(12) United States Patent (10) Patent No.: US 9,512,107 B2 Cianchetta Et Al

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(12) United States Patent (10) Patent No.: US 9,512,107 B2 Cianchetta et al. (45) Date of Patent: Dec. 6, 2016

(54) THERAPEUTICALLY ACTIVE 2003/0213405 A1 11/2003 Harada et al. COMPOSITIONS AND THER METHODS OF 2006, OO84645 A1 4/2006 Pal et al. 2007/0244088 A1 10, 2007 Brickmann et al. USE 2009/0093526 A1 4/2009 Miller et al. 2009,0163508 A1 6/2009 Kori et al. (71) Applicant: Agios Pharmaceuticals, Inc., 2009,0163545 A1 6, 2009 Goldfarb Cambridge, MA (US) 2010/0129350 A1 5/2010 Zacharie et al. 2010, O144722 A1 6/2010 Alexander et al. Inventors: 2011/OO73OO7 A1 3/2011 Yasuda et al. (72) Giovanni Cianchetta, Waltham, MA 2011/0288065 A1 11/2011 Fujihara et al. (US); Byron DeLaBarre, Arlington, 2012fO164143 A1 6/2012 Teeling et al. MA (US); Janeta Popovici-Muller, 2012/02028.18 A1 8, 2012 Tao et al. Waltham, MA (US); Francesco G. 2012fO238576 A1 9/2012 Tao et al. Salituro, Marlborough, MA (US); 2012/0277233 A1 11, 2012 Tao et al. 2013.0035329 A1 2/2013 Saunders et al. Jeffrey O. Saunders, Lincoln, MA 2013,0183281 A1 7/2013 Su et al. (US); Jeremy Travins, Southborough, 2013, O184222 A1 7/2013 Popovici-Muller et al. MA (US); Shunqi Yan, Irvine, CA 2013, O190249 A1 7/2013 Lemieux et al. (US); Tao Guo, Dayton, NJ (US); Li 2013, O190287 A1 7/2013 Cianchetta et al. Zhang, Shanghai (CN) 2013, O197106 A1 8, 2013 Fantin et al. 2013/0316385 A1 11/2013 Cantley et al. 2014/O187435 A1 7/2014 Dang et al. (73) Assignee: Agios Pharmaceuticals, Inc., 2014/0206673 A1 7/2014 Cao et al. Cambridge, MA (US) 2014/0213580 A1 7/2014 Cao et al. 2015,0018328 A1 1/2015 Konteatis et al. (*) Notice: Subject to any disclaimer, the term of this 2015.OO31627 A1 1/2015 Lemieux et al. patent is extended or adjusted under 35 2015,00876OO A1 3/2015 Popovici-Muller et al. U.S.C. 154(b) by 0 days. 2015,0240286 A1 8/2015 Dang et al. (21) Appl. No.: 15/173,519 FOREIGN PATENT DOCUMENTS CN 1O1575408 11/2009 (22) Filed: Jun. 3, 2016 CN 102659765 9, 2012 CN 103097340 5/2013 (65) Prior Publication Data DE 3314663 10, 1983 DE 3512630 10, 1986 US 2016/0318903 A1 Nov. 3, 2016 EP O945446 9, 1999 JP 11158073 6, 1999 JP H-11-158073 A * 6, 1999 Related U.S. Application Data JP 2004 107220 4/2004 (63) Continuation of application No. 13/735,467, filed on JP 20092371.15 10/2009 Jan. 7, 2013. JP 2010O79.130 4/2010 (60) Provisional application No. 61/584.214, filed on Jan. (Continued) 6, 2012. OTHER PUBLICATIONS (51) Int. C. Wang et al., Polyhedron, 2006, vol. 25, pp. 195-202.* CO7D 40/4 (2006.01) Ansell et al. “The interactions of artificial coenzymes with alcohol CO7D 25L/8 (2006.01) dehydrogenase and other NAD(P)(H) dependent enzymes' Journal A6 IK3I/53 (2006.01) of Molecular Catalysis B: Enzymatic (1999) vol. 6, No. 1-2, pp. (52) U.S. C. 111-123. CPC ...... C07D 401/14 (2013.01); A61 K3I/53 Bhushan et al. "Reversed-phase liquid chromatographic resolution (2013.01); C07D 251/18 (2013.01) of diastereomers of protein and non-protein amino acids prepared Field of Classification Search with newly synthesized chiral derivatizing reagents based on (58) cyanuric chloride” Amino Acids (2011) vol. 40, pp. 403-409. None Braun et al. “Triazine-based polymers: 4. MALDI-MS of triazine See application file for complete search history. based polyamines' Polymer (1996) vol. 37, No. 5, pp. 777-783. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — James D Anderson 2,390,529 A 12/1945 Friedheim Assistant Examiner — Gregg Polansky 3,755,322 A 8, 1973 Winter et al. (74) Attorney, Agent, or Firm — Jones Day 3,867,383 A 2, 1975 Winter 4,084,053 A 4, 1978. Desai et al. 4,693,726 A 9/1987 Meininger et al. (57) ABSTRACT 5,489,591 A 2/1996 Kobayashi et al. 6,274,620 B1 8/2001 Labrecque et al. Provided are compounds useful for treating cancer and 7,173,025 B1 2/2007 Stocker et al. methods of treating cancer comprising administering to a 7,858,782 B2 12/2010 Tao et al. subject in need thereof a compound described herein. 8,133,900 B2 3/2012 Hood et al. 8.465,673 B2 6, 2013 Yasuda et al. 2003.0109527 A1 6, 2003 Jin et al. 9 Claims, No Drawings US 9,512.107 B2 Page 2

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CLAIM OF PRIORITY

This application is a continuation of U.S. application Ser. No. 13/735,467, filed Jan. 7, 2013, which claims priority from U.S. Ser. No. 61/584,214, filed Jan. 6, 2012 which is 10 incorporated herein by reference in its entirety. wherein: BACKGROUND OF INVENTION ring A is an optionally Substituted 5-6 member monocy 15 clic aryl or monocyclic heteroaryl; Isocitrate dehydrogenases (IDHs) catalyze the oxidative ring B is an optionally Substituted 5-6 member monocy decarboxylation of isocitrate to 2-oxoglutarate (i.e., C.-keto clic aryl or monocyclic heteroaryl; glutarate). These enzymes belong to two distinct Subclasses, one of which utilizes NAD(+) as the electron acceptor and R" and Rare each independently selected from hydrogen, the other NADP(+). Five isocitrate dehydrogenases have C-C alkyl, C-C haloalkyl, —O-C-C alkyl, and been reported: three NAD(+)-dependent isocitrate dehydro CN, wherein any alkyl portion of R is optionally genases, which localize to the mitochondrial matrix, and two substituted with —OH, NH, NH(C-C alkyl), or NADP(+)-dependent isocitrate dehydrogenases, one of N(C-C alkyl); which is mitochondrial and the other predominantly cyto 25 R is selected from: —(C-C alkyl). —(C-C alkenyl or solic. Each NADP(+)-dependent isozyme is a homodimer. alkynyl), —(C-C alkylene)-N(R)-(C-C alky IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochon lene)-O (C-C alkyl). —(C-C alkylene)-N(R)— drial) is also known as IDH: IDP; IDHM; IDPM; ICD-M; or (Co-C alkylene)-Q, —(C-C alkylene)-N(R)(R), mNADP-IDH. The protein encoded by this gene is the —(C-C alkylene)-N(R)-S(O), 2 (C-C alkyl). NADP(+)-dependent isocitrate dehydrogenase found in the 30 —(C-C alkylene)-N(R)-S(O) (Co-Calkyl)-Q, mitochondria. It plays a role in intermediary metabolism and —(C-C alkylene)-S(O), N(R)(R), —(C-C, energy production. This protein may tightly associate or alkylene)-S(O), N(R)-(C-C, alkylene)-Q, interact with the pyruvate dehydrogenase complex. Human —C(O)N(R)—(C-C alkylene)-C(O)—(C-C alky IDH2 gene encodes a protein of 452 amino acids. The lene)-O (C-C alkyl). —C(O)N(R)-(C-C alky nucleotide and amino acid sequences for IDH2 can be found 35 lene)-C(O)—(Co-Co alkylene)-O-(Co-C alkylene)- as GenBank entries NM 002168.2 and NP 002159.2 Q. —(C-C alkylene)-O-C(O)—(C-C alkyl). respectively. The nucleotide and amino acid sequence for —(C-C alkylene)-O-C(O)—(Co-Co alkyl)-Q, —(C-C alkylene)-O-(C-C alkyl), —(C-C alky human IDH2 are also described in, e.g., Huh et al., Submit lene)-O-(C-C alkylene)-Q, —(C-C alkylene)-C ted (November-1992) to the EMBL/GenBank/DDBJ data 40 (O)—(Co-Co alkylene)-O-(C-C alkyl). —(Co-C bases; and The MGC Project Team, Genome Res. 14:2121 alkylene)-C(O)—(Co-Co alkylene)-O-(C-C alky 2127(2004). lene)-Q, —(C-C alkylene)-O-C(O)—(C-C alkyl). Non-mutant, e.g., wild type, IDH2 catalyzes the oxidative —(C-C alkylene)-O-C(O)—(Co-C alkylene)-Q, decarboxylation of isocitrate to C.-ketoglutarate (C-KG) —(C-C alkylene)-C(O)N(R)—(C-C alkyl). —(Co thereby reducing NAD" (NADP) to NADH (NADPH), 45 Calkylene)-C(O)N(R)-(Co-Co alkylene)-Q, —(C- e.g., in the forward reaction: C alkylene)-N(R)C(O)—(C-C alkyl). —(C-C, alkylene)-N(R)C(O)–(Co-C alkylene)-Q, —(Co-Co Isocitrate+NAD"(NADP)->C-KG+CO+NADH alkylene)-S(O) (C-C alkyl). —(Co-C alkylene)- (NADPH)+H". 50 S(O) (C-C alkylene)-Q, —(C-C alkylene)-N It has been discovered that mutations of IDH2 present in (R) C(O) N(R)-(C-C alkyl). —(Co-C alky certain cancer cells result in a new ability of the enzyme to lene)-Q, —(C-C alkylene)-C(O)—(C-C alkyl). catalyze the NAPH-dependent reduction of C.-ketoglutarate —(Co-Co alkylene)-C(O)—(Co-Co alkylene)-Q, to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wherein: wild-type IDH2. The production of 2HG is believed to 55 any alkyl or alkylene moiety present in R is optionally contribute to the formation and progression of cancer (Dang, substituted with one or more —OH, - O(C-C alkyl) Let al, Nature 2009, 462:739-44). or halo: The inhibition of mutant IDH2 and its neoactivity is any terminal methyl moiety present in R is optionally therefore a potential therapeutic treatment for cancer. replaced with —CHOH, CF, —CHF, —CHCl, Accordingly, there is an ongoing need for inhibitors of IDH2 60 C(O)CH, C(O)CF, CN, or COH: mutants having alpha hydroxyl neoactivity. each R is independently selected from hydrogen and C-C alkyl; and SUMMARY OF INVENTION Q is selected from aryl, heteroaryl, carbocyclyl and het 65 erocyclyl, any of which is optionally substituted; or Described herein are compounds of Structural Formula I, R" and Rare optionally taken together with the carbon to or a pharmaceutically acceptable salt or hydrate thereof: which they are attached to form C(=O); or US 9,512,107 B2 3 4 R" and R are optionally taken together to form substi 2-chloro-4-(methylsulfonyl)-N-4-(phenylamino)-6-(2- tuted carbocyclyl, optionally substituted heterocyclyl pyridinyl)-1,3,5-triazin-2-yl)-benzamide, or optionally substituted heteroaryl, wherein: N'-(2-methoxyethyl)-N'-phenyl-6-5-6-(2,2,2-trifluoroeth a. when ring A is unsubstituted phenyl, and ring B is phenyl oxy)-3-pyridinyl-1,2,4-oxadiazol-3-yl-1,3,5-triazine-2, substituted by methoxy or ethoxy; then said phenyl of ring 4-diamine, B is not further substituted by oxazolyl; N'-(2-furanylmethyl)-6-phenyl-N'-[3-(trifluoromethyl)phe b. when ring A is optionally Substituted phenyl or optionally nyl-1,3,5-triazine-2,4-diamine, substituted pyridyl, and ring B is optionally substituted 6-(3-methoxyphenyl)-N'-methyl-N'-(3-nitrophenyl)-1,3,5- phenyl; then the portion of the compound represented by triazine-2,4-diamine, NH C(R)(R)(R) is not NH(CH)-aryl; 10 N-butyl-N'-(4-methylphenyl)-6-phenyl-1,3,5-triazine-2,4- c. when ring A is optionally Substituted phenyl, and ring B diamine, and is optionally substituted phenyl or pyrrolyl; then the 4-4-(5-chloro-2-methylphenyl)-6-(methylamino)-1,3,5- portion of the compound represented by NH-C(R') triazin-2-ylamino-benzenemethanol. (R)(R) is not NH(CH.)C(O)NH: The compound of Formula I or II or as described in any d. when ring A is phenyl substituted with 2 or more hydroxyl 15 one of the embodiments herein inhibits mutant IDH2, par or methoxy, and ring B is optionally Substituted phenyl: ticularly mutant IDH2 having alpha hydroxyl neoactivity. then the portion of the compound represented by —NH Also described herein are pharmaceutical compositions C(R')(R)(R) is not NH-cycloheptyl: comprising a compound of Formula I and methods of using e. when ring A is optionally Substituted phenyl and ring B is Such compositions to treat cancers characterized by the optionally substituted phenyl; then R' and R do not form presence of a mutant IDH2. 2.2.6,6,-tetramethylpiperidin-4-yl; f, when ring A and ring B are optionally Substituted phenyl: DETAILED DESCRIPTION then the portion of the compound represented by —NH C(R')(R)(R) is not cysteine, optionally substituted phe The details of construction and the arrangement of com nylalanine or leucine or methyl ester thereof; 25 ponents set forth in the following description or illustrated in g. when ring A is phenyl or pyridin-3-yl optionally Substi the drawings are not meant to be limiting. Other embodi tuted with one or more substituents selected from halo, ments and different ways to practice the invention are methyl or CF, and ring B is phenyl optionally substituted expressly included. Also, the phraseology and terminology with one or more substituents selected from halo, methyl, used herein is for the purpose of description and should not CF, methoxy, CH=C(phenyl)CN; then the portion of the 30 be regarded as limiting. The use of “including.” “compris compound represented by NHC(R')(R)(R) is other ing,” or “having.” “containing”, “involving, and variations than - NH(C-C alkylene)-N(R')(R'), NH-1-(amin thereof herein, is meant to encompass the items listed omethyl)cyclopentylmethyl, -NH-4-(aminomethyl)cy thereafter and equivalents thereof as well as additional clohexylmethyl, wherein each R" is hydrogen, C-C, items. alkyl or two R's are taken together with the nitrogen to 35 which they are commonly bound to form morpholin-4-yl DEFINITIONS or pipieridin-1-yl; h. when ring A is phenyl, 4-chlorophenyl or 4-methyl phenyl The term “halo' or “halogen refers to any radical of and ring B is 4-chlorophenyl or 3,4-dichlorophenyl; then fluorine, chlorine, bromine or iodine. the portion of the compound represented by NHC(R) 40 The term “alkyl refers to a fully saturated or unsaturated (R)(R) is not NH-isopropyl: hydrocarbon chain that may be a straight chain or branched i. when ring A is unsubstituted phenyl and the portion of the chain, containing the indicated number of carbon atoms. For compound represented by NHC(R')(R)(R) is example, C-C alkyl indicates that the group may have —NH CHCHN(CH), —NH CHCH-morpholin from 1 to 12 (inclusive) carbon atoms in it. The term 4-yl or NH-CH2CH2OH; then ring B is other than 45 “haloalkyl refers to an alkyl in which one or more hydrogen oxadiazole, imidazole, thiazole or oxazole each of which atoms are replaced by halo, and includes alkyl moieties in is substituted with–C(O)NHR', wherein R is isopropyl, which all hydrogens have been replaced by halo (e.g., cyclopropyl or 2-chloro-6-methylphenyl, perfluoroalkyl). The terms “arylalkyl or “aralkyl refer to j. when ring A is phenyl substituted with SOOH or SONa an alkyl moiety in which an alkyl hydrogen atom is replaced and ring B is phenyl, or when ring B is phenyl Substituted 50 by an aryl group. Aralkyl includes groups in which more with SOOH and ring A is substituted phenyl; then the than one hydrogen atom has been replaced by an aryl group. portion of the compound represented by NHC(R')(R) Examples of “arylalkyl or “aralkyl include benzyl, 2-phe (R) is not NH(CH)OH or -NH(CH)CH(OH)CH: nylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl and groups. The term “alkyl includes “alkenyl' and “alkynyl'. k. the compound is other than: 55 The term “alkylene' refers to a divalent alkyl, e.g., (E)-3-(4-((4-((3-(diethylamino)propyl)amino)-6-phenyl-1, —CH2—, —CH2CH2—, —CH2CH2CH2— and —CHCH 3,5-triazin-2-yl)amino)-2-methoxyphenyl)-2-phenylacry (CH)CH2—. lonitrile, The term “alkenyl refers to a straight or branched hydro 4-((4-((furan-2-ylmethyl)amino)-6-(pyridin-4-yl)-1,3,5-tri carbon chain containing 2-12 carbon atoms and having one azin-2-yl)amino)phenol, 3-(4-((5-aminopentyl)amino)-6- 60 or more double bonds. Examples of alkenyl groups include, ((3-fluorophenyl)amino)-1,3,5-triazin-2-yl)phenol, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl N,6-bis(3-fluorophenyl)-N'-(piperidin-3-yl)-1,3,5-triaz and 3-octenyl groups. One of the double bond carbons may ine-2,4-diamine, optionally be the point of attachment of the alkenyl sub N-butyl-6-phenyl-N'-(p-tolyl)-1,3,5-triazine-2,4-diamine, stituent. N'-cyclohexyl-N,6-diphenyl-1,3,5-triazine-2,4-diamine, 65 The term “alkynyl refers to a straight or branched (R)-3-((4-(3-chlorophenyl)-6-(pyrrolidin-3-ylamino)-1,3,5- hydrocarbon chain containing 2-12 carbon atoms and char triazin-2-yl)amino)-4-methylbenzamide, acterized in having one or more triple bonds. Examples of US 9,512,107 B2 5 6 alkynyl groups include, but are not limited to, ethynyl, tuted at one or more Substitutable atoms with, unless speci propargyl, and 3-hexynyl. One of the triple bond carbons fied otherwise, substituents independently selected from: may optionally be the point of attachment of the alkynyl halo, -C=N, C-C alkyl, =O, —OR. -OR', SR, substituent. —SR, -(C-C alkyl)-N(R)(R), —(C-C alkyl)-N(R) The term “alkoxy' refers to an —O-alkyl radical. The (R), N(R)(R), N(R)(R), O (C-C alkyl)-N term “haloalkoxy' refers to an alkoxy in which one or more (R')(R), O (C-C alkyl)-N(R)(R), (C-C alkyl)- hydrogen atoms are replaced by halo, and includes alkoxy O (C-C alkyl)-N(R)(R), —(C-C alkyl)-O (C-C, moieties in which all hydrogens have been replaced by halo alkyl)-N(R)(R), C(O) N(R)(R), —(C-C alkyl)-C (e.g., perfluoroalkoxy). (O) N(R)(R), —(C-C alkyl)-C(O) N(R)(R), Unless otherwise specified, the term “aryl refers to a 10 —OR, R = C(O)(C-C alkyl), C(O)R’ –C(O)N fully aromatic monocyclic, bicyclic, or tricyclic hydrocar (R)(R), N(R)C(O)(R), N(R)C(O)(R), N(R) bon ring system. Examples of aryl moieties are phenyl, SO.(R), SON(R)(R), N(R)SO.(R), and SON naphthyl, and anthracenyl. Unless otherwise specified, any (R')(R'), wherein any alkyl substituent is optionally further ring atom in an aryl can be substituted by one or more substituted with one or more of OH, - O (C-C alkyl). Substituents. The term "monocyclic aryl' means a monocy 15 halo. —NH2, —NH(C-C alkyl), or —N(C-C alkyl); clic fully romatic hydrocarbon ring system, optionally Sub each R is independently selected from hydrogen, and stituted by one or more substituents which can not form a —C-C alkyl, or fused bicyclic or tricyclic ring. two R's are taken together with the nitrogen atom to The term “carbocyclyl refers to a non-aromatic, mono which they are bound to form a 4- to 8-membered hetero cyclic, bicyclic, or tricyclic hydrocarbon ring system. Car cyclyl optionally comprising one additional heteroatom bocyclyl groups include fully saturated ring systems (e.g., selected from N. S., and O; and cycloalkyls), and partially saturated ring systems. each R is independently selected from C-C, carbocy The term "cycloalkyl as employed herein includes satu clyl phenyl, heteroaryl, and heterocyclyl, wherein one or rated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon more Substitutable positions on said phenyl, cycloalkyl, groups having 3 to 12 carbons. Any ring atom can be 25 heteroaryl or heterocycle substituent is optionally further Substituted (e.g., by one or more substituents). Examples of Substituted with one or more of —(C-C alkyl). —(C-C, cycloalkyl moieties include, but are not limited to, cyclo fluoroalkyl). —OH, -O-(C-C alkyl). —O—(C-C, propyl, cyclohexyl, methylcyclohexyl, adamanty1, and nor fluoroalkyl), halo, NH, -NH(C-C alkyl), or N(C- bornyl. Calkyl). Unless otherwise specified, the term "heteroaryl” refers to 30 Heterocyclyl groups, either alone or as part of a group, are a fully aromatic 5-8 membered monocyclic, 8-12 membered optionally substituted on one or more any substitutable bicyclic, or 11-14 membered tricyclic ring system having nitrogen atom with oxo. —C-C alkyl, or fluoro-substituted 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, C-C alkyl. or 1-9 heteroatoms if tricyclic, said heteroatoms selected The term “substituted” refers to the replacement of a from O, N, or S (or the oxidized forms such as N' O, S(O) 35 hydrogen atom by another group. and S(O)). The term “monocyclic heteroaryl' means a As used herein, the term "elevated levels of 2HG' means monocyclic fully romatic ring system having 1-3 heteroa 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more toms, optionally substituted by one or more Substituents 2HG then is present in a subject that does not carry a mutant which can not form a fused bicyclic or tricyclic ring. IDH2 allele. The term “elevated levels of 2HG” may refer to The term "heterocyclyl refers to a nonaromatic, 3-10 40 the amount of 2HG within a cell, within a tumor, within an membered monocyclic, 8-12 membered bicyclic, or 11-14 organ comprising a tumor, or within a bodily fluid. membered tricyclic ring system having 1-3 heteroatoms if The term “bodily fluid includes one or more of amniotic monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms fluid Surrounding a fetus, aqueous humour, blood (e.g., if tricyclic, said heteroatoms selected from O, N, or S (or the blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, oxidized forms such as N' O, S(O) and S(O)). The 45 Cowper's fluid, female ejaculate, interstitial fluid, lymph, heteroatom may optionally be the point of attachment of the breast milk, mucus (e.g., nasal drainage or phlegm), pleural heterocyclyl substituent. Examples of heterocyclyl include, fluid, pus, saliva, sebum, semen, serum, Sweat, tears, urine, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, vaginal Secretion, or vomit. piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, and pyrro As used herein, the terms “inhibit or “prevent include lidinyl. Heterocyclyl groups include fully saturated ring 50 both complete and partial inhibition and prevention. An systems, and partially saturated ring systems. inhibitor may completely or partially inhibit the intended Bicyclic and tricyclic ring systems containing one or more target. heteroatoms and both aromatic and non-aromatic rings are The term “treat’ means decrease, Suppress, attenuate, considered to be heterocyclyl or heteroaryl groups. Bicyclic diminish, arrest, or stabilize the development or progression or tricyclic ring systems where an aryl or a heteroaryl is 55 of a disease? disorder (e.g., a cancer), lessen the severity of fused to a carbocyclyl or heterocyclyl and the point of the disease/disorder (e.g., a cancer) or improve the Symp attachment from the ring system to the rest of the molecule toms associated with the disease/disorder (e.g., a cancer). is through an aromatic ring are considered to be aryl or As used herein, an amount of a compound effective to heteroaryl groups, respectively. Bicyclic or tricyclic ring treat a disorder, or a “therapeutically effective amount systems where an aryl or a heteroaryl is fused to a carbo 60 refers to an amount of the compound which is effective, cyclyl or heterocyclyl and the point of attachment from the upon single or multiple dose administration to a subject, in ring system to the rest of the molecule is through the treating a cell, or in curing, alleviating, relieving or improv non-aromatic ring are considered to be carbocyclyl (e.g., ing a subject with a disorder beyond that expected in the cycloalkyl) or heterocyclyl groups, respectively. absence of Such treatment. Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and 65 As used herein, the term “subject' is intended to include heterocyclyl groups, either alone or a part of a group (e.g., human and non-human animals. Exemplary human Subjects the aryl portion of an aralkyl group), are optionally Substi include a human patient (referred to as a patient) having a US 9,512,107 B2 7 8 disorder, e.g., a disorder described herein or a normal each R is independently selected from hydrogen and subject. The term “non-human animals” of one aspect of the C-C alkyl; and invention includes all vertebrates, e.g., non-mammals (such Q is selected from aryl, heteroaryl, carbocyclyl and het as chickens, amphibians, reptiles) and mammals, such as erocyclyl; and Q is optionally substituted; or non-human primates, domesticated and/or agriculturally R" and Rare optionally taken together with the carbon useful animals, e.g., sheep, dog, cat, cow, pig, etc. to which they are attached to form C(=O); or Compounds R" and R are optionally taken together to form an Provided is a compound of Structural Formula I, or a optionally substituted carbocyclyl, optionally Substi pharmaceutically acceptable salt or hydrate thereof: tuted heterocyclyl or optionally substituted het 10 eroaryl; wherein: a. when ring A is unsubstituted phenyl, and ring B is (I) phenyl substituted by methoxy or ethoxy; then said phenyl of ring B is not further substituted by oxazolyl; b. when ring A is optionally substituted phenyl or option 15 ally Substituted pyridyl, and ring B is optionally Sub stituted phenyl; then the portion of the compound represented by NH C(R)(R)(R) is not NH (CH)-aryl; c. when ring A is optionally Substituted phenyl, and ring B is optionally substituted phenyl or pyrrolyl; then the portion of the compound represented by NH-C(R') wherein: (R)(R) is not NH(CH)C(O)NH: ring A is an optionally Substituted 5-6 member monocy d. when ring A is phenyl substituted with 2 or more clic aryl or monocyclic heteroaryl; 25 hydroxyl or methoxy, and ring B is optionally substi ring B is an optionally Substituted 5-6 member monocy tuted phenyl; then the portion of the compound repre clic aryl or monocyclic heteroaryl; sented by NH-C(R')(R)(R) is not NH-cyclo R" and Rare each independently selected from hydrogen, heptyl: C-C alkyl, C-C haloalkyl, —O-C-C alkyl, and e. when ring A is optionally Substituted phenyl and ring B CN, wherein any alkyl portion of R is optionally 30 is optionally substituted phenyl; then R' and R do not substituted with —OH, NH, NH(C-C alkyl), or N(C-C alkyl); form 2.2.6.6.-tetramethylpiperidin-4-yl; R is selected from: —(C-C alkyl), —(C-C alkenyl or f, when ring A and ring B are optionally Substituted alkynyl), —(C-C alkylene)-N(R)-(C-C alky phenyl; then the portion of the compound represented lene)-O (C-C alkyl). —(C-C alkylene)-N(R)— 35 by NH COR')(R)(R) is not cysteine, optionally (Co-C alkylene)-Q, —(C-C alkylene)-N(R)(R), substituted phenylalanine or leucine or methyl ester —(C-C alkylene)-N(R)-S(O)12 (C-C alkyl). thereof; —(C-C alkylene)-N(R)-S(O)-2-(Co-Co alkyl)-Q, g. when ring A is phenyl or pyridin-3-yl optionally —(C-C alkylene)-S(O), N(R)(R), —(C-C, Substituted with one or more substituents selected from alkylene)-S(O), N(R)—(C-C, alkylene)-Q, 40 halo, methyl or CF, and ring B is phenyl optionally —C(O)N(R)-(C-C alkylene)-C(O)—(Co-Co alky Substituted with one or more substituents selected from lene)-O (C-C alkyl), —C(O)N(R)—(C-C alky halo, methyl, CF, methoxy, CH=C(phenyl)CN; then lene)-C(O)—(Co-Co alkylene)-O-(Co-C alkylene)- the portion of the compound represented by NHC Q. —(C-C alkylene)-O-C(O)—(C-C alkyl). (R')(R)(R) is other than -NH(C-C alkylene)-N —(C-C alkylene)-O-C(O)—(Co-Co alkyl)-Q, 45 (R)(R), NH-1-(aminomethyl)cyclopentylmethyl, —(C-C alkylene)-O-(C-C alkyl), —(C-C alky —NH-4-(aminomethyl)cyclohexylmethyl, wherein lene)-O-(C-C alkylene)-Q, —(C-C alkylene)-C each R" is hydrogen, C-C alkyl or two R's are taken (O)—(Co-Co alkylene)-O-(C-C alkyl). —(Co-C together with the nitrogen to which they are commonly alkylene)-C(O)—(C-C alkylene)-O-(C-C alky bound to form morpholin-4-yl or pipieridin-1-yl: lene)-Q, —(C-C alkylene)-O-C(O)—(C-C alkyl). 50 h. when ring A is phenyl, 4-chlorophenyl or 4-methyl —(C-C alkylene)-O-C(O)—(Co-C alkylene)-Q, —(Co-Calkylene)-C(O)N(R)—(C-C alkyl). —(Co phenyl and ring B is 4-chlorophenyl or 3,4-dichloro Calkylene)-C(O)N(R)-(Co-Co alkylene)-Q, —(C- phenyl; then the portion of the compound represented C alkylene)-N(R)C(O)—(C-C alkyl). —(C-C, by NHC(R)(R)(R) is not NH-isopropyl: alkylene)-N(R)C(O)–(Co-C alkylene)-Q, —(Co-Co 55 i. when ring A is unsubstituted phenyl and the portion of alkylene)-S(O) (C-C alkyl). —(C-C alkylene)- the compound represented by NHC(R')(R)(R) is S(O) (Co-Co alkylene)-Q, —(C-C alkylene)-N —NH CHCHN(CH), NH CHCH-morpho (R) C(O) N(R)-(C-C alkyl), —(Co-C alky lin-4-yl or —NH CHCH-OH; then ring B is other lene)-Q, —(Co-C alkylene)-C(O)—(C-C alkyl). than oxadiazole, imidazole, thiazole or oxazole each of —(Co-Co alkylene)-C(O)—(Co-Co alkylene)-Q, 60 which is substituted with –C(O)NHR', wherein R is wherein: isopropyl, cyclopropyl or 2-chloro-6-methylphenyl; any alkyl or alkylene moiety present in R is optionally j. when ring A is phenyl substituted with SOOH or substituted with one or more —OH, - O(C-C alkyl) SO.Na and ring B is phenyl, or when ring B is phenyl or halo: substituted with SOOH and ring A is substitituted any terminal methyl moiety present in R is optionally 65 phenyl; then the portion of the compound represented replaced with —CH2OH. CF, —CHF, —CHCl, by NHC(R)(R)(R) is not NH(CH)OH or C(O)CH, C(O)CF, CN, or COH: - NH(CH2)CH(OH)CH; and

US 9,512,107 B2 11 12 i. when ring A is unsubstituted phenyl and the portion of the (C-C alkyl). —CN. —S(O) (C-C alkyl), C-C, compound represented by NHC(R')(R)(R) is alkoxy, NH(C-C alkyl). —OH, - OCF, —CN, NH, —NH CHCHN(CH), —NH CHCH-morpholin —C(O)NH2. —C(O)NH(C-C alkyl), —C(O)—N(C-C, 4-yl or NH-CH2CH2OH; then ring B is other than alkyl), and cyclopropyl optionally substituted with OH. oxadiazole, thiazole or oxazole each of which is substi In some embodiments, ring A is selected from phenyl, tuted with C(O)NHR', wherein R is isopropyl, cyclo pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrimidinyl, propyl or 2-chloro-6-methylphenyl: pyrazinyl, and thiazolyl, wherein ring A is optionally Sub j. when ring A is phenyl substituted with SOOH or SO-Na, stituted with up to two substituents independently selected and ring B is phenyl; then the portion of the compound from halo. —C-C alkyl, -C-C haloalkyl, -C-C, represented by NHC(R')(R)(R) is not NH(CH), 10 hydroxyalkyl, - NH S(O)—(C-C alkyl). —S(O)NH OH or - NH(CH2)CH(OH)CH; and k. the compound is other than: (C-C alkyl). —CN. —S(O) (C-C alkyl), C-C, (E)-3-(4-((4-((3-(diethylamino)propyl)amino)-6-phenyl-1, alkoxy, NH(C-C alkyl). —OH, —CN, and —NH. In some embodiments, ring B is selected from phenyl, 3,5-triazin-2-yl)amino)-2-methoxyphenyl)-2-phenylacry pyrazolyl, oxazolyl, isoxazolyl, thiazolyl pyridinyl, pyrim lonitrile, 4-(4-((furan-2-ylmethyl)amino)-6-(pyridin-4- 15 yl)-1,3,5-triazin-2-yl)amino)phenol, 3-(4-((5- idinyl, pyridazinyl, and pyrazinyl, wherein ring B is option aminopentyl)amino)-6-((3-fluorophenyl)amino)-1,3,5- ally substituted with up to two substituents independently triazin-2-yl)phenol, N°,6-bis(3-fluorophenyl)-N'- selected from halo. —C-C alkyl, -C-C alkynyl, —C- (piperidin-3-yl)-1,3,5-triazine-2,4-diamine, N-butyl-6- C haloalkyl, -C-C hydroxyalkyl, C-C cycloalkyl, phenyl-N'-(p-tolyl)-1,3,5-triazine-2,4-diamine, —(Co-C alkylene)-O-C-C alkyl, —O—(C-C alky N°-cyclohexyl-N,6-diphenyl-1,3,5-triazine-2,4-diamine, lene)-C-C cycloalkyl, -NH S(O) (C-C alkyl). and (R)-3-((4-(3-chlorophenyl)-6-(pyrrolidin-3- —S(O)NH(C-C, alkyl). —S(O). NH (C-C, ylamino)-1,3,5-triazin-2-yl)amino)-4-methylbenzamide. cycloalkyl). —S(O)-(saturated heterocyclyl), —CN. —S(O) (C-C alkyl). —NH(C-C alkyl). —N(C-C, In some embodiments, R' is independently selected from alkyl). —OH, C(O)—O—(C-C alkyl), saturated hetero hydrogen, —CH, -CHCH, CH-OH, CN, or R' and R' 25 are taken together to form —O. cyclyl, and —NH. In some embodiments, R' and R are taken together to In another embodiment, the compound is a compound form carbocyclyl or heterocyclyl, either of which is option having Structural Formula II: ally substituted with up to 3 substituents independently selected from halo. C-C alkyl, C-C haloalkyl, C-C, 30 alkoxy, —CN, =O. —OH, and —C(O)C-C alkyl. (II) In some embodiments, R is —(C-C alkyl) optionally substituted with fluoro or —OH: —(C-C alkylene)-O- (C-C alkyl). —(Co-C, alkylene)-N(R)-(C-C alkyl). 35 —(C-C alkylene)-Q, and —O—(C-C alkylene)-Q. N n N R1a wherein Q is optionally substituted with up to 3 substituents R2a s independently selected from C-C alkyl, C-C haloalkyl, 2 C-C alkoxy, =O. —C(O)—C-C alkyl, —CN, and halo. N N N R3a In one aspect of these embodiments, Q is selected from H H pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phe 40 nyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is or a pharmaceutically acceptable salt thereof, wherein: optionally substituted with up to 2 substituents indepen Ring A' is selected from phenyl and pyridin-2-yl, wherein dently selected from C-C alkyl, C-C haloalkyl, =O. ring A' is optionally substituted with one or two substituents fluoro, chloro, and bromo. In another aspect of these independently selected from chloro, fluoro. —CF, —CHF embodiments, Q is selected from pyridinyl, tetrahydrofura 45 —CH, —CHCH. —CFCH —OH, - OCH, nyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl —OCHCH —NH —NH(CH), and —N(CH): and oxetanyl, wherein Q is optionally substituted with up to Ring B' is selected from pyridin-3-yl pyridin-4-yl, isox 2 substituents independently selected from —CH and —O. aZoly-4-yl, isoxazol-3-yl, thiazol-5-yl, pyrimidin-5-yl and In some embodiments, R' and R are taken together to pyrazol-4-yl, wherein ring B' is optionally substituted with form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tet 50 one to two substituents independently selected from halo: rahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo2.2.1 —CN; —OH: C-C alkyl optionally substituted with halo, heptanyl, Oxobicyclo3.1.0 hexanyl, azetidinyl, phenyl and CN or —OH: —S(O). C-C alkyl; —S(O)—C-C alkyl: pyridinyl, any of which is optionally substituted with up to —S(O). NH-C-C alkyl; —S(O), N(C-C alkyl); 2 substituents independently selected from C-C alkyl, —S(O)-azetidin-1-yl; —O—C-C alkyl; —CH2—O— C-C alkoxy, C-C cycloalkyl, -OH, -C(O)CH, fluoro, 55 CH, morpholin-4-yl, cyclopropyl. —S(O). NH-cyclopro and chloro. pyl: C(O) O CH; and C(R)(R)(R) is selected In some embodiments, ring A is an optionally substituted from C-C alkyl optionally substituted with halo or —OH: 6-membered monocyclic aryl. In some embodiments, ring A —(Co-C alkylene)-cycloalkyl, wherein the alkylene is is an optionally substituted 5-6 membered heteroaryl. In optionally substituted with methyl and the cycloalkyl is Some embodiments, ring A is an optionally Substituted 6 60 optionally substituted with halo, —OCH or methyl; satu membered heteroaryl. rated heterocyclyl optionally substituted with halo or In some embodiments, ring A is selected from phenyl, methyl, -C(O)—O—C-C alkyl; —C(O)—(Co-C alky pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrimidinyl, lene)-cyclopropyl; and C(O)-benzyl. pyrazinyl, and thiazolyl, wherein ring A is optionally Sub In certain embodiments of Formula II, ring A' is selected stituted with up to two substituents independently selected 65 from 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, from halo. —C-C alkyl, -C-C haloalkyl, -C-C, 3-hydroxyphenyl, 6-aminopyridin-2-yl, 6-chloropyridin-2- hydroxyalkyl, - NH S(O)—(C-C alkyl). —S(O)NH y1, 6-trifluoromethylpyridin-2-yl, and phenyl.

US 9,512,107 B2 17 18 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

103 112 10 HN O.C.-l 15 cCC 108 CN 113

114 109

115 45 110

55 116

111

65 US 9,512,107 B2 19 20 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

117 122 C 10

N N N H H

118

123

30 N N N H H

126 119 35 HN1s NCF, 40 Nals N H

45 128 CN 120

N N N H H 55

121 129

C 60

N21 N1 NN 65 N------US 9,512,107 B2 21 22 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

130 139 10

15 CN

132 140

30 133

141 OH 35

135

45 143

137 145

65 US 9,512,107 B2 23 24 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

146 151 10

Ns ----- 15 / \, o H H

147 154

N 1. H 30

148 35 155

149 es 45

N N ICl. 50 es C

150 158

65 US 9,512,107 B2 25 26 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

159 168 10

HN N

15 lelsN. N. H colo 160 169

25 N1 NN

162

35 170

45 16S 172

CN 55 173 167

65 US 9,512,107 B2

TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds 5 Cmpd Cmpd No Structure No Structure

174 O 179 O 10 HN s 15 O NN

% N O N N N H H H

175 U 181

1.n 25 N

N ses 30 -COH

176 YC 182 35

N N als O N1 NN N N 40 ls als N N N N O H H

177 45 1s 183 esHN 4.els N s1NN 50 O N1 SN M \,

H H O O 55 x', 's 178

HN 1. 184 F

1.n 60 %els N F N21 NN

65 N --- N 1s H H US 9,512,107 B2 29 30 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd No

185

N21 S JC-l 186

21 C C N 1C-1- 187

21 C C S

188

21 C N -C-O 189

N21 C C S JCX JC 190

21 C C S. ZEI:ZIZIZIJC, US 9,512,107 B2 31 32 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

2O3 10 198

N ls Nals N H H N N N H H OH 20

199 204

H O 25 C N-N-2SO r is 1s N -sels, 30 N N N H H H H

200 205 35 O 1No 1N SSo2

40 OJClusN ---, H H

45 201

HO 50

N N N H H 55

202

60 CF N21 N1 NN

65 US 9,512,107 B2 33 34 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd No Cmpd 213 No Structure

208 10

214

209

215

210 35

216

45 211

217

212 218

65 US 9,512,107 B2 35 36 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd No Cmpd No

219 N21N N H N JClc

220

N 21 C N JCl C N2 221 N

2 C N JC NaN 222

21 C N JC

223 US 9,512,107 B2

TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

5 Cmpd Cmpd No Structure No Structure

230 235 N 10

N C 2

N1 SN N21 N1 NN

N 1.1N 2 N- " N lulN Nals N O H H H H

231 N 2O 236 HO 2N N1 SN 25 C

Oulu.H H OluN N 4. JJN 30 232

237 HN

1.n 35 1. l, N1 NN C’s 17 40 Ol - 1 - -

233

45 238 -HN C. als 50 Ol N NN

234 55 239

NN Ol

N OH US 9,512,107 B2 39 40 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd No Structure Structure

240

l als ZEI: N l Nals

241

N H JC N H

242 247 35

OH 40

243 45 248

244 249

65 US 9,512,107 B2 41 42 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds Cmpd Cmpd No Structure No Structure 255 250 10

21 15 N N N H JCl H

2O 2S6 251

257

252 35

40 N v H OMe 258 45

253

50 F O

N Ofs H 55 259

2S4

Of 65 US 9,512,107 B2 43 44 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No No Structure

260 26S 10

15 N21 NN

N H -----H

261

266

30 OH

262 267 abs 35

263 45

268

264 269

O 65 US 9,512,107 B2 45 46 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds

Cmpd No

270 FC

271

21 C N ul OH

272

21 C N JC ON

273

N21 C N JCl

274

21 C N JC US 9,512,107 B2 47 48 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds Cmpd Cmpd No Structure No Structure 286

281 10

OH 15

287

282

288

30 OH

283 abs 35

289

45 284

285 --(--(O-OO-OE N-l.21 ZEI:ZI H US 9,512,107 B2 49 50 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

292 297 10

2O 298 293

294 35 299

295

296 301

65 US 9,512,107 B2 51 52 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds Cmpd No

3O2 s 303 C Pl JCl 3O4

OH 305 C Cr" JCl 306 C O 3O8 C es US 9,512,107 B2 53 54 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

32O 315 10

15 21 n N r is N& S ----- N - H H

316 321

25 21 N1 NN CN C. N N N l 4n.els 1. d N1 NN H H 30 ul-l-l H H

317 322 N 35 Ysof F

21 N n N 40 N N N l als -D H H

318 45 323 C

F F

50 1 21 N n N allN N 4\l-D H H

319 324

CF F 60 N21 N1 NN JC O 65 N 2, OH US 9,512,107 B2 55 56 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd No Structure 5 Cmpd 325 N C No Structure l 10 331 H F N N 1 is N NS N l Nals N -O 15 2 H H 326 C N1 SN N lO N N % N No 2 2O H H

C N1 NN 332

H----- H 25 327 NH2 \ { N1 NN C 30 SluluN --- N Nr usis als 1. 35 334 N N N rs N 328 OH CF 2

40 Na NN r is N N N S ----- 45 H H

329 335 s1's

N CF3 C 50 CF 2 21 n 21 n N N N

55 CulluN N l-lN N------H H 330 N 336 N

N 60 N C 2 CF3 2 Clu l-O a Sulu l-O US 9,512,107 B2 57 58 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

337 344 10

340 345

25 21 N& 30

341 346

35 OMe

45 347 342

Ns /\, 55

343 348

60 NYN NS 65 US 9,512,107 B2 59 60 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

350 355

Na O N l als Na N N N H S l

351 356

CF3

O N21 N

us Nals N N N l H H OH

357 CF 352

C abs N NN N

ClS N l N N H H 2. O

358 353 O rs2N N4 -o

N N ral s l N

3S4 N 359 O C l Yo

N21 N N l N US 9,512,107 B2 61 62 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

360 365 10

361 OMe 366

362 367 35

45 363 368

ZEI: 55 OH

364 369

65 S US 9,512,107 B2 63 64 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds Cmpd Cmpd No Structure

370 378

CF3 10 N 21 NC N l NPl N N 1s 15

371 379

d NC N us N NPl N 1. 25

372 380

CF 30 N 21 NC N l N NPl N 1s 35

374 381

1 NC l N NPl N 1. 45

376 382

50 S R O

N N N 1. 55 CuH H 377 CF 383

rs2N 60

N1 NN l als JJ 65 US 9,512,107 B2 65 66 TABLE 1-continued TABLE 1-continued

Representative Compounds

Cmpd No Structure

384

385

21 NS OH OH

386 CF

N OH

45 392 387

388 393

21 N21 NS N ÕZEI: US 9,512,107 B2 67 68 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds Cmpd Cmpd No Structure No Structure 399 N 394 10 2N

N1 NN

395 400

396

35 2 N

n N

N l als 1. N H

397 45

55 403 398

n N n N

65 US 9,512,107 B2 69 70 TABLE 1-continued TABLE 1-continued

Representative Compounds

Cmpd No Structure

404

CN N21 N OH

4.08 US 9,512,107 B2 71 72 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

414

454 415 /

455

416 35

450 456

451 458

65 US 9,512,107 B2 73 74 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

459 464 10

|----

460 |IZ

461 ,,

462

55 463 468

--(--(--( 60

65 |---- ZEI: US 9,512,107 B2 75 76 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

469 474 10

2O 475 470

OH 30

476 471 35

45 477 472

473 478

65 US 9,512,107 B2 77 78 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

479 484 F 10 F rs, N 2 2N 15 ---N n 480 485

486 481

487

45 HO N F 482

55 488

483 C

1. 65 N H N N US 9,512,107 B2 79 80 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

5 Cmpd Cmpd No Structure No Structure

489 F NH2 494 N 10

N F 2

21 N 15

F N ls N us N H H

20 495 490 C HO N

N F 2 25

F N N N H H 30

496 C 491 N NH N

2N 35 F F 2 N F F

N21 NN N 21 n N

F N lsN ls N F 40 N H-sels, H H H F F HO

492 NH 45 497 2

rsN 2 F HO 50 N21 NN Na N s N H H N 55

493 N F 498 N Cl F H F F F 2N. 60 Ns 29 2N SO N21Null-l-k N1 NN ---NN US 9,512,107 B2 81 82 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds 5 Cmpd Cmpd No Structure No Structure SO4 499 10

15 N&

505 500

US 9,512,107 B2 83 84 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd 5 No Structure Cmpd No Structure S1.4 N C

509 F F F 2N F 10 21 F r is F 2 N-N 15 N N l N 2. N 1s H H 21 n O N l N AO 515 s1''' N N Nals N H H HO 2N 2O

510 F F N21 NN

25 N N N N H H S16 N 2N 30 F

511 F l alss F 35 F N N N

517 N

F F 2N 40 r is S N l Nals N 45 H H

512 21 C 518 N

N F F 2N F 50 1 is AO r is s1n H 1 N4N H 55 N---->H H

513 C 519 CF 21 N 3 N-N 60 FCin 1 Ysé,O 2 N OUCAO . JC-l US 9,512,107 B2 85 86 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds

Cmpd 5 Cmpd No Structure No Structure

527 F 521 CF F 21 N1 NF N 10 F F N F F 2N

N n N

F O. N - Nals2 N OH 15 r lu-lis2 O H H N N N N N H H

528 F 522 CF 21 2O F N F N F F F 2N N r N1 NN 25 all-lN 2 N21N| N1|| NN N N N N 2 OH N N N H H 523 F s29 F F F

21 F F 35 F F N N

N21 NN 40 N N - als4. 1N1 O N H H

524 F 530 F F F

45 N F F F F 2N

N21 50 N

531 526 F 55 F

F F F 60 N21 N

65 HO US 9,512,107 B2 87 88 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd Cmpd No Structure No Structure

532 537 F F 10 21 F

N N H

538 F 533 F 21 F

N N 25 F N21 NN

N N N N 30 H H

540 F 534 F

35 rts,N F 2

F 21 N1 NN 40

535 45 S41 N CF

50 N l,Pl, 1. 55

536

65 US 9,512,107 B2 89 90 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd No Structure Cmpd 543 F No Structure F N F

OH 10 2N S48 N21 h 15 F F F N N N H H

544 F Nr

OH F F F / 25 S49 N21 NM N N A F F 30

545 F F r F F 35 N N F H Na 550 N 40

S46 F F F F

F 45

547 F 551 F 55 F

rs,2N 60 r is N F S N l Nals N 1. 65 H H F US 9,512,107 B2 91 92 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

552 557 F 10 F 21 F F F F

H H 20 N ro, OH O

25 554 558 F F 21 F F F F 30

Nr ------isis -- H H

40 559 F 555 F N F O l 45 sus-s-s-sr is 1 H H

55 560 556

65 US 9,512,107 B2 93 94 TABLE 1-continued TABLE 1-continued

Cmpd No

561

S62

563

S64

565 US 9,512,107 B2 95 96 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd Cmpd No Structure No Structure 571

577 F F 10 N F

N 2 O

15 NN ---

als N H 572 578 F F N F

N 2 O 25 NN 1s

Nals N 30 H 573 58O F F N F 35 2N O\1 NN N1 \ 40 O

Nals N H

574 581 F 45 F

rs,2N

55 576 582

65 US 9,512,107 B2 97 98 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd 5 No Structure Cmpd 583 No Structure

588 F 10 F

15 NN

als N S84 H 2O OH

589 F 25 F 21 F

Nan-N

n 585 N

l Nals N H 35 OH

40 590 F F

S86 F F 45

rts,2N

N 50 M N1 NN NN || || 2 N N N H H ss 591 F 587 F F F N F

F 2N 60 N1 SN O 2 N N 65 H OH US 9,512,107 B2 99 100 TABLE 1-continued TABLE 1-continued

Representative Compounds o Representative Compounds Cmpd Cmpd 5 No Structure No Structure 597 F 592 F F F N F N F 10 F O F F N Os 1. 2N 2 N1 N N21 NN NN 15 21 ls ls F N ls Nals N NH N NH H H

593 CF 598 F N 2O F O N s 1. 2N F N F 2 lN NN 25 l als F NH N N ry 594 30 599 F F N F 35 N OESEO 2

N1 NN 40 - als2 C NH N N ry 595 600 F 45 F

rts,N OESEO 2 50

C N N N H H 55 596 6O1 F F N F F F 60 F 2 N

Nr 65 F O. N N N H H US 9,512,107 B2 101 102 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd 5 No Structure Cmpd

No Structure 602 F F N F 10 607 F F 2

N1 NN rts,2N l -k 15 O=S=O Nals N NN 603 F -sels, F 2O H rv

rs,N F 2 * 608 F F N1 NN l 2. N F F N 4. N N H H n 2N 30 604 F

F N F F F 2N 35

N21

S. 40 609

60S

F F

r 50 N

55 610 606 F 21 F N Šs N N 60 N21Sull-l-k N21 US 9,512,107 B2 103 104 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd 5 Cmpd No Structure No Structure

611 616

10 N sa' So

617 F 612 2O F N F N 2 2N

25 Na Na h

N N lsN us N H H 30

618 F 613 F

35 s

N21 40 N F

614 F 619 F 45

Ns 29 so 50

C 55 615 621

Nsa O 60 F F so 21 N21 NN n N lus!N C N N N 65 H H OH US 9,512,107 B2 105 106 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Structure No Structure

622

N21 l

lsN ls

623 - N21

624

625

21 NS

626

21 NS N US 9,512,107 B2 107 108 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds Cmpd No

633 Structure

1. Cr N l Nals N 1. 634 H H

OH 1s

635 N l Nals N 1. H H

636 NN

l Nals N H ~!

637

N l Nals H s

F F 638 C F

l Nals N H US 9,512,107 B2 109 110 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure 645

651

646

652 647 35

45 653

55 649

654

65 US 9,512,107 B2 111 112 TABLE 1-continued TABLE 1-continued

Cmpd No

655

657

658

660

662 US 9,512,107 B2 113 114 TABLE 1-continued TABLE 1-continued Representative Compounds Representative Compounds Cmpd 5 Cmpd No Structure No Structure

670 675

15 OH Nr

671 2O 676 F F N F NC F l 25 N21N------NN 672 677

35 NC

1. 40

673 678 45

55 674 679

HO US 9,512,107 B2 115 116 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

68O H N 685 t O 10 N N F F F 2N O

15 N21 N21 N -----k H H

681 686 O n N F F 2N O 25 r r N N N N 30 H H

682 687 NH N 2 35 F F F 2N

N21 N21 40 N ----- H H

683 45 689 NH N 2 F F F 2N

50 N21 Na N -s-s H H 55 684 O 690 NH 21 2

F 2 N-N 60 N21

F N ls N N H H 65 OH US 9,512,107 B2 117 118 TABLE 1-continued TABLE 1-continued

Representative Compounds Representative Compounds

Cmpd Cmpd No Structure No Structure

696 NH2 691 10

697

692

30 698 NH

2 N F 693 35 N21 N

F N 11 -k H H 40 699 N 2

2 N F 45 694 N21 h F N H 50 1st

Included herein are also methods for making compounds of Formula I or a compound of any one of the embodiments 55 described herein comprising reacting

695

65 US 9,512,107 B2 119 120 with In other embodiments, the preceding methods comprise step (1) reacting

5 O NH2. C

N 1. N In some embodiments, the preceding methods comprise step l els (1) reacting 10 C 4. C

with

R R R3 N1 NN - als 2O NH2 C N C to give with 25

R R R 3 N1NN1. R 30 R2 NH2 2 C N N R3: H to give 35 step (2) reacting

40 N11. NN R N1 NN R els uk R2: C 4N R 2 H 3 C N N R3 H 45 with and step (2) reacting

N n N R 55 to 9.give R2 2 C N N R3 H with 60

N NN R 2 O-St. 65 C N N R3 US 9,512,107 B2 121 122 and step (3) reacting to give

N n N R R. 10 N1 NN C N N R3 2 H N N Cl; with 15 and step (2) reacting

NH2.

Also included are methods for making compounds of Formula I or a compound of any one of the embodiments N1 NN described herein comprising reacting 25 l 2els

with 30

R R3. N N C H 35 NH2 with In other embodiments, the preceding methods wherein R' 40 and R are taken together with the carbon atom to form R C(=O), comprise step (1) reacting

NH2 45 In some embodiments, the preceding methods comprise step (1) reacting n 50 N

N - Nals C H

N1 NN 55 with NH to give

C - Nals C

60 with NN

O-Ni, 65 Ol Nals NH2: US 9,512,107 B2 123 124 and step (2) reacting and step (2) reacting

C 1s, R 2 n l 2. k O l als 10 N. N. N. R. N N NH2 with with RC(O)C1 or RC(O)OMe. 15 Also included are methods for making compounds of B(OH)2. Formula I or a compound of any one of the embodiments described herein comprising reacting Also included are methods for making compounds of o Formula I or a compound of any one of the embodiments C described herein comprising reacting 1s. R 2 25 N l N als N uk R3 H H N1 NN R with 30 l els2 uk HN N N R3 H O- B(OH).(OH)2 with 35 In some embodiments, the preceding methods comprise step halide (1) reacting

40 C In some embodiments, the preceding methods comprise step 1. (1) reacting N1 NN R 2 C l N els N uk R3 45 H with N1 NN R 50 R 2 C N N R3 O-Nil, H 55 with NH to give to give

C 60

N ul N lukN R JC k. H H 3 65 US 9,512,107 B2 125 126 and step (2) reacting and step (2) reacting

5 O lsNH lsNH RI R2 N1 SN R. N N N R3 R2 2 10 H.N. N. N. R. with with 15

halide. On

2O Also included are methods for making compounds of Formula I or a compound of any one of the embodiments In other embodiments, the preceding methods comprise ste described herein comprising reacting (1) converting p 9. p p

25 NH NH RI luluk" NH N R3 to ls CN: N N H N N1 NH2 H H 30 with step (2) reacting

35 NH N. l -CN

In some embodiments, the preceding methods comprise step 40 (1) reacting with

R1 45 R2 NH2 N N -CN H H R3 with 50 to give

RI NH NH RI

55 N N N R3 R3 H H H to give and step (3) reacting 60

N N N R3 65 H H H US 9,512,107 B2 127 128 with limited to, alkali metal ions such as Na" and K", alkaline earth cations such as Ca" and Mg", and other cations such as Al". Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH) and substi tuted ammonium ions (e.g., NHR", NHR", NHR", NR"). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicy clohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, The compounds of one aspect of this invention may 10 phenylbenzylamine, choline, meglumine, and trometh amine, as well as amino acids, such as lysine and arginine. contain one or more asymmetric centers and thus occur as An example of a common quaternary ammonium ion is racemates, racemic mixtures, Scalemic mixtures, and diaste N(CH).". reomeric mixtures, as well as single enantiomers or indi If the compound is cationic, or has a functional group that vidual stereoisomers that are substantially free from another 15 may be cationic (e.g., -NH may be —NH), then a salt possible enantiomer or stereoisomer. The term “substantially may be formed with a suitable anion. Examples of suitable free of other stereoisomers' as used herein means a prepa inorganic anions include, but are not limited to, those ration enriched in a compound having a selected Stereo derived from the following inorganic acids: hydrochloric, chemistry at one or more selected Stereocenters by at least hydrobromic, hydroiodic, Sulfuric, Sulfurous, nitric, nitrous, about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, phosphoric, and phosphorous. 97%, 98%, or 99%. The term “enriched” means that at least Examples of Suitable organic anions include, but are not the designated percentage of a preparation is the compound limited to, those derived from the following organic acids: having a selected Stereochemistry at one or more selected 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, cam Stereocenters. Methods of obtaining or synthesizing an indi phorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, eth vidual enantiomer or Stereoisomer for a given compound are 25 anesulfonic, fumaric, glucoheptonic, gluconic, glutamic, known in the art and may be applied as practicable to final glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, compounds or to starting material or intermediates. isethionic, lactic, lactobionic, lauric, maleic, malic, meth In certain embodiments, the compound of Formula I or II anesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantoth is enriched for a structure or structures having a selected enic, phenylacetic, phenylsulfonic, propionic, pyruvic, Sali Stereochemistry at one or more carbon atoms. For example, 30 cylic, Stearic, succinic, Sulfanilic, tartaric, toluenesulfonic, the compound is enriched in the specific stereoisomer by at and Valeric. Mesylates of each compound in Table 1 are least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, explicitly included herein. Examples of suitable polymeric 96%, 97%, 98%, or 99%. organic anions include, but are not limited to, those derived The compounds of Formula I or II may also comprise one from the following polymeric acids: tannic acid, carboxym or more isotopic Substitutions. For example, H may be in any 35 ethyl cellulose. isotopic form, including 'H, H (D or deuterium), and H (T The compounds provided herein therefore include the or tritium); C may be in any isotopic form, including 'C, compounds themselves, as well as their salts, hydrates and 'C, and ''C: O may be in any isotopic form, including 'O their prodrugs, if applicable. The compounds provided and 'O; and the like. For example, the compound is herein may be modified and converted to prodrugs by enriched in a specific isotopic form of H, C and/or O by at 40 appending appropriate functionalities to enhance selected least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, biological properties, e.g., targeting to a particular tissue. 96%, 97%, 98%, or 99%. Such modifications (i.e., prodrugs) are known in the art and Unless otherwise indicated when a disclosed compound is include those which increase biological penetration into a named or depicted by a structure without specifying the given biological compartment (e.g., blood, lymphatic sys Stereochemistry and has one or more chiral centers, it is 45 tem, central nervous system), increase oral availability, understood to represent all possible stereoisomers of the increase solubility to allow administration by injection, alter compound. metabolism and alter rate of excretion. Examples of prod The compounds of one aspect of this invention may also rugs include esters (e.g., phosphates, amino acid (e.g., be represented in multiple tautomeric forms, in Such valine) esters), carbamates and other pharmaceutically instances, one aspect of the invention expressly includes all 50 acceptable derivatives, which, upon administration to a tautomeric forms of the compounds described herein, even Subject, are capable of providing active compounds. Cal though only a single tautomeric form may be represented cium and sodium phosphates of each compound in Table 1, (e.g., alkylation of a ring system may result in alkylation at if applicable, are explicitly included herein. Amino acid multiple sites, one aspect of the invention expressly includes (e.g., valine) esters of each compound in Table 1, if appli all Such reaction products; and keto-enol tautomers). All 55 cable, are explicitly included herein. Such isomeric forms of Such compounds are expressly Compositions and Routes of Administration included herein. The compounds utilized in the methods described herein It may be convenient or desirable to prepare, purify, may be formulated together with a pharmaceutically accept and/or handle a corresponding salt of the active compound, able carrier or adjuvant into pharmaceutically acceptable for example, a pharmaceutically-acceptable salt. Examples 60 compositions prior to be administered to a Subject. In of pharmaceutically acceptable salts are discussed in Berge another embodiment, such pharmaceutically acceptable et al., 1977, “Pharmaceutically Acceptable Salts.” J. Pharm. compositions further comprise additional therapeutic agents Sci. Vol. 66, pp. 1.-19. in amounts effective for achieving a modulation of disease For example, if the compound is anionic, or has a func or disease symptoms, including those described herein. tional group which may be anionic (e.g., -COOH may be 65 The term “pharmaceutically acceptable carrier or adju —COO), then a salt may be formed with a suitable cation. vant” refers to a carrier or adjuvant that may be administered Examples of Suitable inorganic cations include, but are not to a Subject, together with a compound of one aspect of this US 9,512,107 B2 129 130 invention, and which does not destroy the pharmacological similar emulsifying agents or bioavailability enhancers activity thereof and is nontoxic when administered in doses which are commonly used in the manufacture of pharma Sufficient to deliver a therapeutic amount of the compound. ceutically acceptable Solid, liquid, or other dosage forms Pharmaceutically acceptable carriers, adjuvants and may also be used for the purposes of formulation. vehicles that may be used in the pharmaceutical composi- 5 The pharmaceutical compositions of one aspect of this tions of one aspect of this invention include, but are not invention may be orally administered in any orally accept limited to, ion exchangers, alumina, aluminum Stearate, able dosage form including, but not limited to, capsules, lecithin, self-emulsifying drug delivery systems (SEDDS) tablets, emulsions and aqueous Suspensions, dispersions and Such as d-C-tocopherol polyethyleneglycol 1000 Succinate, solutions. In the case of tablets for oral use, carriers which Surfactants used in pharmaceutical dosage forms such as 10 are commonly used include lactose and corn starch. Lubri Tweens or other similar polymeric delivery matrices, serum cating agents. Such as magnesium Stearate, are also typically proteins, such as human serum albumin, buffer Substances added. For oral administration in a capsule form, useful Such as phosphates, glycine, Sorbic acid, potassium Sorbate, diluents include lactose and dried corn starch. When aque partial glyceride mixtures of Saturated vegetable fatty acids, ous Suspensions and/or emulsions are administered orally, water, salts or electrolytes, such as protamine Sulfate, diso- 15 the active ingredient may be suspended or dissolved in an dium hydrogen phosphate, potassium hydrogen phosphate, oily phase is combined with emulsifying and/or Suspending Sodium chloride, Zinc salts, colloidal silica, magnesium agents. If desired, certain Sweetening and/or flavoring and/or trisilicate, polyvinyl pyrrolidone, cellulose-based sub coloring agents may be added. stances, polyethylene glycol, Sodium carboxymethylcellu The pharmaceutical compositions of one aspect of this lose, polyacrylates, waxes, polyethylene-polyoxypropylene- 20 invention may also be administered in the form of Supposi block polymers, polyethylene glycol and wool fat. tories for rectal administration. These compositions can be Cyclodextrins such as C-, 3-, and Y-cyclodextrin, or chemi prepared by mixing a compound of one aspect of this cally modified derivatives such as hydroxyalkylcyclodex invention with a suitable non-irritating excipient which is trins, including 2- and 3-hydroxypropyl-3-cyclodextrins, or Solid at room temperature but liquid at the rectal temperature other solubilized derivatives may also be advantageously 25 and therefore will melt in the rectum to release the active used to enhance delivery of compounds of the formulae components. Such materials include, but are not limited to, described herein. cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of one aspect of this Topical administration of the pharmaceutical composi invention may be administered orally, parenterally, by inha tions of one aspect of this invention is useful when the lation spray, topically, rectally, nasally, buccally, vaginally 30 desired treatment involves areas or organs readily accessible or via an implanted reservoir, preferably by oral adminis by topical application. For application topically to the skin, tration or administration by injection. The pharmaceutical the pharmaceutical composition should be formulated with compositions of one aspect of this invention may contain a Suitable ointment containing the active components Sus any conventional non-toxic pharmaceutically-acceptable pended or dissolved in a carrier. Carriers for topical admin carriers, adjuvants or vehicles. In some cases, the pH of the 35 istration of the compounds of one aspect of this invention formulation may be adjusted with pharmaceutically accept include, but are not limited to, mineral oil, liquid petroleum, able acids, bases or buffers to enhance the stability of the white petroleum, propylene glycol, polyoxyethylene poly formulated compound or its delivery form. The term paren oxypropylene compound, emulsifying wax and water. Alter teral as used herein includes Subcutaneous, intracutaneous, natively, the pharmaceutical composition can be formulated intravenous, intramuscular, intraarticular, intraarterial, intra- 40 with a suitable lotion or cream containing the active com synovial, intrasternal, intrathecal, intralesional and intracra pound suspended or dissolved in a carrier with suitable nial injection or infusion techniques. emulsifying agents. Suitable carriers include, but are not The pharmaceutical compositions may be in the form of limited to, mineral oil, Sorbitan monostearate, polysorbate a sterile injectable preparation, for example, as a sterile 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, injectable aqueous or oleaginous Suspension. This suspen- 45 benzyl alcohol and water. The pharmaceutical compositions sion may be formulated according to techniques known in of one aspect of this invention may also be topically applied the art using Suitable dispersing or wetting agents (such as, to the lower intestinal tract by rectal suppository formulation for example, Tween 80) and Suspending agents. The sterile or in a suitable enema formulation. injectable preparation may also be a sterile injectable solu Topically-transdermal patches are also included in one tion or Suspension in a non-toxic parenterally acceptable 50 aspect of this invention. diluent or solvent, for example, as a solution in 1,3-butane The pharmaceutical compositions of one aspect of this diol. Among the acceptable vehicles and solvents that may invention may be administered by nasal aerosol or inhala be employed are mannitol, water, Ringer's Solution and tion. Such compositions are prepared according to tech isotonic sodium chloride solution. In addition, sterile, fixed niques well-known in the art of pharmaceutical formulation oils are conventionally employed as a solvent or Suspending 55 and may be prepared as Solutions in saline, employing medium. For this purpose, any bland fixed oil may be benzyl alcohol or other suitable preservatives, absorption employed including synthetic mono- or diglycerides. Fatty promoters to enhance bioavailability, fluorocarbons, and/or acids, Such as oleic acid and its glyceride derivatives are other solubilizing or dispersing agents known in the art. useful in the preparation of injectables, as are natural phar When the compositions of one aspect of this invention maceutically-acceptable oils, such as olive oil or castor oil, 60 comprise a combination of a compound of the formulae especially in their polyoxyethylated versions. These oil described herein and one or more additional therapeutic or Solutions or Suspensions may also contain a long-chain prophylactic agents, both the compound and the additional alcohol diluent or dispersant, or carboxymethyl cellulose or agent should be present at dosage levels of between about 1 similar dispersing agents which are commonly used in the to 100%, and more preferably between about 5 to 95% of the formulation of pharmaceutically acceptable dosage forms 65 dosage normally administered in a monotherapy regimen. Such as emulsions and or Suspensions. Other commonly The additional agents may be administered separately, as used Surfactants such as Tweens or Spans and/or other part of a multiple dose regimen, from the compounds of one US 9,512,107 B2 131 132 aspect of this invention. Alternatively, those agents may be mutation. In another aspect of this embodiment, the R140X part of a single dosage form, mixed together with the mutation is a R140L, mutation. In another aspect of this compounds of one aspect of this invention in a single embodiment, the mutant IDH2 has an R172X mutation. In composition. another aspect of this embodiment, the R172X mutation is The compounds described herein can, for example, be a R172K mutation. In another aspect of this embodiment, administered by injection, intravenously, intraarterially, Sub the R172X mutation is a R172G mutation. dermally, intraperitoneally, intramuscularly, or Subcutane Also provided are methods of treating a cancer charac ously; or orally, buccally, nasally, transmucosally, topically, terized by the presence of a mutant allele of IDH2 compris in an ophthalmic preparation, or by inhalation, with a dosage ing the step of administering to Subject in need thereof (a) a ranging from about 0.5 to about 100 mg/kg of body weight, 10 alternatively dosages between 1 mg and 1000 mg/dose, compound of Structural Formula I or II, a compound every 4 to 120 hours, or according to the requirements of the described in any one of the embodiments herein, or a particular drug. The methods herein contemplate adminis pharmaceutically acceptable salt thereof, or (b) a pharma tration of an effective amount of compound or compound ceutical composition comprising (a) and a pharmaceutically composition to achieve the desired or stated effect. Typi 15 acceptable carrier. cally, the pharmaceutical compositions of one aspect of this In one embodiment, the cancer to be treated is character invention will be administered from about 1 to about 6 times ized by a mutant allele of IDH2 wherein the IDH2 mutation per day or alternatively, as a continuous infusion. Such results in a new ability of the enzyme to catalyze the administration can be used as a chronic or acute therapy. The NAPH-dependent reduction of C.-ketoglutarate to R(-)-2- amount of active ingredient that may be combined with the hydroxyglutarate in a patient. In one aspect of this embodi carrier materials to produce a single dosage form will vary ment, the mutant IDH2 has an R140X mutation. In another depending upon the host treated and the particular mode of aspect of this embodiment, the R140X mutation is a R140O administration. A typical preparation will contain from about mutation. In another aspect of this embodiment, the R140X 5% to about 95% active compound (w/w). Alternatively, mutation is a R140W mutation. In another aspect of this such preparations contain from about 20% to about 80% 25 embodiment, the R140X mutation is a R140L, mutation. In active compound. another aspect of this embodiment, the mutant IDH2 has an Lower or higher doses than those recited above may be R172X mutation. In another aspect of this embodiment, the required. Specific dosage and treatment regimens for any R172X mutation is a R172K mutation. In another aspect of particular Subject will depend upon a variety of factors, this embodiment, the R172X mutation is a R172G mutation. including the activity of the specific compound employed, 30 A cancer can be analyzed by sequencing cell samples to the age, body weight, general health status, sex, diet, time of determine the presence and specific nature of (e.g., the administration, rate of excretion, drug combination, the changed amino acid presentat) a mutation at amino acid 140 severity and course of the disease, condition or symptoms, and/or 172 of IDH2. the Subject's disposition to the disease, condition or symp Without being bound by theory, applicants believe that toms, and the judgment of the treating physician. 35 mutant alleles of IDH2 wherein the IDH2 mutation results in Upon improvement of a subjects condition, a mainte a new ability of the enzyme to catalyze the NAPH-depen nance dose of a compound, composition or combination of dent reduction of O-ketoglutarate to R(-)-2-hydroxyglut one aspect of this invention may be administered, if neces arate, and in particular R140O and/or R172K mutations of sary. Subsequently, the dosage or frequency of administra IDH2, characterize a subset of all types of cancers, without tion, or both, may be reduced, as a function of the symptoms, 40 regard to their cellular nature or location in the body. Thus, to a level at which the improved condition is retained when the compounds and methods of one aspect of this invention the symptoms have been alleviated to the desired level. are useful to treat any type of cancer that is characterized by Subjects may, however, require intermittent treatment on a the presence of a mutant allele of IDH2 imparting such long-term basis upon any recurrence of disease symptoms. activity and in particular an IDH2 R140O and/or R172K The pharmaceutical compositions described above com 45 mutation. prising a compound of Structural Formula I or II or a In one aspect of this embodiment, the efficacy of cancer compound described in any one of the embodiments herein, treatment is monitored by measuring the levels of 2HG in may further comprise another therapeutic agent useful for the subject. Typically levels of 2HG are measured prior to treating cancer. treatment, wherein an elevated level is indicated for the use Methods of Use 50 of the compound of Formula I or II or a compound described The inhibitory activities of the compounds provided in any one of the embodiments described herein to treat the herein against IDH2 mutants (e.g., IDH2R140O and cancer. Once the elevated levels are established, the level of IDH2R172K) can be tested by methods described in 2HG is determined during the course of and/or following Example 12 or analogous methods. termination of treatment to establish efficacy. In certain Provided is a method for inhibiting a mutant IDH2 55 embodiments, the level of 2HG is only determined during activity comprising contacting a Subject in need thereof with the course of and/or following termination of treatment. A a compound of Structural Formula I or II, a compound reduction of 2HG levels during the course of treatment and described in any one of the embodiments herein, or a following treatment is indicative of efficacy. Similarly, a pharmaceutically acceptable salt thereof. In one embodi determination that 2HG levels are not elevated during the ment, the cancer to be treated is characterized by a mutant 60 course of or following treatment is also indicative of effi allele of IDH2 wherein the IDH2 mutation results in a new cacy. Typically, the these 2HG measurements will be utilized ability of the enzyme to catalyze the NAPH-dependent together with other well-known determinations of efficacy of reduction of C.-ketoglutarate to R(-)-2-hydroxyglutarate in a cancer treatment, such as reduction in number and size of subject. In one aspect of this embodiment, the mutant IDH2 tumors and/or other cancer-associated lesions, improvement has an R140X mutation. In another aspect of this embodi 65 in the general health of the subject, and alterations in other ment, the R140X mutation is a R140O mutation. In another biomarkers that are associated with cancer treatment effi aspect of this embodiment, the R140X mutation is a R140W cacy. US 9,512,107 B2 133 134 2HG can be detected in a sample by LC/MS. The sample leukemia (AML), sarcoma, melanoma, non-Small cell lung is mixed 80:20 with methanol, and centrifuged at 3,000 rpm cancer, chondrosarcoma, cholangiocarcinomas or angioim for 20 minutes at 4 degrees Celsius. The resulting Superna munoblastic lymphoma in a patient by administering to the tant can be collected and stored at -80 degrees Celsius prior patient a compound of Formula I or Formula II in an amount to LC-MS/MS to assess 2-hydroxyglutarate levels. A variety 5 effective to treat the cancer. In a more specific embodiment of different liquid chromatography (LC) separation methods the cancer to be treated is glioma, myelodysplastic Syn can be used. Each method can be coupled by negative drome (MDS), myeloproliferative neoplasm (MPN), acute electrospray ionization (ESI, -3.0 kV) to triple-quadrupole myelogenous leukemia (AML), melanoma, chondrosar mass spectrometers operating in multiple reaction monitor coma, or angioimmunoblastic non-Hodgkin’s lymphoma 10 (NHL). ing (MRM) mode, with MS parameters optimized on 2HG is known to accumulate in the inherited metabolic infused metabolite standard solutions. Metabolites can be disorder 2-hydroxyglutaric aciduria. This disease is caused separated by reversed phase chromatography using 10 mM by deficiency in the enzyme 2-hydroxyglutarate dehydroge tributyl-amine as an ion pairing agent in the aqueous mobile nase, which converts 2HG to C-KG (Struys, E. A. et al. Am phase, according to a variant of a previously reported 15 J. Hum Genet 76,358-60 (2005)). Patients with 2-hydroxy method (Luo et al. J Chromatogr A 1147, 153-64, 2007). glutarate dehydrogenase deficiencies accumulate 2HG in the One method allows resolution of TCA metabolites: t—0, 50% brain as assessed by MRI and CSF analysis, develop leu B; t—5, 95% B; t-7, 95% B; t—8, 0% B, where B refers to koencephalopathy, and have an increased risk of developing an organic mobile phase of 100% methanol. Another method brain tumors (Aghili, M., Zahedi, F. & Rafiee. J Neurooncol is specific for 2-hydroxyglutarate, running a fast linear 91,233-6 (2009): Kolker, S., Mayatepek, E. & Hoffmann, G. gradient from 50%-95% B (buffers as defined above) over 5 F. Neuropediatrics 33,225-31 (2002); Wajner, M., Latini, A., minutes. A Synergi Hydro-RP 100 mmx2 mm, 2.1 um Wyse, A. T. & Dutra-Filho, C. S. J. Inherit Metab Dis 27, particle size (Phenomonex) can be used as the column, as 427-48 (2004)). Furthermore, elevated brain levels of 2HG described above. Metabolites can be quantified by compari result in increased ROS levels (Kolker, S. et al. Eur J Son of peak areas with pure metabolite standards at known 25 Neurosci 16, 21-8 (2002); Latini, A. et al. EurJ Neurosci 17, concentration. Metabolite flux studies from C-glutamine 2017-22 (2003)), potentially contributing to an increased can be performed as described, e.g., in Munger et al. Nat risk of cancer. The ability of 2HG to act as an NMDA Biotechnol 26, 1179-86, 2008. receptor agonist may contribute to this effect (Kolker, S. et In one embodiment 2HG is directly evaluated. al. EurJ Neurosci 16, 21-8 (2002)). 2HG may also be toxic In another embodiment a derivative of 2HG formed in 30 to cells by competitively inhibiting glutamate and/or CKG process of performing the analytic method is evaluated. By utilizing enzymes. These include transaminases which allow way of example such a derivative can be a derivative formed utilization of glutamate nitrogen for amino and nucleic acid in MS analysis. Derivatives can include a salt adduct, e.g., biosynthesis, and CKG-dependent prolyl hydroxylases Such a Na adduct, a hydration variant, or a hydration variant as those which regulate Hif1-alpha levels. which is also a salt adduct, e.g., a Na adduct, e.g., as formed 35 Thus, according to another embodiment, one aspect of the in MS analysis. invention provides a method of treating 2-hydroxyglutaric In another embodiment a metabolic derivative of 2HG is aciduria, particularly D-2-hydroxyglutaric aciduria, in a evaluated. Examples include species that build up or are patient by administering to the patient a compound of elevated, or reduced, as a result of the presence of 2HG, such Structural Formula I or II or a compound described in any as glutarate or glutamate that will be correlated to 2HG, e.g., 40 one of the embodiments described herein. R-2HG. Treatment methods described herein can additionally Exemplary 2HG derivatives include dehydrated deriva comprise various evaluation steps prior to and/or following tives such as the compounds provided below or a salt adduct treatment with a compound of Structural Formula I or II or thereof: a compound described in any one of the embodiments 45 described herein. In one embodiment, prior to and/or after treatment with a compound of Structural Formula I or II or a compound described in any one of the embodiments described herein, the method further comprises the step of evaluating the 50 growth, size, weight, invasiveness, stage and/or other phe notype of the cancer. In one embodiment, prior to and/or after treatment with a compound of Formula I or II or a compound described in HO any one of the embodiments described herein, the method 55 further comprises the step of evaluating the IDH2 genotype of the cancer. This may be achieved by ordinary methods in the art, Such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG. In one embodiment the cancer is a tumor wherein at least In one embodiment, prior to and/or after treatment with a 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an 60 compound of Formula I or II or a compound described in IDH2 mutation, and in particular an IDH2 R140O, R140W. any one of the embodiments described herein, the method or R140L and/or R172K or R172G mutation, at the time of further comprises the step of determining the 2HG level in diagnosis or treatment. the Subject. This may be achieved by spectroscopic analysis, In another embodiment, one aspect of the invention e.g., magnetic resonance-based analysis, e.g., MRI and/or provides a method of treating a cancer selected from glio 65 MRS measurement, sample analysis of bodily fluid, such as blastoma (glioma), myelodysplastic syndrome (MDS). serum or spinal cord fluid analysis, or by analysis of Surgical myeloproliferative neoplasia (MPN), acute myelogenous material, e.g., by mass-spectroscopy. US 9,512,107 B2 135 136 Combination Therapies tane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, In some embodiments, the methods described herein Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Pacli comprise the additional step of co-administering to a subject taxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, in need thereof a second therapy e.g., an additional cancer Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, therapeutic agent or an additional cancer treatment. Exem Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapac plary additional cancer therapeutic agents include for itabine, Semustine, Sitimagene ceradenovec, Strataplatin, example, chemotherapy, targeted therapy, antibody thera Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temo pies, immunotherapy, and hormonal therapy. Additional Zolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, cancer treatments include, for example: Surgery, and radia Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, tion therapy. Examples of each of these treatments are 10 Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, provided below. Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubi The term “co-administering as used herein with respect cin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflu to an additional cancer therapeutic agents means that the nine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic additional cancer therapeutic agent may be administered or cytotoxic agents described herein. together with a compound of one aspect of this invention as 15 Because Some drugs work better together than alone, two part of a single dosage form (such as a composition of one or more drugs are often given at the same time. Often, two aspect of this invention comprising a compound of one or more chemotherapy agents are used as combination aspect of the invention and an second therapeutic agent as chemotherapy. described above) or as separate, multiple dosage forms. In some embodiments, the additional cancer therapeutic Alternatively, the additional cancer therapeutic agent may be agent is a differentiation agent. Such differentiation agent administered prior to, consecutively with, or following the includes retinoids (such as all-trans-retinoic acid (ATRA), administration of a compound of one aspect of this inven 9-cis retinoic acid, 13-cis-retinoic acid (13-cRA) and 4-hy tion. In Such combination therapy treatment, both the com droxy-phenretinamide (4-HPR)); arsenic trioxide; histone pounds of one aspect of this invention and the second deacetylase inhibitors HDACs (such as azacytidine (Vidaza) therapeutic agent(s) are administered by conventional meth 25 and butyrates (e.g., sodium phenylbutyrate)); hybrid polar ods. The administration of a composition of one aspect of compounds (such as hexamethylene bisacetamide this invention, comprising both a compound of one aspect of ((HMBA)); vitamin D; and cytokines (such as colony the invention and a second therapeutic agent, to a subject stimulating factors including G-CSF and GM-CSF, and does not preclude the separate administration of that same interferons). therapeutic agent, any other second therapeutic agent or any 30 In some embodiments the additional cancer therapeutic compound of one aspect of this invention to said subject at agent is a targeted therapy agent. Targeted therapy consti another time during a course of treatment. The term "co tutes the use of agents specific for the deregulated proteins administering as used herein with respect to an additional of cancer cells. Small molecule targeted therapy drugs are cancer treatment means that the additional cancer treatment generally inhibitors of enzymatic domains on mutated, over may occur prior to, consecutively with, concurrently with or 35 expressed, or otherwise critical proteins within the cancer following the administration of a compound of one aspect of cell. Prominent examples are the tyrosine kinase inhibitors this invention. such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, In some embodiments, the additional cancer therapeutic imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semax agent is a chemotherapy agent. Examples of chemothera anib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin peutic agents used in cancer therapy include, for example, 40 dependent kinase inhibitors such as Alvocidib and Seliciclib. antimetabolites (e.g., folic acid, purine, and pyrimidine Monoclonal antibody therapy is another strategy in which derivatives), alkylating agents (e.g., nitrogen mustards, the therapeutic agent is an antibody which specifically binds nitrosoureas, platinum, alkyl Sulfonates, hydrazines, tri to a protein on the Surface of the cancer cells. Examples aZenes, aziridines, spindle poison, cytotoxic agents, topoi include the anti-HER2/neu antibody trastuzumab (HER Somerase inhibitors and others), and hypomethylating agents 45 CEPTINR) typically used in breast cancer, and the anti (e.g., decitabine (5-aza-deoxycytidine), Zebularine, isothio CD20 antibody rituximab and Tositumomab typically used cyanates, azacitidine (5-azacytidine), 5-flouro-2'-deoxycyti in a variety of B-cell malignancies. Other exemplary anti dine, 5,6-dihydro-5-azacytidine and others). Exemplary bodies include Cetuximab, Panitumumab, Trastuzumab, agents include Aclarubicin, Actinomycin, Alitretinoin, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtu Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, 50 Zumab. Exemplary fusion proteins include Aflibercept and Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Denileukin diftitox. In some embodiments, the targeted Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomy therapy can be used in combination with a compound cin, Bortezomib, Busulfan, Camptothecin, Capecitabine, described herein, e.g., a biguanide Such as metformin or Carboplatin, Carboquone, Carmofur, Carmustine, Cele phenformin, preferably phenformin. coxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, 55 Targeted therapy can also involve Small peptides as "hom Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, ing devices” which can bind to cell surface receptors or Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, affected extracellular matrix surrounding the tumor. Radio Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Eles nuclides which are attached to these peptides (e.g., RGDs) clomol, Elsamitrucin, Enocitabine, Epirubicin, Estramus eventually kill the cancer cell if the nuclide decays in the tine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluo 60 vicinity of the cell. An example of such therapy includes rouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, BEXXARCR). Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, In some embodiments, the additional cancer therapeutic Irinotecan, Irofulven, IXabepilone, Larotaxel, Leucovorin, agent is an immunotherapy agent. Cancer immunotherapy Liposomal doxorubicin, Liposomal daunorubicin, refers to a diverse set of therapeutic strategies designed to Lonidamine, Lomustine, Lucanthone, Mannosulfan, Maso 65 induce the Subjects own immune system to fight the tumor. procol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Contemporary methods for generating an immune response Methyl aminolevulinate, Mitobronitol, MitoguaZone, Mito against tumors include intravesicular BCG immunotherapy US 9,512,107 B2 137 138 for superficial bladder cancer, and use of interferons and -continued other cytokines to induce an immune response in renal cell carcinoma and melanoma Subjects. EXAMPLES Allogeneic hematopoietic stem cell transplantation can be ABBREVIATIONS considered a form of immunotherapy, since the donors NaHMDS - sodium hexamethyldisilylamide immune cells will often attack the tumor in a graft-versus LAH - lithium aluminum hydride tumor effect. In some embodiments, the immunotherapy NaBH4 - sodium borohydride agents can be used in combination with a compound or LDA - lithium diisopropylamide composition described herein. EtN - triethylamine 10 DMAP - 4-(dimethylamino)pyridine In some embodiments, the additional cancer therapeutic DIPEA - N,N-diisopropylethylamine agent is a hormonal therapy agent. The growth of some NHOH - ammonium hydroxide cancers can be inhibited by providing or blocking certain EDCI - 1-ethyl-3-(3- hormones. Common examples of hormone-sensitive tumors dimethylaminopropyl)carbodiimide include certain types of breast and prostate cancers. Remov HOBt - 1-hydroxybenzotriazole ing or blocking estrogen or testosterone is often an important 15 HATU - O-(7-azabenzotriazol-1- additional treatment. In certain cancers, administration of yl)-N,N,N'-N'-tetramethyluronium hormone agonists, such as progestogens may be therapeu BINAP-2,2'-bis(diphenylphosphanyl)- tically beneficial. In some embodiments, the hormonal 1,1'-binaphthyl therapy agents can be used in combination with a compound or a composition described herein. In the following examples, reagents were purchased from Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, commercial sources (including Alfa, Acros, Sigma Aldrich, synthetic chlorotoxins, and radiolabeled drugs and antibod TCI and Shanghai Chemical Reagent Company), and used 1CS without further purification. Nuclear magnetic resonance 25 (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland). Chemical shifts were reported in EXAMPLES parts per million (ppm, 8) downfield from tetramethylsilane. ABBREVIATIONS Mass spectra were run with electrospray ionization (ESI) anhy. - anhydrous from a Waters LCT TOF Mass Spectrometer (Waters, USA). aq. - aqueous 30 For exemplary compounds disclosed in this section, the min - minute(s) mL - milliliter specification of a stereoisomer (e.g., an (R) or (S) stereoi mmol - millimole(s) Somer) indicates a preparation of that compound Such that mol - mole(s) the compound is enriched at the specified Stereocenter by at MS - mass spectrometry least about 90%, 95%, 96%, 97%, 98%, or 99%. The NMR - nuclear magnetic resonance 35 TLC - thin layer chromatography chemical name of each of the exemplary compound HPLC - high-performance liquid described below is generated by ChemDraw software. chromatography HZ - hertz 8 - chemical shift Example 1 J - coupling constant S - singlet 40 d - doublet t - triplet Preparation of Compounds of Formula I Wherein Ring A q – quartet is Phenyl, and C(R)(R)(R) is Isopropyl. The com m - multiplet pounds of this Example are prepared by general Scheme 1, br - broad set forth below. qd - quartet of doublets 45 dquin - doublet of quintets dd - doublet of doublets dt - doublet of triplets Scheme 1 CHCl - chloroform DCM - dichloromethane C DMF - dimethylformamide 50 Et2O - diethyl ether es PhMgBr EtOH - ethyl alcohol THF EtOAc - ethyl acetate MeOH - methyl alcohol l als MeCN-acetonitrile C N C PE - petroleum ether 55 THF - tetrahydrofuran 1 AcOH - acetic acid HCl - hydrochloric acid H2SO - Sulfuric acid NHC - ammonium chloride KOH - potassium hydroxide NH2 NaOH - sodium hydroxide 60 -- K2CO3 - potassium carbonate THF.r.t. Na2CO3 - Sodium carbonate TFA - trifluoroacetic acid Na2SO - sodium sulfate s NaBH4 - sodium borohydride C - Nals C NaHCO - sodium bicarbonate 65 LiHMDS - lithium hexamethyldisilylamide 2 US 9,512,107 B2 139 140 -continued stirred at room temperature for 16 hrs. The reaction was quenched by water and extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, NH2 concentrated and purified by a standard method to give 4 N-(3-fluoro-phenyl)-N'-isopropyl-6-phenyl-1,3,5 triazine -- n Procedure 2,4-diamine. N A, B, or C

C us Nals N H 10

O NN H NMR (METHANOL-d) & 8.37-8.33 (m, 2H), 7.87 N Nals N 1. H H 7.84 (m. 1H), 7.52-748 (m, 5H), 7.27-7.25 (m, 1H), 6.73 6.69 (m. 1H), 4.24 (m. 1H), 1.16 (d. J=6.4 Hz, 6H). LC-MS: m/z 323.9 (M--H). Other compounds produced by Step 3, Formula I Procedure A of this example using the appropriate reagent 4 25 are set forth below.

Example 1, step 1: Preparation of Compound 195 N-isopropyl-N'-(3-(methoxym 2,4-dichloro-6-phenyl-1,3,5-triazine (2) ethyl)phenyl)-6-phenyl-1,3,5-triazine-2,4-diamine 30 To a solution of 2,4,6-trichloro-1,3,5 triazine (1, 120g, 0.652 mol) in anhydrous THF (1200 mL) was added phe nylmagnesium bromide (217 mL, 0.651 mol, 3M in ether) dropwise at -10 to -0° C. under N protection. After the addition, the mixture was warmed to room temperature and 35 stirred for 2 hrs. The reaction was cooled to 0° C. and quenched by addition of saturated NHCl (200 mL), then extracted with ethyl acetate. The organic layer was dried, concentrated and purified via column chromatography (eluted with petroleum ether) to afford 2,4-dichloro-6-phe 40 -O-O-l nyl-1,3,5-triazine as a white solid. "H NMR (CDC1) & 7.51-7.55 (m, 2H), 7.64-7.67 (m. 1H), 8.49-8.63 (m, 2H). "H NMR (METHANOL-d) 8.40-8.34 (m. 2H) 7.99-7.83 Example 1, step 2: Preparation of 4-chloro-N-iso (m. 1H), 7.62-7.60 (m, 1H), 7.53-7.44 (m, 3H), 7.31-7.27 propyl-6-phenyl-1,3,5-triazin-2-amine (3) 45 (m. 1H), 7.00-6.99 (m. 1H), 4.48 (s. 2H)4.29-4.27 (m. 1H), 3.41 (s, 3H), 1.16 (d. J=6.8 Hz, 6H). LC-MS: m/z. 350.3 To a solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (2: (M+H)". 20 g, 0.089 mol) in anhydrous THF (150 mL) was added Compound 198 2-(3-(4-(isopropylamino)-6-phe dropwise a solution of isopropylamine (5.25 g, 0.089 mol) nyl-1,3,5-triazin-2-ylamino)phenyl)acetonitrile in THF (10 mL) at room temperature via syringe under N. 50 After the addition, the mixture was stirred at room tempera ture under N for 16 hrs. The reaction was quenched by water (150 mL) and extracted with ethyl acetate. The organic layer was dried, concentrated and purified via SiO, chroma tography to afford 4-chloro-N-isopropyl-6-phenyl-1,3,5-tri 55 azin-2-amine (3) as white solid. "H NMR (CDC1) & 1.17-1.24 (m, 6H), 4.16-4.35 (m, 1H), 5.46-5.54 (m, 1H), 7.18-7.50 (m, 3H0, 8.31 (dd, J=8.4 Hz, J-34.4 Hz, 2H). 60 Example 1, Step 3 (Procedure A). Preparation of Compound 178 N-(3-Fluoro-phenyl)-N'-isopropyl c. 6-phenyl-1,3,5 triazine-2,4-diamine H NMR (METHANOL-d) 8.42-8.38 (m, 2H) 8.18-8.11 A mixture of (4-chloro-6-phenyl-1,3,5 triazin-2-yl)-iso 65 (m. 1H), 7.61-7.60 (m, 1H), 7.52-7.45 (m, 3H), 7.35-7.31 propyl-amine (3; 200 mg. 0.806 mmol) and 3-fluoro-phe (m. 1H), 7.02-7.00 (m, 1H), 4.34 (m. 1H), 3.92 (s. 2H), 1.16 nylamine (135 mg, 1.215 mmol) in anhydrous THF was (d. J=6.8 Hz, 6H). LC-MS: m/z 345.2 (M+H)".

US 9,512,107 B2 157 158 Example 2 The procedure set forth in Example 2, step 1 was used to produce the following intermediates (5) using the appropri Preparation of Compounds of Formula I Wherein Ring A ate starting material 4. is Optionally Substituted Pyridin-2-yl or Pyrimidin-2-yl. 1-(3-cyanophenyl-2-cyanoguanidine as a brown solid. The compounds of this Example are prepared by general 5 Scheme 2, set forth below.

Scheme 2 10 NH 1.HC 2. NaN(CN)2 He NH2 HO N lesN1 H H 4 15 LC-MS: m/z 185.9 (M+H)". 1-methanesulfonyl-benzenyl-2-cyanoguanidine as a pale NH R3 gray Solid. l -CN Hess1. cuso,6 so EtOHIHO 5 2. HCl, Na2S NaOHIHO

25 NH O O N N lesN1 NH NH R1 2 O H H

30 N lulukN N R3 MeONa,8 MeOH LC-MS: m/z 238.8 (M+H)". H H H 1-3-fluoro-pyridin-2-cyanoguanidine as a pale solid. 7

35 21 NH N1 SN RI N N N ls N1 CN 2 40 H H N N N R3 H H Formula I H NMR (DMSO-d4) & 7.42 (s. 2H), 7.85-8.01 (m. 1H), 8.24 (s, 1H), 8.38 (s, 1H). 1-3-chloro-pyridin-2-cyanoguanidine as a pale gray solid. 45 Example 2, step 1: Preparation of 1-phenyl-2-cyanoguanidine (5) C 21 NH To a solution of NaN(CN), (50 g., 0.5618 mol) in water 50 (430 mL) at 80°C. was added a solution of aniline (26.2 g, N N N l N1 CN 0.28 mol) in water and conc. HCl (132 mL/23.5 mL). The H H mixture was heated to 90° C. for 16 hours. The mixture was cooled to room temperature and quenched by adding Satu rated sodium bicarbonate (317 mL). The mixture was fil 55 H NMR (DMSO-d4) & 8.06 (s, 1H), 8.29 (s, 1H), 8.47 (s, tered and the filter cake was dried via vacuum to afford 1H). 1-phenyl-2-cyanoguanidine as a white solid. 1-2-fluoro-pyridin-2-cyanoguanidine as a brown solid.

F NH 60

N ls.N1 -- N OS N lNH N1 CN H H H H

65 H NMR (DMSO-d4) & 6.95 (s. 2H), 7.02-7.06 (m, 1H), H NMR (DMSO-d4) & 7.10-7.20 (m, 1H), 7.95-7.99 (m, 7.26-7.32 (m, 4H), 9.00 (s, 1H). 1H), 8.15 (s, 1H). US 9,512,107 B2 159 160 1-3,5-difluoro-phenyl-2-cyano-guanidine as white solid, which was directly used in the next step without further O purification. N429

10 F N ls N -CN. H H LC-MS: m/z 298 (M+H)". 1-3-fluoro-pyridin-2-cyclobutyl-diguanidine as a red solid. LC-MS: m/z 196.8 (M+H)". 15 Example 2, step 2: Preparation of F 1-phenyl-2-isopropylamine-diguanidine (7) To a mixture of 1-phenyl-2-cyanoguanidine (5.0 g, 0.031 d NH NH mol) in ethanol/water (46 mL/18.4 mL) was added CuSO4.5H2O (3.91 g, 0.01563 mol), followed by isopropyl N& ---O amine (5.53 g, 0.03975 mol). The mixture was heated to reflux for 16 hours. To the mixture was added water (137 LC-MS: m/z 251 (M+H)". mL) and aq.HCl (15.5 mL in 93 mL of water) at 25-30°C. 1-3-chloro-pyridin-2-cyclobutyl-diguanidine as a red The resultant mixture was stirred at r,t. for 30 min. Then 25 solid. NaS (12.4 g in 62 mL of water) was added and stirred for another 30 min. The insoluble CuS was filtered off. The filtrate was cooled to 10° C. and added aqueous NaOH (7 g C NaOH in 50 mL water) dropwise. The mixture was extracted with dichloromethane (100 mLX3). The organic layer was 30 combined, dried over NaSO and concentrated to give d NH NH 1-phenyl-2-isopropylamine-diguanidine as a brown solid. Nan ---O

35 s1 LC-MS: m/z 267 (M+H)". 1-2-fluoro-pyridin-2-cyclobutyl-diguanidine as a red l solid.

40 "Ne N1 SN F N& --l. -D Sa N N N H H H 45 "H NMR (DMSO-d4) & 1.25 (d. J=4.8 Hz, 6H), 4.91-4.97 LC-MS: m/z 250.8 (M+H)". (m. 1H), 7.17-7.39 (m, 5H). 1-3,5-difluorophenyl-2-isopropyl-diguanidine as a brown The procedure set forth in Example 2, step 2 was used to solid, which was used in the next step without further produce the following intermediates (7) using the appropri purification. ate intermediate 5 and the appropriate amine 6. 50 1-3-cyanophenyl-2-isopropylamine-diguanidine as a brown solid. F 55 O. NH NH 1. F H ---,H H

60 LC-MS: m/z 256 (M+H)". Example 2, step 3: Preparation of Compound 214 N-Isopropyl-N'-phenyl-6-pyridin-2-yl-1,3,5 triaz ine-2,4-diamine LC-MS: m/z 245 (M+H)". 65 1-methanesulfonyl-2-isopropyl-diguanidine as a pale To a mixture of N-isopropyl-N'-phenyl-6-pyridin-2-yl-1, solid. 3.5 triazine-2,4-diamine (0.5g, 2.28 mmol) and pyridine-2-

US 9,512,107 B2 171 172 -continued 6-trifluoromethyl-pyridine-2-carboxylic acid methyl R4 R1 ester

2Ny sR3 6 F He F N F 10 C - Nals C 2 N 12 R4 O o1 SAS 15 2N LC-MS: m/z. 206 (M+H)". NH2 Example 3, step 2: Preparation of N1 NN R1 4 6-(6-chloropyridin-2-yl)-1,3,5-triazine-2,4-dione R2 -- 2 C N N R3 H To a solution of Na (32 g, 0.16 mol) in ethanol (500 mL) 13 was added methyl 6-chloropicolinate (32 g, 0.16 mol) and biuret (5.3.g., 0.052 mol). The mixture was heated to reflux R4 25 S for 1 hour. Then concentrated to give residue which was as poured to water and added SatNaHCO solution to adjust pH to 7, the precipitated solid was collected by filtration and 2N dried to give 6-(6-chloropyridin-2-yl)-1,3,5-triazine-2,4-di 30 one as a white Solid. N1 NN RI R2 2 N N N R3 H H Formula I 35

Example 3, step 1: Preparation of 6-chloro-pyridine-2-carboxylic acid methyl ester 40 (10)

To a solution of 6-chloro-pyridine-2-carboxylic acid (48 LC-MS: m/z 225 (M+H)". g, 0.31 mol) in methanol (770 ml) was added concentrated 45 The procedure set forth in Example 3, step 2 was used to HCl (6 ml). The mixture was stirred at 80° C. for 48 hours produce the following intermediates (11) starting with then concentrated to remove the volatile. The crude product was diluted with ethyl acetated and washed with Sat. appropriate intermediate 10. NaHCO solution. The organic layer was dried with anhy 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4- drous NaSO and concentrated to give 6-chloro-pyridine 50 dione as a pale white Solid. 2-carboxylic acid methyl ester as a white solid. F C F. N 55 2N rs,2N O o1 60 HN1 NN

LC-MS: m/z. 172.0 (M+H)". ess The procedure set forth in Example 3, step 1 was used to 65 produce the following intermediates (10) using the appro priate starting material 9. LC-MS: m/z 259 (M+H)". US 9,512,107 B2 173 174 6-pyridin-2-yl-1H-1,3,5-triazine-2,4-dione N 2N

N1 SN

10 C us Nals C.

LC-MS: m/z 227.0 (M+H)".

"H NMR (DMSO-d4): 8 11.9-12.5 (s, 1H), 11.3-11.6 (s, 15 Example 3, step 4: Preparation of 4-chloro-6-(6- 1H), 8.7-8.9 (m. 1H), 8.2-8.4 (m. 1H), 8.0-8.2 (m, 1H), chloropyridin-2-yl)-N-isopropyl-1,3,5-triazin-2- 7.6-7.8 (m, 1H). amine Example 3, step 3: Preparation of 2,4-dichloro-6- To a solution of 2,4-dichloro-6-(pyridin-2-yl)-1,3,5-triaz (6-chloropyridin-2-yl)-1,3,5-triazine ine (2.0 g, 0.0077 mol) in anhydrous THF (20 mL) was added isopropyl amine (0.45 g, 0.0077 mol). The mixture To a solution of 6-(pyridin-2-yl)-1,3,5-triazine-2,4(1H, was stirred at room temperature for 1 hour. The mixture was 3H)-dione (3.0 g., 013 mol) in POCl (48 mL) was added quenched by water and extracted with ethyl acetate. The PC1 (23 g, 0.1 mol). The mixture was stirred at 100° C. for 25 organic layer was dried over anhydrous Na2SO4 and con 2 hours then concentrated to remove the volatile. The centrated to give 4-chloro-6-(6-chloropyridin-2-yl)-N-iso residue was diluted with ethyl acetated and washed with propyl-1,3,5-triazin-2-amine which was used directly in the SatNaHCO solution. The organic layer was dried over next step. anhydrous Na2SO4 and concentrated to give 2,4-dichloro 6-(6-chloropyridin-2-yl)-1,3,5-triazine as a brown solid. 30

N1 NN 40 C us Nals C LC-MS: m/z 221.1 (M+H)". LC-MS: m/z 260.9 (M+H)". The procedure set forth in Step 4 using the appropriate The procedure set forth in Example 3, step 3 together with 45 intermediate 12 and amine 6 was used to produce the the appropriate starting intermediate 11 was used to produce following intermediates (13). the following intermediates (12). 2, 4-dichloro-6-(6-trifluoromethyl-pyridin-2-yl)-1,3,5-tri 4-Chloro-6-(6-trifluoromethyl-pyridin-2-yl)-1,3, azine as light yellow solid. 50 5triazin-2-yl-isopropyl-amine

F F. F 55 F rns,2N rs,2N N1 NN 60 us als N1 NN C N C ----- LC-MS: m/z 294.9 (M+H)". 65 2,4-Dichloro-6-pyridin-2-yl-1,3,5 triazine (1.0 g, 80%) as brown solid. LC-MS: m/z. 318.1 (M+H)".

US 9,512,107 B2 191 192 8.24 (m. 1H), 8.10-8.12 (m, 1H), 3.98 (d. J–8.0 Hz, 2H), 3.69 (d. J–8.0 Hz, 2H), 2.57-2.61 (m. 1H), 1.97 (s. 2H). LC-MS: m/z 434.2 (M+H)". Example 4 1s. Preparation of Compounds of Formula I Wherein --- Ring A is Substituted Phenyl H NMR (CDC1) & 1.24-1.27 (m, 6H), 4.21-4.26 (m, The compounds of this Example are prepared by general 10 1H), 5.68 (brs, 1H). Scheme 4, set forth below. The following intermediates (13) were prepared follow ing the procedure of Step 1 using the appropriate amine 6. 4,6-dichloro-N-(oxetan-3-yl)-1,3,5-triazin-2-amine, Scheme 4 which was directly used in the next step. 15 RI 2 C s C N 1. N R3 1s, ul als THF6 C N C --- B(OH)2 25 "H NMR (CDC1) & 1.71-1.83 (m, 2H), 1.90-2.04 (m, N N N R1 o 2H), 2.37-2.46 (m, 2H), 4.46-4.56 (m, 1H), 6.04 (br. 1H). R2 14 1-(4,6-Dichloro-1,3,5 triazin-2-ylamino)-2-methyl-pro 2 C N N R3 pan-2-ol, which was directly used in the next step. H 13 30 R4 C S4 2 35 uci, N1NN RI NH2 4 R2 -- 2 Procedure A, B, or C C N N R3 H LCMS: m/z 237.0 (M+H)". 40 4,6-dichloro-N-isobutyl-1,3,5-triazin-2-amine, which was 15 directly used in the next step.

C 45

N1 NN RI R2 u). 2 N N N R3 50 H H Formula I "H NMR (CDC1) & 0.85 (d. J=8.6 Hz, 6H), 1.75-194 (m, 1H), 3.30-3.33 (m, 2H), 6.29 (br. 1H).

55 Example 4, step 2: Preparation of 1-4-chloro-6-(2- Example 4, step 1: Preparation of fluoro-phenyl)-1.3.5 triazin-2-ylamino-2-methyl 4,6-dichloro-N-isopropyl-1,3,5-triazin-2-amine propan-2-ol To a solution of 2,4,6-trichloro-1,3,5-triazine (4.0 g, To a mixture of 4,6-dichloro-N-isopropyl-1,3,5-triazin-2- 0.0217 mol) in THF (25 mL) was added isopropyl amine 60 amine (1.0 g, 4.83 mmol), 3-fluorophenylboronic acid (1.27 g., 0.0217 mmol) at 0°C. The mixture was stirred at (0.671 g, 0.00483 mol) and CsCO, (3.15g, 0.00966 mol) room temperature for 12 hours. The mixture was adjusted in dioxane?water (12 mL/2.4 mL) was added Pd(PPh.) pH7 by aq NaHCO, and extracted with ethyl acetate (100 (0.56 g. 483 mmol). The mixture was heated to 80°C. for 2 mL*2). The combined organic layer was dried over NaSO, hours. The mixture was concentrated and purified by SiO, concentrated and purified by column chromatography to 65 chromatography to give 1-4-chloro-6-(2-fluoro-phenyl)-1, give 4,6-dichloro-N-isopropyl-1,3,5-triazin-2-amine as a 3.5 triazin-2-ylamino-2-methyl-propan-2-ol as a white colorless oil. solid. US 9,512,107 B2 193 194 4-chloro-6-(3-fluorophenyl)-N-isopropyl-1,3,5-tri azin-2-amine

- als 10 N1NN LCMS: m/z 297.1 (M+H)". Additional intermediates 15 were prepared by the method --- of Example 4, step 2 using the appropriate boronic acid 14 15 and the appropriate starting intermediate 13. LCMS: m/z 266.9 (M+H)". 4-chloro-6-(3-chloro-phenyl)-1.3.5 triazin-2-yl)- isopropyl-amine 3-(4-Chloro-6-isopropylamino-1.3.5 triazin-2-yl)- phenyl-carbamic acid tert-butyl ester

C 25 risk 30 C-l LCMS: m/z 282.9 (M+H)". 35 4-chloro-6-(2-fluorophenyl)-N-isopropyl-1,3,5-tri LCMS: m/z. 364.2 (M+H)". azin-2-amine 4-Chloro-6-(3-methoxy-phenyl)-1,3,5 triazin-2-yl)- isopropyl-amine 40

45 N1 NN -----> 1n 50 LCMS: m/z 266.8 (M+H)". --- 4-chloro-6-(2-chlorophenyl)-N-isopropyl-1,3,5-tri azin-2-amine LCMS: m/z 279.1 (M+H)". 55 Example 4, step 3 (Procedure A): Preparation of Compound 227—6-(2-fluorophenyl)-N-isopropyl N'-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine C 60 A mixture of 4-chloro-6-(2-fluorophenyl)-N-isopropyl-1, NN 3.5-triazin-2-amine (290 mg, 1.1 mmol), pyridine-4-amine (103 mg, 1.1 mmol), CsP (554 mg, 2.2 mmol) and DIPEA (0.425 g, 3.3 mmol) in DMSO (4 mL) was heated to 80° C. C N N 65 for 2 hours. The mixture was filtered and purified by a H standard method to give 6-(2-fluorophenyl)-N-isopropyl LCMS: m/z 282.8 (M+H)". N'-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine.