing cnmpounds cisplatin, carboplatin, Lucanthone, Lurtotecan. Mafosfamide. Mitozolomide, (e 8 oxaliplatin)„vince alkaloids (e.g. vincristine, vinblastine. Nafoxidine, Nedaplatin, Olaparib. Ortatnxel. PAC-I, Paw- vindesine. and vinorelbine). taxoids (e.g paclitaxel or apacli- paw, Pixantmne, Proteasome inhibitor, Rebeccnmycin, taxcl cquivalcnt such as nanoparticlc albumin-bound pacli- Rcsiquimod, Rubitccan, SN-38. Salinosporanudc A. Sapac- taxcl (Abraxanc), docosahcxaenoic acid bound-pachiaxel itabuic, Stanlbrd V. Swainsoninc, Talaporlin, Tariquirhir, 'I' (I)I IA-paciitaxel, 'I'axnprexin). polyglutaniate bound-pacli- 'I'egafiir uracil. 'I emod sr, 'I'asetaxel, 'I'rip tetranitrate. s latin taxel (V(i-paclitaxel, paclitaxel poliglumex. ("I(2103, XYO- (2-chlornethyl)amme, 'I'mxacitabine, Uramustine, Vadime- 'I'AX), the tunmr-activated prodnig I'A AN(i1005 (Angio- zan. Vinflunine. ZD6126, and Zosuquidar. ( V) pep-2 bound to three molecules of pachtaxel), paclitaxel- [0617] In some embodiments, the chemotherapeutic is EC-I (paclitaxel bound to the erbB2-recognizing peptide sclcctcd from hcdgchog inlubitors uicluding. but not lunitcd EC-I), and glucose-coniugatcd paclitaxcl, c.g.. 2upachiaxel to IPI-926 (Scc U.S. Pat. No. 7,812,164). Other suitublc methyl 2-glucopyranosyl succuratc, docetaxcl, taxol), cpi- luxlgchog utfubttors include. for example, those descnbcd podophyllins (c.g. etoposidc, ctoposide phosphate. Icnipo- and provided in U 8 Vat. No 7.230,004, U S Patent Appli- side, tnpotecan, ')-aminocamptothecin. caniptoinnotecan, 'R cation Publication No 2008/0293754, U 8 Vatent Applica- innotecan. crisnatoi, mysomycin ('). anti-metabolites, Dl II tion Publication No. 2008/0287420, and U.S. Patent Appli- inhibitors (e.g. methotrexate, dichloromethotrexate. trimetr- cation Publication No. 2008/0293755. the entire disclosures exate, edatrexate). IMP dehydro cease inlubitors (e.g. myco- of which arc incorporated by rcli:rance hcrcui. Exmnplcs of phcnolic acid, tiazol'unn, ribai inn, and EICAR), ubonuclc- other suitable hcdgchog uihibitors uicludc those dcscubcd in oudc rcductasc mlubitors (c.g. hydroxyurea and U.S. Patent Application Publicauon Nos. US 2002/0006931, deli:roxamine). uracil aimlogs (c g. 5-fluorouracil (S-FU). US 2007i0021493 and I IS 2007i0060546, and International tloxuridine, doxifluridine. ratitrexed, tegafiir-umcil, capecit- Applicatinn Vubhcation Nos. WO 2001/19800. WO 2001/ abme), cytnsine analogs (e 8, cytarabine (ara 0). cytosine 26644, WO 2001/27135. WO 2001/49279, WO 2001/74344, arabinoside. and fhidarabine). purine analo s (e g. mercap- SVO 2003/011219, WO 2003/088970. WO 2004/020599, topurine and Thioguanine). Vitamin D3 analogs (e.g. EB WO 2005/013800. WO 200Si033288, WO 2005/032343, 1089, CB 1093, and KH 1060), isoprcnylauon utlubitors (c.g. WO 2005/042700. WO 2006i028958, WO 2006/0503SI, loves)a)in), dopmnincrgic ncurotoxins (c.g. I-methyl-4-phc- WO 2006/078283. WO 2007i054623, WO 2007/0591S7, nylpyriduuum ion), cell cycle inhibitors (c. staurosporuic). Vv'0 2007i120827. WO 2(X)7/131201. Vv'0 2008/070357, actinnmycin (e g. actinnmycin D. dactinomycin), bleomycin Vv'0 2008 i I 1061 1. WO 2008/ I 12913, and WO 2008/13 1354 (e g. bleomycin A2, bleomycin 132, peplomycin), anthracy- Additional examples of hedgehog inhibitors include, but are cline (e g. daunonibicin, doxonibicin, pegylated liposomal not limited to. CiDC-0449 (also known as RCI3616 or vismo- doxorubicin. idarubicin, epirubicin, pimrubicin. zorubicin. dcgib) dcscribcd in, c.g., Von HolT D. ct al., 3/ Engl. J. Mad. nutoxantrunc). MDR inlubitors (c. vernpamil), Ca2+ 2009; 361(12):1164-72, Robargc K. D. ct al.. Bi oorg Mev/ ATPasc inhibitors (c.g. thapsigargui), nuauiub, thahdonudc. C/iem. Lc//. 2009, 19(19). 5 S76-81, Ymich, R. L. ct al. (2009) lcnalidomnle, tyrosuic kuiase uthibitors (c.g., axiunib Bcii race 326: 572-574; Sciencexpress 1-3 (10 1126/science (A(i013736), bosutinib (SKI-606), cediranib (Rii('I iN- 117')386): Rudin, ('t al. (2009) /Veri /'ngfvvnv/ J vv/ vr/rv/vvv ne 'I'INsu, A/02171). dasatinib (SVI(Y('lil St, 13M.'3-354825), 361-366 (10.1056/nejma0902903): BMS-833923 (also erlotinib (TARCEVA8), gefitinib (IRESSA8), imatinib known as XL 139) descnbed in. e.g.. in Siu L. et al .. J. Clm. (Cileevec/(i, CCiP57148B, STI-571). Iapatinib (TYKERB8 Onco!. 2010, 28.15s (suppl, abstr 2S01), and Nauonal Inst&- TYVERBttt). Icstmirunib (CEP-701). ncratuiib (HKI-272). tutc ol'ealth Cluucal Trial Identifier No. NCT006701891, nilotinib (TASIGNA((i'). scmaxanib (scmaxuiib. SU54i6). LDE-225 dcscnbcd. e.g., in Pan S. ci ul, 4CB v)fev/. Chere. sunitinib (SUTENT(a( SU11248), toccranib (PALLADIACK).

/.rn . 2010: 1(3): 130-134; I,I:O-506 described. e.g . in vandetanib (/A(71'IMAmh /06474), vatalanib (Vl'K787, National Institute of Ilealth ('finical 'I rial Identitier No Vl'K//K), trastummab (I IER('I:V I'INS(). bevaciiuunab US 20]4/0275 [35 A1 Sep. 18, 2014

(AVASTIN',a'), rituximab (RITUXAN!Su), cetuximab (ER- (e ., Novartis BEZ235). In one embodiment, the PI3K BITUX'8). panitunnimab (VECTIBIXN), rambizumab (Lu- uihibitor is iui isoquinoluione. cenus 8). iulotinib (TASIGNA&ig), sorali:iub (NEXAVAR,(&'), [0622] In some cmbodunmits, provided hcrcin is a method evemlimus (Al&INCIOIC)t), alemtuzuniab (('AMPA'I litt), for usiilg tltc. B collipiiuiid Bs plovidcsl llcrciii, ol B plialitia- gemtuzumab ozoganiicin (MYI,OIARGS(). temsirolinnis ceutically acceptable foun (e.. pharmaceutically acceptable (TORISEL8), ENMD-2076. PCI-32765. AC220. dovitiriib salts, hydrates, solvates, isomers, prodrugs, and isotopically lactate (TKI258. CHIR-258), BIBW 2992 (TOVOKS&&), Labeled derivatives) thereof, or pharmaceutical compositions SCJX523. PF-04217903, PF-02341066. PF-299804. BMS- as provided herein, in combination with radiation therapy in 777607, ABT-NC&9, MP470 BIBF 1120 (VARGATEF,S'), uihibiting abnormal cell growth or treating the hypcrprolil- AP24534, JNJ-26483327, MGCD265. DCC-2036, BMS- crativc disorder in thc subject. Techniques I'or mhnuustcnng 690154, CI:P-11981. tivozanib (AV-951). OSI-930, radiation therapy arc ktiown ui the art, and these tixluuques MM-121, Xl -184, XI,-647, and/or XI.228). proteasome can be used in the combination therapy described herein. 'I he inhibitors (e.g.. bortezomib (Velcade)), mTOR inhibitors administratimi of the compound as provided herein in this (e.g.. rapamycin, temsirohmus (CC'1-779). everolimus c&iiiilimation therapy can be determined as described herein. (R.«D-OOI). ridaforolimus.AP23573(Ariad).AZD8055 (As- [0623] Radiation therapy can be administered tlmiugh one traZcucca), BEZ235 (Novartis), BGT226 (Norvurtis). XL765 of several methods, or a combination of methods. includin (Sanoli A&mitts), PF-4691502 (Plizcr), GDC0980 without limitanon cxtcnml-bemn therapy. &ntcrnal radiation &1126 081-027 ((ienetech), Sl (Ben&afric) and (OS I)), tllcrapv, ill&plait& i'iid&B&loli. stele'iitBC&lc i'ddiostir'gcrv, svs- obli&Tlat'scil, gcmcltablllc, cailuliom)'ciii, lcilcivv&illli. pciiicti'- tenuc radiatimi thempy, radiotherapy and permanent or teni- exed, cyclophosphamide, dacarbazine, procarbizine, pred- porary interstitial brachytherapy. I he tern& "brachytherapyy nisolone. dexamethasone. campathecin. plicnmycin. aspam- as used herein, refers to radiation thempy delivered by a ginase, mninopterin, methopterin, porhromycin. melphalan, spatially confined radioactive material inserted into the body lcurosulinc, lcurosuic. chlormubucil, udbcctcdm, procarba- at ornear a tumor or other proliferative tissue disease site. The LiilC. iliSCOOCIiliolldC, CdilllllolllVClil, alllllloptCllli. Bixl llCS- tenn is intended without lnuitation to include cxposurc to amethyl melamine. radioactive isotopes (c g.. At 211, 1-131. 1-125. Y 90. Rc-i 86. [0619] ExempLary biothemspeutic agents include, but are Re-INN, Sm-153, Bi-212. P-32. and radioactive isotopes of not limited to, interferons, cytokines (e.g.. tumor necrosis I u) Suitable radiation sources for use as a cell conditioneras lactor. &Oterferon &i. &nterfemn I), vaccmcs, hematopoictic pmvided herein include both solids and liquids By way of growth factors. monocloual scrothcrapy, mununosfimulants non-limiting example, the radiation source can be a radionu- and/or immunodulatory agents (e, IL-I, 2. 4, 6, Or 12), clide. such as 1-125, 1-131, Yb-169. Ir-192 as a solid source. immune cell growth factors (e g, GM-('SI&) and antibodies 1-125 as a solid source. or other mdionucltdcs that emit pho- (e . Ilerceptin (tmstuzumab). T-l)MI, AVAS'I'IN (bevaci- tons. beta particles, gamma radiation, or other therapeutic zumab), ERBITUX (cetuximab), Vectibix (panitumumab), mays 'lite radioactive inaterial can also be a fluid inade front Rituxan (rituximab), Bexxar (tositumomab)). any solution of radionuclide(s), e.g, a solution of 1-125 or [0620] In some embodiments, the chcmothcrapeutic is 1-131, ore radioactive thiid can be produced using a slurry of selected from I ISP90 inhibitors 'I'he I ISP90 inhibitor can be a suitable thiid containing small particles of solid radionu- a geldanamycin denvative, e g, a benzoquinone or hygro- clides, such as Au-198. Y-90. Moreover, the msdionuclide(s) quinone ansamycin HSP90 inhibitor (e.g.. IPI-493 and/or can bc cmbodicd ui a gcl or radioucuvc nucro sphcrcs. I PI-504). Non-limiting examples ofHSP90 inhibitors include [0624] Without being lunitcd by miy theory, the com- IP1-493, IPI-504, 17-AACi (also knovvn as tanespimycin or pounds as prov&desi hcrmn, or a phannaccuticdlly acccptablc CNF-1010). BEB-021 (CNF-2024), BHB-028. AUY-922 foun (e g.. pharmaceutically acceptable salts. hydrates. sol- (also known as VER-49009), SNX-5422, STA-9090, vates, isomers, prodnigs, and isotopically labeled derivatives) A'IC133 87, XI.-8N8, M P('-3100. CI1-0305, 17-1)MA(i, CNI&- thereof. or pharmaceutical compositions as provided herein. 1010, Macbecin (e 8, Macbecin I. Macbecin II). C('T- can render abnomial cells more sensitive to treatment with OIN159, ('("IC129397 PU-I 171, or PIC04928473 (SNX- radiation for purposes of killing and/or inhibiting the growth 2112). of such cells. Accorduigly. provided hercu»s a method for [0621] In some embodiments, the chcmothcrapeutic is smisitizing abnomial cells ui a subject to treatment with radia- sclcctcd from PI3K inhibitors (c.g., includmg those PI3K tion which comprises administering to the subject an aniount inhibitor provided herem and those PINK inhibitors not pro- of a compound as provided herein or pharmaceutically vided herein). In some embodunent, the PI3K inhibitor is an acceptable fonna (e.g., pharmaceutically acceptable salts. inhibitor of delta and ganuna isofonns of PI3K. In sotne hydmstes. solvates, isomers, prodrugs, and isotopically embodiments, the PI3K inhibitor is an inhibitor of alpha Labeled derivatives) thereof, v.hich amount is elfective is sen- isolbnus of PI3K. In other cmboduncnis, thc PI3K inlubitor sitizing abnormal cells lo treatmmit with radiation. Thc is mi mlubitor of onc or morc alpha, bcm, delta un&1 gamma amount of the compound used in tlus method can bc dctcr- isolbnus of P13K. Exemplary PI3K uilubitors tlmt can bc nuned according to the means for ascertaining effective used in combination are described in, e g., WO 0')/ONN,990, amounts of such compounds described herein. WO 09,'088.086. WO 2011/008302. )VO 2010/0363NO. WO [t)625[ I he compounds as provided herein, or a pharma- 2010/00608(i, WO 09/114.870, WO 05/11355(i; US 2009/ ccut i cally acceptable form (e.g .. phannac cut i cally acceptable 0312310. and US 2011/0046165. Additional P13K inhibitors salts, hydrates, solvates, isomers, pmdnigs, and isotopically that can bc used in combuiauon with thc pluinnaccutical labchx! dcnvativcs) thereof, or phannaccuucal compositions composiuons. include but arc not linutcd to, AMG-319. GSK as providml hcrcui, can bc used in combination with dn 2126458. GDC-0980, GDC-0941, Smioli XL147, XL499, amount of onc or murc subsuuiccs sclcctcd from anti-angio- XI 756, X1,147 Plu46915032 l3KM 120. ('AI.-101 (Cig- cenesis agents, signal transduction inhibitors. and antiprolif- 1101), CAI 263, SI&1 126, PX-886. and a dual PINK inhibitor erative agents. glycofysis inhibitors. or mitoplmgy inhibitors US 20]4/0275 [35 A] Sep. 18, 2014

[0626] Anti-angio enesis agents, such as MMP-2 (matrix- pidrogel. vasodilating agents. e, nitmtes, calcium channel metalloproteinasc 2) inlubitors, MMP-9 (matrix-metallopro- blockmg drugs. antiprolifcratn c agents. c.g., colclucinc and ticiwsc 9) uihibitors, and COX-11 (cyclooxygenasc 11) alkylanng agents. uitcrcalating agents, growth modulating inhibitor, can be used in conjunction with a compound as factors such as interleukins, transformation growth factor- pmvided herem and pharmaceutical coinpositions descnbed beta and congeners of platelet derived growth factor, mono- herein. Anti-angiogenesis agents include, for example. rapa- clonal antibodies directed against growth factors, anti-in- mycin, temsirolimus (CC1-779), everolimus (RAD001), sor- flanunatory agents, both steroidal and non-steroitksl, and afenib, sunitinib, and bevacizumab. Examples of useful other agents that can modulate vessel tone. function, arterio- COX-II udubitors include CELEIJREXrv (alccoxib), vuldc- sclerosis, iuid thc hcalmg rcsponsc to vessel or organ iniury coxib. mid roli coxib Examples ol'uselbl nuitnx metallopro- post intcrvcntion. Antibiotics can also be included in combi- teinase inhibitors are described in 9'0 96i/33172 (pubhshed nations or coatings Moreover. a coating can be used to effect Oct. 24. 1996). WO 96/27583 (published Mai 7. I')96). Eiuro- therapeutic delivery fiscally within the vessel wall liy incor- pean Patent Application No 97304971.1 (filed Jul. 8. 1997), poration ofthe active agent in a swellable polymer, the active Eumpean Patent Application No. 99308617.2 (filed Oct. 29, agent v ill be released upon six elling of the polymer. 26i, WO 1999), WO 98/07697 (published Feb. 1998), [0630] The compounds as presided hcrmn, or a phannd- 98/03516 (publwhcd Jan. 29, 1998), WO 98/34918 (pub- ccutically acceptable form (c.g., pharmaccuucdlly acccptablc lished Aug. 13, 1998). WO 98/349i5 (pubhshcxl Aug 13, salts, hydrates, solvates, isomers, prodrugs, and isotopically 1998), WO 98/33768 (published Aug 6, 1998), WO labeled derivatives) thereof, or pharmaceutical conipositions 98i30566 (published .lul. 16. 1998), European Patent Publi- as provided herein, can be formulated or administered in cation 606.046 (published .Iul 13. 199-1). Iiuropean Patent conjunction xvith liquid or solid tissue barriers also known as

Publication 931. 788 (published;ful. 28. 1999). WO 90/05719 lubncants. Examples of tissue barriers include, but arc not (published(filed May 31, 1990), WO 99/52910 (published Oct. 21, limited to, polysaccharidcs. polyglycans, sepraiilm, interccixl 1999), WO 99/52889 (pubhshcd Oci. 21, 1999), WO dllxl lly"llilrolliC iiCliL 99/29667 Jun. 17. POT Intcruatioiial (publwhcd 1999), [0631] Medicaments which can be administered in con- Application No. P(71'/II)98/01113 (filed.lul. 21, 19')8), Eiuro- junction v, ith the compounds as provided herein, or a phar- pean Patent No 993022321 (tiled Mar. 25, Application maceutically acceptable form (e.g.. phannaceutically accept- 199')),Drear liritain PatentApplication No 9912961.1 (filed able salts. hydrates, solvatcs. isomers, prodrugs, and ;lun. Provisional 6i0/148,46i4 3. 1999). U.S. Application No. isotopically labeled derivatives) thcrcol: uicludc any suitable 12, U S. Pat No. 5 8ti3 949 (issued Jan. 26, Au. 1999), dnigs usefully delivered by inhalation for exaniple, analge- 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19. 1999). and sics, e g., codeine, dihydmmorphine, ergotamine, fentanyl or European Patent Publication 780,386 (published Jun 25, morphine; anginal preparations, e.g.. diltiazem: antiallergics. 1997), all of which are incorporated herein in their entireties e . cromoglycate, ketotifen or nedocromil: anti-infectives. reference In some enibodiments, MMP-2 and MMP-9 by e ., cephalosporins, penicillins. streptomycin, sulphona- are have little inhibitor those that or no activity inlubiting nudcs. tctracycluies or pcntamidinc, anuhistamincs, c.g.. MMP-l. include those selectively Other embodiments that mcthapyrilcne: anii-infl;mimatorms, c.g., bcclomcthasonc, inhibit MMP-2 and/or AMP-9 relative to the other matrix- tlunisolide, budesonide, tipredane, triamcinolone acetonide metalloproteinascs (i.ix, MAP-I, MMP-3. MMP-4, MMP-5, or fluticasone; antitussives. e .. noscapine: bronchodilators, MMP-6. MMP-7, MMP-8. MlvIP-10, MMP-JI, MMP-12, e ., ephedrine. adrenaline, fenoterol, formoterol, isoprena- and MMP-13). Some non-limiting examples inlnbi- of MME line. metaproterenoL phenylephnne, phenylpropanolamine. A(1-3340, ITO 32-3555, 13-0830. tors are and RS pirbuterol, reproteroL rimiterol, salbutamol. salmeterol, terb- [0627] Autophagy inhibitorsinclude.but are not limitedto, utahn, isoctharine, tulobuterol, orciprcnaluic or ( — )-4-dmuio- chloroquine. 3-mcthyladeuinc. hydroxychloroquuic (Plaquc- 3,5-dichloro-ix-[[[6-[2-(2-pyrnlinyl)ethoxy]hcxyl]anuno] nil '). baiilomycui Al. 5-amino-4-inudazolc carboxiunnlc methylJbenzenemethanok diuretics, e g.. arniloride; ribosidc (AICAR), okadaic acxl, autopluigy-supprcssivc anticholinergics e.g, ipratropium. atmpine or oxitropium; al al toxins which inlubit pmtein phosphatases oftype 2A or hormones, e g, cortisone, hydrocortisone or prednisolone; type I, analogues of cAMP, and drugs which elevate cAMP xanthmes e.g.. aminophylline, choline theophyllinate. lysins levels such as adenosine. LY204002. N6-mercaptopurine theophyllinate or theophylline: and therapeutic proteins and riboside. and vinblastine. In addition, antisense or siRNA that pcptidcs. c.g., insulin or glucagon. It will bc clear to a person inhibits cxprcssiou ol'proteins uicluduig, but not lumtcd to skilled in the art that. v lmrc appropn ate. the mcdwdmcnts cdn ATG5 (which are unplicated ui can also bc u sexi. autopliagy), be used in the form of salts (eg . as alkali metal or amine salts [0628J In some embodiments, pmvided herein i ~ a metlxid or as acid addition salts) or as eaters (e g, lower alkyl eaters) ofandior a pharmaceutical composition fiir treating a cardio- to optmiize the activity andior stability of the medicament vascular disease in a subject wluch comprises an amount of a [0632] Other cxcmplary thcrapcutic agents useful liir a compound as provided herein, or a phamiaceutically accept- combmation therapy mcludc, but are not 1nni ted to, agmits as able form (c.g., phannaccuncally acccqxcdblc salts, hydrates, dcscribcd above. radiation therapy. hormone antagonists. solvates, isomers, prodrugs, and isotopicdlly labclwl denva- hormones and their releasing factors, thyroid and antithyroid tives) thereof. and an amount of one or more of therapeutic dnigg estrogens and progestins, androgens. adrenocortico- agents use for the treatment of cardiovascular diseases tropic hormone; adrenocortical stemids and their synthetic [0629] ExempLary agents for use in cardiovascular disease analo s: inlfibitors ofthe synthesis and actions of adrenocor- applmdtions arc anti-fluombonc agents, e, prostacyclui and tical honmuics, insulm, oral hypoglycemic agmits, and thc salicylatcs. tltrombolyttc agents, c.g., strcptokinasc. Crokt- pll'dmldcologv of tile i:llxlocilllc pallcri as. agcllts dflcctlllg nasc. tissue plasminogmi acuvator (TPA) and amsoylutcd calcilication and bone turnover: calcium, phosphate, parathy- plasininogen-streptokinase activator coinplex (APSAO), roid hornione, vitamin D, calcitonm, vitamins such as water- anti-platelets agents. e g, acetylsalicylic acid (ASA) and clo- soluble vitamins, vitamin 13 complex, ascorbic acid. fat- US 20]4/0275]35 A1 Sep. 18, 2014

soluble vitamins, vitamins A. K. and E, po&vth factors, poietic a ents. yowth factors, minerals, and v&tamins, anti- cyiokuics. chmnok&ncs. muscanmc riocptor agonists and coagulant, thrombolytic. and;mtiplatclet drugs. antagomsts: ant&chohncstcrasc agcnml agents Bctui at thc [0638] For treating renal carcinoma, one can combine a neuromuscular junction and/or autonomic Banglia, cat- compound as provided hcrcin. or a phannaccutically acccpt- echolamines. sympathomimetic dmgs, and Bdrenerg&c recep- ablc fi&rm (e.g.. phannaccutically acccptablc salts, hydrates. tor agonists or antagonists: and 5-hydroxytryptamine (5-HT, solvutcs, isomers, prodrugs. mid isotop&cally labchxl deriva- serotonin) receptor agonists and anta onists. tives) thereof, or phar&uaceutical compositions as provided [0633J 'I herapeutic agents can also include agents for pain herein, with so rafenib and'or avast&n. I&or treat&ng an endome- and inflanunation such as histamine and histamine antago- tnal disorder, one can combine a compound as provided nists, bradykinin and bradyl inin antagonists. 5-hydrox- herein with doxorubincin, taxotere (taxol). and/or cicplatin yuvpt;unine (scrotonu&). Iipul substances that arc gmlerutcd (carboplat&n). For trcaung ovarian cancer. onc can combine a by biotransfonnauon ofthe products of lhe select&ve hydroly- compound as provided hcrcin w&th cwplat&n (carboplaun). sis ofmcmbranc phosphol&pids, eicosanoids. prostaglanduis, taxotcrc, doxorubincm, topotccan, and/or tamox&fen. For thro&uboxanes. Ieukotrienes, aspirin, nonsteroidal ant&-in- treating breast cancer, one can comb&ne a compound as pro- flammatory agents, analgesic-antipyretic agent ~ . agents that vided herein with taxotere (taxol), gemcitabine (capecitab- inhibit the synthes&s of prostaglandins and tluomboxanes, ine). tamoxifen. Ietrozole, tarceva, Lspatinib, PD0325901. selective inhibitors of the inducible cyclooxygenase. selec- avastin. herceptin. OS1-906, mid/or OSI-930 For treatin tive inhibitors of the &nducible cyclooxy enase-2. autucoids, lung cancer. one can combine a compound as provided herein paracrmc honnoucs, soma&os&ann, gas&Un, cytokincs tlmt with taxotcre (taxol). gemcitabulc. c&spin&in, pcmctrexixk med&atc intcracuous &nvolvcd in humoral Bnd cellular Tarccva. PD0325901,;md/or avastul. immune responses, lipid-derived autacoids, eicosanoids, [0639] In some embod&ments, thc d&sordcr to bc treated,

Jf-adrenergic agonists. ipratropium. glucocorticoids. meth- prcvcntcd uncpor mimagcd is hcmatolog&ca 1 cancer, c.g., lym- ylxanthines. sodium chiumel blocl ers, opioid receptor ago- phoma (c.g., T-cell lymphoma; NHL), myeloma (c.g., mul- nists, calcium cluumel blockers. membrane stabilizxrs and tiple myelmna), and leukemia (e g., GI I.), and a compound leukotriene inhibitors. prov&ded herein is used in combinat&on with I IDA('nhibi- [0634] Additional therapeutic agents contempLated herein tors such as vorino stat and romi dep sin, mTOR inhibitors such include diuretics. vasopressin. agents affecting the renal con- as everolmus: anti-folates such as pralatrexate: nitrogen mus- sixvatiou of wB&cr. &canal, Bug&0&cllsul, 0 eum Uscli&l ul thc tard such as bendamustine. gcmci tab&nc, opt&onally in further trentmmlt of myocarihal &schcmia, anti-hypcrtcnsivc agmlts, combmation with oxal&pie&in, utuxunab cyclophosphmnidc angiotcnsin convert&ng enzyme inhib&tora. 0-adrcncrg&c combmation: PI)K inhib&lors such as GS-1101. XL 499. receptor antagon&sts, agents for the treatment ofhypercholes- (ID(x0')41, and AM(i-319: Or B I'K inhibitors such as ibru- terolemia, and agents for the treat&nent of dyslipidemiainflamm- tinib and AVI,-2')2. [0635J Other therapeutic agents conten&plated herein [t)640J In certain embodiments, wherein infla&nmation include drugs used for control ofgastric acidity, agents for the (e g., arthritis, asthma) is treated. prevented and/or managed, treatment ot peptic ulcers, agents for the treatnleilt Ot gastroe- a con£ provided herein can be combmed with, for sophageal refhix d&sease, prokinetic agents, antiemetics, example: PI3K inlubitors such as (IS-1101, XL 499, GDC- a ents used in irritable bov el syndrome. 1 ents used for 0941, and AM(i-319: BTK inlfibitors such as ibrutinib and d&arrhen, agmlts used for const&pelion, agenm used lor AVL-292, JAK &nlub&tora such as tolhc&un&b, lbstamaunib, atoryy bowel d&seasc, agents used li&r bihary d&scasc, agents and GLPG0636. used fi&r pancreat&c disease. '!'herapeutic agent ~ include. but [0641] In certain emboduncnts whercu& as&luna &s &reeled, are not limited to. those used to treat protozoan intections, prevented and/or managed, a compound provided herein can dn&gsusedtotreat Malaria,An&ebiasig Giardiasisyf'richon&o- be cmnb&ned with. for example: beta 2-agonists such ag but niasis. Trypanosomiasis, and/or Leislunaninsis. and/or dnigs not limited to. albuterol (Proventil',B) or Ventoling). Salme- used in the chemotherapy ofhelmintluasis. Other therapeutic teml (Sereventa'). fonnoterol (Foradiliy), metaproterenol agents ulcludc. but arc uot lunited to, anlimicrob&al agmlts, (Alupenttti), pirbuterol (MaxAiriy). and terbutaline sulfite: sUllo&laululcs. &&laic&hop&lilt-BUlfanlc&hoxazolc ifUU&okuics, cort&costcroids such as. but not limited to, budcson&de (c.g.. and agents for urinary tract inli:ct&ons, pmnc&llins. ccplm- Pulmicort'il:). flurusol&dc (c.g., AcroBid Oral Aerosol losporins. and other, [1-1 Sctam antibiotics, an agent contain- Inhalerlr or Nasalide Nasal Ae&osolft ). fluticasone (e.g . I&lo- ing an aminoglycoside. protein synthesi ~ inhibitors, dnms nasesn or I&ioventft') and triamcinolone (e.g. Azrnacort)t:); used in the chemothemspy of tuberculosis. m&zo/&ac&Br&0m mast cell stabilizers such as cromolyn sodium (e.g., Intel/x'r Uvuua complex d&sease, and leprosy. antifungal agents, miti- Nasalcromx') and nedocromil (e.g.. T&lade 0), xanthine 1 &ral agents ulcludu&g nouretrov&ra 1 a cnts;uid ant&rctrov&ral derivatives such as, but not limited to, theophylline (e... agents. Anunophyllin&tt, Tlmo-24,B or Thcolmrg), leukotricnc [0636] Exmuplcs ofthcrapcuuc ant&bodies tluu can bc com- rccc)&&or mitagonists such as, but are not l&mitcxf to, zafirlukast bined ivith a subject compound include but are not hn&itcd to (Accolate&X). montefukast (Singulairft), and zileuton (yy- anti-receptor tyrosine kinase antibodies (cetuximab, pamtu- float), and adrenergic agonists such as. but are not lunited to, mumab, trastuzumab), anti CD20 antibodies (rituximub, tos&- ep&nephrine (Adrenafi&rit, Bronitin Bb Epi Pen 0 or Primatene tumomab), and other ant&bod&ec such as alemtuzumab, beva- Mistx). cizumab. mid emtuzumab. [0642] In certain embodiments wherein arthntis is treated. [0632] Morix&vcr, thcrapcuuc agcms used lbr unmuuo- prcvcntcd tuid/or mmiagcd, a compound provided hcrcin can modulation, such as &nunuuomodulators, mununosupprcs- bc combined with. for cxmnple: TNF ants onwt (c.g.. a TNF slic agents, tolcrogclls, Bud ulul&Uuostuulllaum Blc coll&ca&- ant&body or fragment, a soluble TNF receptor or fragmen( plated by the methods herein In addition, therapeutic agents fusiim proteins thereof, ore small molecule I'Nl& antagonist); acting On the blood and the blood-forming organs, hemato- an antirheumatic (e g . methotrexate. auranofin. aurothiOgl- US 20]4/0275 [35 A1 Sep. 18, 2014

cose. aznthiopnne, etanercept, gold sodium thiomnLSte, compound provided herein can be combined with, for hydroxychloroquule sullbte, lcflunomidc, sulfusalzinc). a example, Boscn&an (Traclccr), p144, pcntox&fyllinc, p&rli:ni- muscle relaxan&, a narco»c, a non-steroid un&i-inflanmuitory donc: pravastatui, STI571, Vit;unul E, or combinations dnig (NSAID); an analgesic; an anesthetic; a sedative: a local thereof. anesthetic: a neumnniscular blocker: an antimicrobial (e g., [0648] In certain embodiments wherein hbrosis or fibrotic an aminoglycoside. an antifungal, an antipnrnsitic. on anrivi- condition of the gastrointestinal system is treated, prevented rnl. a carbapenem. cephnlosporin. a fluoroquinolone, n mac- dill/Or Illa&lager( a Co&llpou&ld providCd 1&CI'c&11 Cail bC Coni- rolide, a penicillin, a sulfonamide. a tetracycline. another bincd wi&h, I'or cxamplc, ALTU-135, bucclipasc alfa (INN). antnnicrobial), an miupsona&ic: a cor&icos&cnudi an mlabol&c DCH020, EUR-1008 (ZENPEPrw), &buprofcn, Lym-X-Sorb cvtoklilc a&ling&111&st. su:Ioldi a or a cytoklilc powder, pancrease M I; pancrelipase (e.g . pancrelipase [0643] In certain embodiments wherein psonasis is trcatcxf, delayed release), pen&ada canoic acid (PA), repaglinide, proven&cd mid/or mmlaged, a compound provided hcrcui can TheraCLECTrsg triheptadecanoin (THA), UI.TRASE be combulcd with, for example. budesomdc, cpidennal MT20, ursodiol. or combinations thereof. gmivth factor, corticostemids, cyclosporine, sulfasalazn&e, [0649] In certain cmbodimcnts wherein fibros&s or libmuc aminosalicylates, 6-mercaptopurine. azathioprine. metrml- condition of the lung is treated. prevented and/or managed. a idazole, lipoxygenase inhibitors. mesaliunin. olsalazine, compound provided herein can be combined with fiir bnlsalazide, antioxidants, thromboxane inhibitors. IL-I example, 18-FDG, AB0024, ACT-064992 (macitentan). receptor antagonists, anti-IL-1 [3 monoclonal antibodies, mtti- aerosol interferon-gamma, aerosolized human plasma-de- IL-6 monoclonal an»bo&hcs, grow&h lactors, alas&sac inlubi- rived alpha-I antitrypsin. alpha 1-pmteinase inhibitor. tors. pynduiyl-Imidnzolc compounds, ant&bod&cs or ngoms&s ambnscn&an, amikacin. anulondc, amitnp&yluic. Snti- 'I — of'I N I ', I . I I,- I I I -2, I I -6, I I .-7, I I .-8, I I . I 5 . I I - I 6. I I - I 8, , pscudomoiia s IgY gargle. ARIKACE™ AU REX I SIT (&atibd- GM-('SI'. Ii(il'. I!MAP-II, and PDGI( antibodies of ('D2, zu&nab), A/APRED. azathioprine, azithromycin. arithromy- ('D3, CD4, CD8. CD25, CD28. CD30, CD40. CD45. CD69, cin, A/I.l, art&Conan& lysine, 13113111120, I)io-25 probiotic, ('D90 or their ligands, methotrexate. cyclosporine, FK506, bosentan. Bramitob'8, calfnctant aerosol, captopril, CC-930. rnpamycin, mycophenoLSte mofetil. Iefhmomide, NSAIDs, ceftazidime, ceflazidime, cholecalciferol (Vitamin D3). ibuprofen, curt&costcroids, prcdnisolonc, plxlsphodmstcrasc ciprofloxacin (CIPRO(3, BAYQ3939), CNTO 888. colistin inhibitors, adcnos&nc agonis&s, anutluombotic agml&s, CF, combined Plasma Excliange (PEX), ntuxnuab, mid cor- complement inhibitors, adrenergic agents. IRAK. NI K. IKK, ticos&croids, cyclophosphamidc, dapsonc, dasaumb, dcnulo- p38. MAP ki nave mhibitora. 11.-1[3 converting enzyme inlnbi- sol tetrasodium (INS37217), dornase alfa (PUI,- tors, TNFO converting enzyme inhibitor~. T-cell signalin MO/YMEIC), I!PI-hNE4. Crythmmycin. etanercept, inhibitors, metalloproteinase inhibitors. sulfasalazine, nzn- FC1-3019, fluticasone, FTI, CiC1008, CIS-9411, hypertonic thioprine, 6-mercnptopurines. angiotensin convertin saline, ibuprofen, iloprost inhalation. imatinib mesylate cnzymc udubi&ors, soluble cytokuic reccp&ors, soluble p55 (CILEEVECa'). inhaled sodium bicarbonate, inhaled sodium TNF rcccquor, soluble p75 TNF receptor, sIL-IRI, sIL-I RH, pyruvatc, intcrfi:ron gmmna-lb. intcrli:ron-alpha loden cs. 11,-4. 11-10, II -11, sll -6R, anti-inflammatory cytokines, &so&onic saluic, IWOOI, KB001. loser&an. Iucuiac&an&, maruu- I'Gli[3 11,-13 and hydroxy- tol, meropenem, meropenem infiision, miglustat, minocy- [0644] In ccrtaui embodiments wherein librosis or libro»c cline, Molil')01, MP-376 (levofioxacin solution for inhala- condition of the bone marrow is treated, prevented and/or tion). mucoid exopolysnccharide P derugn&os&r inunune mana ed, a compound provided herein can be combined globulul IV, mycophenohste mofetil, n-acetylcysteine, N-ace- with. fiir example, n Iak2 inhibitor (including, but not limited tylcysteine (NAC), NaCI 6%, nitric oxide for inhalation. to, INCB018424. XL019, TG101348. or TG101209), nn obramycui, octrcoudc, ollgoG CF-5/20, Omni&zumab, p&ogli- immunomodulator, c.g., an IMIDIL (includmg, but not Iim- tazonc. pipcracillin-tazobactmn, pirfi:rudonc, pomalidomnlc i&cd to thalidomide. Ienahdomidc, or panolinom&dc), (('('-4047). prednisone, prevastatin. PRM-151. QAX576, v'ul'ca. Sll ill&dinge&1, ciythropolc&lc s&i&&lulu&lllg iigcllts, piixi- rhDNAse, 813656933. 813-656933-AAA. sildenafil, tainox- nisone. danazol. I IDA('nhibitors. or other ag&nits or I'c-99 ifen, technetium [ mJsulfurcolloid and Indium [In-111 J therapemic modalities (e.g . stem cell transplant ~ . or radia- DTP %. tetrathiomolybdate, thalidomide, ticnrcillin-clavulan- tion). ate. tiotropium bromide. tiotropnun RESPIMAT 8 inhaler. [0645J In certain embodiments wherein fibrosi ~ or fibnitic tobramycin (GERNEBCI¹), &rc7&rostin&l, undine, valgan- condition ofthe heart Is treated, prevented and/or managed, n ciclovir (VALCYTE(c). vardenalil, vitamin D3, xylitol. compound provided herein can be combined with, for zlleuton, or combinations thereof'. example, eplerenone, fiirosemide, pycno cool, spironolac- [0650] In certain embodiments wherein hbrosis or fibrotic tonc. TcNC1 00692. &o res cnndc (c, prolonged ref o& ac film& condition of the liver is treated. prevented and/or managed. a of torasemide), or combulauons &hereof. compound provnlcd hcrcin can bc combulcxf with, lor [0646] In ccrtaui embodiments wherein librosis or libro»c cxilillplc, ildcfovu illpivoxil, ca&&fess&&dil, colchlclilc, coni- condition ofthe kidney is treated. prevented and/nr managed, bincd ATG, mycophcnola&e mofctil, and &acrolunus, com- a compound provided herein can be con&fined ivith, for bined cyclosporine micmemulsion and tacrolimus. eLSstoni- example, cyclosporine. cyclosporine A, daclizumnb, everoli- etry, eveiolimu, I'G-301'). I'uzheng lluayu. (11262570, mus, adofiiveset trisodium (ABI AVARS&I). imatinib mesy- glycyrrhizin (monoanunonium glycyrrhizinate, glycine. late (GLEEVECC3&). matinib mesylate. methotrexate. myco- L-cysteine monohydrochloride), interferon ganuna-lb. irbe- phcnolatc mofetil, prcdn&sonc, sirohmus, spironolactonc, sar&an. loser&an, olupraz. ORAL IMPACT&In, pcgui&crl'cron STX-100, uunoxifmi. ThcraCLEC™, or comb&i&ann&Is alfa-2d, combined pcgintcrii:ron all'd-2a and ribavirin. thereof pcgui&crfcron alfd-2b (SCH 54031), combo&cd pcgui&crl'cron [0647J In certain embodiments wherein fibrosi ~ or fibnitic alpha-2b and ribavirin, pmziquantel, prazosin, raltegravir, condition ofthe skin is treated, prevented and/or managed. n ribavirin (RI.I3I ITOI.I&, 8( I I 18908). ritonavir boosted pm- US 20]4/0275 [35 A1 Sep. 18, 2014

tease inhibitor, pentoxyphilline. tacrolimus, taumursodeoxy- mofetil, an anti-IL-6 antibody (e.g, toc&lizumab)), corticos- cholm ac&d, tocopherol, ursod&ol. warfann, or combuuit&ons temids: nonsteroidal anti-inflanm&story dru s; light thempy: &bc&cof. and blood pressure medications (e.g.. A('I: &nh&bitors) [(1654J In certain embodiments wherein inflammatory [0651] In certain embodiments wherein cystic fibros&s &s treated, prevented and/or managed. a compound prov&ded myopatlucs arc tres&cd. Prevented and/or mm&aged, a com- herein can be combined with, for example, 552-02, 5-meth- pound providixl herc&n can bc combined with, for example. yltetrahydrofolate and v&tamm 1312. Ad5-('13('Irl R. Adeno- topical creams or ointments (e, topical corticosteroids, tac- associated i &rus-CFTR vector, albuterol, ulcndronatc, alpha rolimus, pimecrolimus); cyclosporine (e.g.. top&cal cyclospo- tocopherol plus ascorb&c acul. amilorulc FICI. BquADEK™M, rine); an anti-interfemn therapy. e g, A(iS-009, Rontali- ataluren (PTC124), AZDI236. AZD9668. Bzithromycin, &nuuab (rln&MAb Il&Nalpha), Vitam&n D3, S&falinnuuab bevacizmnab, biaxin (clanthromycin). BIIL 283 BS (mue- (MEDI-54S), AlVIG 811, IFNo Kinoid, or CEP334S7. In lubent), buprofen, calcium carbonate, ceftazidime, cholmal- some embodiments. thc otlmr therapy &s an IFN-o therapy. ciferol. clx&hne supplementation. CPX, cystic tibrosis trans- e ., AC&S-009. Rontalizumab, Vitamin D3, Sifalimumab membranc ta&nductancc regulator, DHA-nch supplmncut, (MEDI-545) or IFNo Kinoid, corticosteroids such as pred- d&gitoxu&, tawosahcxacnoic acid (DHA), doxycyclu&c, nism&e (e.g, oral prednisone): immunosuppressive therapies ECCiC, ecombinant human IC&F-I. educed glumth&one such as methotrexate ('I rexall&t. Methotrexatelt: Rheu- sodium salt, er ocalciferol (vitamin D2). fluorometholone, nultrcx,sl), iizath&oprh&c (An&san&&A lu&urau&T), u&&ravenous gadobutrol ((iADOV IS fX, IIAY86-4875), gentamicin. ghre- unnnmoglobulin, tacrolnuus (Pro rafit(), p&mecrohmus. lin, glargine, gluten&ine, growth hormone, (iS-9411, cyclophosphamide (Cyzoxang), and cyclosponne (Cien- H5.001CBCFTR, human rccombu&ant growth honnonc, gmfs'. Neoralts, Sandimmuneg); anti-malarial agents such hydroxychloroquu&c, hypcrbanc oxygen, hypcrtomc seine, as hydroxychloroquine (Plaquenillt) and chloroquine IH636 grape seed pmanthocyanidin extract. insulin. inter- (Aralen&(): total body irradiation: rituxin&ab (Rituxanit;); feron ganuna-I b, Iofien (molecular iodine). iosartan potas- TNF u&h&bitors (c.g.. ctanerccpt (Eubrel&X&), udlixunab sium. isotonic saline, &traconazole. IV gallium nitrate ((IAN- (Rcnucadc&x)), AGS-009. Rontalizumab (rhuMAb IFNal- Vitamin 11'Ibtt) infusion, ketorolac acetate, lansoprazole, I -argiome, pha): D3; Sifalimumab (MEDI-545); AM(i 811: lu&czolid. Iub&pros&one, mcropencm, nuglustat, MP-376 IFNO Kinoid; CEP33457; agents that inhibit IgE production (leiofloxacu& soluuou for u&halauon), normal saline IV, such as ll/I-')874. 2-(4-(6-cyclohexyloxy-2-naphtyloxy) ana- Nutropin AQ, omega-3 triglycerides. pGMIG9/CiL67A, phenylacetamide)benzoic acid, rapamycin. rapamycin pfiT-I gene lipid complex, pioglitazone. PTC124, QAUI 45, logs (&.c. rapalogs), TORCI mlub&tora, TORC2 u&lub&tora. sahneterol, SI3656933. 813656933. simvastatin, sitagliptin, and m&y other compou&xls that u&h&bit mTORCI and sodium 4-phenylbutyrate, standardized turmeric root extract, mTORC2: agents that inhibit I E activ&ty such as anti-IgE tgAAVCF, TNF blocker. TOBI, tobmn&ycin, tocotricnol, antibodies (e.g.. Omalizumab and TNX-90); and additional unconlugatcd Isotlavoncs 100. v&tamin. cholu&c b&tartrate therapies such as physical therapy. exercise, rest, speech (2-hydroxyethyl) trimethylanunonium salt I:1. VX-770, therapy, sun avoidance, heat therapy, and surgery. VX-809, Zinc acetate. or combinations thereof. [0655] Incor&a&nemboduuents whcrmnmyos&us (c.g., dcr- matomys&t&s) is a com- [0652] In some mnbodunm&&a, a compound prov&dcd hcrcu& trcatcd. prcvcnted and/or managed, pound provided herein can be combined with. for example: is aihnim ster&xi &n comb &nation w &th m& agent that udubi &s I gE production or activ&ty. In some embodiments, the PI3K corticosteroids: corticosteroid sparin agents such as. but not inhibitor (e.g.. PI3K6 inlfibitor) is administered in comb&na- linuted to, azathioprine and methotrexate; intravenous in&mu- noglobuiin: such as, but not lin&- tion ivith an inhibitor of m'I'OR. Agents that inhibit Igli pro- immunosuppressive agents &ted to, tacruhmus, cyclophosphanudc aud cyclosponnci nt- duction are known &n the art and they include but are not lun&ted to one or morc of TEI-9874, 2-(4-(6-cyclohcxyloxy- ux&mab: TNF&x &nh&b&tora such as, but not linu&ed to. 2-naphtyloxy)phcnylacctanndc)bcnzo&c ac&d, rap;unyc&n, etanercept and intliximab; growth horn&one; growth horn&one secreta o ues such as. but not hmited to, MK-0677. rapamycin m&alo s (i.e. rapalogs). TORCI inhib&tora, I -162752, I -163022, TORC2 inlfibitors, and any other compounds that inhibit NN703 ipamorelin, hexarelu&, (iPA- 748 (it IRP-2). and I.Y444711 0&li other m'I'OR('I and m'I'ORC2. Agents that inhibit Igfii act&vity (KP102, I.illy); growth hormone release stimulators such as, but not limit&st include. Ii&r example, anti-Ig! 1 antibodies such as tier example to. Cicrct; GHRH Somatorclu& (CiRF 1-44). ThGRF Omal&zumab m&d TNX-901. (1-44), genotropin, L-DOPA. glucagon, and vasopressin, and insu- [0653J In certain embodiments wherein scleroderma &s lh&-hkc &Uwth facto&'. treated, prevented and/or n&anaged, a compound pn&v&ded [0656] In certain embodiments wherein Sjogren's sy'n- hcrcu& can bc comb&ncd with. for example. m& immunosup- dmme is treated, prevented ancgor managed. a compound prcssant (e.g . methotrexate, azatluoprmc (Imuran,s'), cyclosporine. mycophenolate mofetil (('ellceptts), and prov&ded herein can be combined ivith, for exan&pie: pilo- ccvuuehne: cyclophosphamide (Cytoxang)); T-cell-directed therapy carpine, nonstcroidal ant»-ntkunmatory drugs. sr&in&is medica&iona,;mtifungal agents, cyclosporine. (e .. halofuginone, bas&liximab, ate&utuzua&ab, abatacept, hydroxychlomquine; prednisone, azathioprine; and cyclo- rapamycin), 13-cell directed therapy (e 8,, rituximab): autolo- pham&de. gous hcmatopo&ct&c stmn cell transplm&&etio&u a chcmoku&c 1&gaud rcccptor untagomst (c.g., an agent that targets thc [0657] Further therapeutic agents that can be combined ('XCL12/CSCR4 axis (e.g., AMD3100)); a DNA methyka- v ith a subject compound can be found in Cioodman and "7he s" tion inhibitor (e ., 5-azacytidine); a lustone dactyiase inlub&- Gilnmn's /'har&aa&"a/agi&"a/ Basis af /herapca/i& 'I'anth I .dition edited I lardman, l,imbird and (iiln&an or the tor (e g . trichostatin A); a statin (e g., atorvastatin. ~ imvasta- by tin, pravastatin): an endothelin receptor antagonist (e g., Physician*s Desk Rcfcrm&cc, both of wluch are u&corpora&cd Boscntan,s): a phosphodicstcrasc type V inhib&tor (c.g., hcrcin by rclercncc in their entirety. S&ldcnaf&l &3). a prostacychn Bnalog (c.g.. &&Opus&Oui). Bn [0658] The compounds described hcrcu& can be used in inhibitor of cytolone synthesis and/or signaling (e... Ima- combmation v, ith the agents prov& ded herein or other suitable tinib mesylate, Rosiglitazone. rapmnycin. Bntitransfom&in agents, depending on the condition be&n treated. Hence. in gmivth factor []I (antisl(il&[]I) antibody, mycophenolate some en&bodiments, the compounds as provided herein will US 20]4/0275 [35 A] Sep. 18, 2014

be co-administered with other agents as described above. -con(fined When used in combination therapy. the compounds descnbed Nuns 'Descr herein can be admmistered with the second agent simulta- Abbrev tt cns A rnn, ms I'uu pt on neously or separately 'l Itis administration in combination can hichalc sanultancous adnunislrstton ol thc twit agcnm ul lhc DMF dunctlt Ifouttuttrdc smnc dosage form, simultaneous admmistration ui separate EtOAc ctliyl acctatc dosage fomts, and sepamste aihninistration. That is. a compound descnbed herein and any ofthe s ents described above 1st p pyi Ih can be formulated together in the same dosage tiyrm and vu K Ihyl Ihyl 1 to administered simultaneously Alternatively. a compound as 2 'VieTHF 2 rnethylterrahy droftu;tn 'VIIBK the methyl so butyl ketone provided herein and auy of agents dcbvnbcd above can bc 'VITBE nr TBMF ren butyl merh,tether simull;mcously adminmlercd, whcrcin boih thc agents arc THF I'snail'I'dr'ofter;lll present in sepamste formulations. In another alternative, a TBME Methyl tert-but I cthcr compound as provided herein can be administered just fol- loyved by and any ofthe agents described above, or vice versa In the separate administration pmtocol. a compound as pro- 9. EXAMPLES 1 idcd hcrem and uny of thc agents described above can bc Itxample I adnumslcred a li:w minutes apart, or 0 lcw hours apart, or a few days apart. Free lqase Soluability Assessment [0659] Administration of the compounds as provided [0662J Appmximately 11 m (0.022 mmol) pomona ofthe herein can be effected by any ntethod that enables delivery of free base Form I of Compound I (I.e., the compound of the compounds to the site of action An effective anxynnt of 0 fornuda (I)) were weighted into 2 ml screv -topped HPI C compound as provided hcrcui can be aihnunstcrcd m either vials One of 15 solvents was added to each vial in a mtntber single or muluple doses by any of the accepted modes of ofaliquots (up to 100 volumes). with shaking and ifnecessary adnumslration of agmtls having similar ulrhtmb, includuig with heating to 40'.. in an attempt to achicvc dissolution. rectal, buccal, intranasal and transdemtal routes. by intm- [0663] It was obscmcd that Compound I dissolved in arterial injection. intmvenously. intmsperitoneaily. parenter- MeOH (75 vol.). MIBR (40 vol.), chloroform (40 vol.). ally, intramuscularly. subcutaneously, orally. topically, as an 2-MeTHF (50 vol.)r THF (40 vol.). DMSO (5 vol.), and inhalant. or via an intpregnated or coated dey ice such as 0 MeOI I/anisole (50i50 v,iv) (10 vol ): and that ('ompound I stean foi cxaniplc, or an at(em:-ulscitcd cvlhuhlcdl poly'nn:r. did not dissolve in EtOI I. acetonitrile, I:tOA(', acetone, [0660] When a mympouud as provided hcrmn is admints- TBME. musolc, HSO, or E(OH/HSO in up to 100 vol. tcrcxl in a phannacculical composition that comprises onc or more a ents, and the agent has a shorter half-life than the Example 2 compound as provided herein. unit dose forms of the agent Salt Formation Assessment with the Hydrochloric and the compound as pmvided herein can be adjusted accord- Acid I It g1ys [0664J 25 ml of a IM stock solution nfl l('I in I'I II'(0 025 [0661J 'I he examples and preparations provided bdov fur- mmol-1. I was added to each vial prepared for the solu- ther illustrate and exemplify the compounds as pntvtded eq ) bility usbessmcnt (Example I ) at RT. All the samples yy ere hcrcui and methods ofpreparing such compounds. 11 is ui bc slmkcu at RT, then cooled to 5' (fnd r:) and lcli at tins understood that Ihc scope of Ihc prcscnt disclosure is nol temperature for 24 hours. The suspensions v ere filtered and limited in any way by the scope ofthe following examples and analyzed by XRPD: the clear solutions were evaporated at preparations. In the following examples molecules with a R'I; and the gums were placed under maturation (Ii'I'i50'(I 4 chiral center, unless otherwise noted, exist as a nscentic single hours cycle) mixture 'lltose molecules with two or more chiral ctutters, [0665] The results for the hydrochlondc salts ofCompound unless othcrwisc noledr exist as a racenuc nnxture ol'diastc- I arc sunuuarizcxi in Table 1. lite mal onty ofthc cxpcnmcnls ruxymcrs. Single cnanttomcrsidiastcrrmmers c;ui bc obtauicd resulted in gums or amorphous solids. Tv o different XRPD by methods known to those skilled in the art. patterns (FI(k 21A and Flfi. 21B) were identified: Hydro- chloride pattern I from methanol, anisole and water 'I'he 'I I N MR analysis ofthe sample crystallized from methanol (data not shown) shrnvs peak shifts compurcd to thc Free Base AC. I a etorutr le Form I which is consistent with sall I'onnauon. Hydrochlo- DC'vl ticltlomntctltauc ride pattern 2 from 2-Methyl THF which contains 1.0 eq. of HCI as detemtined by IC (data not shown).

TABLE I

Snlyear t&bs atter HCI Further Solvent nl addi on Obs I' Fap 0 ollclumoll

M OII 1 ut (Ir ('I:n. Hul p It I EtOH 100 nt Clcai Clear E 'spoltlttorl Gtrtrt s 'ctollltl lie 100 nt Clcai Clear E 'spoltlttorl Gtrtrt EtoAC 100 yot sation sh sol d KA Amorphnus

. Irnw

yc I I(tlt ut I Fti stuns I Fti st r 0 b' I MIBK 40 nt sluny Gum Matur:stion Gtrtrt US 20]4/0275]35 A] Sep. 18, 2014

TABLE I-m)nunumi

hair I'aim it on Assessment uah the Hvdrochlonde Salt Formal on

Sol cnf Ohs aller HCI Fiufhci Sol int ~ I addition Ohs C Eyp Coll liisioii

TBlvlE If)i) vol slurry sol d I lfmron Lou cr,st him t'n 40 vol L eht stun y Gum Mflfuiaif' Guin an sole If)i) vol yeuou sh sol d I A Lou cr,st slurry HCI pattern I "A 2-MeTHF . if i ol sluip solid I HCI pattern 2 THF di) vol Lislif stun) Giiiii Msfiilafioii Guff) Hro lail i ol lure slufo solid I "A Lo 'f)sf HCI pattern I l)hf SO ('Ie ( M Ou'Ann ('Ie ( ((0 hi 0 I 1 I I zo I fill I, phl . Iu v ( i,(if vvl xi I 'A=i iAppl hl . L of=L yuaani I =VI», rationn

]06661 Metitanoi and 2-MeTHF )vere chosen as the so)- gums were fully evaporated. TBME/I-BuOH/Acetone were vents for further salt screening because it soiubilized the free added respectively to the samples initially prepared in base and gay c a crystallute salt with hydrochlouc acid. MIBK MeOI I/MII3K/2-Me'I'I Ill I'he samples were placed in matu- was also chosen as solvent for Ihc salt scrccning. TBME was bet)( eca RT/6 O'. (4 hours ut each temp era lure) li)r a I identified as suitable anti-solvent. least 24 hours, and Uicn sonicaied. Thc sohds obiauied duung the sequence of manipulations were filtered and analyzed by Example 3 XRPD. ]067(l] I he crystalline solidsweretiltered,dried at ambient Salt Scrccnuig conditions, and stored at 40',/75%o RH for I week and analyzed by 'H NMR/IC. The stable salts were further char- ]0667] Approximately 35 mg (0.07 nunol) of free base actcrizrxi by XRPD/TGA/DSC. Form I ofCompound I was u elghed into 2 mi HPLC vial and ]0671] The results oi'he salt scrccn are siunnmrizcd in dissoh Lxl in 43 vol ().50 ml) of IVIcOHr 26 vol. (0.87 ml) of Table 2. Scvcral crystalline solids werc Isolnirxi. Thc hydro- 2-MeTHF. or suspended in 2S vol. (0.87 ml) ol'MIBK. chloride and the isethionate salts deliquesced after storage at 50" C'.. 'I'he ]0668] The solutions were heated to and an appro- 40" ('76% Rl I fiyr up fo I week salts stabie on storage pualc volume of stock acid solution y(as added io c mh vial at 40" C./75% RH for at )east I week include mono-1.2- (2.2 cq. for targctcd bm salts, 1.1 cq. for lurgclcd mono salts, ethanedlsuifonic acid salt. mono-maleic acid salt, and bis- 'I'I and 0 5 eq fiyr targeted hemi salts, I M in llf except 1.2- sul furic acid salle. The his-hulfurwacid salt un s characterized ethane disulfonfc acid, 2-hydloxyethanesulfonic acid. and by XRPD (FIG. 1A), TGA (FIG. 2A), and DSC (FIG. 3A). L-aspartic acid) under magnetic ctirrin . The vials were then Thc mono-malcic acid salt was ciui rue ten zcd by XRPD (FIG. sealed and cooled to 5" C, within 8 hours to enhance the 12A), 1(rA (I'l(r 13A). and DS('ifl(i 14A). I'he mono-l, crystallization of the salts. 2-etlmnedisulfonic acid salt v as characterized by XRPI) ]0669] The clear solutions were cooled to -20" C, (freezer) (FICi. 17A), TCiA (FICi. 18A)r and DSC (FICi. 19A). The and then evaporated at RT. The experiments which produced isethionate salt yves characterized by XRPD (FICi. ZZ).

TABLE 2

Rcsulfs of the Saff Sciccn

Store e X Rl'I ) ail'('v lfu 'u I Vuf I('

in . I acid TBME Soni stion crystauiz:itiori Mono MIBX Ev Ivliiurat on Amorphous ho I uuouh nc,li r o (iona 2 MeTHI' Ev Ivliiurat on Amorphous ho o s MeOH Ev Ivliiurat on Amorphous ho MeTHI''iTBME Soni stion crystauiz:itiori B s MIBX Ev Ivliiurat on Amorphous ho I-BuOH, yoiucation crystauiz:itiori Bs 2 Ev Ivliiurat on Amorphous ho A 'cfoiie'Soiiiciifioii crystauiz:itiori US 2014/0275135 A1 Sep. 18, 2014

TABLE 2-oonfnttnxf

Results of rhe S.dt S reen

St'oisgc Counter-I n Tmcct Sol cnt Method XRPD a(i'C Ih'H 'HVMP. IC Coiruucut

Hydr chlouc Mono .VleOH Cool anat O' HCI Del quesced Salt iy 'A Del ques ent a d Pittern I t'orrnat on Mono .VHBK f .,Mlahnaton Au in 1'pl toils h 'A iy 'A .Io I BuOH'q'ou cflt ou mysrall zat on Mono 2-McTHF E 'Maturst on Lo crpst Lo crest AcctoricrSon ation Bis McOH E 'Maturst on Arun i pitons Vo TBME(honication crystall(zat(on

li . VIHIK fu t "lo I II Ouhu *d

HI. fu t li«2 VI I I o ryfll Sulflu Mono .VlenH f .,Mlahnaton Auioi'phoiis .Io a d TBVIT 'Sorucat on mysrall zat on Mono .VHBK f .,Mlahnaton Auioi'phoiis .Io I BuOH'q'ou cflt ou mysrall zat on Mono 2-McTHF E 'Maturst on Lo crpst Lo cryst AcctoricrSon ation Bis McOH E 'Maturst on Guu1 TBME(honication B s .VI IBK f .,Mlahnaton Sulhli' fi ' Ht I ~ OH I

HI. fu t li«2 VI I ic; I C q Acctonc salt Pattcni I salt Pattcni I foiin.'it(on Sulfuric a' Henu .VleOH f .,Mlahuaton Auioi'phoiis iy 'A .Io

I I I VI I" Son Hemi MIBK E 'Matursr on FB Pattcni 6 I A Vo I-BuOHrSnn«ation crystall(zat(on Henu .VleTHI f ., Mlahnat on Gum

I 2 I flu M m VI OH 1,2 1,2 ' " d(Hdfoul cthsncdisult'oni ethsricdisulfon« I cq of I.- d flod salr fl 'l s:dt etluned sulf' c Pittern I Pattern 1,1 d M m MHIK I o ryfll h Iv i BuOHrSnn«ation Mono 2-McTHF E 'Maturst on Guu1 A atone Soru at ori li. Vl OH 1,2 et hi r edis»ll'( r s 'ld Sillt'ittern I B s .VI IBK f .,Mlatuiat on I I KA Ht ~ OH et hi r edis»ll'( r s 'ld

Sillt'flttcni I B s .VleTHI f ., Mlahnat on Gum

"1 I 2 I flu Vl OH fu t o d(Hdfoul ' TBME(honication crystall(zat(on d Henu .VHBK f .,Mlatuiat on I I Ht BuOH ethaned sulforu

1 *1 d fl, I 1 Pflttcni I Hemi 2-McTHF E 'Maturst on V 'A Guu1 A atone Soru at ori

fu t "1 pl lu M m VI OH 1 uph o Ihn . IBMI Son :ic id Mono MIBK E 'Maturst on I- Arun i pitons Vo BuOH'q'ou cflt ou mysrall zat on Mono .VleTHI f ., Mlahnat on Gum

Bis McOH E 'Maturst on Guu1 TBME(honication B s .VI IBK f .,Mlatuiat on I Au in 1'pl toils .Io

HI. fu t li«2 VI I AcctoricrSon fltion US 2014/0275135 A1 Sep. 18, 2014 70

TABLE 2-conftmnxf

Results of rhe S.dt S reen

St'or age Cnuntct-I n Tnpct Snl cat Method XRPD eh'C 70'H 'HVMP. IC Coiruucut

Methme Mono .yleOH T ., Mlshnst on 0 1'pl toils .Io sulfou ' TBKIT 'Snrucst on mysrsll zst oa d Mono .CHBK T ., Mlstuist on I Airioi'phone .Io BuOH'('ou cflt orl mysrsll zst oa Moao 2-McTHF E 'Mstursr on uuoipitons Vo AcctoricrSOO stioa crystslhzstroa Bl5 McOH E 'Mstursr on GCO1 TBMErqonrcstron OH IIK "lo

2 yf I HI. fM I I 0( (I

Oxsl c Mono :yleOH T ., Mlshnst on L n cryst KA .I A s d TBKIT 'Snrucst on Mono :CIIBK T ., Mlstuist on I I'B Pattern h A iy 'A I'B BuOH'('ou cflt orl mysrsll zst oa Moao 2-McTHF E 'Mstursr on 1A GCO1 AcctoricrSOO stioa Bl5 McOH E 'Mstursr on uuoipitons TBMErqonrcstron

OH IIK tli lt tte 1 K t I I

2 yf I HI. fM I I 0( (I A stone Soru st ori Mono :yleOH T . Iserluonrre Del quesced h 'A iy'A Del ques eat Hy dr myerhme Prttern I sulforu Mono :CIIBK T .,Mlshnst1'('iryon I I'B P( iy 'A I'B :1C Id BuOHrSnn«stion crystslhzstroa Moao 2-McTHF E 'Mstursr on Lo cryst I 1A Lo crest AcctoricrSOO stioa L-Aspyrtrc Moao McOH Conlui st "C L-Aspsrti imd I A Vo salt :. I

OH IIK tli lt tte 1 K t I I

fM M m 2(I IHI. I tli lt tte 1 K t I I A stone Soru st ori mysrsll zst oa Bs :yleOH Cool unct O' L Aspera .Io salt sic d for'trial'u Bs :CIIBK T ., Mlstuist on I I'B Pattern I'B BuOHrSnn«stion crystslhzstroa Bl5 2-McTHF E 'Mstursr on FB Psncu1 . FB AcctoricrSOO stioa crystslhzstroa Male« Moao McOH E 'Mstursr on Male« imd salt Mslcrc scrd salt Salt Iormstrnn Hit

:. I I HM I full e 1 I I I eq

M em OHIIK C I K I Iy y I 0(

full e 1 Mono .yleTHI T ., Mlshnst on iy 'A Gum A stone Soru st ori Phosphonc Mono .yleOH T ., Mlshnst on L n cryst KA Lon mysr :1C Id TBME Moao MIBK E 'Mstursr on I- FB Psncu1 . FB BuOHrSnn«stion crystslhzstroa Moao 2-McTHF E 'Mstursr on FB Psncu1 . FB

fM "I El lm yl OH I 1 uph o . Ihn I HM I :. I MHIK "I o BuOH'('ou cflt orl mysrsll zst oa Mono .yleTHI T ., Mlshnst on Airioi'phone .Io A stone Soru st ori mysrsll zst oa

TB=T 0 I 'A=1 t,ppl hl US 20]4/0275 [35 A] Sep. 18, 2014 71

Example 4 C./minute) to enhance the crystallization. The sample was

filtered at RT and dried at RT for 20 minutes under reduced 'I'eats pressure, transferred to a vial and weighed I'he sample was Crystallization DS('FIG. clmracterired by XRPD (I'l(i ll3), I'()A (l&I(i 2B). Prior to scale-up. crystallization tests were carried [0672] 3B), GVS (FIG. 4). FT-IR (Flfi. 5A and FIG. SB), and out to assess the the salts to crystallize directly propensity of VT-XRPD (FIG. 9). fmm a solvent by addition ofacid to a free base stock solution [0675J Mono-Maleic Acid Salt: fiilloived by cooling Approximately 50 mg (0 H)2 mniol) of 5(K) the frcc base Foun 2 oi'Compound I was wmgh&xl into 2 ml [0676J Approximately mg (I 02 mmol) ofthe free base scrunv-topped HPLC vial An appmpnuic nuiss of acid was Foun 2 ofCompound I was weighed uiio 30 ml reaction tube. weighed into a sepamte 2 ml screw-topped HPLC vial, dis- Thc frim base was suspcnduxl ui 10 ml (20 vol.) of MIBK 1.1 50" solved in the corresponding solvent and heated to 50'. The eq ofmaleic acid was added to the free base suspension at acid solution was added to the fme base under magnetic C. under magtetic stirring as IM stock solution in THF. The stirring. I'he vials were then sealed and cooled to 5' ivithin san&pie was kept at 50' for 10 minutes and then cooled to 5" 'Ihe 8 hours to enhance ihc crystallization uflhc saks. Thc sobds (2 (0.1" ('/minute) to enhance the crystallization w crc filtered and ana ly scd by XRPD. Thc results;u 0 sunmui- sample was Iilicrcdai RTanddricd at RT Ibr 60muiutcs under rized in Table 3. Based on the results, the most suitable TIKI&iced pious&tie. Iransfctrixl lo 0 vial a&id wclglicil. Thc methods for scale-up were: for mono-maleic acid salt Forin I, sample was characterized by XRPD (FIC). 12B), TGA (FIC). (FILI. CiVS (FIC). FT-IR (FIC). in MII3K ivith I M 'll II'cid stock solution; tiir bis-sulhiric 13B), DSC 14B), weighted15), and 16A acid Iiorm 1. in Acetone/I I,O (90/10 v/v') with concentrated and III(i. 16I3). sulihric acid diluted In water and scixbng ut 50'q and Ibr [0677] Mono-1,2-Eiiuuicdisulfomc Acid Snl& mono-1.2-cthmic&bsulforuc acnl salt pduern 1. in EIOH with [0678] Appmxnnaicly 500 mg (1.02 nunol) oi'thc free base I M THF acid stock solution. Foun 2 ofCompound I was into 30 ml reaction tube.

TABLE 3

Ct stall sat on Test Resnlts

Acta Stock Acta Counter-I n Sol cnt Vol S lutron cq Method XRPD

M& I .:*d MIBK 0 IM II&1 11 C I nato M: I ic& ed.: II Pattern I

MIBK 22 IM THI' I Cool r& ~ to C Male a d salt Pattern I Sulfiu a d I BuOH IM THF Cools" to C Gunn Acctotlc 17 IM THF 2 2 Coolwg to C Gut&1 Acctonc&H&O la Conc ut 22 Sccdcdtoso C Su&fiute surd salt 9&1'I&) & st'cr Coolwg to C Patte&&& I

I 2 I ilu I liuou 0 IM II&1 11 C« I nato

I IM II&1 11 C« I nato

:. I I IOH 4 IM II&1 11 C« I nato d,Itin&I t I KI

Example 5 The free base was suspended in 20 mL (40 vol.) of ethanol. 1.1 cq. of 1,2-cihamxli sulfonic acid was added io thc free base 0.5 g Scale-Up suspension at 50'. under magnetic stirruig as Hvi stock solution in I I llr 'I'he experiment was kept at 50''or 10 [06'73] Bis-Sulfunc Acid Sal&. nunutes and then cooled to 5" ('0 I" G /minute) to enhance [0674J Appmximately 500 nig (I 02 nimol) ofthe free base the crystallization. The sample v as filtered at RT and dried at Irorm 2 of('ompound I was w:eighed into 30 ml reaction tube RT for 20 minutes under reduced pressure. transferred to a Thc frcc base was suspmidcd in 9 ml (i 8 vol ofacetone 2 2 ) vial and v,el/ted. The sample was charactenzed by XRPD cq. ofsulfunc acnl (conccntra&cd. 98%) was diluted m I ml of (FIG. 17B), TGA (FIG. 18B)s DSC (FIG. 19B)r mid VT- distilled water. The acid solution was added to the free base XRPD (FIG. 20). Thc char;m&cnsation oi'he salts is sum- solution at 30" C. under magnetic stirring and the sample was nmrised in lhble 4 seeded v ith his-sulfuric acid salt Iiorm I 'I'be experiment v as kept at 50" (2 for 10 minutes and then cooled to 5'. (0 I"

TABLE 4

('ara ter&sat&on of the Salts Scalcl u at 0 1 rain

& o I t Io

I s. dg I O 0 yield I' 94 99 tls US 20]4/0273]33 A1 Sep. 18, 2014 72

TABLE 4-cont&nucd

Chuacrei sit onofthe Siitsb sled u a&0 ( srmi

Cnutcr-Inn Malcic acid I-2-Etlia&icd15&iltoI&Ic a I 1 Still«I'Ic acid

XRPD&osi S ulfi m ; I a; 8 II Ii n I Pi&tern I 'H.tlvlR I'onnat ou Salt I'onnat on Salt Eorms& ou

& I eq ofulale a d I i& eq. of&. etln&ied sulf ru uic il 0 I cq of EtOH IC ESA V 'A I 9 cq. of siil fir i'Ic (mid HPLC punty 99 6% Peak mes 99 4'eak Arcs 99 9!8 6 Peak Arcs GVS Suiglc yclc Slightli lu groscnp« Mode atclv Iu oioscopic Shoaly hymoscop«

m!a IUI mm 0" RH o

XRPDp .I ( S'8 ((7) t! 1: ged Un.tn f«d TGA :Vlasslossot'1(is u« lemeeri Mass loss of) 6" ii u be«veen :vins loss of 7" «, v (em ceo

40' and 17(i: C I' .ud 100' endo& '" 40 C and 1st '

(su Iiemeen u!O'C uid 0 C DSC Endotherm ar 191' Bi sd endotherm &.it 27''road Bmad endotherm I at I 7' ciirloriicuii at 168' Endothcun 't 219" C VT-XRPD (C)l I 2-cthe&cd&sulfoiuc acid salt Still«I'Ic acid salt P:m(vii I ' Pattcui I at 2&" C bct cert aud 14(.l" C I 2-cthe&cd&sulfoiuc acid salt Sr&if«i'Ic:icid salt P:i&terri:iiio 'c

I t(iil' Im!" ''io''fllt &bile i I m &40''i&tern) ar O'C

('RPD Conve is to I erhuied sulforu oc d salr Patter&i 4 i&ler noluig St rage4('0 76« RH XRPD (DBi Un hai&ged XRPD (D8) L'nchanged (Ds) I-nchanged foi I cck HPL( Punu 99 8'cakmca HPLC Puuu Uu hanscd HPLC Purity Unchanged Storag ' 98% RH XRPD (Ds) Unction cd XRPD (D8) Unchuigcd XRPD(DS) Lnchanpcd foi I cck HPL( Punu 99 8'cakmca HPLC Puuu Uu hanscd HPLC Purity Unchanged " Tlici'iiiodviiaiiiic I 9 iiig'iiil pH. Iuti i& = I 9 ( m«ml pH solutiou = I 7 I mg/mt pu s Iutinn = I I

XRPD I('21 p . I Inp.umne ~ A &*id..I(Inn I ' I '1 KI m(i n ~ &I" I I fu&O

Example 6 [0681] Bib-Sulfunc Acid Salt.

[0682] Approximately 1.5 mg (3 0(i mmol) ofthe lice base 1.5 g Scale-Up Form 2 ol Compound I was weighed into 100 ml react&on [06'79] Mono-Male&c Acid Sal&. tube. The free base tvas suspended in 27 ml (18 voi) of [0680] Approximately 1.5 mg (3.0(i mmol) ofthe free base acetone. 2.2 eq, of sulfuric acid (concentrated: 98%) was Form 2 of Compound I was we&ghed &nu& 100 ml reaction d&lu ted in 3 ml of (h stilled w a ter. Thc ac&d solution was addrxl tube. Thc free base was suspcndcd u& 30 ml (20 vol.) of to thc I'rcc base sulu(ion at 50'. under magnet&c surnng and MIBK. 1.1 cq. of malcic ac&d was added to thc Ibce base thc sample was sccdcd w &ih b&s-bul fun c ac&d salt Form I (1% suspension at 50" ('nder magnetic stirring as IM stock w/w, -15 mg) I'he experiment was kept at 50" C. for 10 solution in 'I IIII 'I'he experin&ent was kept at 50" (1 for 10 nunutes and then cooled to 5" ('0 I" G /minute) to enhance 5" minutes and then cooled to C. (0.1" C./minute)I&PI to enhance the crystallisation. The smnple was filtered at RT and dried at the crystallisat&on. The sample was hltered at RT and dried at RT for 76 hours under reduced pressure, transferred to a vial RT for 76 hours under reduced pressure. trmtsferred to 0 v&al and weighed. The sample O.as charactenzed by XRPD (FICi. and wc&ghcd. 11&c sample was charac&cnzcd by XRPD (FIG. 12C), TGA (FIG. 13C), m&d DSC (Flfi 14C). Thc clruractcri- 1C). TGA (Flfi 2C). mid DSC (FIG. 3C). sat&on of thc sells is summarised u& Table 5.

TABLE 5

Cliaiactc»sation ol'thc Salts Scaled-u at I 6 mn

Coute& Ion Mile a d Sultlu c ac d

Vt.aa(gl I 47 I 66 Y cld(q I 81 XRPD (Dsl .Clalcic ac&(I salt Patte&i& I Sulfiu«acid s:ilt Pattern I 'H RiMR Salt l'onnaton I &eq o&Maleca d Sfllt I'onnat on I( R (!p oi TGA ."visas loss of 0 6% 'ct cm&4(i' uid hiass lossof2 Wr 'ct cmimi''nd US 20]4/0275 [35 A] Sep. 18, 2014 73

TABLE 5-con(muon)

Chiuii tensat on ofthe Salts S sled ~ at l. (am

Center-Ion I lslci:icid Sulfuri acid

17(r C tao''oi'iespoiids i'0 tire loss of I i( eq of Hso DSC rndorheun at 192' Bi (dendotherm I.it 13 'C tire(it( flt 19 C KF t trat n .I A ((i IS(i- C 2 7W (i (i coiscspoitds t'0 tlic loss of I i( cq of Hso Ky I 'A=1 tAppl set.

I:xaniple 7 -continued hfco

SO( Synthesis of Bis Sulfuric Acid Salt of('ompound I 0 Hsq(14 [0683]

H.O

B Y HO OH 7~

Ks PO( s H.O I I-BuOH Hso NI I Step I [0684] Step I: [0685] An appropnu(cly sized rcucuon vessel was cquippcd with a nuuhaiucal s(irrer. gas inlet/outlc(, optical oxygen sensor (for hcadspacc oxygen), rcllux condenser and temperature probe Compound 2 (I kg, I wt, I equiv), 2-ntethoxypyridine-4-boronic acid (I I equiv) and potas- Qi,. sium phosphate monohydrate (2 equiv.) were charged to the reaction vessel. I-BuOH (8 vol) and water (4 vol) were DIYEA charged to thc reaction vessel. The mixture was surrcd a(

I-BuOH (sq i 9(i" C 25 5'. Thc content of(bc vessel u as sparged with incr( gas 2 (nitrogen) f(ir minimum of 30 nun (o rcmove dissolved oxygen I'he palladium catalyst (0 01 equ(v ) was charged via a ~Hi sohd charge port and the mixture was continuously sparged v ith inert gas for minimum of 10 min. The mixture was heated to 80 5" C, (target temperature 80-83' ) under inert Vlco atmosphere, and stirred ut this tcmpcraturc under incr( almo- sphcrc for minuuum ol'4 lu s. After Ihc rcucuon was found (o bc complete (u1.0 Ao Compound 2 relative to Compound 3 as deternnned by I IPI,('), the reaction mixture was cooled to 20 5' 'I'he two layers were split 'I'he aqueous layer (bottom) tvas returned to the reactor mid back extracted by stirring HiSO( v ith I-BuOH (2 vol.) for a minimum of 10 min. The two Step 3 Layers v,ere split. The weight( of the aqueous layer was deter- nuncd und thc aqueous layer was ussaycd by HPLC (o csti- matc thc yield loss ol'Compound 3. The orgnnic layers werc combined, and telescoped into the next step. Where the next step was not carried om on (be same day, the solution was kept V at 20 5'. under inert head space. [0686] Step 2: crude I [0687[ An apptopriately sized reaction vessel was equipped with mechanical stirrer. retlux condenser, tempera- US 20]4/0275 [35 A] Sep. 18, 2014 74

ture pmbe and inert gas inlet/outlet. The solution of Com- 50 5'C. over I hour. held at 50 5" C. for I hour. and cooled pound 3 (10 vol. based on Compound 2, I cxtutv.) from thc to 5 5" C. (target 5" (1) over 2 hours. Additional ethanol (34 'I previous step was charged to thc vcsscl under;ui inert atmo- volumesj was charged over I hour to increase the yield he 5" sphere 'lite funnel and port were rinsed with I-butanol (0 5 nuxture was aged for a ininimum of 6 hours at 5 ( ivith voluines). 'I'he mixture was stirred at 20 5''-Anuno-4- stirnng. Thc solid was liltcred off under house vacuum and elforo-3-cyanopyrimidine (1.2 equiv.) was char ed throu h a washed with ethanol (3x4 volumes). Thc product was dnixl solid charge port under an inert atmosphere with stirring. under house vacuum for a minimum of 2 hours, tmnsferred to vacuum 40" vacuum N,N-Diisopmpylethylamine (1.5 equiv.) was char ed the oven, and dried at C under until constant wei was achieved. ( I bis-sulfuric acid tltrough die same charge port to thc wlntc suspcnsuin Thc Jtt ompound salt was collected as a ivhite crystalline solid (yield 90-95%) reaction mixture was heated to 90 (target tcmpcruturc 5'. Under additional studies, IitOII/ivater, IP/n)1" (2) with stirring under ar on After the reaction was [I)694J exemplary instead of anisoleilitOI I,'ivater, was used as the solvent fiir fiiund to be complete (al 0% Con£ 3 relative to Con&- Step 3. In one exemplary study. 0.75 (yield: 54%) of bis- pound I as determined HPLC), the reaction mixture was g by sulfuric acid salt monohydrate of Compound I was obtamixl cooled dovvn to 20 5" C. over approximately 2 hrs. The from I g ofcrude Compound I using Et OH/water (21: 1. 5 v/v) agtation was sloiied dov n to minimize crystal attrition. as solvent and without the use ofheating cycles in step 3.3. In Upon reaclnng 20 5'., thc suspension was aged for 6 another exemplary study. 3 8 (yield: 54%) of bis-sulhiric hours. Where thc product didn*t nucleated upon rcaclung acid salt nmnohydrate ofCompound I ives obtained from 5 5" g room temperature, the mixture was stirred at 20 t: until of&rude Compound I usuig EIOH/water (30.1.5 v!v) as sol- solid ives observed then the hatch ives aged fora minimum of vent and w ithout Ihc use ofhcatuig cycles ui step 3 3. XRPD 6 hours Potential hold point fiir up to 2 days at 20 5'C. 'I he shov ed that the solid products prepared in these two studies solid was filtered and the wet cal e was ivashed with methyl (v ithout use of the heating cycles) were Form 3 of the bis- tert-butyl ether (MTBE) (2x3 vol, with respect to the sub- sulfuric acid salt of ('ompound I strate). Thc solid was dncd on the liltcr under vacuum for at [0695] In another exemplary study, 1.1 (yield: 78%) of least onc hour, turned over regularly to help evenly dry thc bis-sulfuric acid salt inonohydrate of ('ompound I was solid I'he solid&vs& transferred to a vacuuni oven and dned at obtained from I o of crude ('ompound I using I:tOI Iiwater 40 5" ( under vacuum with nitrogen bleed until constant (12 I v/v) assolveni,withthcuscofhcatingcyclcsuistep3 3. weight was achieved ('rude Compound I was collected as a and without secxting. In another cxcmplary study, 1.1 g (ymld. pale yellow solid (1.48 kg. yield; -90%). 78%) of bis-sulfuric acid salt monohydrate of Compound I v as obtained from I crude Compound I EtOH/ [0688] Step 3.1 (Carbon Trcauncnt). of using water (12: I v/v) as solvent, with the use of heating cycles in [0689J A clean suitably sized vessel equipped v ith an over- step 3.3, and v;ith seeding 'I'hese studies showed that the use head stirrer, rcllux condenser. temperature probe, was of hcatuig cycles in step 33 can improve thc yield of thc a as cmbl &xi and fiu shcd with Cnidc Compound I (20 nitrogen. product. XRPD showed that thesolid products prepared in I weight) was char ed to the reaction vessel. Anisole (12 g. these two studies (with use of the heating cycles) were the volumes) and methanol (8 volumes) were char ed. Crude more stable Form I ofthe bis-sulfuric acid salt ofCompound Compound I may not fully dissolve because it may contain some insoluble impurities 'I'he reaction mixture was stirred I [0696] In one exemplary study, to 1000 mg of crude Com- and hcatcd to 30 2'. (target 30'.), snd was hei&1 for 15 pound I hemi solvate (l3uOI I) was added 4 ml of! ItOI I and muiutcs at 30 2'. with stirnng. 10 wt % of3M activutcd 800 ul of water 'lii the suspension was added 230 pl of carbon Type 5(0 1 v eightv ithrespecttothechargewei htof sulfuric acid. Thc suspension was stirred at RT for 5 min. 100 ('ompound I crude uncorrected for potency) was charged. mg of3M active&cd Carbon Type 5 && as added and the reaction 'I'he reaction mixture was stirred at 30 2" C (target 30' ) was I was fiir a minimum of 4 hours 'I'he black solid was hltered off mixture stirred at RT for 50 min. to 0 Itis. The solid filtered tltrough a whatman biter unit. and the carbon cake was (liltcr media Nylon 0.45 nncron) under house vacuum. Thc 'I washed with 4 ml, I containing 0 2 ml, water he cake was washed with a pre-mixed 40% methane/anisolc of) itOI of cake was then washed ivith 4 ml of I:tOI I. 'I he pale yellow solution (2x2 volumes), follov ed by methanol (2x4 volumes). solution was stirred at RT for 20mui. Thc solution was aced&xi with Fomi I of thc sulfuric acid salt ofCompound I (20 mg). [0690] Step 3.2 (Distillation): After over night at RT (15 Itis), the thick suspension was [0691] The liltratc was translbrred to un sized appropnatcly heated to 50" C. for 27 lus, and then stirred at RT for 18 lus. j;mkcted reaction vessel cquippcd with a short path distilla- 'I'he solid was filtered, ivashed with 2 ml. of I:tOI I, condition head mid ovcrhcad stirrer, and nnscd v ith methanol tioned for 10 min, then dried in vacuum oven at 40" C for 9 ivas (minimum amount). The methanol distilled off under hrs till constant was achieved. XRPD showed that thc reduced pressure (vacuum distillationj under 150 nunHg at weight sohd was Form I of bis sullbric acid salt ol'Compound l. 45" ( Compound I cmshed out towards the end of the distillation. I'he heat was turned off. the iacuuin was released, Example 8 and thc suspmwion was allowed to cool ui 22 2'. with stirring. Synthesis of Mono-Malcic Acid Salt of Compound I [0692J Step 3 3 (Salt liormation): [0693] Ethanol (6 volumes) was charged to the slurry in the [0697] In one exemplary study, en&de Compound I in ani- same jacketed reactor used to carry out the distillation. The sole (from step 3.2 in Example 7, 2.043 mmol) v as heated to mixture ives heated to 50 5" C (target 50'.) A 4 5M 50" ('ith stirring under air I.l equiv ofmaleic acid (0.261 solution of sulfiinc acid was prepared by diluting concen- 8, 2 247 nunol) in 'll lli (2 25 ml.-l M solution) was added to trated sulfunc acid (18M) four liikbn A 4 5M sulfuric acid uq. thc white suspension at 50'. Solid dissolved to provide solution (I iolumc, 2.2 cquiv.) was clrarg&xl dropwisc at clear yellow solution. Thc reaction was held at 50'. Iiir 10 30 5" C. over 5-20 minutes. The mixture was held at 50 5" muiutes. The heating was turned off and the reaction was C. for I hour. cooled to 5 5" C (target 5" C.) over 2 hours, and allowed to cool to RT slowly. The reaction i&as cooled to 5" C. held at 5 5" C for I hour. 'I'he niixture was then heated to with an ice bath. After stirring for 4 days, a white solid US 20]4/0275 [35 A1 Sep. 18, 2014 75

crashed out of solution. The solid was filter otf and washed 29-33" C.) and the reaction mixture v as stirred for a mini- with anisole (5 ml) and dned under vacuum, then pLaced in a mum of 15 minutes. Type 5 carbon (3M. 40 wt %) was vacuum oven at 40" ('vernight to aftiyrd mono-maletc acid clmrged and the mixture was stirred fiyr a mininlunl of 30 salt (667 mg, 66 7% recovery) as a bright white solid. XRPI) nunutes. 'I'he slurry was tiltered on a 0 45 pm tilter IIle cake armlysis of the sohd showed 11 was Fonu I of mono-nuilclc was wushcd withe 1.1 mixture ofacetic acid/water (4.4 vol.). acid sall oi'Compound l. [0702] 28% NH4OH (7.4-7.5 yol ) was charguxl to dn [0698] The process v as scaled up. To a four neck 250 tnl appropnate size vessel equipped with mechanical stirrer. round-bottom-flask was charged with 74.8 of the anlsole refhix condenser, and temperature pmbe. The acidic filtrate suspension containing colds Conlpound I (53)0 g. 10 21 above was charged to the vessel with stirring at a rate to 'I'he m mal) mixture was stirred under argon and heated to 50" nmintain the temperature a25" ('ater (4 5 vol.) was added C. Malcic acid (I M soluuon ln TkiF, 11.24 ml, 11.24 nuuol, (thc pH should bc neutral). 1.1 cquiv.) w as charged to Ihc rencuon. Thc rcuctton mixture [0703] In one exemplary study. the suspension resulted 50" 5" was held at C. for 60 minutes. and was cooled to C. over from above yves filtered and dried to provide a solid product of 2 hours. The was at with reaction mixture held 5'. stirrin free base ('ompimnd I XRPI) shoyved the solid pmduct was overnight After overnight the white suspenston v as stimng Iform I of the free base of( ompound I filtered under vacuunl, washed with M'1131I (2x5 ml) and [0704] In another exemplary study, thc suspension rcsuhtxl dncd under vacuum for I hour before being transihrred ulto irom above wab hcatcd to 90 5'. Ior 10-1 S hrs, cooled to the I acuum oyml ut 40'. for 3 days to provulc thc mouo- 20 5'C, over a minimum of I hr The mixture was stirred at maleic acid salt of Compound I (5.7047, 9.42 mmol. 92% 20 for a minimum of I hr The solid product was yield) as a yylfite to off white solid. Ptuity HPLC and 5'. (by filtered, washed with water (2x4 vol.). and dried at 40" C. to I,('MS): 98 5%. 'I I-NMR confirmed fornlation the maleic of constant v'eight to provide the hydrate of free hase of ('onl- acid salt Palladium analysis (122 mg) 24.6 ppnl. 'I'(iA pound I as a white sohd (ylcltl 75-90%). XRPD showed thc show cd 1. 31 5% w cl ght loss at I 80" C. DSC show ed a thermal sohd product was Ulc morc stable Form 2 of thc frtx: base of cvcnt at 189.12'. Water content KF=0.07%. by Compound l. [0699] Similar reacuous merc camrxl out usulg elthcr EtOAc or I PA In place of THF as the solvent for maleic acid. These reactions provided solid products ofmnleic acid salt of Exmnplc 10 ('ompound 1. which yvere determined to be I'orm I of mono- maleic acid salt of ('ompound I Polymorphism Study: Maturation of Mono-Maleic [0700J In another exemplary study, silnilar reaction v as Acid Salt Form I earned out using 0.25M solution of malcic actd in ethyl [0705] Appmxnuatcly 35 mg (0.057 nunol) ponions of accrete instead oi'M soluuon oi'alcic ucld m THF Thc mono-maleic acid salt Form I of Compound I w ere weighed process provided a sohd maleic acid salt of Compound l. into 2 ml screw-topped HPLC vials. One of 21 solvents was IJnder the microscope the solid didn*t blink when rotated added to each vial in a number of ali quota (up to 30 volumes), through polarized light, indicating the solid v as amorphous with slmking. All the samples yvere then placed under matu- ln tl'i(urn. ration between RT io 50'. (4 hours at each temperaturc) for 3 days Aficr maturation thc samples werc nnnlyscd by Example 9 XRPD. Clear solutions were cooled to -20" C. (freezer). Ifno precipitation occurred samples stere evaporated at RT. Syntlmbis oi'Hydrate oi'Free Base oi Compound I [0706] The results are summarized in Table (i. Mono-ma- [0701J An appropriate size reaction vessel wns equipped leic acid salt lioml I was obtained fmm 8 out of 15 single- with mechanical stirrer. reflux condenser, and temperature solvent systems and 2 out of 6 solvent mixtures 'I'he sanlples probe. Crude Compound I (I'rom step 2 m Ex;unplc 7) was dldn'1 rccrystallizc ul MEK, Acctonc/Water (90/10 v/v)f or clmrged to thc rcacuon vcsscl. Acetic acid (4.S vol.) was methanol. Thc Iree base rccrystalhzcd ul Ethanolf 2-Pro- added. The internal tempemqture was adjusted to 25 5" C. panol. I-Propanol, Acetone, THF, 2-Propanol/Water (90/10

(target temperature 23-26" C.) and the mixture was stirred for v/v), EtOH/Water (90/10 v/v), Acetic acid/Water (25/75 v/v) . 'I a minimum of 15 minutes Water (4 5 I el ) was added. he 'I'he mono-maleic acid salt has a tendency to dissociate in temperature was increased to 32 5" ('tarnet temperature these solvents.

TABLE 6

Polynior h Sciccn Rcsnlts no Cnstiuiiic Mono-Matc«acid sstt

XRPO 'u 'sMR

Ethanol 3fi ol Mfltiifflt oii I'B Pflttefii RA I B reciystall zat on Pf0p i it 0 I 3fi ol Mfltiifflt oii I'B Pflttefii i 4 eq ol male c flc d I B reciystall zat on I-Pinpannl 3P ol M:itiiifltioii FB Pflttmti . Iy A FB rcco stallization I-Butanol 3P ol M:itiiifltioii Malcic flcid salt Pattern I I ii eq nl inalci acid Stable . fllt -Biitalioiic 3P ol E flpnistino mnniplmus I if eq nfinalci acid Ainoiphnus MIBK 3fi ol Mfltiifflt oii :ville i d salt pfltterii I RA St.ible salt .4 etone 3fi ol Mfltiifflt oii I'B Pflttefii RA I B reciystall zat on

I Ihyl Mlitt it«i b 4 Sli b I Aiiisole 3P ol M:itiiifltioii Malcic flcid salt Pattern I Iy A Stable . fllt

AnisolciMcthuml 15uisi i 3P ol E flpnistino Malcic flcid salt Pattern I Iy A Stable . fllt Toluene 3fi ol Mfltiifflt oii :ville i d salt pfltterii I RA St.ible salt

Mlitt it«i b 4 Sli b I

I u vu Mlitt it«i b 4 Sli b I -Methyl-I-prnpannl 3P ol M:itiiifltioii Malcic flcid salt Pattern I Iy A Stable sfllt US 20]4/0275 [35 A] Sep. 18, 2014 76

TABLE 6-r;onttnucd

Pol nio &h Smeen Results on C stall ne Monn Mile amd soir

Sol int Sol nit nl Methnd XRPI3 'H XMR Cnmment

M 11313 tte I'3 n st, II r I A crone u&are! 1st!,In& it !3 vol T 'apoiii'I o!1 .I A X,A (um Piopannl, (Vere& (Pa, la v,vl u vol Mat!i!at ott I'B Pattern eu otmale acd I'B ie rystan zat on EtOHhuater(uc lav i/ u vol Mat!i!at ott I'B Pattern X ernie c a d date ted I'B ie rystan zat on A et s d water( 3 73 v'!I 5 vol Mat!i!at ott I'B Pattern X,A I'B ie rystan zat on

Aureole&TBME i&nisi! 3u 'nl Mahtnitiott Male« ind salt Pattcn! I EA Stable salt Methau I 3u 'nl E apnration AI!to!pl!oils EA &unnrphnus Ky TB=T 0 .. b A = a !Appl I I,

Example 11 1(xample 12

Polymorphism Study. Maturation ol Amorphous First Maleic Acid Salt Fomiatton Experiments Mono-Malcic Acid Salt [0707[ 'I he amorphous monn-maleic acid salt nf (:oni- [0710] Appmxnnalcly 30 mg (0.06 mmol) of frrm base Itorm I of Compound I or free hase Itorm 2 of ( ornpound I I v as at R'I'f a pnund prepared by evaporation methanolic 6'. solution saturated v ith mono-maleic acid salr Form l. was weighed separately into 2 ml I IPI.('ial and diluted in the solvents. to 50" ('. 'H«NMR (hsta (not shown) demonstrated that the amorplmus selected The solutions i(ere heated An volume mono-maleic acid salt contains about 0.9 eq. of maleic acid appropnate of stock acid solution (prepared in water salt and about 0.6 cq. of McOH. and prepared ivithout water) was added to each vial under [0708] Aliquois ol'he scleclcd snlvmtts (10 vnl.) werc magnetic slirnng. lite vials werc then scaled and cooled to within 8 hours io cnhancc thc crystalltyuuon of the sall&. added to the amorphous mono nmleic acid salt in 2 ml I I PI (: 'I'he clear snlutinns were cooled to — 20" (: (freezer) and then vials at ITI Samples ivere placed under maturation between evaporated at RT. of rhe solids obtained the RT/60" C. (4 hours cycle) for 3 days. After maniration the Samples during sequence manipulations u ere filtered and analysed samples were analyzed by XRPD. Clear solutions were then of by cooled to -20'. (freezer), If no precipitation occurred, XRPD. smnples werc cvaporalcd at RT. [0711] The results ofthe lira( salt formution series are sum- [0709] The results arc suntmarizcxi ui Table 7. Mono-nut- mauzcd in Table 8. Free base of Compound I was crystallizrxl leic acid salt ltnrm I was obtained froni 11 sinule-solvent in 13 nut 20 experiments. Mono-maleic acid salt ltorm I was systems I'he samples didn*t recrystallize in anisole/methanol crystalhzed in 4 out of 20 experiments with 2-l3utanone (50/60 v/v), chloroform, 1-4-dioxane, or I-I-I-triflunroetha- (MEK) or ethyl acetate as the solvent. The sample didn*t nol. recrystallize in 3 out of 20 experiments.

TABLE 7

polvmo &h screen Results on Amn»hous Mon Male c ac d s.ilt

Sol int Mctltnd XRPI3 (C Cnnutt ut

I tu(,« I r I St. I I

2 But,« r I St. I I

MIBK M.ihuat on Male c & d hilt Patteut I St.ibis alt

Ethyl acetate M.ihuat on Male c & d hilt Patteut I St.ibis alt

An sole M.ihuat on Male c & d hilt Patteut I St.ibis alt An sole I Iethanol (SC Sn v vl P 'i.ipoi !i'I oit VA Gum To(unite Mahu &tier! Male«:u:id salt Patton I Stable salt Isopiopylacctatc Mahu &tier! Male«:u:id salt Patton I Stable salt TBI IE Mahu &tier! Male«:u:id salt Patte!it I + I peak Stable salt 2-Methyl-I-propatiol Mahu &tier! Male«:u:id salt Patton I Stable salt

2 M r I St. I I I'

St. I I I& n! I' I I I Tntlu r eth.mol P 'i.ipoi !i'I oit VA Gum

I 'A=1 tAppl sbl. US 2014/0275135 A1 Sep. 18, 2014 77

TABLE 8

Salt Format on Ea eiunent Results

Sol cnt Sol mtt nl SM Acrd sto h soluttno XRPD C ottltltcttt

El lu IM n I lon P.ttmn ryat, II mt o Lthanol 3A I'B I'orm I 1)VI m Water I B Pattern 5 FB crvstau zat on I Butanol 3A I'B I'orm I 1)VI m Water I B Patte n FB crvstau zat on Butanone IA I'B I'orm I 1)VI m MEK '.vials a d salt Pattern I Stable salt Butanone IA I'B I'orm I 1)VI m Water I B Patte n 5 FB crvstau zat on

Etln:I acctatc 3tl FB Fnmy I IM m EtClAc Mulct retd salt Pattern I Stable salt

Etln:I acctatc 3tl FB Fnmy I IM ttt Watcl'M FB Pattens 5 FB crystaurzatroa Atttsolc 3tl FB Fnmy I ttt Watcl'M FB Pattens 5 FB crystaurzatroa " AntsolclMcthannl lyul50 ) I tl FB Fnmy I m McOH FRA Cnun I tl IM n Wale I vat. I u Ih ttmn 5 ryat, Il ml o El lu tB I IM n I lon ryat, Il ml o El lu tB I IM n Wale FB P.ttmn ryat, Il ml o

I lut,« I tB I IM n Wale FB P. Itm n 2 ryat, Il ml o Butanone IA I'B I'onn 1)VI m MEK '.vials a d salt Pattern I Stable salt Butanone IA I'B I'onn 1)VI m Water I B Patte n FB crvstau zat on Lthyl acetate 3A I'B I'onn I lvl m F ton '.vials a d salt Pattern I Stable salt

Lthyl acetate 3A I'B I'onn 1)VI m Watcl'BWater I B Patte n FB crvstau zat on Atttsolc 3tl FB Fnmy 2 IM ttt Watcl'M FB Pattens 2 FB crystaurzatroa AntsolclMcthannl lyul50 " )) I tl FB Fnmy 2 m McOH FRA Cnun " AntsolclMcthanol lyul50 ) I tl FB Fnmy 2 IM ttt Lo cryst FB Pattern FB crystaurzatroa x y syl= st ums uat n»t

I 'A=i tAppl bi

Exmnplc 13 Table 9 With 0.5 cq. 01'maleic acid, the free base crystalhzed, 0 ith 1.3 eq. and 1. 3 eq. ofmaleic acid, maleic acid salt Foml Second Malcic Acid Sall Formanon Experunents I was crystallized with an excess of maleic acid tn the crystalline solid: and yvith 2.0 eq, ofmaleic acid, a lov crystallin- [0712] A stxond sall I'ormanon cxpcnmmtt serwb was ity mulclc acid salt Form I was crystalhzcd. In amsolc widt made using venous ranos of malcic acid stock solution to 1.0 cq of malcic acid added as a IM stock solution ui THF, assess lhc process robuslncss. The results arc sununansed ln malcic ucid salt Form I was crystulhzcd.

TABLE 9

Solvent cnl SM solut on ed XRPD 'H EMR Comment

MEK 10 FB IMtnMEK As FB Patt nts h A FB cr stautzat n Form MEK 10 FB I M tn MEK 13 Matc«aced ntlt 12 cq ot Stnall caccss 1 Ihtt m I

Ml K I I 1 IM nMIK Ihtt m I

I 1 b'A Ml K I IM nMIK 0 ls, I lo Form Male c ac d Male c.t d salr Pattern I salt I'onn I Arne le 30 I'B IM n THF I tt Male cued salr h A stable s.tlt Form Pattens I Alttsolc 10 FB I M tn THF 10 Matc«actdntlt RA Stable salt Form Pattcrtt I

yf= yt0 ty, FR=F R, «A= V tAppb bl US 20]4/0275 [35 A1 Sep. 18, 2014 78

Example 14 (2.5 mL). Rotary evaporation was carried out at 45 mbar. in a wutcr bath. 20 un oil was on Polymorphism Study Matunhtion of Bis-Sulfuric 50'. Aficr nunutcs, obscrvcd thc flask walls, which bccumc a solid after scputching with 0 Acid Salt I'orin I spatula. I he amorphous character was confirmed by XRPD [0713] Bis-Sulfunc acid salt Form I ofCompound I (ch. 35

and ' I-N MR confirmed the structure, as well as the presence was weighed into vials '!'he corresponding solvmits and mg) ofresidual methanol (0.3 equivalents). solvent mixtures were added in portions of (a total of) 5, 10, 20. mid 30 & olumcs ai 50'., with shdkuig, amnng for clear [(1716J Further amorphous material was prepared in vials, solutions. Aflcr cue h add iu on, thc vials werc allow ml to shake to be used as input material for a maturation screen. Bis- I &vas for 20 minutes, afler which observations were made. Solu- Sulfuric acid salt i)orna (ca. 250 mg) dissolved in 1.2540'. tions were allowed to evaporate, whereas slurries were set for mL methanol, and pipetted into HPLC vials. The temperature 8 hour temperature cychng maturation. be«veen Ifl and 50" v as set at 80" C, to aid solvent evaporation, ii hich yielded oils (', for 5 days aflcr 20 nnnui ca. Thc oils werc placed in u vacuum oven at [0714] The results are sununanzed m Table 10. Thc mutc- in order io rcmove residual solvent. rial showed clear soluuons in 5 volumes ol acetic acid/wutcr [0717] Basic chamscterisation of these oils highlighted that I:3 and methanol at 50'. Slow evaporation of these solu- thc oils werc wci (broad water peak NMR mid weight loss tions yielded oils, wluch were subjected to maniration, pro- by of7% below 100 C ). ThcDSC was typicalofanamorphous ducing the bis-sulfuric acid salt l)orm I in the case of the methanol experiment The experinient in ethanol/water (90/ material, undue crystallization was observed below degrada- 10 v,iv) initially showed a slurry in 30 volumes but a clear tion solution was observed afler matumhtion Iiir tluee days. Evapo- [0718] The oils obtained by solvent cvapopution werc us&xi ration produced an oil, which crystallized to the bis-culhiric for flm maturation screen. Anhydrous solvents (5 volumes. acid milt Form I after maturation. All other cxpcrimcnis 100 PI,) v;ere used in order to mmimise the amount ofwater show cd slurncs in 30 volumes of solve«i, und nu«urn(ion Ibr present Any solutions were allowed to slowly evaporate, Ii& c days did Iioi sliow ally'liallgcm v hereas slurries were set for 8 hour temperature cyclin maturation, between RT and 50" C. Afler 24 hours, most oils TABLE 10 had not mixed ivith the solvents, and these were scratched with a spa(uk&, producuig slumcs. These werc matured Ibr 0 Pol mo h Screen w fh the C stall ne B s Sulfunc ac d siii further 24 hours before pcrfornung XRPD analysis.

5CI&cnf [0719] The results are sununarized in Table 11. The bis- So) &ni ~ I P&occdinc sulfuric ac«i sal( is diflicult to crystall)ac ui an anhydrous

'!0 cnvironmcnt. Tire cxpcruneni in methanol produced 0 clear Eihanof &of:VIaiuia& on Su) f&u 1& d salt Puieiu I '!0 solution, which then became an oil after solvent evaponhtion P&opanol &of:VIaiuia& on Su) f&u 1& d salt Puieiu I '!0 'I'he I P&opanol &of:VIaiuia& on Su) f&u 1& d salt Puieiu I experiment in acetonitrile produced a slurry, for which '!0 I Buianoi &of:VIaiuia& on Su) f&u 1& d salt Puieiu I nmturation yielded a poorly crystalline solid. with an XRPI ) - .BuI:u& ol& c 3&& ol Mahnafion Sufi'unc 1 id salt Pa&&en& I pattern slightly different to the bis-sulfunc acid salt Form I MIBK 3&& ol Mahnafion Sufi'unc 1 id salt Pa&&en& I manu- &one 3&& ol Mahnafion Sufi'unc 1 id salt Pa&&en& I (FILI. 6) The remainin experiments had to be mixed Eiin:I ace&sic 3&& ol Mahnafion Sufi'unc 1 id salt Pa&&en& I ally with a spatula. and maturation ol'thc slumcs I'or 24 lx) urs did noi induce crystallisniion. Basic characicmsaiion of ihc slurry in acetonitrile experiment showed a poorly crystalline (so sohd, whose crystallinity decreased on standing at rooin con- 'I Toluene !I) '&ol .OI'un&anon Sulf&u 1& d salt Puieiu I ditions fiir 24 luiurs. I-NMR showed residual solvent (0 3 '!0 IPAc &of:VIaiuia& on Sulf&u 1& d salt Puieiu I equivalents of methanol and 0.2 equivalents of acetonitrile). '!0 TBICIE &of:VIaiuia& on Sulf&u 1& d salt Puieiu I '!0 The DSC trace showed an irregular basehne with a small Meihvl I &of:VIaiuia& on Sulf&u 1& d salt Puieiu I cndoihcrmic cvcni ai 191'. p io p.'& oI THF 3&& ol Mahnafion Sufi'unc 1 id salt Pa&&en& I Ac foncoi'afci 3&& ol Mahnafion- 1& )1& TABLE 11 IP&) Ii.& filfiafc fern&cd

M&fui &&ion of Amoi hous Oils uf aud& dious So) cats

&V:1 (W) ll) fpf,i za h as I XXPD '!0 EIOH,iyaiei &ol Evapoii& on Sulf&u 1& d salt Puieiu I

(01 & I 1 & v c) Meifunoi if)0 Scuff Qn « .1 Ol I &ol Evapoii& oi na sei fo&

Waf 1 M ail&&a&1 0n 01 ':&p Ol a&1 011 A cfoi&lfl'ilc f00 Wiuie Whlfc Pnodv An&sole)TBME 3&& ol Mahnafion Sufi'unc 1 id salt Pa&&en& I Sfnnv Sluin co sialliifc &1&) Sf& . Id ;po&I on M I &.I& ofo I suffu * sf Phil

Ifa) 0 I 6 I DCM lho mo.u ih Yellow sluhy An&oiphous Example 15 THF if&0 s Iveni Yellow sluhy An oiphous EIOA if)0 scl'a&el& i&S Yellow sluhy An oiphous Polymorphism Study Maturation ofAmorphous BuOAc If)0 piuduccs Yellow sluhy An oiphous Bis-Sulfunc Acid Salt TBME foll sf&i&&'I Ye)le sluiu An&CIphous Dlo'sane foll Ye)le sluiu An&CIphous [0715J Bis-sulfuric acid salt liorin I (ca 100 mg) was plass weighed in a round bottom flask and dissolved in methanol US 2014/0275 [35 A1 Sep. 18, 2014

TABLE 11-mjnunucd the free base at 60" C., whereas expenments in ethanol and ethyl acctatc started as slurncs. Aller Ihc ad&hi&on ol thc acid. most cxpcrimcnts remained unchangrxl, although some solu- M jturat&oa ofArnoiphous Ods r& mdiydrous Sol cuts tions showed in&a&cd&ate precipitation. Most molalcd solnls werc mmjrphous by XRPD.Alon crystalline solnl was crys- au&I&var i&5 A&i&0&U&t'aturation Manu jt on talhsrx! from the system miisole/methanol/THF, showu&g dn Solvent 4h 4S h XRPI ) pattern slightly different to that ofthe his-sulfuric acid salt Form I (I'l(i. 7) 13asic charactensation suggested that IPA I c& i Y flo . Imi 1 &ufjh tlus material could be an unstable solvate (I'l(i 8A and I&1(i plass 813) I'hree experiments yielded the bis-sulfuric acid salt DI PE i&la Yellow stun Amorphous I&orm I (ethanoli'1111( from evaporation; and MIIKiTIII( from njaturation of gums).

TABLE 12

input Salient C C solut on .idd ton ramp XRPD

F nn I anisol" Solut&ou THF 1'clio solut n Ycllo 5 Intron Oil F nn 2 methanol Solut&ou THF 1'clio solut n Ycllo 5 Intron E aporat&on y&cldcd crystals vlshtlj lfl'ii P;uc I Sofu&mn 0 I

Sofu&mn 0 I

Sofu&mn 0 I Ion&& 2 S lut on Ethanol Yellou solur on Yell i solunon Of four& I stirs&jot Shit v THI Yellou solur on Yell i solunon Lo 5 rystalluie sot d oht.iuied Sulfunc a d salt Pattern I Ion&& 2 Shu v THI Yellou solur on Yell i solunon f'i.jpo&flf ou 'i'ided jn&orphous particles F nnl Sl&tuv etc& 1'clio solut n Ycllo 5 Intron Oil F nn2 Sl&tuv etc& 1'clio solut n Ycllo 5 Intron Oil F nnl Sl&tuv Etlhunol CI ud i clio Ycllo slur&a Fdtr.'jtc trit&&5 to Stint ou st'austria,

ttlmnot &'I i I Yell . Ium

I am

A«10 &P I & 0U 5 four& I MEK S lut on TH I Yellou solur on Gum n walls Wlute sol d after marurat on = Sulfunc a d salt Pattern I Ion&& 2 S lut on THI Yellou solur on Gum n walls Wlute sol d after marurat on = Sulfi&ri acid salt P:itrcrn I F nnl Solut&ou ijtc& T n phases T o phases &i!.'j F nn2 Solut&ou ijtc& T n phases T o phases &i!.'j F nnl Solut&ou Etlh unol Pi ccip t.'jr&on Ycllo slur&a A&i&0&phot&5

Sofu&mn I t lmno I Yell . Iuny I l.&OA I I 0 Y II hm Yell . Iuny I I 0 Y II hm Yell . Iuny

four& I Shitty u.iter Tuo phases Two phases &i &j Ion&& 2 Shu v u.iter Tuo phases Two phases &i &j

loni& I Shu v Ethanol Yellou slmry Yell i sluny A«10 &P I & 0U 5

Ion&& 2 Shu v Ethanol Yellou slmry Yell i slunv A«10 &P I & 0U 5

Example 16 Example 17

Bis-Sull'unc Acid Sall Formation Expcnmmits Characterimtion of the Free Base Fomi I

I'ree I'onn l&orm [0720J liase I and 2 ofCompound I (-26 [11722J I he results of the characterization of Irorni I ofthe nig) was w'eight il a&to vials dnd drasolv&xl tjr s i&spend&xi hi lhc free base of Compound I are summarized in Table 13. Free selected solvents (20 volumes, 600 pl,) at 60' Sulfuric acid base Form I was analysed to be a hydrate (-0 6 equivalents 'I'I (2 2 equivalents. 112 PI solution in ll, 60 pl, solution in v ater by KF). Thermal analysis slmwed dehydration to Fomi water, or 60 solution in ethanol) was added ar 60" C A PL 4 (anhydrous) from around 76'( . fill)owed by a melt (onset 20" 0.1" cooling ramp to C. was set up at C /minute. All sohds at 161" C.). OVS su gested that Form I matenal hydrates to obscncd werc &sole(ed and analyscd XRPD. Solufior&s by a higher hydrate aboi c 80 yo RH, but dus rc-convene to Form w crc scl Ior slow evaporation. I on desorption. One tv eek store e at 26'./93% RH showed 'I [0721J he results are sunimariped in 'I'able 12 Ifxperi- conversion &o Form 3, whereas storage at 40' /76% RH over ments in an&sole/methanol and MIIK started as solutions of the same period of time did not show any changes US 2014/0275 [35 AJ Sep. 18, 2014 80

TABLE 13 TABLE (4-con(BI«cat

Chfln rei xenon d.ita foi Compound I I'ree Base I o&m I Clif)&i)el'ci sano&i dalfl foi Co)tip iiitdl I Free Base I crit&

XRPDII I( 2 'l l «slit

Punrw bv 993.uei" Sun ofmtil unpui tea ieater Re snrpr nupt 7" u,a onunloadutga&4(la

HPLC than t) I area I = I) 4S uea 9 RH bl ghr hsnges b, XRPD afrei the TGAIFIG 241 TGA shone a ae ght ines of I 9" ( I."I eqs expenmenr fiitd 9'ster) orrespnndutg to.i vei bioad eridothetm Stflb I tv at Very sl chmges atter I &reek C''ono Qr DSC (FIO 261 b DSC Mcltutg cudothcm) ith nnsct at 161" aoi'C 7 ', RH cd by deco«&p st&or) fro)n.40 C Stabihty at Very slight images atter I cck VT-XRPD Coincisinu tn aanl»drous t'nrnt. Fon«4 bct ccn .'C 93 RH ' ' 4rb 7 Melt ar I fl KF 'oe 'ter io tl cqs Water) (B S (I )(I 26) Itimm lyn& mfl « I ... I pl I 6 47 tu) 90'tu. Ih hy. I . i o .ol Iuliiy

equ I bnum Xn changes I XRPD idler the cape& ment Stflb I flt .Io ch.u n fnrm.die& I v.eel 40',7ty 'H gee I ixample 19 Stability at Coin cisinu tn Foun (FIG. 31) Clmractcnzauon of the Amorphous Free Base C 93'; RH KF I &','ter (0 st i cqs. Watcm [07241 In onc exemplary study. to 5 g ol'crude Compound Tlirt'iitodviiaitiic i) tit)4tng tnL atpH 6 t! I (from step 2 in I ixample 7) tvas added 400 ml. oft-l3uOI I I b I iv water ('75 5). he mixture tvas heated up with heat gun until a

solution was obtained. then 100 mL ofwater v as added. After 30 min at RT the solution was still homogeneous and brown- Example Ig ish The solution vvas freeze dried (lyoplgltzatton) for 9 days to prov«le 4.7 g ol Compoutxl I as a sol&d malcmal. Picture

Iuxlcl nl&otoscope of lhc sob(i «laic&7«1 show&XI lhdl It was Characterization of the Free Base Fomt 2 amorphous. NMR shotved that the maternal contained about 'I [0723J he results of the characterization of Form 2 of the '/& molar of t-BuOI I 'I'he solid matenal was put mto vacuunt free base of Compound I are summarized in Table 14. Free over at 40" C. for 4 days. and NMR showed that lt contained base Form 2 was analysed to be a higldy crystalline hydmqte75'., aboUt 20%o molar ratio oft-BuOIL (-O.g equivalents water by RF). Themtal analysis showed a [07251 The results ofthe characterization ofthe amorphous &cry slight change tn the XRPD paucrnonhcatm above frrm base of Compound I arc siunmarizcd ul Table 15. Thc follow cd by a mell (onset al 172'.). GVS six&«cd sli ht amorphous frcc base of Compound I wns analyscd to bc moisture uptake on loading (I'rf w/w) be«veen 40-50% RI I, amorphous, with hiCk chemical punty and some residual remaining, stable with 5.7% w/w moisture contmtt between tert-butanol content 'I hermal analysis showed some solvent 90-10/o on desorption. Slight evidence of hysteresis (re-up- loss but no evidence ofcrystallisation before decomposition. take is slop er between 0-10'/o RH) and very SIICtt changes in No crystallisation after storage at elevated humidity. the XRPD after the expenment. One week storage at 25" C /93o/o RH and 40 C /75% RH also showed mmniy lhc sumo TABLE 15 paucm with a fi:w defi:rcnccs. Thc fact thai the XRPD patterns hardly change with moisture content varyinn betv een 0 and 6% w,'w water (0 to 2 equivalents) suggest ~ that tlus XRPD Attic&pl)oaf material iv a clmnnel hydrate where water can easily ntove in 'H F,MR C'ons steat w th sin)eau e -(i 3 equn.ilents and out of the crystal lattice. rcsidu tl tc& I-bntannl Piuity by Ov O flrcfl 'r. Si un nf total &&tip)&rittcfl grc'Itcr tli ui HPLC 0 I mca'n Sl arcs ts TABLE 14 'Ill \:m I

Il'lC DS('tflb XRPD 7) Ciystallute I'iee Bnse I'orm ot'hydrflres. ould be ev den e of some 'H «MR Cons sieur a th stnicuue Xo tes dual snlvent mystflnute c nrertr obscr cd I tv at Ho changes after I neck Punt& bv 99 6 arcs ': Sun& of &otal unpiuitics grcatcr 40'C )7 "RH HPLC thai 0 I m'ca ') 3)) arcs Ivo Stabihty at chang s aficr I cck I( 4 Il I(l 2S! .'C 93 RH :«I DS(' I(l 9&

VT XRPD hr chsnaes ut pattern ttom 7t RH Ho Example 20 further hanges up to smelt at.nourid 190'. Dr rig He it na ut tu& oven at 12( C for me hours expenments shooed ver, sl ghrclflin es b, XRPD Polymorphism Study: Screening Using Amorphous GVS &FIG 301 4 7'; )nnisturc or& loadina Into)cdifltc Free Base Compound I ' mnisnuc uptake(m)-5)PS RH up to ra, hick rmnams stable ou sorpt on up to 9m RH. [(7726[ Amorphous free base Compound I (ca 25 mg) was weighed into vials 'I'he selected solvents and solvent ntix- US 2014/0275 [35 AJ Sep. 18, 2014 81

tures (5 to 20 volumes) were added with stirring. Any solu- investi ated. The best solvent systems (clear solutions) were tions w crc allowcd to slow ly evaporate, w hcrca s slurries werc methanohanisole I I and l)MSO (10 volumes, at lfl'). diox- sct for S hour tmnpcrature cyclutg muluratron, betv,ecn RT ane (10 yohuuesr 50" C.)r chloroform (20 volumes, RT). and 50" ('., for 2 days Expcnmcnls in 2-mcthyllclrahydrolitran. THF 5% water and [0727J 'I he results are summarized in Table 16 Most vials ethanol anisole showed clear solutions using 50 volumes, and shoyved an off-wldte sohd in a brown solution affer solvent methanol, DCM. THF. DME, DCM.mcthmiol I: I and accto- addition. These suspensions v ere set for temperanire cycling, nitrile/5% v'»ter usin 100 volumes. and most of them converted to thick slurries after 24 hours. Thcsc werc allow cd lo cycle for 0 liirlhcr 24 hours pnor to [0729[ The resulis arc sununarizcd ui Table 17. Solutions dnalvsrs. Most of thos(: sollrl ~ showcrl a very sunilru XRPD were placed at 4':., where ei ht experiments show:ed crys- pattern. and yvere denoted as Form 5 (l(if) 36) Slight differ- talhsulion. Crystals vcrc ground in order to nna lyse them by ences yvere observed, suggesting that these are isostnictunnl XI&PI). Suspensions were set for temperature cycling for a solvates, where differences in the solvent result in sh ht total offive days after which time XRPD analysis v as carried differences by XRPD. The only experiment that gave 0 dif- out. Most solids obtained fmm both procedures showed Fomi ferent XRPD was the expenment in water. yvhich showed 5. Similar to the screen in Example 20, these XRPD patterns Form 4. Finally. muluratton in rsopropyl acetate resulted rn show slight dill):rcnccs (FIG. 37) How cvcrr sohds from bodi malcnal with sinular XRPD to Form S. scrccns obtained lhom the same solvent show a matclung

TABLE 16

Solvent t mount Obse(vtt ons on solvent Atler 4 hours Solvent IELI add t on cvclut XRPD

MeOH (1 1V!urc sol 6 m biomt snlut(on Off- lute slurry Crystall(nc Form 5

EIOH 250 Off I te. I ny rby i; It n I m» y. ton tnt 2t(0 Off I te. I ny rby i; It n I m» bio 1 I t(0 Off I te. I ny rby i; It n I m» 1'on I t(0 Off I te. I ny rby i; It n I m» MIBK I (10 yvh te sol d n l»(mr( solut on Off ah te stony C(ysrall ne Form \ TBlvlE 3 (10 yvh te sol d n l»(mr( solut on Off ah te stony C(ysrall ne Form \ MeTHF (10 yvh te sol d n l»(mr( solut on Off ah te stony C(ysrall ne Form \ THF 150 yvh te sol d n l»(mr( solut on Off ah te stony C(ysrall ne Form \ DCM ISU 1V!urc sol 6 m biomt snlut(on Oft- lute slurry Crystall(nc Form 5 I PA ISU 1V!urc sol 6 m biomt snlut(on Oft- lute slurry Crystall(nc Form 5 DME ISU 1V!urc sol 6 m biomt snlut(on Oft- lute slurry Crystall(nc Form 5 DCM 'vfcOH I I ISU 1V!urc sol 6 m biomt snlut(on Oft- lute slurry Crystall(nc Form 5

112 0 450 Off I te. I ny Ib rt(: lty eryst; II 113 P.(tun 4 I 50 rby i; It n I m» THF 5" «are( 150 yvh te sold n l»(mr(solut on Off ah te stony C(ysrall ne Form \ MeCH 5" «are( 150 yvh te sold n l»(mr(solut on Off ah te stony C(ysrall ne Form \ IPAc 3 (10 yvh te sold n l»(mr(solut on Off ah te stony C(ysrall ne Form \ 06 ltoU(s nt.'(t((rat(oitl

Example 21 XRPD pattern, also supportin that tlds is a series oficostruc- tural solvates. Polymorphism Study: Screenin I)sin ~ Foml 2 of [I)73()J I he solid obtained from ethanol water I'I showed Free Base Compound I the unchanged I onu 2. Solutions from 2-methyltetrahydm- furan and dioxane yielded oils. yvhtch crystallised (to ltorm 5 [0728] Crystalline Hydrate Fom12ofCompound I showed or a mixture of Forms 5 and 3 respectively) after temperature chan es in solubility in the whole ran e of solvent systems cychng for two days (same pro@am).

TABLE 17

Solubility, sever nt:md ol mo hs» n Inn I:u to

So(nb(hn at . 0'

10 tt ((i 75 :s R P D

E(OH Mttutatrnn Ciystallutc Fomt 5 :«crorutnle Mttutatrnn Ciystallutc Fomt 5 EtOA Matu(at on Cr, still ne I onn ( sn II n l.

'IBK sn II n l. chlorofomt l (RT) tt,a tt,'a C ohttg ot ft(dge Matuiation of oil produ cd US 2014/0275135 A1 Sep. 18, 2014 82

TABLE 17-conlim&cd

Solub I t assessment sod oi mm ih smeen usu« I B H d&ate I'onn 2

solubil&tv:it i&'1

I&& 2ti XRPD

v elded o I Cosrall ne Form \ MeTHF n'a Eviporat any aided O I Matiiifl't o&t of o& produced C&ye&all&no Form 5 THF A&&most ( rv'5&snizii'tron iu f&icigc C&ye&all&no Form 5 Di xu&c u s &&is n's E aporat&on»cldcd od Matiu &tier& of o&l pr duccd C&ystall&nc Form 5+ For&i&3

DC 51 CO bit r.i i 11&dye (by i;Iln I m IPA M:co, t (by i;Iln I m DCSIM 0011 (by i;Iln I m +tom I M:co, t (by i;Iln I m MeCN 5" Care& Crystall zat on n f& dae Cosrall ne Form IPAc x Miturat on Cosrall ne Form I buranol x Miturat on Cosrall ne Form MeOH,an sole Z (RT) n'a u s n'a Crystall zat on n f& dae Cosrall ne Form EtOH& ster I I M:&trit'&it&on C&ystall&nc Form DMSO J (RTI u s &&is n's I o rystalhzat&on u& tl&dsc An&orphous sct foi c aper&tron

Example 22 Example 23

Polymorphism Study; Matumqtion in Ace&ic Characterization of Screening Samples Acid&Water

[0732] S&uuplcb Irom the screen using amorphous Ircc base

[0731] Maturation ofthe hydrate Form I of free base C'om- Compound I were analysed by 'lT-NMR and DSC. and re- pound I and the amorphous malcnal in acciw. ac&d.water 1.1 analyb&s by XRPD v as also carried out aficr drying at 50'./vacuum for tluee days yielded an XRPD pattern denoted as Form 6. and store e at 40'./75% RH /the same sample Howcvcrr ma(ural&on of the hydrate Form 2 ol'rcc base was dnrx! and stored at cle&a(ed luunnhty). 'I C'ompound I d&d not show any changes in form he results [tt733J I he results are summarized in 'I'able 19 'l l-NMR are summanzed in Table 18. rcvcalcd d&ffcrcnl amounts of residual or muc solvent &n most sohds, v;ith the exception ofthat fmm methanol l)SC: analy- TABLE 18 sis vaned significantly between d&fferent sohds. Cienerally. a

M iturat&on cx cruncnts &n acetic acid itci I I melting endothem& &vas observed fonsets between 15&) and 178" Cd and some traces show solvent loss broad endot- hcrms. MT-XRPD on sclectcd samples (bd not show any I'onn Input material a&col&st'd ti&IC&t ev'eli&tg XRPD changes belo~ the melt. TCiA on selected samples shovved a wc&ghl loss on Ihc melt aran, which suggests that these sol- mnorphous mg loi&PL &Vlurc sol 6 Wiutc solid Crystauuic vates only release the solvents on meltin, w hich &s consistent u &&&own u 110&in Fora& 6 with ihc lack ol form chm&ge XRPD al '&i solut on solut on by Dry&ng 50'. 2'7 my,'ltiti I O'I I Wh& ('ris&, II& under vacuum did not show clmnges XIRPI), and & any by shury elm rv Folic 6 ncithcr dnl storage ai 40'./78%o RH, suggesting that water Form iua'liiii PL &Vhitc Wiutc Crystauuic could have replaced the organic solvent 'I I-NMR of selected slurry sliury Fora& samples atter storage shou ed that these had lost their organic solvent to some extent

'I'AIII,II I')

Res dual XRPD.ifter XRPD.dier solv ntl&V DSC (u&dTGA t drv ng ar Storige at Solvent 'H VMR appl 'able) VT XRPD O' i.icuum 40' 755 RH

McOH 0 &&4 cqs Bmad cnd them& lo T No Iungcs Vo changes Vo ch:inc&a M lt. t 176'2 1101& ti(i qa Bmml I th r lo I ~ . M It.t 17&'2 eqa M&t.t &7 '(L I(&A ~ .

Way&t loss&t I I VMR.h d u&d diuo&g melt no McCl US 2014/0275 135 A1 Sep. 18, 2014 83

TABLE 19-conlim(cd

Clma iei zitonofscieerun smniles Form I'onn4

Res(du:il XRPD atlci XP.PD anm

sol 'ciir DSC Iarid TGA Iiyiiig:ir Sroia c ii'I 1) it'ippli Sol int 'H-NMR able) VT-XRPD (i' acuum 40' 7 '. RH

Eto.a iy 6 eqs Double endothemi ni Xo h.m es No elis(i cs (onsei 172' ) Aecl'oiic I eq vtelt ai 177' ni Xo h.m es No elis(i cs MIBK Very «i, '- I P or ba. clinc iuiablc I o cliangcs chm cs cqs ro iiirccz'iitc

TBI IE 0 ) cqs P or ba. clinc Small I o cliangcs chm cs

midothcmi at 169" C. 2 M 2" 07 q ('u b Io ell 09 q . (I 2'('I ltl:1 NVHI al «d We ghi loss at low lower THF T and du( ngm It tii 7S eqs! DC VI 0 67 eqs Vtelt ai 7(P C No etc(mes Xo h.m es No elis(i cs beloyi melt I PA i) S) cqs Melt ai 17(i ' I o cliangcs chm cs DME i) 4) cqs Melt ai 17 ' il:i I o cliangcs chm cs ' DCM 'ylcOH I I 0 I cqs McOH Melt ai 17S No chmigcs I o cliangcs chm cs 0 cqs DCM bclo melt I (i0 b orga

1' «(. - I 2 eqs ethanol io ntegrate THF 6" ware( Very we(. og Double endothemi ni Xo h.m es No elis(i cs eqs (onsei 174' ) TkII'erynet, MeCN 6" ware( 30 vtelt ai 173' . TGA ni Xo h.m es No elis(i cs cqs McCV Weigh(loss etio T :uid duruie melt

Example 24 Example 25

Clmracterizztion of Foml 6 of Free Base of Characterization of Foml 4 of Free Base of I 'ompound I Compound I JI1735J 13atch I of liorrn 6 of free base of 6'ompound I was J07341 Hydrate Form I of free base Compound I /-90 m ) obtained frnm maturatinn of linrm I of free hase of ('on)- was heated in an oven to 125" C'iyr two hours. 'I'he resulting pound I in acetic acid:water as described in Example 22. solid was analysed to be the anhydrous Form 4. consistent Batch 2 of Fomt 6 yvas obtained in a similar manner. Form I — lbrm I w with thc dehydration of Form I by VT-XRPD. Basic churac- 1 22 mg) ol base ofCompound as suspcndcd in accuc terisation v as carried out and it is summarized in Table 20. acid valcr I. I JI00 HL: 5 volumes) and set for Imnpcralurc Form 4 was unulyscd to bc mdtydroua, and rcsultcd I'rom cychng maturation Jbctw ccn room Icmpcpdture mid 50'., 4 'I'his hours at each temperature) fora total of 16 hours Very small dehydmztion of the I lydmzte ! nrm I material adsorbs w as sn some moisture, as shown in (hernial analysis arxl KF. GVS amount of solid present the liquors were evaporated. JI1736J 13asic characterisation was cerned out and sunl- su geste this material hydrates above X0% I&i I. but reversibly itis nmrised in I able 21 Iiorm v as analysed to be an acetic acid dehydrates back at 40% RH. 6 solvate containing 0 5 equivalents ofacetic acid l)esolvation to the anhydrous Foml 4 occurred at amund 100" C. by TABLE 20 VT-XRPDandat0%oRHontheCVS TCiAandDSC showed Charactcnzarion of(bc arih dmus Form 4 complex thermal behaviour above those temperatures. Stor- age al elevated lnmndily conditions showed conversion Io *tui qu I lydrate Form 3. 'I'he fact that both Solvate I'orm 6 and

XRPD (I I(l I lydrate Form 3 show very similar d(ffractogranls suggests 'll bbul tint they could be annther ser of isostructural snlvates/hy- TGAiFIO 331 TGAsho as cighi loss of I tony cqs zrcr) clrate. fiiid oneqiond ng to a yei, (road endothenn by DSC DSC O'IG 341 Melt ne endothemi w (h onset at 161" C fouoyied 'I'A 1 31.11 21

GVS(FIG 3 I il 9 'iloisrurc oii loiidliig 4.fl rip(abc(i bct ccu 7(1 90% RH, ith hysteresis on desorpt on b,o lurnes XRPD ifle( the by Tech(i Rile Batch(ofi'n6 Bat Ii 2 ol lor(16

KI 2 049( XRPD(FIG 3gl Accric acid sol zrc Acetic acid snl atc Form 6 Fore( 6 US 20[4/0275 [35 A1 Sep. 18, 2014 84

TABLE 21-m&nunucd TABLE 22-m&nunucd

Char ictenz it nn nf I'omi 6 Stab I t ea e&unents on I'ann 2 fhee bise of Cpm ioiutd I

T cliltiquc B:itch I of Form 6 Bereft 2 of Fnmt 6 Sol crit Tcmpcr.'iturc XRPD

'll bMR 90 (' l rb: I I mr 2 & stiu nue 0 I eqa stn&cnuv 0 \ eqs. ho(Cate I ann 6 A et a d Acct c1 d TGAI I'IG 1)) n a TGA shows m ue ht fiitd losses of'&11".nnd

DSC iFIO 40) 3 6a I oinbmcd cqu»a(cut to u . cqs Example 27 A 'ct'I ''I 'id) eottcsf&oitdittp, t'n t '0 Single Crystal Expenments

DS(' I I &md»ti m ia&1 16'1 [t)730J A I'orm 5 free base I md&7&'(''olio ed sample of of of Compound bv de onipos t on finrn (ace(on&tnlc solvatc) was submitted I'or su& lc crystal X-rdy 4(1' diffraction studies. 'I'he results are shown in I'able 23. 'I he VT XRPD Con&era on to Form 4 u .1 stntcture solution was obtained by direct methods. full-ma- from 10(t" C Sl +I " lr ' clungc at 18 C . tnx least-squares refinement on with tveighting w t'onn closely cd 6& (F, )+(0.0453P) +(0.0000P), where P=(F, +2F,.')/3, aniso- »1 alt trop&c displaccmcni parmnclcrs. cmp&ncul nbsorpl&on GVS IFIO 4&l 6, 'ilotsturc ott p(01 correct&on using spherical ham&on&cs, implemented in SCALE3 ABSPACK scaling algonthm. Fu&al wR =»X[w (I', — I',')2)JD.[w(l',2)2]n 0 10gg for all data, conven- desorpt on Second ) t&onal =0 0464 on F values of 9209 rellect&ons w&th F,&4O y le shone 4B)W R, revere ble mo sture (I',), S 1.036 for all data and 762 panqmeters Irinal 6/G(n&ax) uptake bem een 0.001, (3/G(mean), 0.000. Final difference map between 0-90 RH Rc.sita()'sis +0.410 and — e A b XRPD alto cd thc 0350 Fomi 4 mdtyd roue [0739] FILI. 42 sho&vs a view of a molecule of the acetoni- Stability at 111.'I Vcrv aught changes 4(1''7&W Rl( ti I 1 tnle solvate (Form 5) fmm the crystal structure showing the Stabil ly: 1 I uls h, nu.. numbering scheme employed. Anisotmpic atomic dicpiace- 21 '') tm Rl( ti I 1 tncnl clltpsonls for lhc non hvdlogct& alon&s 4&c shown al lhc 50% probability level. Hydrogen atoms are displayed with an arb&tranly small rad&us. FIG. 43 shows a v&cw ol'pan of(bc Exmnplc 26 crystal packing of the acetonit rile solvate (I 'orm 5) in the unit cell looking approxunalcly down thc [Or I, I] d&rect&on of lhc unit cell. For clarity all hydmgen atoms other than the 0 I I Stability of I lydrate Irorm 2 of I ree l lese of and N H are removed. FIG. 44 shows the experimental and Compound I calculated XRPI) patterns of the acetonitrile solvate (I&urn& 5). [0737] Hydrutc Form 2 of free base of Compound I (— 50 mg) was suspended u& pure waicr or a m&xlurc eccl&c acnl w ster I: 3 (10 volumes) and scl lo mature al constant tempera- TABLE 23 ture (25" C. or 90" C ) fora total of 40 hours Aliquots of the suspensions were filtered and analysed by Xlqpl). and the results are summarized in Table 22. Both solids obtained from Mole ulu formula C,CH&s. 1&01 Mole ulu us aht 0 9 maturation at 25" C. (from v ater and the aqueous acetic acid 90" Cn, stzl system Gnhorhombic m&xlurc) show cd the unclrungcxi Fom& 2. At C.. thc sol&d Space grnup Pz(1lz(llzil):i 144137i3)A. a 90 from pure water also show cd Form 2, but thc solid from acct&c b 18 7487i4) A. 0 90 acid.water showed some cvidcncc of lhc ucclic ac&d sulvatc c 20 U&03in) A. 7 90 4tis A Itorm 6 mixed tvith a majonty of i(urn& 2 'I'hermal analysis of 1(2) z 8 ltorm 2 dehydmqtion XO" shows above C, and the presence of D, I (i38 acetic acid could favour the solvate vvhen the water content &s 0696 s — nottoo high. Sot»ca, 1 Cu K!alphal I 4178 A F(0110) 22 4 T lun(11 K TABLE 22 C rvstfll C Inurlessc lunutu 018 00( 0(12nun Dztz tnuicatcd tn 0 SU A 0„... 44m Contplctcncss 1 p«( n Xxl'D Rctlectinns 2'Wsi 11(i(17 " " C Hy unite Fomt R„„ U(1 97 W'(IC(''(IC('cetic 9rr C Hy drate Fomt " " acid:itci I . C Hy drate Fomt US 20]4/0275 [35 A1 Sep. 18, 2014 85

Example 28 Thermo-Ciravimetric Analysis (TCiA) [0746] TGA data werc collected on a Mculcr TGA/SDTA Solid Form Characterizastion 85lc cqutppcd with a 34 posiuon uuto-atunplcr The instrument v as temperature calibrated using certified indium. Typi- X-Ray Powder Diffraction (XRPD) cally S-10 mg of each sample was loaded onto a pre-weighed aluntimum cmcible and was heated at 10" ('min from ambi- Brukcr AXS C2 GADDS: [0740] ent tcnIpcr;dure to 350 ( A nitrogen purge Bt 50 ntl mul ivan [0741] X-Ruy Powder DilTracuon puitcrns were collected nululiaulcd ovcz Ihc sanlphv Thc Insiruntcni connol and dain on a Bruker AXS C2 GADDS dilTraciomctcr usutg Cu Ku analysts sofiwarc was STARc v9.20 radiation (40 kV. 40 ntA). automated XYZ sta e, laser video microscope for auto-sample positionin und a HiStar 2-di- Polarised I.ight Microscopy (Pl M) mensional area detector X-ray optics consists of a single (iael multilayer mirror coupled with a pinhole collimator of 0 3 [0747J Samples v ere studied on a l,eica I.M/DM polarised light microscope with a digital video camera for intage cap- nmt. Thc beam du crgcnccs I e 7 I bc clTec tive size of I bc X-ray beam on thc samples wns approximately 4 nun. A 0-0 mm- ture. A small amount of each sample wus placixl on a glass tinuous scan mode was employed with a sample detector slide. mounted In muncrsion oil and covered w 1th a glass slip. distance of 20 cm which gives an efi'ective 20 range of 3 2"- the individual particles being separated as well as pocsible. 29 7". 'Iypically the sample would be exposed to the X-ray The sample vvas viewed v ith appropriate map»ficafion and beam finr 120 seconds 'I he softivare used for data collection partially polarised light, coupled to a k false-colour filter was GADDS I'or XP/2000 4.143 mid Ihc data werc analyzed and prcscntcdustn DIITrac Plus EVA v13 0 0 2 or v15.0 0 0. Water Determination by Karl Fischer Titration (KF) Samples nut under ambient conditions were prepared as flat [0748] The water content of each atunplc was mcasurcd on plate specimens usin pov der as received without grinding. a Mcirolun 874 Oven Sample Processor at 150'. or 180" C. Approximately 1-2 mg ofthe sainple was lightly pressed on u v ith 851 Titrano Coulometer using Hydranal Coulomat ACI non- glass slide to obtain a flat surface. Samples nm under oven re i ent and nitrogen purge Weighed solid samples were ambu:ni conditions Ccrc mounted on a sihcon walbr with introduced into a sealed sample vial Approx 10 mg ofsample heat-conducting compound. Thc sample v as then hcaicd 10 was used per titration and duphcate determinations were the appropriate temperature at 10' S/min and subsequently made. held isothermally for I minute before data collection was initiated. (iravtmetric Vapour Sorption ((rVS) [0742] Bruker AXS D8 Advance: [0749] Sorption isotheuns were obtained using a Hiden [0743] X-Ray Powder Diffraction patterns vvere collected I(IASorp moisture sorption analyser, controlled by ('IIRSorp on a 13ntker l)8 diffractometer using Cu Ko radiation (40 k V, software 'I'he sample Ieinperature was maintained at 25" C 0-20 40 mA), goniometer, and divergence 0fV4 and recmvi n8 by a Huber re-ctrculatutg water bath. The humidity was con- sins, a Gc monochromator and a dctccior. Thc sufi- Lynxcyc trolled by s Ircams ofdry mtd wet gmt. w 1ih a IoIa I Com- mixing nitro warc used for dais collccuon was Dillrac Plus XRD flov rate of 250 ml/min. The relative humidity (RH) vvas mander v2.6 I and the data were analysed und presented measured by a calibratedVaisala RH probe (dynamic range of v v15.0.0.0. were using Diffrac Plus EVA f3.0.0.2 or Samples 0-95oi RI I), located near the sample 'I he weight change, run as tlat specimens. 'I he under ambient conditions plate (mass relaxation) of the sample as a function of 'rf Rl I was sample v as gently packed into a cavity cut into polished, constantly monitored by tlm microbalancc (accuracy 0.001 zero-background (510) sdimtn wafer. Thc sample was rotutcd mg). Typically 10-20 mg of sample was placed In a tarixl in Im own plane duung analysts. Thc dcIatls of Ihc data mesh stainless steel basket under ambient conditions. The collection are: An ular range. 2 to 42"20. Step size: 0 05'20, sample was loaded and unloaded at 40'io RH and 25" C. and Collection time: 0.5 s/step. (typical room conditions). A moisture sorption isothernt was performed as outlined belov (2 scans giving I complete 'H NMR cycle). Thc standard Isotherm w as performed at 25'. at 10% RH intervals over a 0-90'io RH range. [0744J NMR spectra were collected on a 13ruker 400 Mf lz instrument cquippixl wtih mt auto-sampler and conIrollcd by a DRX400 console. Automaicxf cxpeumcnis werc acquired V:I using ICON-NMR v4 0.7 nmning with Topspin vl 3 usia the stanthsrd Btuker loaded experiments. For non-routine Adsotpt on Scar& I 40 ao spectroscopy. data were acquired through the use of'litpspin Desotpt onAdsotpt on S ut 2 SS Dt,. Dtr 4n Intervals ja Rut 10 alone. Samples were prepared in I )M SO-dro unless otherwise Vtlinscl of scalls 7 stated. Off linc analysts was camcd out using Topspin vl 3 or Flo tate itnl non/ 270 ACD SpccMatmgcr v12.5. TctItpcl.'tttltc i 0 I 21 St: Btj t I''i 00 I

Differential Scanning Calorimetry (DSC) 4 were ' [07451 DSC data collected on a Mettler DSC 823E Accatfl I Pf1 equipped ivith a 34 position auto-sampler. 'I he instniment was calibrated for energy and tentpensture using certified300''. indium. Typically 0 5-1.S mg of each sumplc, ut a put-holed [0750] ThcsoftwarcuscsalcBsisquBrcsnunuulsdttonpro- aluminium pan, was heated at 10'.,'nun lrom 2S'. to ccdurc together with a model of the mass rclaxauon. to pre- A nitrogen purge at 50 ml/min was maintained over the dict iul Bsvnlpioltc vahuv Thc nlcB Bored ntass IclaxBtton cable sample. The instnmtent control and data analysis software nnist be v;ithin 5% of that predicted by the software. before 'I was S I'ARe v9.20 the next% RI I value is selected. he minimum equilibration US 20]4/0275 [35 A1 Sep. 18, 2014 86

time ivas set to I hour and the maximum to 4 hours. The acid salt monohydrate, and Form I of mono-maleic acid salt sample was rccovcrcd after completion of thc iso(hemi and of('ompound I in the folloiving conditions: (i) 6" (2 (closed); rc-analvsed bv XRPD. (ii) ambient (closed): (iii) ambient (closed-exposed to light): (iv) umbicnt (open). (v) 60'. (closed), (vi) RT(75% RH Ion Cluumato raphy (IC) (open), and (vii) 40" C,/75%o RIT (open). No change in [0751] Dale werc collrxtcd on a Metrolun 861 Advanced appcarancc was observed for mly foun across all conditions Compact IC (Ibr aniolm) usuig IC Ncl software v2ck Accu- tested. No significant change of v ster content was observed, rately iveigltmI samples were prepared as stock solutions m an as dctcnnincd by KF (data not shown), for any I'onn acme s all appropriate dissolving solution and diluted appropriately conditions tested. prior to testing. Quantification v as achieved by comparison with known standard solutions of concentration of the ion Solubility: bein analysed

[0754] The solubihty da(c for free base hydra(c. Form I of bis-sulfuric acid salt monohydrate, and lrorm I of mono- malcic acid salt ol Compound I arc sununauzed in Table 24. 2 0(4(r 0 ml When compared to the hydrate, both salts, particularly the C nlumrr Temperature .anrb cist bis-sulfuric salt. shoived (" C i acid significantly higher solubility

up to pi I 3.

I'ABI E 24

Snlubl offreelrasehvdrate be su(1m cwdsut andm noma(a a dealt

Solub I 0 Hvdr.rre H s srrlfrrr' a ' salt :Vials c a d salt

Wu I 6(r rl !pl( I 161 -0- mg' (pit 4 43) mf, W''ther

7" pl I RI ('u Ill pH s I GS cl C12 16 C4 4 19 ct C12 I 3(7 3A7 cl -12 9 I lrr 162 3 Il I (0 3 4( 3 S 0 24 A 31 " t! A.29 (I zg

crtratc Imft'cr, pH " i rrrg rrrL :12 mg.'mL I S r110'rIrL at RT; ' at RT artd 37 ' 3 13 nrgrmL at" I (r tb u('I, 37'L 16 nfml vfr I p, ml.

S I '»nf. ml Sunulated lrrtestmal Flu d Ir (I(12 Irr" rrrL t(04 mg'mL 001 mg,mL

-continued Dissoluuon.

Irrlccl'r (irll IA [t)755J I he dissolution date forlrorm2offreehasehydrate, Detect n C ondu t Y tc dete tor Irorm I of his-sulfuric acid salt monohydrate, and Irorrn I of Floe Rate (ml m nl A7 mono-maleic acid salt ofCompound I are shov n in FKr. 45A Hluenr 3 mM sndnun rrborrare. and FICi. 45B. The dissolution rate for the hydrate was aixiut I 0 rrrM sodrIrrIr lri'droacrr carborratc ur 'queous 80% 111 15 min at pH 1.2 and about 20% in 60 min at pH 2,5. ace(Ccrc Thc dissolution rate of tlm bis-bulfume acid salt was 100% in 15 min at both pH 1.2 and pH 2.5. Thc dissolution mtc of thc mono-maleic acid salt was 100% in 15 ntin at pl I 1.2 and lrourier I'ransform-Infra-Red (! 'I'IR) about 20% in 60 min at pl I 2.5. [0752] Data werc collec(cd on a PcrkmiElmcr Spectrum Particle Size ruid Flov;abili(y: Onc lit(ed with a universal Atlmnialcd Total Rcllcctuncc (ATR) smupling accessory Thc data werc collectc(1 and [0756] The density and liow ab(lity date for Fonu 2 of free analysed using Spectrum v10 0 I software. base hydrate, Irorm I of bib-sulfuric acid salt nionohydrate, and I onu I of mono-maleic acid salt of ('ompound I are I (xample 2() summarized in Table 25. The Hausnerratio and the Carr index Comparative Studies for Free Base Hydmte. are correlated to the Ikiwability of a pov der or granular mate- Bis-Sulhiric Acid Salt. and Mono-Maleic Acid Salt rial The data showed that both the bis-sulhlric acid salt and ol'Compound I thc mono-malcic acid salts have improved tlowabili(y thun thc hydrate has. Thc liow abihty ol'bo(h sal(s are acccptablc Stabili(v for manufacturing,

[0753J 2-Week comparative stability studies were con- [t)757J I he particle size distribution ofthe his-sulfuric acid ducted for I 'Arm 2 offree base hydnnte. I 'orm I ofhis-sulhlric salt and the nnmo-maleic acid salts are shown in III(i. 46 US 2014/0275 [35 A1 Sep. 18, 2014 87

Dog PK Study I A solid form comprisin a compound of formula (I):

[0758J Dog PK studies were cnnducted with four fornuila- tions (Form 2 ol'ycc base hydrate in capsule; Form 2 ol'ree (0 'o Mco base hydrate in solution: I rm I of in el sic acid salt in capsule, and Form I of his-sulfunc acid salt in capsule) ofCompound I 'I'he study group consisted with 3 niale dogs (10 kg each) There u.as a 72-hour wash-out period between each dose.

Blood mimplcs werc drnwn at T=Os 0 2S,0.5, I e 2. 4, 8, 12, and 24 h. The results were summarized in Table 25. The bis- sullhric acid salt capsule (SO mg) formulation achieved a dnse-normalized Al.l(:o aa tlmt was compamsble to that of the hydrate solution (4.S mg/kg) I'ormulauons about 30/o lu hcr than the maleic acid salt capsule (50 mg) fornnllation, and aboiut 12096 higher than the hydrate capsule (50 nig) formulation I'bedog PK data for IPAc solvate (I orm 5 offree base) QY of Compound I and Form 2 of thee base hydrate suspension from sinular studies arc also listed in Table 25. or a salt, snlvate. or solvate of a salt thereof, or a mixture TABLE 25 thereof. 2 -6.(canceled) D PK data of ous Com ound I fonnulat ons ut Male Does tat 7 The solid form of claim 1. comprising Form I of a

sulfuric acid sall ol lhc compound of formuln (I). AUCam't(gimL) 8 -10. (canceled) Fonnulatiou (h) ine"lmnL! (ng h'mLI (hl 11. Thc solid form of clmm 7, huving nn X-ray powder diffraction comprisin peaks at approximately 10 7, Form of m15 I 5 6494 list 6 I pattern Free Base 12 4, and 23 6 degrees 20 Hid( flte 12.-16, (canceled) C apsule 17. The solid t'nmi ofclaim 1. comprising Form I h, Fomi ('i) um! IB. or Form 2 of a sulfilric acid salt of the compound of 'nf 7 Form 1677 oil 12766 2657 7 lorilluld Free Bmc (I). Hid( flte 18.-22. (canceled) 23. I'he solid fiirm of claim 1. comprising l(urn) 3 of a sulfuric acid salt nf the compound of formula (I). Form I nf 1995 I 7 l((114 290 7 5 24.-26, (canceled) Male c oc d 27. The solid form of claim 23, having an X-rdy powder salt Capsule ('i) um! dilfraclion paltcm compnsing peaks al upproximalcly 13.7. Form I nf B(s lt(95 I u 14460 26 u 7 5 15 5, and 20 ') degrees 20 Sulfun:(cid 28.-35, (canceled) salt Capsule 36. Thc sohd form of claim 1. comprising Form I ol 4 ('i) um! nmleic acid salt of the compound of fiirmula (I) I PS 1912 I ) I )4 mm 147 ipnnn 5 of 37.-39, (canceled) Free hase! 40. 1 he snlid form of claim 36, having an X-ray powder Scape(ts o(t diffraction pattern comprisin peaks at approximately &10, ('p-'lgi 16 0, and 22 6 degrees 20 'nf I 5 2 Form 725 4159 Sz 4 41.-48. (canceled) Free Bmc Hid( flte 49. I'he solid fiirm of claim 1. comprising l(orrn I of a 1.2-ethane di sulfonic acid salt ofthe compound offormula (I) . ('p-'lgi 50.-52. (canceled) 53. 1 he snlid form of claim 49, having an X-ray powder diffraction pattern comprising peaks at approximately 10.3. [0759J Pghile exemplary embodiinents of the present dis- 12.7. and 23.3 degrees 20. closure have been shown mid dcscnbcd hcrcuie it will bc 54.-59. (canceled) obvious to those skilled in the art that such einbodiments are 60. The solid form ofclaim Is comprising Form I of a free provided by way of example only. Numerous variations, base of the compound of formula (I). changes. and substitutions will now occur to those skilled in 61.-64 (canceled) the att without departing from the disclosure. It should be 65. The solid form of claim 60, having an X-ray powder understood that various alternatives to the embodinlents diffraction pattern comprising peaks at approximately 11.4. described herein can be employed in practicin ~ the subject 16.8. and 19.9 dcgrccs 20. maucr of lhc disclosure. Il is intended thai Ihc followuig 66.-70 (canceled) claims detine the scope ofthe mvention and that methods and 71. The solid form ofclaim Is comprising Form 2 of a free structures within thc scope ol Ihcac clmms und Ihmr cttutva- busc of Ihc compound of formula (I). lents be covered thereby. 72.-75 (canceled) US 2014/0275135 A1 Sep. 18, 2014 88

76. The solid foun of claim 71, bavin an X-ray powder providing a material comprisin a compound of formula ihffractlon pa«cia conlprwnlg peaks at dpploxn«B(cly 9 I, (I), ol B sdlb solvatc. Cl solvalc of a salt Ihclcol, ol B 10.9, and 16 8 degrees 20. nuxnlri: Ihcrcol; and 77.-81 (canceled) usm a characterization method to determine whether a 82. 'Ihe solid form of clainl I, comprising liorm 3 of a free signatory clmractcrisuc associated with thc solid lilrm ls base of the compound of formula (Ij. present ln Ihc matc«a) by comparulg Ihc characterisnc 83.-86, (canceled) obtained frmu the material with a reference signatory 87. The solid form of claim 82, bavin an X-ray powder characteristic: diffraction pauern compri ~ lng peaks dt approxmu«cly 7 3, wherein Ihc cx la tcncc of a charac(enatic idcn- 10.6, and 11 3 degrees 20. substantially Ili:dl Io thc rclcrcnci: slgnatorv chB1'dc(i:rishi: nuhcdtcs 88.-90 (canceled) the presence of the solid form in the material. 91. '(he solid form of clainl I, comprising liorm 4 of a free base of the compound of formula (Ij. 127.-139. (cancclcd) 92.-95, (canceled) 140. A method preparing Form I of a sulfuric acid salt of 96. The solid form of claim 91, bavin an X-ray powder Compound I; diffraction paucm compri ~ lng peaks at approximately I I I, 11.5, and 20 0 degrees 20. 97.-101. (canceled) I (12 I'he solid form ofclaim I, comprisinu liorm 5 of a free base of the compound of filrmula (I) 103.-107. (canceled) 108. The solid form of claim 102. having an X-ray powder diffraction pauern compri ~ lng peaks dt approxmu«cly 9 0, 10.5, and 18 9 degrees 20. I (19 -I I I (canceled) 112 I'he solid form ofclaim I, comprising liorm 6 of a free base of the compound of filrmula (I) 113.-116. (canceled) 117. The solid form of claim 112. having an X-ray powder diffraction pauern compri ~ lng peaks dt approxmu«cly 7 2, QY(r 10.6, and 11 I degrees 20. 118 -122 (canceled) 123 A pharmaceutical composition ~ ing. a solid conlpri comprising (a) contactins, (:ompound I with sulfuric acid filrm of claim I, and one or nl ore pharmaceutically acceptable in a solvent systeiu or exposmg a material conlprising a excipients. sulfuric acid salt of('ompound I to a solvent system; and A 124. method for treating a PI3K mediated disorder ln a (b) producing and/or recoverin Form I of the sulfuric a subject, mlmpuslng administcnng Ihcrapcuncally cfli:ctlvc acid salt ofCompound I from the mixture resulted from ol'a ol'clauu to amount sohd foun I said subject. stc71 (a). 125 (canceled) 141.-148. (cancclcd) 126 A method for analyzing a nlaterial for the presence or amount of a solid form of cklim I, comprisinu: