USOO9376418B2

(12) United States Patent (10) Patent No.: US 9,376.418 B2 Haidle et al. (45) Date of Patent: Jun. 28, 2016

(54) SUBSTITUTED PYRIDINE SPLEEN 31/5377 (2013.01); A61K3I/5383 (2013.01); KINASE (SYK) INHIBITORS A61 K3I/551 (2013.01); A61K 45/06 (2013.01); C07D401/14 (2013.01); C07D (71) Applicants: Merck Sharp & Dohme Corp., 405/14 (2013.01); C07D 409/14 (2013.01); Rahway, NJ (US); Merck Canada Inc., C07D 413/14 (2013.01); C07D 417/14 Kirkland, Quebec (CA) (2013.01); C07D 471/04 (2013.01); (Continued) Inventors: (72) Andrew M. Haidle, Cambridge, MA (58) Field of Classification Search (US); Sandra Lee Knowles, Princeton, CPC ...... CO7D 401/12: CO7D 401/14: A61 K NJ (US); Solomon D. Kattar, Arlington, 31/5377; A61K31/506 MA (US); Denis Deschenes, Lachine USPC ...... 544/122, 331; 514/235.8, 275 (CA); Jason Burch, Redwood City, CA See application file for complete search history. (US); Joel Robichaud, Dollard-des-Ormeaux (CA); Matthew (56) References Cited Christopher, Brookline, MA (US); Michael D. Altman, Needham, MA U.S. PATENT DOCUMENTS (US); James P. Jewell, Newtown, MA 5,710,129 A 1/1998 Lynch et al. (US); Alan B. Northrup, Reading, VA 6/2001 Uckun et al. (US); Marc Blouin, Saint-Lazare (CA); 6,248,790 B1 John Michael Ellis, Needham, MA (Continued) (US); Hua Zhou, Acton, MA (US); Christian Fischer, Natick, MA (US); FOREIGN PATENT DOCUMENTS Adam J. Schell, Decatur, GA (US); EP 877O2O A1 11, 1998 Michael H. Reutershan, Brookline, MA EP 2441755 A1 4/2012 (US); Brandon M. Taoka, Hoboken, NJ (US); Anthony Donofrio, Cambridge, (Continued) MA (US) OTHER PUBLICATIONS Assignees: Pearce et al., Failure modes in anticancer drug discovery and devel (73) Merck Sharp & Dohme Corp., opment, Cancer Drug Design and Discovery Edited by Stephen Rahway, NJ (US); Merck Canada Inc., Neidle, Chapter 18, pp. 424-435 (2008).* Kirkland, Quebec (CA) Johnson et al., Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials, British Journal of (*) Notice: Subject to any disclaimer, the term of this Cancer (2001) 64(10): 1424-1431.* patent is extended or adjusted under 35 Simone. Oncology: Introduction, Cecil Textbook of Medicine, 20th U.S.C. 154(b) by 13 days. Edition, vol. 1, pp. 1004-1010, 1996.* (Continued) (21) Appl. No.: 14/409,151 Primary Examiner — Deepak Rao (22) PCT Fled: Jun. 17, 2013 (74) Attorney, Agent, or Firm — Eric A. Meade: Anna L. (86) PCT NO.: PCT/US2O13/046151 CocuZZO S371 (c)(1), (57) ABSTRACT (2) Date: Dec. 18, 2014 The invention provides certain substituted pyridines of the Formula (I) or pharmaceutically acceptable salts thereof, (87) PCT Pub. No.: WO2O13/192098 wherein R. R. R. R. R. C., and t are as defined herein. PCT Pub. Date: Dec. 27, 2013 The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the com (65) Prior Publication Data pounds for treating diseases or conditions mediated by Spleen US 2015/O 1483.27 A1 May 28, 2015 Tyrosine Kinase (Syk) kinase.

Related U.S. Application Data (I) (RC), (60) Provisional application No. 61/663,290, filed on Jun. 22, 2012. (O R2 R3 (51) Int. C. 21 NN CO7D 40/12 (2006.01) CO7D 40/4 (2006.01) NN 1. N (Continued) H (52) U.S. C. CPC ...... C07D401/12 (2013.01); A61K3I/505 (2013.01); A61 K3I/506 (2013.01); A61 K 18 Claims, No Drawings US 9,376.418 B2 Page 2

(51) Int. Cl. 2011/0301 175 A1 12/2011 Molteni et al. A6 IK3I/506 (2006.01) 2014/0148474 A1 5/2014 Altman et al. A 6LX3L/505 2006.O1 2014/0243336 A1 8/2014 Altman et al. (2006.01) 2014/0249 130 A1 9, 2014 Deschenes et al. A6 IK 45/06 (2006.01) 2015, 0166486 Al 6, 2015 Haidle et al. A 6LX3/5377 (2006.01) 2015,0175575 A1 6, 2015 Lim et al. A6 IK3I/5383 (2006.01) 33.85: A 58 NE A6 IK3I/55 (2006.01) CO7D 405/4 (2006.01) FOREIGN PATENT DOCUMENTS CO7D 413/4 (2006.01) CO7D 417/4 (2006.01) JP 20042O3748 12/2002 CO7D 47L/04 (2006.01) WO WOO3078.404 A1 9, 2003 CO7D 47L/TO (2006.01) WO WO2004080463 A1 9, 2004 CO7D 487/04 (2006.015 WO WO2005O13996 A2 2, 2005 WO WO2O06093247 A1 2, 2005 C07D 491/107 (2006.01) WO WO2005O26158 A1 3, 2005 CO7D 49 I/II3 (2006.01) WO WO2005033103 A1 4, 2005 CO7D 49.8/04 (2006.01) W: Woo: A 39.

C E. 3:08: WO WO2006050480WO2006O28833 A1A2 3f20065, 2006 CO7D 487/10 (2006.01) WO WO200606877O A1 6, 2006 (52) U.S. Cl WO WO2006078846 A1 T 2006 AV e. we WO WO2006129 100 A1 12/2006 CPC ...... C07D 471/10 (2013.01); C07D487/04 WO WO2006133426 A2 12/2006 (2013.01); C07D 487/10 (2013.01); C07D WO WO2006135915 A2 12/2006 491/08 (2013.01); C07D491/107 (2013.01); WO WO2007OO9681 A1 1, 2007 C07D491/113 (2013.01); C07D498/04 WO WO2007OO9773 A1 1, 2007 (2013.01) WO WO2007028445 A1 3, 2007 WO WO2007042298 A1 4/2007 WO WO2007042299 A1 4/2007 (56) References Cited WO WO2007070872 A1 6, 2007 WO WO2007085540 A1 8, 2007 U.S. PATENT DOCUMENTS WO WO2007 120980 A2 10/2007 WO WO2009084695 A1 12/2007 6.432,963 B1 8/2002 Hisamichi et al. WO WO2009031011 A2 3, 2009 6,552,029 B1 4/2003 Davis et al. WO WO2009097287 A1 8, 2009 6,589,950 B1 7/2003 Hayler et al. WO WO2009102468 A1 8, 2009 6,770,643 B2 8, 2004 Cox et al. WO WO2009 131687 A2 10/2009 6,797,706 B1 9, 2004. Hisamichi et al. 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Models, Science, vol. 278, No. 5340, pp. 1041-1042, Nov. 1997.* 5. g R: 1933 AA et Pamuk et al., Spleen tyrosine kinase inhibition in the treatment of 8,759,366- - B2 6, 2014 Childerstman et et al. al. autoimmune, allergic and autoinflammatoryck diseases, Arthritis 8,796.310 B2 8, 2014 R. tal Research & Therapy, (2010), 12:222, pp. 1-11. - w OO a International Search Report and Written Opinion for PCT/US 13/ 8.987,456 B2 3/2015 Altman et al. 46151 illed on Nov. 1, 2013 9,006,444 B2 4/2015 Altman et al. is mailed on Nov. 1, . 9,120,785 B2 9, 2015 Altman et al. Villasenor et al., Structural Insights for Design of Potent Spleen 2004.00299.02 A1 2/2004 Singh et al. Tyrosine Kinase Inhibitors from Crystallographic Analysis of Three 2004.0054179 A1 3, 2004 Yura et al. Inhibitor Complexes,& 8 Chem Biol Drug Des. 2009, 466-470, 73. 2006, O135543 A1 6/2006 Singh et al. Yamamoto et al, The Orally Available Spleen Tyrosine Kinase 2006/01784.07 A1 8/2006 Argade et al. inhibitor (2-7-(3,4-Dimethoxyphenyl)imidazo[12-elpyrimidin-5- 2006/0211657 A1 9/2006 Singh et al. ylaminol-nicotinamide Dihydrochloride (BAY 6 1.3606) Blocks 2006/0234483 A1 10, 2006 Arak et al. Antigen-Induced Airway. Inflammation in Rodents , The Journal of 2006/0247262 A1 11/2006 Baenteli et al. Pharmacology and Experimental Therapeutics, 2003, pp. 1174-1181. 2007/0004626 A1 1/2007 Masuda et al. vol. 306(3). 2007/0129362 A1 6/2007 Bhamidipati et al. European Search Report for PCT/US2013/046151 mailed Nov. 18, 2007/O197782 A1 8/2007 Clough et al. 2015. 2008, 0221171 A1* 9, 2008 Eberle et al...... 514,352 2011/0245205 A1 10, 2011 Altman et al. * cited by examiner US 9,376,418 B2 1. 2 SUBSTITUTED PYRIDINE SPLEEN mediators and spasmogens (Wong et al. 2004, Expert Opin. TYROSINE KINASE (SYK) INHIBITORS Investig. Drugs (2004) 13 (7) 743-762). Recently, it has been shown that the Syk kinase inhibitor CROSS REFERENCE TO RELATED R112 (Rigel), dosed intranasally in a phase I/II study for the APPLICATIONS treatment of allergic rhinitis, gave a statistically significant decrease in PGD, a key immune mediator that is highly This application is a U.S. National Phase application under correlated with improvements in allergic rhinorrhea, as well 35 U.S.C. S371 of PCT Application No. PCT/US2013/ as being safe across a range of indicators, thus providing the 046151, filed Jun. 17, 2013, which claims priority under 35 first evidence for the clinical safety and efficacy of a topical U.S.C. S 119(e) from U.S. Provisional Application No. 10 Syk kinase inhibitor. (Meltzer, Eli O.; Berkowitz, Robert B.: 61/663,290, filed Jun. 22, 2012. Grossbard, Elliott B. Journal of Allergy and Clinical Immu nology (2005), 115(4), 791-796). In a more recent phase II FIELD OF THE INVENTION for allergic rhinitis (Clinical Trials.gov Identifier NCT0015089). R112 was shown as having a lack of efficacy The present invention relates to certain substituted pyridine 15 Versus placebo. Rheumatoid Arthritis (RA) is an auto-immune disease compounds of the Formula (I) (also referred to herein as the affecting approximately 1% of the population. It is character “compounds of the Formula (I) or “compounds of Formula ised by inflammation of articular joints leading to debilitating (I)”) which are inhibitors of Spleen Tyrosine Kinase (Syk) destruction of bone and cartilage. Recent clinical studies with kinase activity, or are prodrugs thereof. The present invention Rituximab, which causes a reversible B cell depletion, (J. C. also provides compositions comprising such compounds, and W. Edwards et al. 2004, New Eng. J. Med. 350: 2572–2581) methods of using Such compounds for treating conditions or have shown that targeting B cell function is an appropriate disorders associated with inappropriate Syk activity, in par therapeutic strategy in auto-immune diseases such as RA. ticular in the treatment and prevention of disease states medi Clinical benefit correlates with a reduction in auto-reactive ated by Syk. Such disease states may include inflammatory, 25 antibodies (or Rheumatoid Factor) and these studies suggest allergic and autoimmune diseases, for example, , that B cell function and indeed auto-antibody production are chronic obstructive pulmonary disease (COPD), adult respi central to the ongoing pathology in the disease. ratory distress syndrome (ARDS), ulcerative colitis, Crohns Studies using cells from mice deficient in the Spleen disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, Tyrosine Kinase (Syk) have demonstrated a non-redundant Scleroderma, urticaria, rheumatoid arthritis, idiopathic 30 role of this kinase in B cell function. The deficiency in Syk is thrombocytopenic purpura (ITP), multiple Sclerosis, cancer, characterized by a block in B cell development (M. Turner et HIV and lupus. al. 1995 Nature 379: 298–302 and Cheng et al. 1995, Nature 378:303-306). These studies, along with studies on mature B BACKGROUND OF THE INVENTION cells deficient in Syk (Kurasaki et al. 2000, Immunol. Rev. 35 176:19-29), demonstrate that Syk is required for the differ Spleen Tyrosine Kinase (Syk) is a protein tyrosine kinase entiation and activation of B cells. Hence, inhibition of Sykin which has been described as a key mediator of immunorecep RA patients is likely to block B cell function, and thereby tor signalling in a host of inflammatory cells including mast reduce Rheumatoid Factor production. In addition to the role cells, B-cells, macrophages and neutrophils. These immu of Syk in B cell function, and of further relevance to the noreceptors, including Fc receptors and the B-cell receptor, 40 treatment of RA, is the requirement for Syk activity in Fc are important for both allergic diseases and antibody-medi receptor (FcR) signalling. FcR activation by immune com ated autoimmune diseases and thus pharmacologically inter plexes in RA has been suggested to contribute to the release of fering with Syk could conceivably treat these disorders. multiple pro-inflammatory mediators. Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving 45 SUMMARY OF THE INVENTION a multitude of cell types including mast cells, eosinophils, T cells and dendritic cells. Following exposure to allergen, high The present invention provides novel compounds that are affinity immunoglobulin receptors for IgE and IgG become potent inhibitors of Syk, or are prodrugs thereof, as well as cross-linked and activate downstream processes in mast cells pharmaceutical compositions containing them. AS Syk and other cell types leading to the release of pro-inflamma 50 inhibitors compounds of Formula (I) are useful in the treat tory mediators and airway spasmogens. In the , for ment and prevention of diseases and disorders mediated by example, IgE receptor cross-linking by allergen leads to the Syk protein. Such diseases and disorders include, but are release of mediators including from pre-formed not limited to, asthma, COPD, rheumatoid arthritis, cancer granules, as well as the synthesis and release of newly syn and idiopathic thrombocytopenic purpura. thesized lipid mediators including prostaglandins and leukot 55 rienes. DETAILED DESCRIPTION OF THE INVENTION Syk kinase is a non-receptor linked tyrosine kinase which is important in transducing the downstream cellular signals Definitions associated with cross-linking FcRI and or FcRI receptors, and is positioned early in the signalling cascade. In 60 The terms used herein have their ordinary meaning and the mast cells, for example, the early sequence of FcRI meaning of Such terms is independent at each occurrence signalling following allergen cross-linking of receptor-IgE thereof. That notwithstanding and except where stated other complexes involves first Lyn (a Src family tyrosine kinase) wise, the following definitions apply throughout the specifi and then Syk. Inhibitors of Syk activity would therefore be cation and claims. Chemical names, common names, and expected to inhibit all downstream signalling cascades 65 chemical structures may be used interchangeably to describe thereby alleviating the immediate allergic response and the same structure. If a chemical compound is referred to adverse events initiated by the release of pro-inflammatory using both a chemical structure and a chemical name, and an US 9,376,418 B2 3 4 ambiguity exists between the structure and the name, the The term "halo,” as used herein, means —F. —Cl, —Br or structure predominates. These definitions apply regardless of —I. In one embodiment, a halo group is —F or —Cl. In whether a term is used by itself or in combination with other another embodiment, a halo group is —F. terms, unless otherwise indicated. Hence, the definition of The term "heteroarylas used herein, refers to an aromatic “alkyl applies to “alkyl as well as the “alkyl portions of 5 monocyclic or multicyclic ring system comprising about 5 to “hydroxyalkyl,” “fluoroalkyl,” “ O-alkyl,” etc. about 14 ring atoms, wherein from 1 to 3 of the ring atoms is As used herein, and throughout this disclosure, the follow independently N, O, or S and the remaining ring atoms are ing terms, unless otherwise indicated, shall be understood to carbonatoms. In one embodiment, a heteroaryl group has 5 to have the following meanings: 10 ring atoms. In another embodiment, a heteroaryl group is A patient' is a human or non-human mammal. In one 10 monocyclic ring system and has 5 or 6 ring atoms. In another embodiment, a patient is a human. In another embodiment, a patient is a chimpanzee. embodiment, a heteroaryl group is a bicyclic ring system. A The term “therapeutically effective amount’ as used heteroaryl group is joined via a ring carbon atom. The term herein, refers to an amount of the compound of Formula (I) "heteroaryl also includes a heteroaryl as defined above fused and/or an additional therapeutic agent, or a composition 15 to a heterocyclyl as defined below. The term "heteroaryl also thereof that is effective in producing the desired therapeutic, encompasses a heteroaryl group, as defined above, which is ameliorative, inhibitory or preventative effect when adminis fused to a benzene, a cyclohexadiene or a cyclohexene ring. tered to a patient Suffering from a disease or condition medi Non-limiting examples of heteroaryls include pyridyl, ated by Syk. In the combination therapies of the present pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including invention, a therapeutically effective amount can refer to each N-Substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, individual agent or to the combination as a whole, wherein the oxadiazolyl, thiazolyl pyrazolyl, furyl, pyrrolyl, triazolyl, amounts of all agents administered are together effective, but 1,2,4-thiadiazolyl pyrazinyl, pyridazinyl, indolyl, quinoxali wherein the component agent of the combination may not be nyl, phthalazinyl, OXindolyl, imidazol-2-alpyridinyl, imi present individually in an effective amount. dazo[2.1-bithiazolyl, and the like. In one embodiment, a het The term “preventing, as used herein with respect to can 25 eroaryl group is a 5-membered heteroaryl. In another cer or an inflammatory disease or disorder, refers to reducing embodiment, a heteroaryl group is a 6-membered heteroaryl. the likelihood of cancer pain or an inflammatory disease or The term "heterocyclyl as used herein, refers to a non disorder. aromatic Saturated or partially saturated monocyclic or mul The term “alkyl, as used herein, refers to an aliphatic ticyclic ring system containing 3 to 11 ring atoms, wherein hydrocarbon group having one of its hydrogen atoms 30 replaced with a bond having the specified number of carbon from 1 to 4 of the ring atoms are independently O, S, or N, and atoms. In different embodiments, an alkyl group contains the remainder of the ring atoms are carbon atoms. In one from 1 to 6 carbonatoms (C-C alkyl) or from 1 to 3 carbon embodiment, a heterocyclyl group is monocyclic and has atoms (C-C alkyl). Non-limiting examples of alkyl groups from 3 to 7 ring atoms. In another embodiment, a heterocyclyl include methyl, ethyl, n-propyl, isopropyl. n-butyl, sec-butyl, 35 group is monocyclic and has from about 4 to 7 ring atoms. In isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, another embodiment, a heterocyclyl group is bicyclic and has isohexyl and neohexyl. In one embodiment, an alkyl group is from 7 to 11 ring atoms. In still another embodiment, a het linear. In another embodiment, an alkyl group is branched. erocyclyl group is monocyclic and has 5 or 6 ring atoms. In The term “fluoroalkyl as used herein, refers to an alkyl one embodiment, a heterocyclyl group is monocyclic. In group as defined above, wherein one or more of the alkyl 40 another embodiment, a heterocyclyl group is bicyclic. A het group's hydrogenatoms has been replaced with a fluorine. In erocyclyl group can be joined to the rest of the molecule via one embodiment, a fluoroalkyl group has from 1 to 6 carbon a ring carbon or ring nitrogen atom. The nitrogen or Sulfur atoms. In another embodiment, a fluoroalkyl group has from atom of the heterocyclyl can be optionally oxidized to the 1 to 3 carbon atoms. In another embodiment, a fluoroalkyl corresponding N-oxide, S-oxide or S.S.-dioxide. Non-limit group is substituted with from 1 to 3 F atoms. Non-limiting 45 ing examples of monocyclic heterocyclyl rings include oxeta examples of fluoroalkyl groups include —CHF, —CHF, nyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thio and —CF. The term "C-C fluoroalkyl” refers to a fluoro morpholinyl, thiazolidinyl, dihydropyranyl, pyran, 1.4- alkyl group having from 1 to 3 carbon atoms. dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta The term “alkoxy” as used herein, refers to an —O-alkyl lactam, delta-lactone, and the like. group, wherein an alkyl group is as defined above. Non 50 In one embodiment, a heterocyclyl group is a 5- to 6-mem limiting examples of alkoxy groups include methoxy, ethoxy, bered monocyclic heterocyclyl. In another embodiment, a n-propoxy, isopropoxy, n-butoxy and t-butoxy. An alkoxy heterocyclyl group is a 5-membered monocyclic heterocy group is bonded via its oxygen atom to the rest of the mol clyl. In another embodiment, a heterocyclyl group is a ecule. 6-membered monocyclic heterocyclyl. The term “5- to The term “aryl, as used herein, refers to an aromatic 55 6-membered heterocyclyl refers to a monocyclic heterocy monocyclic or multicyclic ring system comprising from clyl group having from 5 to 6 ring atoms. about 6 to about 14 carbonatoms. In one embodiment, an aryl The term “spiroheterocyclic ring as used herein, refers to group contains from about 6 to 10 carbonatoms (C-Caryl). a bicyclic heterocyclic ring as defined above wherein the two In another embodiment an aryl group is phenyl. Non-limiting rings are joined through a common ring carbon atom. In one examples of aryl groups include phenyl and naphthyl. 60 embodiment, a spiroheterocyclic ring is a 8- to 11-membered The term “cycloalkyl, as used herein, refers to a saturated ring system containing one to three heteroatoms, e.g., one to ring containing the specified number of ring carbon atoms, two heteroatoms, selected from the group consisting of Nand and no heteroatom. In a like manner the term "C-C, O. Non-limiting examples of heterocyclic rings include 1.9- cycloalkyl refers to a saturated ring having from 3 to 6 ring diazaspiro5.5undecane; 2,8-diazaspiro5.5undecane; 2.8- carbon atoms. Non-limiting examples of monocyclic 65 diazaspiro4.5 decane, 1,7-diazaspiro4.4nonane; 1,7-dia cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and Zaspiro4.5 decane; 2,7-diazaspiro4.5 decane, 1-Oxa-8- cyclohexyl. aZaspiro5.5undecane: 2-Oxa-7-azaspiro4.5 decane; 1-Oxa US 9,376,418 B2 5 7-azaspiro4.5 decane; 1,4-dioxa-7-azaspiro4.5 decane; 1,4-dioxa-8-azaspiro4.5 decane, and 1,4-dioxaspiro4.5de CaC. The term “substituted” means that one or more hydrogens on the atoms of the designated are replaced with a selection from the indicated group, provided that the atoms normal Valencies under the existing circumstances are not exceeded, and that the Substitution results in a stable compound. Com binations of substituents and/or variables are permissible only if Such combinations result in stable compounds. By 10 The term “in purified form, as used herein, refers to the “stable compound' or “stable structure' is meanta compound physical state of a compound after the compound is isolated that is sufficiently robust to survive isolation to a useful from a synthetic process (e.g., from a reaction mixture), a degree of purity from a reaction mixture, and formulation into natural source, or a combination thereof. The term “in puri an efficacious therapeutic agent. 15 fied form, also refers to the physical state of a compound When any substituent or variable occurs more than one after the compound is obtained from a purification process or time in any constituent or the compound of Formula (I), its processes described herein or well-known to the skilled arti definition on each occurrence is independent of its definition san (e.g., chromatography, recrystallization and the like), in at every other occurrence, unless otherwise indicated. sufficient purity to be characterizable by standard analytical When a structural formula specifies a methylene or substi techniques described herein or well-known to the skilled tuted methylene group in parentheses which bridges two artisan. adjacent moieties, and a variable to indicate the number of It should also be noted that any carbon as well as heteroa Such methylenes, when such variable is 0, it is meant that Such tom with unsatisfied Valences in the text, schemes, examples methylene group is replaced by a bond. By way of example, and tables herein is assumed to have the sufficient number of in the group of the formula 25 hydrogen atom(s) to satisfy the Valences. One or more compounds of the invention may exist in

unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and 30 unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent mol ecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for 35 example when one or more solvent molecules are incorpo rated in the crystal lattice of the crystalline solid. “Solvate encompasses both solution-phase and isolatable solvates. when s is 0, it is meant that Y is bonded to D2 as shown in the Non-limiting examples of Suitable solvates include ethano following structural formula: lates, methanolates, and the like. “Hydrate is a solvate 40 wherein the solvent molecule is H.O. The compounds of Formula (I) may contain one or more Stereogenic centers and can thus occur as racemates, racemic (,ity mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers 45 may be present depending upon the nature of the various Substituents on the molecule. Each Such asymmetric center v-O will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastere In the structural formula for the group omers in mixtures and as pure or partially purified com 50 pounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. 55 When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion. Diastereomeric mixtures can be separated into their indi vidual diastereomers on the basis of their physical chemical 60 differences by methods well known to those skilled in the art, Such as, for example, by chromatography and/or fractional for R, it will be understood that the moiety R' may be crystallization. Enantiomers can be separated by converting substituted on the ring carbon atom which joins D2 to the the enantiomeric mixture into a diastereomeric mixture by remaining structure of group (and may be substituted on other reaction with an appropriate optically active compound (e.g., ring atoms), where the Valency of Such ring carbon atom 65 chiral auxiliary such as a chiral alcohol or Mosher's acid permits Substitution. By way of example in Some embodi chloride), separating the diastereomers and converting (e.g., ments, the group R has the formula hydrolyzing) the individual diastereomers to the correspond US 9,376,418 B2 7 8 ing pure enantiomers. Also, some of the compounds of For as lower alkylhalides (e.g., methyl, ethyl, and butyl chlorides, mula (I) may be atropisomers (e.g., Substituted biaryls) and bromides and iodides), dialkyl Sulfates (e.g., dimethyl, are considered as part of this invention. Enantiomers can also diethyl, and dibutyl Sulfates), long chain halides (e.g., decyl. be separated by use of chiral HPLC column. lauryl, and Stearyl chlorides, bromides and iodides), aralkyl It is also possible that the compounds of Formula (I) may halides (e.g., benzyl and phenethyl bromides), and others. exist in different tautomeric forms, and all such forms are The present invention further includes the compounds of embraced within the scope of the invention. Formula (I) in all their isolated forms. For example, the All Stereoisomers (for example, geometric isomers, optical above-identified compounds are intended to encompass all isomers and the like) of the present compounds (including forms of the compounds such as, any Solvates, hydrates, those of the salts and solvates of the compounds as well as the 10 salts, Solvates and esters of the prodrugs). Such as those which Stereoisomers, and tautomers thereof. may exist due to asymmetric carbons on various Substituents, As used herein, the term “composition' is intended to including enantiomeric forms (which may exist even in the encompass a product comprising the specified ingredients in absence of asymmetric carbons), rotameric forms, atropiso the specified amounts, as well as any product which results, mers, and diastereomeric forms, are contemplated within the 15 directly or indirectly, from combination of the specified Scope of this invention. Individual stereoisomers of the com ingredients in the specified amounts. pounds of the invention may, for example, be substantially In the compounds of generic Formula (I), the atoms may free of other isomers, or may be admixed, for example, as exhibit their natural isotopic abundances, or one or more of racemates or with all other, or other selected, Stereoisomers. the atoms may be artificially enriched in a particular isotope The chiral centers of the present invention can have the S or R having the same atomic number, but an atomic mass or mass configuration as defined by the IUPAC 1974 Recommenda number different from the atomic mass or mass number pre tions. dominantly found in nature. The present invention is meant to The compounds of Formula (I) can form salts which are include all Suitable isotopic variations of the compounds of also within the scope of this invention. Reference to a com generic Formula (I). For example, different isotopic forms of pound of Formula (I) herein is understood to include refer 25 hydrogen (H) include protium (H) and deuterium (H). Pro ence to salts thereof, unless otherwise indicated. The term tium is the predominant hydrogen isotope found in nature. 'salt(s)', as employed herein, denotes acidic salts formed Enriching for deuterium may afford certain therapeutic with inorganic and/or organic acids, as well as basic salts advantages, such as increasing in vivo half-life or reducing formed with inorganic and/or organic bases. In addition, dosage requirements, or may provide a compound useful as a when a compound of Formula (I) contains both a basic moi 30 standard for characterization of biological samples. Isotopi ety. Such as, but not limited to a pyridine orimidazole, and an cally-enriched compounds within generic Formula (I) can be acidic moiety, such as, but not limited to a carboxylic acid, prepared without undue experimentation by conventional Zwitterions (“inner salts') may be formed and are included techniques well known to those skilled in the art or by pro within the term "salt(s) as used herein. Such acidic and basic cesses analogous to those described in the examples herein salts used within the scope of the invention are pharmaceuti 35 using appropriate isotopically-enriched reagents and/or inter cally acceptable (i.e., non-toxic, physiologically acceptable) mediates. salts. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an Compounds of the Invention amount of acid or base. Such as an equivalent amount, in a medium such as one in which the salt precipitates or in an 40 The present invention provides a compound of Formula (I) aqueous medium followed by lyophilization. or a pharmaceutically acceptable salt thereof, wherein R. R. Exemplary acid addition salts include acetates, ascorbates, R. R. R. C., and t are as defined below. Described below benzoates, benzenesulfonates, bisulfates, borates, butyrates, are embodiments of the compound of Formula (I). The com citrates, camphorates, camphorsulfonates, fumarates, hydro pounds of the Formulas (IA) and (IB), shown below, are chlorides, hydrobromides, hydroiodides, lactates, maleates, 45 embodiments of the compound of Formula (I). methanesulfonates, naphthalenesulfonates, nitrates, oxalates, In embodiment no. 1, the invention provides a compound phosphates, propionates, salicylates. Succinates, Sulfates, tar of Formula (I), tarates, thiocyanates, toluenesulfonates (also known as tosy lates), and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically 50 (I) useful salts from basic pharmaceutical compounds are dis (RC), cussed, for example, by P. Stahl et al. Camille G. (eds.) RI Handbook of Pharmaceutical Salts. Properties, Selection R2 and Use. (2002) Zurich: Wiley-VCH. S. Berge etal, Journal a NN of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, 55 International.J. of Pharmaceutics (1986) 33 201-217: Ander son et al. The Practice of Medicinal Chemistry (1996), Aca N N ls N demic Press, New York; and in The Orange Book (Food & H Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference. 60 or a pharmaceutically acceptable salt thereof, wherein Exemplary basic salts include ammonium salts, alkali R" is selected from the group consisting of H, C-C alkyl, metal salts such as Sodium, lithium, and potassium salts, C-C fluoroalkyl, C-C alkoxy, C-C cycloalkyl, and alkaline earth metal salts such as calcium and magnesium 4-piperidinyloxy; salts, salts with organic bases (for example, organic amines) R’ is selected from the group consisting of H. methyl, Such as dicyclohexylamines, t-butyl amines, and salts with 65 methoxy, —CHF, —CF, halo, and cyano; amino acids such as arginine, lysine and the like. Basic nitro R is selected from the group consisting of H, C-C alkyl gen-containing groups may be quarternized with agents such and halo; US 9,376,418 B2 9 10 R" is selected from the group consisting of H, C-C alkyl, C.)alkyl, -(CH2)5OCH —C(O)—(C-C)alkyl, C-C fluoroalkyl, C-C cycloalkyl, halo, N(R'), —(CH), C(O)N(R'), —S(O) (C-C)alkyl, N(R)C(O)R, N(R)C(O)N(R), COH, —C(O)CHCN, and –C(O)CHOH, or wherein when two R' moieties are geminally substi 5 tuted on a common ring carbon atom of D", the two geminally substituted R' moieties together with the A. ?k ^- —C(O)—;carbon atom on which they are attached form C) S- NR“a, and 10 eachn5 is R0, is1, independently2, or 3: selected from the group con sisting of: r (i) H: N (ii) C-C alkyl; N- 15 (iii) a group of the formula -M-R, wherein O; M is a bond or —(CH) , wherein né is 1 or 2. each R" is independently selected from the group con R’ is (a) aryl or C-C cycloalkyl optionally sisting of H and C-C alkyl, substituted with 1-3 groups independently R" is C-C alkyl: 2O selected from halo, C-C alkyl, or C-C, C” is a 6-membered heteroaryl selected from the group alkoxy; or (b) a 5- to 6-membered monocyclic consisting of: heterocycle containing 1 or 2 heteroatoms inde pendently selected from the group consisting of N and O, wherein said heterocycle of R' is O 25 optionally Substituted with 1 or 2 groups inde (RC), R (Roy), 4a pendently selected from the group consisting of N1SS x N X N - s OXO and C alkyl; ? (iv) a group of the formula —(CH) R' or 2 —(CH), O (CH) R" wherein 30 R" is COR", C(O)N(R"), or O(CO) Rn; R" is C-C alkyl; and N O O R" is H or C-C alkyl: 21 35 nó is 1 or 2: (v) a group of the formula—(CH) R', 2 S N R4a. R" is OH, - O (C-C alkyl). —O—(CH)— s s O—(C-C alkyl), NH, N(H)(C-C alkyl) or —N(C-C alkyl); 40 vi) a group of the formula t is 0, 1, 2, or 3: each R" is independently selected from the group consist- O ing of H Ro

A. a group of the formula 45 vX O lsO -R, (R'), wherein R is H or C-C alkyl; and D1 50 R is C-C alkyl, C-C cycloalkyl, or phenyl: N -A-Y.F and, Yl Y. (vii) a group of the formula

wherein 55 o, 9 Y' is a bond, —CH2—, or—C(O)—: H R ls D' (i)is a 4- to 9-membered mono- or bicyclic heterocyclic vX, RP ring optionally containing one to two additional heteroatoms selected from the group consisting of 60 N, O, S, S(O), and S(O); wherein R and Rare as set forth above; (ii) a 9- to 11-membered spiroheterocyclic ring con- each R" is independently H, C-C alkyl, C-C, taining one to two additional heteroatoms selected cycloalkyl, -CHCOH, —CHC(O)NH2. from the group consisting of N and O. —S(O) C-C alkyl, or —S(O). NH2, each R" is independently selected from the group con- 65 q is 0, 1, 2, 3, 4, or 5: sisting of C-C alkyl, C-C alkoxy, halo, hydroxyl, the group Y-E is absent or present, and if present, C-C fluoroalkyl, -(CH2)COR, hydroxyl (C- - Y is a bond or C(O)–: US 9,376,418 B2 11 12 E is wherein (i) a C-C cycloalkyl ring; Y is (i) a bond, (ii) a 5- or 6-membered heterocyclic ring contain ing one Natom; or 5 (ii) (iii) an indolyl, Ra Ra wherein E is unsubstituted or substituted by one to three R' moieties, wherein said R' moieties are selected from the group consisting of C-C alkyl, 10 a Re X. s —CO.H, or wherein when two R' moieties are (iii) geminally Substituted on a common ring carbon O atom of E, the two geminally substituted R' moi eties together with the carbon atom on which they are attached form —C(O)—: 15 k B. a group of the formula (iv) Q Ra Ra

2O 'sRé s (v) Ra Ra O 25 '^ 1. Re , or (vi) O O Re Re wherein Y Y is a bond, —CH2—, —C(O)—, N(R)-, -O-, C(O) N(R') , S(O), N(R')—, or Re -N(R) S(O) ; R’ is H or C-C alkyl; R is H. C-C alkyl; hydroxyl (C-C)alkyl, or D is selected from the group consisting of: 35 —(CH2)CN: (i) a C-C cycloalkyl, wherein n3 is 2 or 3 each “is independently selected from the group con (ii) a 5- to 9-membered mono- or bicyclic heterocy sisting of H. C-C alkyl, C-C fluoroalkyl, hydroxy clyl containing 1 or 4 heteroatoms selected from (C-C)alkyl, —(CH), O—(C-C)alkyl, the group consisting of N, O, S, S(O), and S(O); 40 —(CH2)C(O)NH2. —(CH), S-(C-C)alkyl, (iii) a 5- to 6-membered heteroaryl containing 1 to 2 and —(CH), S(O) (C-C)alkyl: heteroatoms selected from the group consisting of wherein each nA is independently 1, 2 or 3: N, O, and S, wherein said heteroaryl of D2 is other each R is independently selected from the group con than indolyl; and sisting of H, hydroxyl, fluoro, C-C alkyl, C-C (iv) phenyl: 45 fluoroalkyl, hydroxy(C-C)alkyl, -(CH2), O— each R is independently H, C-C alkyl, hydroxyl, & -U)alSana'ak, Kyl, and — Sc.E.g.-(U-U)al Kyl, - COH, or - N(H)C(O)NH; each R i. independently sited from the group CO each R is independently H, C-C alkyl, or cyclopro- 50 sisting of H and C-C alkyl: ja pyl; R is H, CHF, CF, CORs, C(O)N(R'), CN, s is 0, 1, 2, or 3; and hydroxyl, N(R'). or (C-C)alkoxy, n1 is 0, 1, 2, or 3: R'' and q are as described above; n2 is 0 or 1; C. a group of the formula 55 Rand R" are as defined above: D. amino; E. halo: F. C(O)NH; G. —S(O)NH; RC RC 60 H. a group of the formula US 9,376,418 B2 13 14 wherein R" is H or F; and RC RC R’ is hydroxyl, C-C alkoxy, or NH; Y3 n2 I. —C(O) R, wherein R is C-C alkyl, or 5 R, —(CH2)CN, wherein na is as defined above; Rb Rb J. —C(O)N(H)—S(O) R, wherein R is C-C alkyl, pal —NH, N(H)(C-C alkyl), or N(C-C alkyl); wherein Y. R. R. R. n1 and n2 are as set forth in embodi K. a group of the N(H)C(O)-CH C(O)OR or 10 ment no. 1. - N(H)S(O), CH, C(O)OR8; and In embodiment no. 6, the invention provides a compound L. - N(H)S(O)—(C-C alkyl); of Formula (I), wherein or two R' moieties when substituted on adjacent carbon R" is selected from the group consisting of C-C fluoro atoms of Cy optionally form a 5- or 6-membered ring alkyl: Selected from the group consisting of pyrroline, imida 15 R is H: Zolidone, or dihydrooxazine, wherein said 5- or 6-mem R is H: bered ring is unsubstituted or substituted by C-C alkyl. R" is selected from the group consisting of C-C alkyland In embodiment no. 2, the invention provides a compound N(H)C(O)R': of Formula (I) wherein In embodiment no. 2, the invention R" is C alkyl: provides a compound of Formula (I) wherein C is a 6-mem C is bered heteroaryl selected from the group consisting of: (RC) (RC), (RC), d (RC), 25 1SA x's s 8 r r:2 21 2 Na2 30 t is 1: R" is a group of the formula and the remaining variables are as described in embodiment no. 1. In embodiment no. 3, the invention provides a compound 35 (R'), of Formula (I), whereint is 1; and R is a group of the formula D1 40 A wherein Y1 is a bond; 45 D' is a 4- to 8-membered mono- or bicyclic heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of N and S. wherein Y', D', R', q, Y, and E are as set forth in embodi each R" is independently selected from the group con ment no. 1. sisting of C-C alkyl, hydroxyl, -COH, In embodiment no. 4, the invention provides a compound 50 -CHCOR, C(O)N(H)–(CH-COH), or of Formula (I), whereint is 1 and R is a group of the formula wherein when two R' moieties are geminally substi tuted on a common ring carbon atom of D", the two geminally substituted R' moieties together with the (R'), carbon atom on which they are attached form 55 —C(O)—; R is as set forth in embodiment no. 1; and q is 1. In embodiment no. 7, the invention provides a compound of Formula (I), wherein 60 R" is selected from the group consisting of C-C alkyl, C-C fluoroalkyl, C-C alkoxy, and cyclopropyl: R’ is Horhalo: R is H: wherein Y, D, R', R. R', s, q, and E are as set forth in R" is selected from the group consisting of H. C-C alkyl, embodiment no. 1. 65 and halo; In embodiment no. 5, the invention provides a compound C” is a 6-membered heteroaryl selected from the group of Formula (I), whereint is 1 and R is a group of the formula consisting of: US 9,376,418 B2 15 16 t is 1: (R), and (RC), R" is a group of the formula s h Nn 21 2

t is 1: 10 R” is a group of the formula wherein

(R'), 15 Y is a bond,

Ra Ra O w Re , or Re

wherein R is H. C-C alkyl, or —(CH2)CN: 25 wherein n3 is 2 or 3: Y is a bond or N(H)–: each R" is independently selected from the group con s is 0, 1 or 2: sisting of H. C-C alkyl, hydroxy(C-C)alkyl, R is H. methyl, hydroxyl, or -COH: -(CH2), O—(C-C)alkyl, R is Hor methyl: -(CH2)C(O)NH2. —(CH2)S (C-C)alkyl, 30 and -(CH), S(O) (C-C)alkyl; wherein each D is selected from the group consisting of: n4 is independently 1, 2, or 3: (i) cyclohexyl: each R" is independently selected from the group con (ii) a 5- to 6-membered heterocyclyl containing one to sisting of H, hydroxyl, C-C alkyl, fluoro, C-C, two Natoms; fluoralkyl, hydroxy(C-C)alkyl, 35 —(CH), O (C-C)alkyl, -(CH),C(O)NH, (iii) a 5-membered heteroaryl containing two to three -(CH2), S-(C-C)alkyl, and -(CH2), S(O) Natoms; and —(C-C)alkyl; (iv) phenyl: each R is independently selected from the group con each R" is independently selected from the group con sisting of H and C-C alkyl; sisting of C-C alkyl, hydroxyl, -COR8, C(O) 40 Ris-CO.R., hydroxyl, or -C(O)N(R'); NH, C(O)CHCN, and –C(O)CH-OH: R is as set forth in embodiment no. 1; R is as set forth in embodiment no. 1; and wherein each R" is independently H, C-C, alkyl, or —CH-COH: q is 0, 1, 2, 3, or 4. n1 is 0, 1 or 2; and In embodiment no. 8, the invention provides a compound 45 n2 is 0 or 1. of Formula (I), wherein In embodiment no. 9, the invention provides a compound R" is selected from the group consisting of C-C fluoro having the Formula (IA), alkyl and cyclopropyl; R is Horhalo; 50 R is H; O st) r (IA) R" is selected from the group consisting of H, C-C alkyl, 2 and N(H)C(O)R; Y-c', <&x R" is C-C, alkyl: R8O C” is a 6-membered heteroaryl selected from the group 55 I 2 consisting of: 21 NN

(RC), ' , and (R') : 60 N N ls N R4 N1)^ h's r H 2 21 NS4 wherein R" is selected from the group consisting of C-C, alkyl, 65 C-C fluoroalkyl, and C-C cycloalkyl: R" is selected from the group consisting of H, C-C alkyl and C-C fluoroalkyl: US 9,376,418 B2 17 18 one of X and X is N and the other is C; has the formula r is 1, 2, or 3; and R is as set forth in embodiment no. 1. In embodiment no. 10, the invention provides a compound 5 having the Formula (IA), R8O) (>N wherein the group

10

15 and the remaining variables areas set forth in embodiment no. 10. In embodiment no. 12, the invention provides a compound has the formula having the Formula (IB),

(IB)

25

30

35 wherein R" is selected from the group consisting of C-C alkyl, C-C fluoroalkyl, and C-C cycloalkyl, 40 R" is selected from the group consisting of H, C-C alkyl and C-C fluoroalkyl, one of X" and X is N and the other is C; R" is selected from the group consisting of methyl, -CFs, R is Hor hydroxyl: and cyclopropyl; 45 R’ is H or C-C alkyl: R is selected from the group consisting of H. methyl, and s is 0, 1, 2, or 3: —CF; and R" is C-C alkyl or hydroxyl: r is 1 or 2. 50 q1 is 0, 1, 2, or 3: In embodiment no. 11, the invention provides a compound u is 1 or 2; and having the Formula (IA), wherein the group R is as set forth in embodiment no. 1. In embodiment no. 13, the invention provides a compound 55 having the Formula (IB), wherein. R" is selected from the group consisting of methyl, -CF, ul and cyclopropyl; Ro1X):N ) R" is selected from the group consisting of H, methyl, and —CF; and 60 R is Hor hydroxyl: r R is H or methyl; 21 s is 0 or 1; and R" is methyl or hydroxyl; and 65 X' and X’ are as set forth in embodiment no. 12; R is as set forth in embodiment no. 1.

US 9,376,418 B2 25 26 N-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) 3-(5-3-(4-cyclopropylpyrimidin-2-yl)amino-5- amino)phenyl)pyridin-2-yl)-D-histidine methylphenylpyridin-3-yl)propanoic acid; and 4-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) 4-((5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) amino)phenyl)pyridin-2-yl)aminopyrrolidin-2-one; amino)phenyl)pyridin-2-yl)aminomethyl)cyclohexan 3-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) ecarboxylic acid. amino)phenyl)pyridin-2-yl)aminopyrrolidin-2-one; The invention also provides a compound of Formula (I) or 4-hydroxy-4-5-(3-methyl-5-4-(trifluoromethyl)pyrimi a pharmaceutically acceptable salt thereof in purified form. din-2-yl)amino)phenyl)pyridin-3-yl)-1-car boxamide: Uses of the Compounds 10 4-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) Compounds of Formula (I) or its pharmaceutically accept amino)phenyl)pyridin-3-yl)piperazin-2-one; able salts and pharmaceutical compositions containing Such N-(3-6-(3-oxopiperazin-1-yl)pyridin-3-yl)-5-[4-(trifluo compounds can be used to treat or prevent a variety of con romethyl)pyrimidin-2-yl)amino)phenyl)acetamide; ditions or diseases mediated by Spleen tyrosine kinase (Syk). N,N-dimethyl-N-2-5-(3-methyl-5-4-(trifluoromethyl)py 15 Such conditions and diseases include, but are not limited to: rimidin-2-yl)amino)phenyl)pyridin-2-yl)glycinamide: (1) arthritis, including rheumatoid arthritis,juvenile arthritis, 3-(4-3-(4-cyclopropylpyrimidin-2-yl)amino-5- psoriatic arthritis and osteoarthritis; (2) asthma and other methylphenylpyridin-2-yl)propanoic acid: obstructive airways diseases, including chronic asthma, late trans-4-(5-3-(5-chloro-4-methylpyrimidin-2-yl)amino asthma, severe asthma, asthma exacerbations, airway hyper 5-methylphenylpyridin-2-yl)aminocyclohexanecar responsiveness, bronchitis, bronchial asthma, allergic boxylic acid; asthma, intrinsic asthma, extrinsic asthma, dust asthma, adult N-methyl-N-5-(3-methyl-5-4-(trifluoromethyl)pyrimi respiratory distress syndrome, recurrent airway obstruction, din-2-yl)amino)phenyl)pyridin-2-yl)-L-alanine; and chronic obstruction pulmonary disease including emphy trans-4-(5-3-(5-fluoro-4-methoxypyrimidin-2-yl)amino sema; (3) autoimmune diseases or disorders, including those 5-methylphenylpyridin-2-yl)aminocyclohexanecar 25 designated as single organ or single cell-type autoimmune boxylic acid; disorders, for example Hashimoto's thyroiditis, autoimmune 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) hemolytic anemia, autoimmune atrophic gastritis of perni amino)phenyl)pyridin-2-yl)piperidine-3-carboxylic acid; cious anemia, autoimmune encephalomyelitis, autoimmune N-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) orchitis, Goodpasture's disease, autoimmune thrombocy amino)phenyl)pyridin-2-yl)-D-leucine; 30 topenia including idiopathic thrombopenic purpura, sympa (2S)-4-(methylsulfonyl)-2-5-(3-methyl-5-4-(trifluorom thetic ophthalmia, myasthenia gravis, Graves disease, pri ethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl) mary biliary cirrhosis, chronic aggressive hepatitis, ulcerative aminobutanoic acid; colitis and membranous glomerulopathy, those designated as N-(2-cyanoethyl)-N-5-(3-methyl-5-4-(trifluoromethyl) involving systemic autoimmune disorder, for example sys pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)glycine; 35 temic lupus erythematosis, immune thrombocytopenic pur 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) pura, rheumatoid arthritis, Sjogren's syndrome, Reiter's Syn amino)phenyl)pyridin-2-yl)-L-prolylglycine; drome, polymyositis-dermatomyositis, systemic sclerosis, 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) polyarteritis nodosa, multiple Sclerosis and bullous pemphig amino)phenyl)pyridin-2-yl)-L-proline; oid, and additional autoimmune diseases, which can be B-cell 2,2-difluoro-3-hydroxy-3-(5-(3-methyl-5-4-(trifluorom 40 (humoral) based or T-cell based, including Cogan's Syn ethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)pro drome, ankylosing spondylitis, Wegener's granulomatosis, panoic acid; autoimmune alopecia, Type I or juvenile onset diabetes, and 2,2-difluoro-3-5-(3-methyl-5-4-(trifluoromethyl)pyrimi thyroiditis; (4) cancers or tumors, including alimentary/gas din-2-yl)amino)phenyl)pyridin-2-yl)propanoic acid; trointestinal tract cancer, colon cancer, liver cancer, skin can 3-hydroxy-2,2-dimethyl-3-5-(3-methyl-5-4-(trifluorom 45 cer including mast cell tumor and squamous cell carcinoma, ethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)pro breast and mammary cancer, ovarian cancer, prostate cancer, panoic acid; lymphoma and leukemia (including but not limited to acute 3-hydroxy-3-5-(3-methyl-5-4-(trifluoromethyl)pyrimi myelogenous leukemia, chronic myelogenous leukemia, din-2-yl)amino)phenyl)pyridin-3-ylpyrrolidine-1-car mantle cell lymphoma, NHL B cell lymphomas (e.g., precur boxamide: 50 Sor B-ALL, marginal Zone B cell lymphoma, chronic lym {1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) phocytic leukemia, diffuse large B cell lymphoma, Burkitt amino)phenyl)pyridin-2-yl)piperidin-2-yl)acetic acid: lymphoma, mediastinal large B-cell lymphoma), Hodgkin 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) lymphoma, NK and T cell lymphomas; TEL-Syk and ITK amino)phenyl)pyridin-2-yl)azetidine-3-carboxylic acid; Syk fusion driven tumors) myelomas including multiple (3 S)-3-hydroxy-1-5-(3-methyl-5-4-(trifluoromethyl)py 55 myeloma, myeloproliferative disorders kidney cancer, lung rimidin-2-yl)amino)phenyl)pyridin-2-yl)-L-proline; cancer, muscle cancer, bone cancer, bladder cancer, brain 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) cancer, melanoma including oral and metastatic melanoma, amino)phenyl)pyridin-2-yl)piperidine-4-carboxylic acid; Kaposi's sarcoma, proliferative diabetic retinopathy, and 3-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) angiogenic-associated disorders including solid tumors, and amino)phenyl)pyridin-2-yl)-1,3-thiazolidine-4-carboxy 60 pancreatic cancer; (5) diabetes, including Type I diabetes and lic acid; complications from diabetes; (6) eye diseases, disorders or N-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) conditions including autoimmune diseases of the eye, kera amino)phenyl)pyridin-2-yl)glycylglycine; toconjunctivitis, Vernal conjunctivitis, uveitis including uvei {4-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) tis associated with Behcet’s disease and lens-induced uveitis, amino)phenyl)pyridin-2-yl)piperazin-1-yl)acetic acid; 65 keratitis, herpetic keratitis, conical keratitis, corneal epithe N-5-(3-5-bromo-4-(trifluoromethyl)pyrimidin-2-yl) lial dystrophy, keratoleukoma, ocular premphigus, Mooren’s amino-5-methylphenyl)pyridin-2-yl)-2-methylalanine: ulcer, Scleritis, Grave's ophthalmopathy, Vogt-Koyanagi US 9,376,418 B2 27 28 Harada syndrome, keratoconjunctivitis sicca (dry eye), mediated by Syk activity, which comprises administering to phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalm said patient an effective amount of a compound of Formula (I) opathy, sympathetic ophthalmitis, allergic conjunctivitis, and or a pharmaceutically acceptable salt, Solvate, or a physi ocular neovascularization; (7) intestinal inflammations, aller ologically functional derivative thereof. In a further embodi gies or conditions including Crohn's disease and/or ulcerative ment, the present invention provides for the use of a com colitis, inflammatory bowel disease, coeliac diseases, procti pound of Formula (I), or a pharmaceutically acceptable salt or tis, eosinophilic gastroenteritis, and mastocytosis; (8) neuro solvate thereof, or a physiologically functional derivative degenerative diseases including motor neuron disease, Alzhe thereof, in the preparation of a medicament for the treatment imer's disease, Parkinson's disease, amyotrophic lateral of a disorder mediated by Syk activity. Sclerosis, Huntington's disease, cerebral ischemia, or neuro 10 degenerative disease caused by traumatic injury, Strike, In a further embodiment said disorder mediated by Syk glutamate neurotoxicity or hypoxia; ischemic/reperfusion activity is asthma. In a further embodiment said disorder is injury in stroke, myocardial ischemica, renal ischemia, heart rheumatoid arthritis. In yet another embodiment, said disor attacks, cardiac hypertrophy, atherosclerosis and arterioscle der is cancer. In a further embodiment said disorder is ocular rosis, organ hypoxia; (9) platelet aggregation and diseases 15 conjunctivitis. associated with or caused by platelet activation, Such as arte Yet another aspect of the present invention provides a riosclerosis, thrombosis, intimal hyperplasia and restenosis method for treating diseases caused by or associated with Fc following vascular injury; (10) conditions associated with receptor signaling cascades, including FceRI and/or FcgRI cardiovascular diseases, including restenosis, acute coronary mediated degranulation as a therapeutic approach towards the syndrome, myocardial infarction, unstable , refractory treatment or prevention of diseases characterized by, caused angina, occlusive coronary thrombus occurring post-throm by and/or associated with the release or synthesis of chemical bolytic therapy or post-coronary angioplasty, a thromboti mediators of such Fc receptor signaling cascades or degranu cally mediated cerebrovascular syndrome, embolic stroke, lation. In addition, Syk is known to play a critical role in thrombotic stroke, transient ischemic attacks, venous throm immunotyrosine-based activation motif (ITAM) signaling, B bosis, deep venous thrombosis, pulmonary embolus, coagul 25 cell receptor signaling, T cell receptor signaling and is an lopathy, disseminated intravascular coagulation, thrombotic essential component of integrin beta (1), beta (2), and beta (3) thrombocytopenic purpura, thromboangiitis obliterans, signaling in neutrophils. Thus, compounds of the present thrombotic disease associated with heparin-induced thromb invention can be used to regulate Fc receptor, ITAM, B cell ocytopenia, thrombotic complications associated with extra receptor and integrin signaling cascades, as well as the cellu corporeal circulation, thrombotic complications associated 30 lar responses elicited through these signaling cascades. Non with instrumentation Such as cardiac or other intravascular limiting examples of cellular responses that may be regulated catheterization, intra-aortic balloon pump, coronary stent or or inhibited include respiratory burst, cellular adhesion, cel cardiac valve, conditions requiring the fitting of prosthetic lular degranulation, cell spreading, cell migration, phagocy devices, and the like; (11) skin diseases, conditions or disor tosis, calcium ion flux, platelet aggregation and cell matura ders including atopic dermatitis, eczema, psoriasis, Sclero 35 tion. derma, pruritus and other pruritic conditions; (12) allergic reactions including anaphylaxis, allergic rhinitis, allergic der Compositions and Administration matitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, drugs, or pollen: (13) While it is possible that, for use in therapy, a compound of transplant rejection, including pancreas islet transplant rejec 40 Formula (I), as well as pharmaceutically acceptable salts tion, bone marrow transplant rejection, graft-Versus-host dis thereof, may be administered as the raw chemical, it is pos ease, organ and cell transplant rejection Such as bone marrow, sible to present the active ingredient as a pharmaceutical cartilage, cornea, heart, intervertebral disc, islet, kidney, composition. Accordingly, the invention further provides a limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, pharmaceutical composition, which comprises a compound Small intestine, or trachea, and Xeno transplantation; (14) low 45 of Formula (I) and pharmaceutically acceptable salts thereof, grade Scarring including Scleroderma, increased fibrosis, cys and a pharmaceutically acceptable carrier. The compounds of tic fibrosis, keloids, post-Surgical Scars, pulmonary fibrosis, the Formula (I) and pharmaceutically acceptable salts vascular spasms, migraine, reperfusion injury, and post-myo thereof, are as described above. The carriers must be accept cardial infarction. able in the sense of being compatible with the other ingredi The invention thus provides compounds of Formula (I) and 50 ents of the formulation and not deleterious to the recipient pharmaceutically acceptable salts thereof for use in therapy, thereof. In accordance with another aspect of the invention and particularly in the treatment of diseases and conditions there is also provided a process for the preparation of a phar mediated by inappropriate Syk activity. The inappropriate maceutical composition including admixing a compound of Syk activity referred to herein is any Sykactivity that deviates the Formula (I), or a pharmaceutically acceptable salt thereof, from the normal Syk activity expected in a particular patient. 55 with one or more pharmaceutically acceptable carriers. Inappropriate Syk activity may take the form of, for instance, Pharmaceutical compositions of the present invention may an abnormal increase inactivity, oranaberration in the timing be presented in unit dose forms containing a predetermined and or control of Syk activity. Such inappropriate activity amount of active ingredient per unit dose. Such a unit may may result then, for example, from overexpression or muta contain, for example, 5ug to 1 Jug, preferably 1 mg to 700 mg. tion of the protein kinase leading to inappropriate or uncon 60 more preferably 5 mg to 100 mg of a compound of the For trolled activation. mula (I), depending on the condition being treated, the route In a further embodiment, the present invention is directed of administration and the age, weight and condition of the to methods of regulating, modulating, or inhibiting Syk for patient. Such unit doses may therefore be administered more the prevention and/or treatment of disorders related to than once a day. Preferred unit dosage compositions are those unregulated Syk activity. 65 containing a daily dose or Sub-dose (for administration more In a further embodiment, the present invention provides a than once a day), as herein above recited, or an appropriate method of treatment of a patient suffering from a disorder fraction thereof, of an active ingredient. Furthermore, such US 9,376,418 B2 29 30 pharmaceutical compositions may be prepared by any of the a lubricant and disintegrant and pressing into tablets. A pow methods well known in the pharmacy art. der mixture is prepared by mixing the compound, Suitably Pharmaceutical compositions of the present invention may comminuted, with a diluent or base as described above, and be adapted for administration by any appropriate route, for optionally, with a binder Such as carboxymethylcellulose, an example by the oral (including buccal or Sublingual), rectal, aliginate, gelatin, or polyvinyl pyrrolidone, a solution retar topical, inhaled, nasal, ocular, or parenteral (including intra dant Such as paraffin, a resorption accelerator Such as a qua venous and intramuscular) route. Such compositions may be ternary salt and/or an absorption agent such as bentonite, prepared by any method known in the art of pharmacy, for kaolin or dicalcium phosphate. The powder mixture can be example by bringing into association the active ingredient granulated by wetting with a binder Such as syrup, starch with the carrier(s) or excipient(s). Dosage forms include tab 10 paste, acadia mucilage or Solutions of cellulosic or polymeric lets, troches, dispersions, Suspensions, solutions, capsules, materials and forcing through a screen. As an alternative to creams, ointments, aerosols, and the like. granulating, the powder mixture can be run through the In a further embodiment, the present invention provides a machine and the result is imperfectly formed slugs broken pharmaceutical composition adapted for administration by into granules. The granules can be lubricated to prevent Stick the oral route, for treating, for example, rheumatoid arthritis. 15 ing to the tablet forming dies by means of the addition of In a further embodiment, the present invention provides a Stearic acid, a Stearate salt, talc or mineral oil. The lubricated pharmaceutical composition adapted for administration by mixture is then compressed into tablets. The compounds of the nasal route, for treating, for example, allergic rhinitis. the present invention can also be combined with a free flow In a further embodiment, the present invention provides a ing inert carrier and compressed into tablets directly without pharmaceutical composition adapted for administration by going through the granulating or slugging steps. A clear or the inhaled route, for treating, for example, asthma, COPD or opaque protective coating consisting of a sealing coat of ARDS. shellac, a coating of Sugar or polymeric material and a polish In a further embodiment, the present invention provides a coating of wax can be provided. Dyestuffs can be added to pharmaceutical composition adapted for administration by these coatings to distinguish different unit dosages. the ocular route, for treating, diseases of the eye, for example, 25 Oral fluids such as Solution, syrups and elixirs can be conjunctivitis. prepared in dosage unit form so that a given quantity contains In a further embodiment, the present invention provides a a predetermined amount of the compound. Syrups can be pharmaceutical composition adapted for administration by prepared by dissolving the compound in a Suitably flavored the parenteral (including intravenous) route, for treating, for aqueous Solution, while elixirs are prepared through the use example, cancer. 30 of a non-toxic alcoholic vehicle. Suspensions can be formu Pharmaceutical compositions of the present invention lated by dispersing the compound in a non-toxic vehicle. which are adapted for oral administration may be presented as Solubilizers and emulsifiers such as ethoxylated isostearyl discrete units such as capsules or tablets; powders or gran alcohols and polyoxyethylene Sorbitol ethers, preservatives, ules; Solutions or Suspensions in aqueous or non-aqueous flavor additive Such as peppermint oil or natural Sweeteners or liquids; edible foams or whips; or oil-in-water liquid emul 35 saccharin or other artificial Sweeteners, and the like can also sions or water-in-oil liquid emulsions. be added. For instance, for oral administration in the form of a tablet Where appropriate, dosage unit compositions for oral or capsule, the active drug component can be combined with administration can be microencapsulated. The formulation an oral, non-toxic pharmaceutically acceptable inert carrier can also be prepared to prolong or Sustain the release, for Such as ethanol, glycerol, water and the like. Powders are 40 example, by coating or embedding particulate material in prepared by comminuting the compound to a suitable fine polymers, wax or the like. size and mixing with a similarly comminuted pharmaceutical The compounds of Formula (I) and pharmaceutically carrier Such as an edible carbohydrate, as, for example, starch acceptable salts thereof can also be administered in the form or mannitol. Flavoring, preservative, dispersing and coloring of liposome delivery systems, such as Small unilamellar agent can also be present. 45 vesicles, large unilamellar vesicles and multilamellar Capsules are made by preparing a powder mixture, as vesicles. Liposomes can be formed from a variety of phos described above, and filling formed gelatin sheaths. Glidants pholipids, such as cholesterol, Stearylamine orphosphatidyl and lubricants such as colloidal silica, talc, magnesium Stear cholines. ate, calcium Stearate or solid polyethylene glycol can be The compounds of Formula (I) and pharmaceutically added to the powder mixture before the filling operation. A 50 acceptable salts thereof may also be delivered by the use of disintegrating or solubilizing agent Such as agar-agar, cal monoclonal antibodies as individual carriers to which the cium carbonate or sodium carbonate can also be added to compound molecules are coupled. The compounds may also improve the availability of the medicament when the capsule be coupled with Soluble polymers as targetable drug carriers. is ingested. Such polymers can include polyvinylpyrrolidone, pyran Moreover, when desired or necessary, suitable binders, 55 copolymer, polyhydroxypropylmethacrylamide-phenol, lubricants, disintegrating agents and coloring agents can also polyhydroxyethylaspartamidephenol, or polyethyleneoxide be incorporated into the mixture. Suitable binders include polylysine substituted with palmitoyl residues. Furthermore, starch, gelatin, natural Sugars such as glucose or beta-lactose, the compounds may be coupled to a class of biodegradable corn Sweeteners, natural and synthetic gums such as acacia, polymers useful in achieving controlled release of a drug, for tragacanth or sodium alginate, carboxymethylcellulose, 60 example, polylactic acid, polyepsilon caprolactone, polyhy polyethylene glycol, waxes and the like. Lubricants used in droxybutyric acid, polyorthoesters, polyacetals, polydihy these dosage forms include Sodium oleate, sodium Stearate, dropyrians, polycyanoacrylates and cross-linked or amphip magnesium Stearate, Sodium benzoate, Sodium acetate, athic block copolymers of hydrogels. sodium chloride and the like. Disintegrators include, without Dosage forms for inhaled administration may conveniently limitation, starch, methyl cellulose, agar, bentonite, Xanthan 65 be formulated as aerosols or dry powders. gum and the like. Tablets are formulated, for example, by For compositions suitable and/or adapted for inhaled preparing a powder mixture, granulating or slugging, adding administration, it is preferred that the compound or salt of US 9,376,418 B2 31 32 Formula (I) is in a particle-size-reduced form, and more pref Optionally, in particular for dry powder inhalable compo erably the size-reduced form is obtained or obtainable by sitions, a pharmaceutical composition for inhaled administra micronisation. The preferable particle size of the size-re tion can be incorporated into a plurality of sealed dose con duced (e.g., micronised) compound or salt or Solvate is tainers (e.g., containing the dry powder composition) defined by a D50 value of about 0.5 to about 10 microns (for mounted longitudinally in a strip or ribbon inside a Suitable example as measured using laser diffraction). inhalation device. The container is rupturable or peel-open Aerosol formulations, e.g., for inhaled administration, can able on demand and the dose of e.g., the dry powder compo comprise a solution or fine Suspension of the active Substance sition can be administered by inhalation via the device such as in a pharmaceutically acceptable aqueous or non-aqueous the DISKUS(R) device (GlaxoSmithKline). Other dry powder Solvent. Aerosol formulations can be presented in single or 10 inhalers are well known to those of ordinary skill in the art, multidose quantities in sterile form in a sealed container, and many Such devices are commercially available, with rep which can take the form of a cartridge or refill for use with an resentative devices including AerolizerR) (Novartis), Air atomising device or inhaler. Alternatively the sealed con maxTM (IVAX), ClickHalerR (Innovata Biomed), Dis tainer may be a unitary dispensing device Such as a single khaler R (GlaxoSmithKline). Accuhaler (GlaxoSmithKline), dose nasal inhaler oran aerosol dispenser fitted with a meter 15 Easyhaler R. (Orion Pharma), EclipseTM (Aventis), Flow ing valve (metered dose inhaler) which is intended for dis Caps(R (Hovione), Handihaler(R) (Boehringer Ingelheim), posal once the contents of the container have been exhausted. Pulvinal(R) (Chiesi), Rotahaler(R) (GlaxoSmithKline), Skye Where the dosage form comprises an aerosol dispenser, it HalerTM or CertihalerTM (SkyePharma), Twisthaler (Schering preferably contains a suitable propellant under pressure Such Corporation), TurbuhalerR (AstraZeneca), Ultrahaler(R) as compressed air, carbon dioxide or an organic propellant (Aventis), and the like. such as a hydrofluorocarbon (HFC). Suitable HFC propel Dosage forms for ocular administration may beformulated lants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2- as Solutions or Suspensions with excipients Suitable for oph tetrafluoroethane. The aerosol dosage forms can also take the thalmic use. form of a pump-atomiser. The pressurised aerosol may con Dosage forms for nasal administration may conveniently tain a solution or a Suspension of the active compound. This 25 be formulated as aerosols, Solutions, drops, gels or dry pow may require the incorporation of additional excipients e.g., ders. co-solvents and/or Surfactants to improve the dispersion char Pharmaceutical compositions adapted for administration acteristics and homogeneity of Suspension formulations. by inhalation include fine particle dusts or mists, which may Solution formulations may also require the addition of co be generated by means of various types of metered, dose Solvents such as ethanol. Other excipient modifiers may also 30 pressurised aerosols, or insufflators. be incorporated to improve, for example, the stability and/or For pharmaceutical compositions Suitable and/or adapted taste and/or fine particle mass characteristics (amount and/or for intranasal administration, the compound of Formula (I) or profile) of the formulation. a pharmaceutically acceptable salt or Solvate thereof may be For pharmaceutical compositions Suitable and/or adapted formulated as a fluid formulation for delivery from a fluid for inhaled administration, it is preferred that the pharmaceu 35 dispenser. Such fluid dispensers may have, for example, a tical composition is a dry powder inhalable composition. dispensing nozzle or dispensing orifice through which a Such a composition can comprise a powder base such as metered dose of the fluid formulation is dispensed upon the lactose, glucose, trehalose, mannitol or starch, the compound application of a user-applied force to a pump mechanism of of Formula (I) or salt or solvate thereof (preferably in particle the fluid dispenser. Such fluid dispensers are generally pro size-reduced form, e.g., in micronised form), and optionally a 40 vided with a reservoir of multiple metered doses of the fluid performance modifier Such as L-leucine or another amino formulation, the doses being dispensable upon sequential acid, and/or metals salts of Stearic acid such as magnesium or pump actuations. The dispensing nozzle or orifice may be calcium stearate. Preferably, the dry powder inhalable com configured for insertion into the nostrils of the user for spray position comprises a dry powder blend of lactose and the dispensing of the fluid formulation into the nasal cavity. A compound of Formula (I) or salt thereof. The lactose is pref 45 fluid dispenser of the aforementioned type is described and erably lactose hydrate e.g., lactose monohydrate and/or is illustrated in WO-A-2005/044354, the entire content of preferably inhalation-grade and/or fine-grade lactose. Prefer which is hereby incorporated herein by reference. The dis ably, the particle size of the lactose is defined by 90% or more penser has a housing which houses a fluid discharge device (by weight or by volume) of the lactose particles being less having a compression pump mounted on a container for con than 1000 microns (micrometers) (e.g., 10-1000 microns e.g., 50 taining a fluid formulation. The housing has at least one 30-1000 microns) in diameter, and/or 50% or more of the finger-operable side lever which is movable inwardly with lactose particles being less than 500 microns (e.g., 10-500 respect to the housing to cam the container upwardly in the microns) in diameter. More preferably, the particle size of the housing to cause the pump to compress and pump a metered lactose is defined by 90% or more of the lactose particles dose of the formulation out of a pump stem through a nasal being less than 300 microns (e.g., 10-300 microns e.g., 55 nozzle of the housing. A particularly preferred fluid dispenser 50-300 microns) in diameter, and/or 50% or more of the is of the general type illustrated in FIGS. 30-40 of WO-A- lactose particles being less than 100 microns in diameter. 2005/044354. Optionally, the particle size of the lactose is defined by 90% The following are examples of representative pharmaceu or more of the lactose particles being less than 100-200 tical dosage forms for the compounds of this invention: microns in diameter, and/or 50% or more of the lactose par 60 ticles being less than 40-70 microns in diameter. It is prefer able that about 3 to about 30% (e.g., about 10%) (by weight or Injectable Suspension (I.M.) mg/mL by volume) of the particles are less than 50 microns or less Compound of Formula (I) 10 than 20 microns in diameter. For example, without limitation, Methylcellulose S.O a suitable inhalation-grade lactose is E9334 lactose (10% 65 Tween 8O O.S fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 J D Benzyl alcohol 9.0 Zwolle, Netherlands). US 9,376,418 B2 34 -continued formulation or co-administered as separate formulations with at least one additional therapeutic agent to treat or prevent the Benzalkonium chloride 1.O diseases and conditions described herein. For the treatment of Water for injection to a total volume of 1 mL the inflammatory diseases, rheumatoid arthritis, psoriasis, Tablet mg tablet inflammatory bowel disease, COPD, asthma and allergic rhinitis, these additional therapeutic agents include, but are Compound of Formula (I) 25 not limited to: (1) TNF-C. inhibitors such as infliximab (Remi Microcrystalline Cellulose 415 Providone 14.0 cade(R), etanercept (EnbrelR), adalimumab (HumiraR), cer Pregelatinized Starch 43.5 tolizumab pegol (CimziaR), and golimumab (SimponiR); (2) Magnesium Stearate 2.5 10 non-selective COX-1/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, 500 fenoprofen, ketoprofen and ibuprofen, fenamates such as Capsule mg capsule mefenamic acid, indomethacin, Sulindac, etodolac, azapropa Zone, pyrazolones such as phenylbutaZone, Salicylates Such Compound of Formula (I) 25 15 as aspirin); (3) COX-2 inhibitors (such as meloxicam, cele Lactose Powder 573.5 coxib, rofecoxib, Valdecoxib and etoricoxib); (4) other agents Magnesium Stearate 1.5 for treatment of rheumatoid arthritis including methotrexate, 600 leflunomide, Sulfasalazine, azathioprine, cyclosporin, tac rolimus, penicillamine, bucillamine, actarit, mizoribine, Aerosol Per canister lobenzarit, , hydroxychloroquine, d-penicil Compound of Formula (I) 24 mg lamine, aurothiomalate, auranofin or parenteral or oral gold, Lecithin, NF Liquid Concentrate 1.2 mg cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors Trichlorofluoromethane, NF 4.025 gm and CTLA-4-Igor mimetics thereof; (5) leukotriene biosyn Dichlorodifluoromethane, NF 12.15 gm thesis inhibitor. 5-lipoxygenase (5-LO) inhibitor or 5-lipoxy 25 genase activating protein (FLAP) antagonist Such as ; It will be appreciated that when the compound of the (6) LTD4 receptorantagonist Such as , present invention is administered in combination with other and ; (7) PDE4 inhibitor such as , cilo therapeutic agents normally administered by the inhaled, milast, AWD-12-281 (Elbion), and PD-168787 (Pfizer); (8) intravenous, oral or intranasal route, that the resultant phar antihistaminic H1 receptor antagonists such as cetirizine, maceutical composition may be administered by the same 30 levocetirizine, loratadine, desloratadine, fexofenadine, rOuteS. astemizole, azelastine, levocabastine, olopatidine, methapy It should be understood that in addition to the ingredients rilene and chlorpheniramine; (9) C1- and C2-adrenoceptor particularly mentioned above, the compositions may include vasoconstrictor sympathomimetic agent, such as pro other agents conventional in the art having regard to the type pylhexedrine, , , pseu of formulation in question, for example those suitable for oral 35 doephedrine, hydrochloride, administration may include flavouring agents. A therapeutically effective amount of a compound of the hydrochloride, tetrahydrozoline hydrochloride, Xylometazo present invention will depend upon a number of factors line hydrochloride, and ethylnorepinephrine hydrochloride: including, for example, the age and weight of the animal, the (10) agents such as , precise condition requiring treatment and its severity, the , , aclindinium bro nature of the formulation, and the route of administration, and 40 mide, glycopyrrolate, (R,R)-glycopyrrolate, pirenzepine, and will ultimately be at the discretion of the attendant physician telenzepine; (11) B-adrenoceptor such as metaprot or veterinarian. However, an effective amount of a compound erenol, isoproterenol, , albuterol, of Formula (I) for the treatment of diseases or conditions (particularly the fumarate salt), (particularly the associated withinappropriate Sykactivity will generally be in Xinafoate salt), , , mesylate, the range of 5 ug to 100 mg/kg body weight of recipient 45 , and , or methylxanthanines including (patient) per day and more usually in the range of 5ug to 10 and , Sodium cromoglycate; (12) mg/kg body weight per day. This amount may be given in a insulin-like growth factor type I (IGF-1) mimetic; (13) glu single dose per day or more usually in a number (such as two, cocorticosteroids, especially inhaled with three, four, five or six) of sub-doses per day such that the total reduced systemic side effects, such as prednisone, predniso daily dose is the same. An effective amount of a salt or Solvate, 50 lone, , acetonide, beclomethasone thereof, may be determined as a proportion of the effective dipropionate, , propionate, amount of the compound of Formula (I) perse. ciclesonide and furoate; (14) kinase inhibitors The compositions of the invention can further comprise such as inhibitors of the Janus Kinases (JAK 1 and/or JAK2 one or more additional therapeutic agents, as discussed in and/or JAK3 and/or TYK2) such as tofacitinib (Pfizer), bar further detail below. Accordingly, in one embodiment, the 55 icitinib (Incyte), VX-509 (Vertex), ASP-015K (Astellas), present invention provides compositions comprising: (i) a GLPG0634 (Galapagos), SB-1578 (SBIO), and AC-430 compound of Formula (I) or a pharmaceutically acceptable (Ambit Biosciences); p38 MAPK and IKK2: (15) B-cell tar salt thereof; (ii) one or more additional therapeutic agents, geting biologics such as rituximab (Rituxan R); (16) selective that are not compounds of Formula (I); and (iii) a pharma costimulation modulators such as abatacept (Orencia); (17) ceutically acceptable carrier, wherein the amounts in the 60 interleukin inhibitors, such as IL-1 inhibitor anakinra (Ki composition are together effective to treat one of the disease neret) and IL-6 inhibitor tocilizumab (Actemra). or conditions discussed above. The present invention also provides for so-called “triple combination therapy, comprising a compound of Formula Combination Therapy (I) or a pharmaceutically acceptable salt thereof together with 65 beta-adrenoreceptor agonist and an anti-inflammatory cor The compounds of Formula (I) or their pharmaceutically ticosteroid. Preferably this combination is for treatment and/ acceptable salts may be used in combination, eitherina single or prophylaxis of asthma, COPD or allergic rhinitis. The US 9,376,418 B2 35 36 beta-adrenoreceptor agonist and/or the anti-inflammatory thalidomide, angiostatin, troponin-1, angiotensin II antago corticosteroid can be as described above and/or as described nists, heparin, carboxypeptidase U inhibitors, and antibodies in WO 03/030939 A1. Representative examples of such a to VEGF, endostatin, ukrain, ranpirinase, IM862, acetyl “triple” combination are a compound of Formula (I) or a dinanaline, 5-amino-1-3,5-dichloro-4-(4-chlorobenzoyl) pharmaceutically acceptable salt thereof in combination with 5 phenyl-methyl)-1H-1,2,3-triazole-4-carboxamide, CM101, the components of Advair R (salmeterol Xinafoate and fluti squalamine, combretastatin, RPI4610, NX31838, sulfated casone propionate), Symbicort(R) (budesonide and formoterol mannopentaose phosphate, and 3-(2,4-dimethylpyrrol-5-yl) fumarate), or Dulera.R. (mometasone furoate and formoterol methylene-2-indolinone (SU5416); (9) PPAR-Y agonists, fumarate) or a pharmaceutically acceptable salt thereof (e.g., PPAR-8 agonists, thiazolidinediones (such as DRF2725, salmeterol Xinafoate and ). 10 CS-011, troglitaZone, rosiglitaZone, and pioglitaZone), For the treatment of cancer a compound of Formula (I) may fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, be combined with an one or more additional therapeutic AR-HO39242, JTT-501, MCC-555, GW2331, GW409544, agents which are anticancer agents. Examples of such agents NN2344, KRP297, NPO110, DRF4158, NN622, GI262570, can be found in Cancer Principles and Practice of Oncology PNU182716, DRF552926, 2-(5,7-dipropyl-3-trifluorom by V.T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 15 ethyl-1,2-benzisoxazol-6-yl)oxy-2-methylpropionic acid 2001), Lippincott Williams & Wilkins Publishers. A person of (disclosed in U.S. Ser. No. 09/782,856), and (2R)-7-(3-(2- ordinary skill in the art would be able to discern which com chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchro binations of agents would be useful based on the particular mane-2-carboxylic acid (disclosed in U.S. Ser. No. 60/235, characteristics of the drugs and the cancer involved. Such 708 and 60/244,697); (9) an inhibitor of inherent multidrug anticancer agents include, but are not limited to, the follow resistance including inhibitors of p-glycoprotein (P-gp). Such ing: (1) an estrogen Such as diethylstibes as LY335979, XR9576, OC144-093, R101922, VX853 and tral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, PSC833 (valspodar); (10) an inhibitor of cell proliferation toremifene, fluoxymestero, and SH646; (2) other hormonal and survival signaling such as inhibitors of EGFR (for agents including aromatase inhibitors (e.g., aminoglutethim example gefitinib and erlotinib), inhibitors of ERB-2 (for ide, tetrazole anastroZole, letrozole and exemestane), lutein 25 example trastuzumab), inhibitors of IGF1R such as MK-0646 izing hormone release hormone (LHRH) analogues, keto (dalotuzumab), inhibitors of CD20 (rituximab), inhibitors of conazole, goserelin acetate, leuprolide, megestrol acetate and cytokine receptors, inhibitors of MET, inhibitors of PI3K mifepristone; (3) an androgen receptor modulator Such as family kinase (for example LY294.002), serine/threonine finasteride and other 5C-reductase inhibitors, nilutamide, kinases (including but not limited to inhibitors of Akt such as flutamide, bicalutamide, liarozole, and abiraterone acetate; 30 described in (WO 03/086404, WO 03/086403, WO (4) a retinoid receptor modulator Such as bexarotene, tretin 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, oin, 13-cis-retinoic acid, 9-cis-retinoic acid, C.-difluorom WO 02/083140 and WO 02/083138), inhibitors of Rafkinase ethylornithine, ILX23-7553, trans-N-(4-hydroxyphenyl) (for example BAY-43-9006), inhibitors of MEK (for example retinamide, and N-4-carboxyphenyl retinamide; (5) an anti CI-1040 and PD-098059) and inhibitors of mTOR (for proliferative agent such as antisense RNA and DNA oligo 35 example Wyeth CCI-779 and Ariad AP23573); (11) a bispho nucleotides such as G3139, ODN698, RVASKRAS, sphonate such as etidronate, pamidronate, alendronate, GEM231, and INX3001, and antimetabolites such as enocit risedronate, Zoledronate, ibandronate, incadronate or cimad abine, carmofur, tegafur, pentostatin, doxifluridine, trimetr ronate, clodronate, EB-1053, minodronate, neridronate, piri exate, fludarabine, capecitabine, galocitabine, cytarabine dronate and tiludronate; (12) Y-secretase inhibitors, (13) ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, 40 agents that interfere with receptor tyrosine kinases (RTKs) emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, including inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met; nelzarabine, 2'-deoxy-2-methylidenecytidine, 2'-fluorom (14) an agent that interferes with a cell cycle checkpoint ethylene-2'-deoxycytidine, N6-4-deoxy-4-N2-2(E),4(E)- including inhibitors of ATR, ATM, the Chk1 and Chk2 tetradecadienoylglycylamino-L-glycero-B-L-manno-hep kinases and cdk and cdckinase inhibitors and are specifically topyranosyladenine, aplidine, ecteinascidin, troxacitabine, 45 exemplified by 7-hydroxystaurosporin, flavopiridol, aminopterin, 5-flurouracil, floXuridine, methotrexate, leuco CYC202 (Cyclacel) and BMS-387032; (15) BTK inhibitors Varin, hydroxyurea, thioguanine (6-TG), mercaptopurine such as PCI32765, AVL-292 and AVL-101; (16) PARP (6-MP), cytarabine, pentostatin, fludarabine phosphate, inhibitors including iniparib, olaparib, AGO 14699, ABT888 cladribine (2-CDA), asparaginase, gemcitabine, alanosine, and MK4827: (16) ERK inhibitors: (17) mTOR inhibitors Swainsonine, lometrexol, dexraZOxane, methioninase, and 50 Such as sirolimus, ridaforolimus, temsirolimus, everolimus; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) a and (18) cytotoxic/cytostatic agents. prenyl-protein transferase inhibitor including farnesyl-pro “Cytotoxic/cytostatic agents’ refer to compounds which tein transferase (FPTase), geranylgeranyl-protein transferase cause cell death or inhibit cell proliferation primarily by type I (GGPTase-I), and geranylgeranyl-protein transferase interfering directly with the cell's functioning or inhibit or type-II (GGPTase-II, also called Rab GGPTase); (7) an 55 interfere with cell mytosis, including alkylating agents, tumor HMG-CoA reductase inhibitor such as lovastatin, simvasta necrosis factors, intercalators, hypoxia activatable com tin, pravastatin, atorvastatin, fluvastatin and rosuvastatin; (8) pounds, microtubule inhibitors/microtubule-stabilizing an angiogenesis inhibitor Such as inhibitors of the tyrosine agents, inhibitors of mitotic kinesins, inhibitors of histone kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR deacetylase, inhibitors of kinases involved in mitotic progres (VEGFR2), inhibitors of epidermal-derived, fibroblast-de 60 Sion, antimetabolites; biological response modifiers; hor rived, or platelet derived growth factors, MMP (matrix met monal/anti-hormonal therapeutic agents, haematopoietic alloprotease) inhibitors, integrin blockers, interferon-C. growth factors, monoclonal antibody targeted therapeutic interleukin-12, erythropoietin (epoietin-C), granulocyte-CSF agents, topoisomerase inhibitors, proteasome inhibitors and (filgrastin), granulocyte, macrophage-CSF (sargramostim), ubiquitin ligase inhibitors. pentosan polysulfate, cyclooxygenase inhibitors, steroidal 65 Examples of cytotoxic agents include, but are not limited anti-inflammatories, carboxyamidotriazole, combretastatin to, Sertenef cachectin, chlorambucil, cyclophosphamide, A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, ifosfamide, mechlorethamine, melphalan, uracil mustard, US 9,376,418 B2 37 38 thiotepa, buSulfan, carmustine, lomustine, Streptozocin, metrexate, fludarabine, capecitabine, galocitabine, cytara tasonermin, lonidamine, carboplatin, altretamine, dacarba bine ocfosfate, fosteabine sodium hydrate, raltitrexed, palti Zine, procarbazine, prednimustine, dibromodulcitol, rani trexid, emitefur, tiazofurin, decitabine, nolatrexed, mustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, pemetrexed, nelZarabine, 2'-deoxy-2-methylidenecytidine, heptaplatin, estramustine, improSulfan tosilate, trofosfamide, 2'-fluoromethylene-2'-deoxycytidine, N6-4-deoxy-4-N2 nimustine, dibrospidium chloride, pumitepa, lobaplatin, 2,4-tetradecadienoylglycylamino-L-glycero-B-L-manno satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, heptopyranosyladenine, aplidine, ecteinascidin, troxacitab cis-aminedichloro(2-methyl-pyridine)platinum, benzylgua ine, aminopterin, 5-flurouracil, floXuridine, methotrexate, nine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu leucovarin, hydroxyurea, thioguanine (6-TG), mercaptopu (hexane-1,6-diamine)-mu-diamine-platinum(II)bisdi 10 amine(chloro)platinum (II) tetrachloride, rine (6-MP), cytarabine, pentostatin, fludarabine phosphate, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino cladribine (2-CDA), asparaginase, gemcitabine, alanosine, 10-hydroxyundecyl)-3,7-dimethylxanthine, Zorubicin, doxo Swainsonine, lometrexol, dexraZOxane, methioninase, and rubicin, daunorubicin, idarubicin, anthracenedione, bleomy 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. cin, mitomycin C, dactinomycin, plicatomycin, bisantrene, 15 Non-limiting examples of suitable additional therapeutic mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, agents used in cancer therapy that may be combined with antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hy compounds of Formula (I) include, but are not limited to, droxycarminomycin, annamycin, galarubicin, elinafide, abarelix; aldesleukin; alemtuzumab; allitretinoin, allopurinol; MEN10755, and 4-demethoxy-3-deamino-3-aziridinyl-4- altretamine; amifostine; anastroZole; arsenic trioxide; aspara methylsulphonyl-daunorubicin. ginase; azacitidine, bendamustine; bevacuzimab; bexaro An example of a hypoxia activatable compound is tira tene; bleomycin; bortezomib; buSulfan, calusterone; capecit paZamine. abine; carboplatin: carmustine, cetuximab, chlorambucil; Examples of proteasome inhibitors include but are not cisplatin: cladribine; clofarabine; cyclophosphamide; cytara limited to lactacystin and bortezomib. bine; dacarbazine; dactinomycin, actinomycin D; dalteparin; Examples of microtubule inhibitors/microtubule-stabilis 25 darbepoetinalfa, dasatinib, daunorubicin; degarelix; denileu ing agents include Vincristine, vinblastine, Vindesine, Vinzo kin diftitox; dexraZoxane; docetaxel, doxorubicin; dromo lidine, vinorelbine, vindesine sulfate, 3',4'-didehydro-4'- stanolone propionate; eculizumab; Elliott's B Solution; deoxy-8-norvincaleukoblastine, podophyllotoxins (e.g., eltrombopag; epirubicin; epoetin alfa, erlotinib; estramus etoposide (VP-16) and teniposide (VM-26)), paclitaxel, doc tine: etoposide phosphate: etoposide; everolimus; exemes etaXol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, 30 tane; filgrastim; floxuridine; fludarabine; fluorouracil; fulves cemadotin, RPR109881, BMS.184476, vinflumine, crypto trant, gefitinib, gemcitabine; gemtuzumab ozogamicin; phycin, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl goserelin acetate; histrelin acetate; hydroxyurea; ibritumo N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, mab tiuxetan, idarubicin; ifosfamide; imatinib mesylate; TDX258, the epothilones (see for example U.S. Pat. Nos. interferon alfa 2a: interferon alfa-2b: irinotecan; ixabepilone: 6,284,781 and 6,288,237) and BMS188797. 35 lapatinib; lenalidomide; letrozole; leucovorin; leuprolide Some examples oftopoisomerase inhibitors are topotecan, acetate; levamisole; lomustine; meclorethamine, nitrogen hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'- mustard; megestrol acetate; melphalan, L-PAM; mercaptopu O-exo-benzylidene-chartreusin, lurtotecan, 7-2-(N-isopro rine; mesna; methotrexate; methoXSalen, mitomycin C, mito pylamino)ethyl-(20S)camptothecin, BNP1350, BNPI1100, tane; mitoxantrone; nandrolone phenpropionate; nelarabine; BN80915, BN80942, etoposide phosphate, teniposide, sobu 40 nilotinib: Nofetumomab. ofatumumab; oprelvekin; oxalipl Zoxane, 2-dimethylamino-2'-deoxy-etoposide, GL331, atin: paclitaxel; palifermin; pamidronat: panitumumab: paZo N-2-(dimethylamino)ethyl-9-hydroxy-5,6-dimethyl-6H panib, pegademase; pegaspargase; Pegfilgrastim; pemetr pyrido4.3-bcarbazole-1-carboxamide, asulacrine, 2.3-(me exed disodium; pentostatin: pipobroman; plerixafor, thylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzoc plicamycin, mithramycin); porfimer Sodium; pralatrexate; phenanthridinium, 5-(3-aminopropylamino)-7.10 45 procarbazine, quinacrine; Rasburicase; raloxifene hydro dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo.4, chloride; Rituximab, romidepsin; romiploStim; sargra 5,1-delacridin-6-one, N-1-2-(diethylamino)ethylamino-7- mostim; SargramoStim; satraplatin; Sorafenib, Streptozocin, methoxy-9-oxo-9H-thioxanthen-4-ylmethylformamide, Sunitinib maleate; tamoxifen, temozolomide; temsirolimus; N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-2- teniposide; testolactone; thioguanine; thiotepa; topotecan; (dimethylamino)ethylamino-3-hydroxy-7H-indeno.2.1-c. 50 toremifene; to situmomab; trastuzumab; tretinoin, uracil mus quinolin-7-one, and dimeSna. tard; valrubicin; vinblastine; Vincristine; vinorelbine; Vori Examples of inhibitors of mitotic kinesins include, but are nostat; and Zoledronate. not limited to inhibitors of KSP, inhibitors of MKLP1, inhibi When administering a combination therapy to a patient in tors of CENP-E, inhibitors of MCAK, inhibitors of Kifl4, need of Such administration, the therapeutic agents in the inhibitors of Mphosph1 and inhibitors of Rab6-KIFL. 55 combination, or a pharmaceutical composition or composi Examples of “histone deacetylase inhibitors' include, but tions comprising the therapeutic agents, may be administered are not limited to, Vorinostat, trichostatin A, oXamflatin, in any order Such as, for example, sequentially, concurrently, PXD101, MG98, valproic acid and scriptaid. together, simultaneously and the like. “Inhibitors of kinases involved in mitotic progression” These combinations are of particular interest in respiratory include, but are not limited to, inhibitors of aurora kinase, 60 diseases and are conveniently adapted for inhaled or intrana inhibitors of Polo-like kinases (PLK; in particular inhibitors sal delivery. of PLK-1), inhibitors of bub-1 and inhibitors of bub-R1. An In one embodiment, the compound of Formula (I) is example of an “aurora kinase inhibitor is VX-680. administered during a time when the additional therapeutic Antiproliferative agents’ includes antisense RNA and agent(s) exert their prophylactic or therapeutic effect, or vice DNA oligonucleotides such as G3139, ODN698, RVASK 65 WSa. RAS, GEM231, and INX3001, and antimetabolites such as In another embodiment, the compound of Formula (I) and enocitabine, carmofur, tegafur, pentostatin, doxifluridine, tri the additional therapeutic agent(s) are administered in doses US 9,376,418 B2 39 40 commonly employed when Such agents are used as mono The following solvents, reagents, protecting groups, moi therapy for treating the disorder. eties, and other designations may be referred to by their In another embodiment, the compound of Formula (I) and abbreviations in parenthesis: the additional therapeutic agent(s) are administered in doses Me-methyl: Et-ethyl; Pr propyl; iPrisopropyl, lower than the doses commonly employed when Such agents 5 Bu-butyl; t-Bu-tert-butyl: Ph phenyl, and Ac-acetyl are used as monotherapy for treating the disorder. ul-microliters In one embodiment, the compound of Formula (I) and the AcOH or HOAc=acetic acid additional therapeutic agent(s) are present in the same com APCI-atmospheric-pressure chemical ionization position, which is Suitable for oral administration. aqaqueous The compound of Formula (I) and the additional therapeu 10 Bn=benzyl tic agent(s) can act additively or synergistically. A synergistic Boc or BOC-tert-butoxycarbonyl combination may allow the use of lower dosages of one or BZ-benzoyl more agents and/or less frequent administration of one or Boc=tert-butoxycarbonyl more agents of a combination therapy. A lower dosage or less Cbz-benyzloxycarbonyl frequent administration of one or more agents may lower 15 toxicity of the therapy without reducing the efficacy of the DCM-dichloromethane: therapy. DMAP-4-Dimethylaminopyridine The doses and dosage regimen of the additional therapeutic DIBAL diisobutylaluminum hydride agent(s) used in the combination therapies of the present DIEA or Hinig's Base-N,N-diisopropylethylamine invention for the treatment or prevention of a disease or dis 2O DMA=1,2-dimethylacetamide order can be determined by the attending clinician, taking into DMF-dimethylformamide consideration the approved doses and dosage regimen in the DMSO-dimethyl sulfoxide package insert; the age, sex and general health of the patient; DTT=dithiothreitol and the type and severity of the disease or condition mediated EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide by Syk. 25 EDTA ethylenediamine tetraacetic acid Another aspect of this invention is a kit comprising athera ESI-electrospray ionization peutically effective amount of the compound of Formula (I) EtOAc-ethyl acetate or a pharmaceutically acceptable salt of said compound, g grams optionally at least one additional therapeutic agent listed GST glutathione S-transferase above and a pharmaceutically acceptable carrier, vehicle or h-hour diluent. HMDS-1,1,1,3,3,3-hexamethyldisilazane HATU=N.N.N',N-tetramethyl-O-(7-azabenzotriazol-1- Methods of Preparing the Compounds of Formula (I) yl)uronium hexafluorophosphate HEX=hexanes The compounds of this invention may be made by a variety 35 of methods, including standard chemistry. Any previously HPLC-high-performance liquid chromatography defined variable will continue to have the previously defined HOBt=1-hydroxybenzotriazole meaning unless otherwise indicated. Illustrative general Syn LDA=lithium diisopropylamide thetic methods are set out below and then specific compounds LCMS-liquid chromatography mass spectrometry of the Formula (I) are prepared in the Examples. 40 min minute Compounds of general Formula (I) may be prepared by mg milligrams methods known in the art of organic synthesis as set forth in mL milliliters part by the following synthesis schemes. In all of the schemes mmol=millimoles described below, it is well understood that protecting groups Me-methyl for sensitive or reactive groups are employed where necessary 45 MeOH: methanol in accordance with general principles of chemistry. Protect MS-mass spectrometry ing groups are manipulated according to standard methods of NBS=N-bromosuccimide organic synthesis (T. W. Green and P. G. M. Wuts (1991) NMR nuclear magnetic resonance spectroscopy Protecting Groups in Organic Synthesis, John Wiley & Sons). rac These groups are removed at a convenient stage of the com 50 RT or rt-room temperature (ambient, about 25°C.) pound synthesis using methods that are readily apparent to sat=Saturated those skilled in the art. The selection of protecting groups as SFC Supercritical fluid chromatography well as the reaction conditions and order of reaction steps TBSC1-t-butyldimethylsilyl chloride shall be consistent with the preparation of compounds of TBS-t-butyldimethylsilyl Formula (I). Those skilled in the art will recognize whether a 55 Stereocenter exists in compounds of Formula (I). Accord TEA triethylamine (EtN) ingly, the present invention includes all possible stereoiso TFA=trifluoroacetic acid mers and includes not only mixtures of stereoisomers (such as TFAA=trifluoroacetic anhydride racemic compounds) but the individual stereoisomers as well. THF-tetrahydrofuran When a compound is desired as a single enantiomer, it may be 60 TLC thin layer chromatography obtained by stereospecific synthesis or by resolution of the TMS-trimethylsilyl final product or any convenient intermediate. Resolution of Tris-tris(hydroxymethyl)aminomethane the final product, an intermediate, or a starting material may General Methods be effected by any suitable method known in the art. See, for Compounds of the Formula (I) can be prepared according example, Stereochemistry of Organic Compounds by E. L. 65 to one of the general synthetic schemes procedures set forth in Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, Schemes 1-28 below, and/or by methods similar to those 1994). described in the Examples below. US 9,376,418 B2

Scheme 1 I

HNRaRa Her ON F (2) I V Sl P-R ON B -O O O R5 R4a - - N ON N1 Pd//base 2 4a 2 N R4a R ON N1 Pd/ligand/ R4a base (3) (4) R4a ON X A. Base, ketone RCy N O s N R4a He 2 N B. NHRR,, bbase 2 N (7)

Br Br (5) (6) Fe, NH, HCI

RCy R5 N RI N 2N 2 2N R1 R NN R2 21 N als ls N C N N N 1. - - HN N 1. Pd(ligand/base R4a R4a (1) (8)

Compounds (3) are prepared by SAr displacement of 1-fluoro-3-iodo-5-nitrobenzene (2) with commercially avail- Scheme 2 able amines. Miyaura coupling of (3) with bis(pinacolato) 55 diboron provides boronic esters (4). Preparation of function alized bromopyridines begins with dihalopyridine (5), either l 1 Nn via selective lithiation and addition to an electophile or SAr RI NY (RC), Nue X displacement by an amine provides bromide (6). Suzuki cou- 60 R2 2 pling of compounds (4) and (6) yields nitroarenes (7). Reduc- NN (10) tion with- iron and ammonium chloride provides anilines- (8). als Pd(ligand/base Buchwald coupling of compound (8) with substituted pyrim- 65 N N R4 idines (9) results in compounds with the general structure of (I) (1). US 9,376,418 B2 43 44 -continued N / XV(R), RI 5 R2 r Nals N R4 (11) 10

As shown in Scheme 2, the compounds (11) are prepared by Suzuki coupling of arylhalides (10) and intermediate I.

Scheme 3 O X

NN HeriPrNH NN nBuLi 21 BocO 2

Br Br Pd(ligand/base (12) (13) RI | - R2 NN O O R1 N B1 2 R2 r N Nals N R4 H (I)

O Rh NHRRh Y N EDC HOBt Rh DIEA n N a

R1 2 R R2 R2 n n N N

2 Nals N N R4 H

As shown in Scheme 3, Compound (13) is prepared by treating 5-bromo-2-methylpyridine (12) with LDA followed by BOCO. Suzuki coupling of bromide (13) and Intermedi ate I provides tricyclic compound (14) which is hydrolyzed 65 into acid (15). Amide coupling of (15) with dimethylamine affords amide (16). US 9,376,418 B2 45 46 -continued Scheme 4 l-O N OH e (RC), ) i? 5 RI N h N-4 Yo NaI, MeI H R2 -- O n N N O als RI Br 1 N / 10 N N R4 (RC), R H R2 N4 O (20) NN els2 Pd(ligand/base N N R4 H 15 (17) (R'), */ \, RI o 2O 2 R n N

Nals N R4 25 (18)

Compounds 18 are prepared by Suzuki coupling of aryl halides (17) with boronic acids or esters. 30

Scheme 5 No O / 35 N a NN CN X R2 RI \ / O O Br 40 n N R N1B (19) 2.2 Pd(ligand/base N N R4 R2 n H N (21) als 45 N N R4 H As shown in Scheme 5, compounds (20) are prepared by (I) Suzuki coupling of Intermediate I with pyridyl bromides (19) followed by the de-methylation/methylation sequence.

Scheme 6

(RC), -HX Sl N-4 (5 (RC), OS -O (10)10 RI R B Pd/ligand/base Fe R2 -- R2 n NN N 2 2 N N NO N N NO H H (23) US 9,376,418 B2 47 48 -continued N / V-(R'),X R1 R2 r Nals N NH2 H (24)

RaNCO O RbCOC / y-X (RC), /N y-X (RC), R1 RI

2 2 R NN O or R NN O

N N N N(R“a) N N N R4b H H H H (25A) (25B)

Compounds 23 are prepared by Suzuki coupling of boronic As shown in Scheme 7, compounds 27 are prepared by esters (22) and heteroaryl bromides (10) as shown in Scheme SAr reaction of 26 with known or commercially available 6 above. Iron-mediated reduction of nitroarenes (23) results " amines, wherein RandR are various amino substituents, in anilines (24). Subsequent reaction with commercially e.g., alkyl. available isocyanates or acyl chlorides provides compounds of the general structure of (25A) and (25B). 35 Scheme 8 NH2 Scheme 7 n F 40 Sl N n 2 N OS -O Rey RI B I -> R1 2 HN(R-1)(R22) 45 Ré 21 Pd/ligand/base -e- R2 base 21 NN N ls N N R4 N H N N R4 50 (I) O (26) Generalprepared Scheme as per4 and 6 us NRZIR22 NH2 C R 55 O n O RC -H N n N \, -R RI 2 RI 2 C 1 \,\ R2 60 R2 21 NN 21 NN

(27) 65 (28) US 9,376,418 B2 49 50 -continued -continued O\/ O HN1 NR O 5 ins, r RI 2 NN 10 R 2 O a NN RI

R2 S. N ls N R4 21 NN H 15 (29B) N N ls N R4 H Compounds (29A) and (29B) are prepared by Suzuki cou (29A) pling with commercially available 5-iodopyridin-2-amine 20 yields tricyclic compounds (28) followed by acylation/sulfo nylation with known or commercially available acyl or Sul fonyl chlorides.

Scheme 9 | - RC O O RI N1 R2 '4

n-BuLi n N ort-BuLi Rey s ls N R4 HO H N (w or who N s3T. 1 RI 21 nx RMe s (I) 4. O=CRR - e Rs. 1 Poliganb1gan base R2 an N Br B A. a o r (30) (31) Sa N ls N H (32)

HCI (R = Acetal) NaOH or KOH Re” = COR

r S4 Rs.3 R Rs.3 : 's4 NN n N Rs.3 R HO HO n N RI 21 NaBH4 R1 2 HO -e- R2 R2 RI 21 21 NN a NN N "Se N N N ls N R4 H N NH R4 N ls 4 (34) (33) N N R US 9,376,418 B2 51 52 Compounds (32) are prepared by selective lithiation of dihalopyridine (30) with known or commercially available Sch 11 ketones to afford alcohols (31) followed by Suzuki coupling Clele with Intermediate I. Compounds (32) (R'-acetal) are further O modified into ketones (33) by removal of acetal group and 5 subsequent reduction affords alcohol (34). Alternatively, acids (35) are prepared by the Saponification of compound HO (32) (R-COR). n 10 N NaN RI 2 SO3CH3 Scheme 10 R2 a NN NH 15 ls )n s N R4 H HO Xs (38) prepared as per R1 21 2O General Scheme 9 NE-O K R2 21 NN N ls 25 O N N R4 H (36) NH prepared as per general Scheme 9 30 HO r R1 2 35 R2 a NN

N N ls N R4 40 (39)

As shown in Scheme 11, compounds (39) are prepared by 45 azido-Schmidt reaction of compounds (38).

O Scheme 12 X- NH2 so COH2 )n HO Xs NN ss R1 2 RI 21 NHCI 2 R2 EDC, HOBt R 21 NN a NN 60 N N N N R4 N N R4 H H (37) (40) prepared as per 65 General Scheme 2 Compounds (37) are prepared by treating amines (36) with potassium cyanate. US 9,376,418 B2 53 54 -continued CONH2

5 r RI 2 10 R2 a NN

N N ls N R4 H 15 (41)

Amides (41) are formed by treatment of acids (40) with NHC1 and amide coupling reagents, such as EDC and HOBt.

Scheme 13 CN Br O O SN 1-4"ZnX RI NY Negishi NN -- R2 21 NN 2 Br 2 (42) Br N N R 4 (43) (I) Plants

CN

R NN HO O

Sir se-1. HONHCI -e-hydrolysis O={ -N 2. CDI, DBU RI 21 R 2 (45) (48) Ne N

NN 1. N R4 H (44) / No. N-N HNY O | X-R R (46) US 9,376,418 B2 55 56 -continued

where R =

Preparation of the general core (44) in Scheme 13 begins -continued with 2,5-dibromopyridine (42), which is carried forward in a B r selective Negishi coupling reaction to provide compound 25 n (43). Suzuki coupling of bromide 43 with Intermediate I N yields compound (44). Nitrile (44) is then a key intermediate 21 HNRh1R2 for the formation of compounds with the general structure of R2 base 30 (45)-(48), which all contain the same basic core (R=N-3-(6- 21 NN ethylpyridin-3-yl)-5-methylphenyl)-4-(trifluoromethyl)pyri- N ls midin-2-amine). H 35 (50)

40

45

Scheme 14 N 50 Rh2 OH

N N R4 (51) (49) Generalprepared Scheme as per 2 Compounds 51 are prepared by bromination of benzyl 65 alcohols (49) to afford bromides (50) followed by displace ment with known or commercially available amines or amides.

US 9,376,418 B2 59 60 -continued O O Rs.5 N O1 N OH HNRS3Rs4 O R1 21 NaOH RI 2 RSONH2 2 s 2 s Nals N R4 Nals N R4 H H (60) (61)

Rs.3 N N Rs4

RI 2 R2 r Nals N R4 (62)

Compounds (52), (54), (56), (58), and (60) are prepared by -continued Suzuki coupling of Intermediate I with corresponding pyridyl O NRS3Rs4 bromides. Buchwald-Hartwig amination of bromides (52) is provides amines (53). SAr reaction of bromides (56) and s (58) with known or commercially available amines gives 2 amines (57) and (59), respectively. Amines (55) are prepared RI O by reductive amination of compounds (54) with commer- 40 R2 21 cially available aldehydes. Amides (62) are formed by saponi- lsN fication of esters (60) followed by amide coupling with com- s N R4 mercially available amines. H 45 (64) O

OES-R

O NH 50 Scheme 16 S. HO O HNRS3Rs 2 N RI NN O. O. 55 Né R2 R1 2 R /N NH 21 NN R2 coupling reagent S. N ls N 21 NN 60 H (65) NullsN N R4 (63) Compounds (64) and (65) are prepared by treating acids prepared as per 65 (63) with known or commercially available amines or Sul GeneralScheme 2 fonamides in the presence of coupling reagents such as CDI and HOBt. US 9,376,418 B2 61 62 -continued Scheme 17

h 5 H O N Rh n N NH R1 21 PFC. Il-2HHC 10 R2 NN r als RI 21 N N R4 15 H R2 (66) NN prepared as per General Scheme 2 2 NHCI N N R4 H 2O C 2O (68)68 rs RI 21 - 25 R2 r als 4 N N R Compounds (68) are prepared by reduction of nitrile (66) 30 (67) to provide ammonium chloride (67) followed by urea forma tion with commercially available isocyanates.

Scheme 18

R R NC

HN X^n N On-O CN R RI B 2 Rj NN R X R2 NN R2 CN els R1 21 NN 2 N1 N N N R4 R2 als 4 n N N R (I) N O H 21 Pd(ligand/base es prepared as per 2 4 General Scheme 2 N N R (72) Br H (69) Ri Rj y (70) \

NH2 Ri O HN OH NaN, HNOH-HCI ZnCl2 S 9 NHCI K2CO3 O (s TMSCN N i R 2 21

R (71) (79) US 9,376,418 B2 63 64 NH N -continued 2 N? YN A f Rj Ri HN Ri N N2V N HN Rj NH HN OH or HO NH2 S. NH N Br n N O (s n N 2 r 21 C 2 2 R R R R (73) (74) (75) (76)

CDI DBU

O Rj Ri - N O NS N HN O Xa, O 2 21

R R (77) (78) R= R R2 nN.

asH R4

Preparation of the general core (70) in Scheme 18 begins -continued with a Strecker reaction using 5-bromopyridin-2-amine and 45 O o commercially available ketones to afford nitriles (69) fol- V Br \ / I lowed by a palladium-mediated coupling reaction of nitriles S-N N (69) with Intermediate I. The compound (70) is then used a X-R iPrMgBr key intermediate for the formation of compounds with the so Ra general structures of (71), (73), (75) and (77). In a similar (80) fashion, a key intermediate (72) (prepared as per Scheme 2) is transformed into the general structures of (74), (76), (78) and (79). 55 O O Y- RI NY Scheme 19 Ra R2 n N O o2S, S-NH. 60 N R Nals N R4 NN H O (I) X-R —not - 2 Pd/ligand/base Ra 65 US 9,376,418 B2 65 66 -continued -continued

Br O O N M Y B-B O2S N 5 M M N Ra O O H He NN HN Y Pd(ligand/base HCI (86) RI 21 10 R2 / t- 21 Br ON-O r B N Nals N R4 15 N H Pd/ligand/base (82) Ra HN Y HN Ra (87) r R1 21 HeKOCN 25 R2 NN r 21 Nals N R4 H 30 (83)

Ra HN R4 HN N Ra 35 (88) H r RI 21 40 R2 RI NN R2 SN Pd(ligand/base (88) -- -e- Nals R4 45 2 N C (84) (89) The formation of sulfimines (80) is accomplished by con densation of known ketones with 2-methylpropane-2-sulfina 50 r mide. Compound (80) is reacted with a prepared Grignard to RI 21 yield compound (81). Suzuki reaction of (81) with Interme diate I yields adduct (82). Deprotection and reaction with R2 potassium isocyanate provides ureas with the general struc 55 r ture of (84). Nals N R4 H (90) Scheme 20

Br 60 Iron-mediated reduction of nitroarenes (85) yields anilines Fe (86). Miyuara coupling with bis(pinacolato) diboron pro He NHCI duces boronic esters (87). Suzuki coupling of compound (87) and 3-bromopyridine yields compounds (88). Buchwald cou ON Y 65 pling of anilines (88) with prepared or known functionalized (85) chloropyrimidines (89) generated compounds of the general structure of (90). US 9,376,418 B2 67 68 -continued Scheme 21 O

OES-C 5 Rs.3 M SN NHRR. PA- o=i-N RS4 2 10 NN Br 2 (91) R R2 N ItO is als RI N B1 N N Y R2 (93) NN 2O

O Rs.3 Nals N R4 | / H OES- N (I) e n RS4 Pd/ligand/base 25 N 2 Displacement of 5-bromopyridine-2-sulfonyl chloride B (91) with commercially available amines provides sulfona r (92) mides (92). Suzuki coupling of compound (92) and Interme diate I provide compounds of the general structure of (93).

Scheme 22 O

Br o CHO Prsus 1N N N/ (94)

O O RI NY 21 R2 n NN N

Nals N Y R 21 H 2 / COEt (I) R NN Br / \ Pd/ligand/base o 4. N R4 N H (95) (96)

Pd/C, H2 NaOH US 9,376,418 B2 69 70 -continued

NaOH -a-

R4

Preparation of the general core (96) in Scheme 23 begins -continued with commercially available 5-bromopyridine-2-carbalde hyde (94). Homologation via Wittig reaction provides com pound (95). Suzuki coupling of compound (95) and Interme diate I provides compound (96), which is either saponified to 25 acid (97) or reduced to (98). Bis-alkylation of compound (99) and Subsequent Saponification provides compound (100).

30 Scheme 23

35

40 (I) Pd(ligand/base

45 NaOH

50

RC 55

OMe 60

Suzuki coupling of compound (101) and Intermediate I 65 provides compound (102). Mukaiyama Aldol reaction pro vides compound (103) which is subsequently saponified to provide compound (104). US 9,376,418 B2 72

Scheme 24 CHO

n N O

RI 21 OEt F B 2 r R N N Zn

Nals N R4 H (105) prepared as per General Scheme 2

F F F F HO HO COEt CO2H nN NN RI 2 NaOH RI 21 R2 R2 nN nN

Nals N R4 N als N R4 H H (106) (107) CS MeI

F F F F S O 1 Y COEt COEt S nN nN. R1 21 t-BuO RI 2 NaOH R&1s 2 RS-1s als als 4 N N R4 N N R US 9,376,418 B2 73 74 Preparation of the general core (106) in Scheme 24 begins -continued with compound (105), which was synthesized using the HOC-1\ method outlined in General Scheme 2. A Reformatsky reac N-N tion of aldehyde (105) with ethyl bromodifluoroacetate pro \ vides product (106). Compound (106) is saponified to acid 5 R10 N (107) or alternatively the adjacent hydroxyl group is elimi nated in a two-step process to yield compound (109). Saponi fication of compound (109) leads to the formation of com pounds (110) and (111). r 10 RI 2 R2 Scheme 25 CHO r O als 15 N N R4 n H VP -OMe N YM (111) RI 2 N KOBu An Ohira-Bestmann reaction of aldehydes (105) provides Ohira-Bestmann acetylenes (109). In a one-pot reaction, compounds (109) are transformed into triazoles (110). Saponification of com r pounds (110) leads to the formation of compounds (111). Nals N H 25 (105) Scheme 26 prepared as per General Scheme 2 RI HOS -OH R2 30 NN acid -e- 2 N C HN R4 (112) (113) 35

Rey RI Hos 1. OH r OH 40 R2 21 NN OH Pd(ligand/base

susN N R4 H 45 (114)

50 RI ().=/ 55 R2 21 h N-s, R4 (115) 60 Compounds (114) are prepared by SAr reaction of com mercially available or prepared pyrimidines (112) with boronic acids (113). Subsequent Suzuki coupling reaction of 65 compounds (114) with commercially available functional ized bromopyridines provides compounds of the general structure of (115). US 9,376,418 B2 75 76

Scheme 27 O RO O

ls O1. O l RP

(n) = 1, 2

(118)

(n) l X = Cl, Bir X 1SN O R” (n) = 1,s 2 (B1) Alkylation

RS

RS2)—on He Mitsunobu conditions

(116) RO O X = Cl, Br X - O - O1- (C1) Alkylation US 9,376,418 B2 77 78 -continued O RO O

s O - O - O1-

As shown in Scheme 27, compounds of structural subtype -continued (117) are prepared from the trans-cyclohexane carboxylic acid (116) by a Mitsunobu reaction with various primary and 25 secondary alcohols. Compounds of structural subtype (118) are prepared by the alkylation of the trans-cyclohexane car boxylic acid (116) by alkyl halides of formula (B1). Com pounds of structural subtype (119) are prepared by the alky 30 lation of the trans-cyclohexane carboxylic acid (116) by alkyl halides of formula (C1). 35

(120) 40 As shown in Scheme 28, compounds of structural Subtype (120) are prepared by the reaction of the trans-cyclohexane carboxylic acid (116) with trimethylsilyldiazomethane and 45 methanol. For ease of reference, various intermediates are referred in the Examples below as precursors of various moieties of Scheme 28 Compounds of the Formula (I). These moieties are illustrated in the structural formula below. 50

55

TMS-CHN He MeOHFDCM 60

65 pyrimidin-2-ylaminophenyl moiety (116) US 9,376,418 B2 79 80 The starting materials and reagents used in preparing com anesulfonic acid (97.5g, 1.02 mol) were added sequentially. pounds described are either available from commercial Sup The resulting solution was heated to reflux overnight. The pliers or were prepared by literature methods known to those resulting mixture was cooled and concentrated in vacuo. The skilled in the art. residue was diluted with 2 L of water, then adjusted to pH 7-8 These examples are being provided to further illustrate the with aqueous saturated Sodium bicarbonate Solution, fol present invention. The examples provided below are for illus lowed by extraction with EtOAc (2x2 L). The organic layers trative purposes only; the scope of the invention is not to be were combined, washed with water (2x2 L), dried over anhy considered limited in any way thereby. drous sodium sulfate and concentrated in vacuo to afford Where the compounds in the examples include the desig N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimi nations “(R) or (S) or “(R or S) for a given chiral center in 10 din-2-amine as a light yellow solid. MS ESI calc’d for the molecule Such designations mean that the compounds CHBrFN, M+H 332,334. found 332,334. "H NMR were isolated as single enantiomers and the stereochemical (400 MHz, CDC1): 8 8.68 (d. J=4.9 Hz, 1H), 7.79 (s, 1H), configurations of Such compounds were not determined. 7.33-7.23 (m, 2H), 7.10-7.06 (m, 2H), 2.36 (s.3H). Similarly, when a compound includes the designation “1R,4S or 1S.4R, this designation means that the compound has 15 Step 2: been isolated as a single diastereomer of unknown absolute To a solution of N-(3-bromo-5-methylphenyl)-4-(trifluo configuration. romethyl)pyrimidin-2-amine (250 g, 753.01 mmol) in 1,4- Where mass spectral (MS) data are presented in the dioxane (3 L) were added 4.4.5.5-tetramethyl-2-(4.4.5.5-tet examples below, analysis was performed using an Agilent ramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane Technologies 6120 quadrupole LC/MS. Resolution of enan (225 g, 885.83 mmol), KOAc (225g, 2.30 mol) and Pd(dppf) tiomers was typically performed using Supercritical fluid Cl2 (19 g, 25.23 mmol). The resulting solution was heated to chromatography utilizing a Chiral Technologies stationary reflux overnight. The solid was filtered and the filtrate was phase such as OJ-H or OJ column (stationary phase with decolorized by passing through a silica gel column. The frac particle size of 5 or 10 micron) with a mobile phase of CO 25 tions were collected and concentrated in vacuo. This resulted and a lower alcohol Such as methanol or isopropanol. in a portion of purified product and a portion of crude product. The crude product was decolorized again with active carbon EXAMPLES to provide an additional aliquot of product. The two portions Preparative Example 1 of purified product were combined to afford N-3-methyl-5- 30 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tri Preparation of Pyrimidin-2-ylaminophenyl fluoromethyl)pyrimidin-2-amine as a white solid. MS ESI Precursors Suitable for Coupling with C Precursors calc'd for C.HBFN.O. M+H 380. found 380. 1H NMR (400 MHz, CDC1) & 8.61 (d. J=5.2, 1H), 7.75 (s, 1H), Preparative Example 1.1 7.64 (s, 1H), 7.40-7.30 (m, 2H), 7.00 (d. J=5.2, 1 H), 2.39 (s. 35 3H), 1.35 (s, 12H). N-3-methyl-5-(4.4.5.5-tetramethyl-1,3,2-dioxaboro lan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2- amine Preparative Example 1.2 40 N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimi din-2-amine

45

PrepEx-1.1 PrepEx. 1.2 Br

50 l. N N H 55 To a solution of 2-chloro-4-cyclopropyl-pyrimidine (12.5 g, 81 mmol) and 3-bromo-5-methylaniline (18.1 g, 97 mmol) in 1,4-dioxane (100 mL) was added pivalic acid (9.3 mL. 81 60 mmol). The resulting mixture was heated to reflux and left stirring for 10 hours. The mixture was allowed to cool to room temperature and hexanes were added (80 mL). The slurry was filtered and the filtrate was washed with MeOH to afford a Step 1: portion of N-(3-bromo-5-methylphenyl)-4-cyclopropylpyri A solution of 3-bromo-5-methylaniline (162.5 g., 873.66 65 midin-2-amine. The mother liquors were concentrated, mmol) in 1,4-dioxane (2 L) was prepared, and 2-chloro-4- absorbed on silica gel and purified by silica gel column chro (trifluoromethyl)pyrimidine (182g,994.54 mmol) and meth matography (EtOAc/Hex) to afford additional N-(3-bromo US 9,376,418 B2 81 82 5-methylphenyl)-4-cyclopropylpyrimidin-2-amine as a Preparative Example 2 white solid. MS ESI calc’d for CHBrN, M+H 304 and 306. found 304 and 306. Preparation of C” Precursors Suitable for Coupling Preparative Example 1.3 with Pyrimidin-2-ylaminophenyl Precursors 5-Fluoro-4-methoxy-N-3-methyl-5-(4.4.5.5-tetram ethyl-1,3,2-dioxaborolan-2-yl)phenylpyrimidin-2- Preparative Example 2.1 amine 10 4-(5-Bromopyridin-2-yl)-1,4-diazepan-2-one

PrepEx. 1.3 PrepEx 2.1 Sl 15 No O NYO -O F NN als, H

A solution of 2-chloro-5-fluoro-4-methoxypyrimidine 25 (0.32 g, 1.97 mmol) and 3-methyl-5-(4.4.5.5-tetramethyl-1, 3.2-dioxaborolan-2-yl)aniline (0.40g, 1.72 mmol) in dioxane A solution of 3-bromo-6-fluoropyridine (315 mg, 1.79 (17 mL) and methanesulfonic acid (0.13 mL, 1.97 mmol) was mmol), 1,4-diazepan-2-one (200 mg, 1.75 mmol), and tri heated to 100° C. overnight. The reaction was then cooled to ethylamine (0.269 ml, 1.93 mmol) in N,N-dimethylaceta room temperature, diluted with ethyl acetate, washed with 30 water, dried over magnesium Sulfate, filtered and concen mide (3 mL) was irradiated in a microwave reactor for twenty trated in reduced pressure. The residue was purified by chro minutes at 220° C. The reaction mixture was diluted with matography on silica gel to afford 5-fluoro-4-methoxy-N-3- ethyl acetate (35 mL) and thenwashed with saturated aqueous methyl-5-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl) sodium bicarbonate (15 mL), water (3x10 mL), and brine (15 phenylpyrimidin-2-amine. MS ESI calc’d for 35 mL). The organic layer was dried over Sodium Sulfate, fil CHBFN.O. M+H" 360. found 360. H NMR (500 tered, and concentrated under reduced pressure. The residue MHz, DMSO-d) 89.51 (s, 1H), 8.27 (d. J=3.2, 1H), 8.00 (s, was purified by chromatography on silica gel (0.5-8.5% 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.01 (s.3H), 2.25 (s.3H), 1.26 methanol/dichloromethane) to afford 4-(5-bromopyridin-2- (s, 12H). yl)-1,4-diazepan-2-one. MS ESI calc’d. for CHBrNO The following intermediates were prepared using the route 40 M+H+ 270 and 272. found 270 and 272. "H NMR (500 shown in Intermediate X. MHz, DMSO-d): 8 8.14 (d. J=2.4 Hz, 1H), 7.68 (dd, J=9.1,

Prep Ex Exact Mass No. Structure Name M+H" 1.4 5-chloro-4- Calc'd 376, found methoxy-N-3- 376 /O methyl-5-(44.5.5- O N B tetramethyl-1,3,2- 1. 2 NO dioxaborolan-2- yl)phenylpyrimidin 1s N 2-amine

1.5 5-chloro-4-methyl- Calc’d 360, found N-3-methyl-5- 360 (4,4,5,5-tetramethyl O O 1,3,2-dioxaborolan N B1 2 yl)phenylpyrimidin C 2-amine r Nals US 9,376,418 B2 83 84 2.7 Hz, 1H), 7.48 (m. 1H), 6.70 (d. J=9.1 Hz, 1H), 4.11 (s, 272. "H NMR (500 MHz, CDC1) & 8.72 (s, 1H), 8.69 (d. 2H), 3.85 (s. 2H), 3.18 (m, 2H), 1.62 (m, 2H). J=2.5 Hz, 1H), 8.10-8.08 (m. 1H), 2.58 (s, 1H), 1.82 (s.3H). Preparative Example 2.2 Preparative Example 2.4 Ethyl 4-(5-bromopyridin-2-yl)oxycyclohexanecarboxylate Trans-4-(5-bromopyridin-2-yl)aminocyclohexan ecarboxylic acid

10 PrepEx 2.2 O

O 15 O N

NN PrepEx 2.4 2 OH Br

25 NaH (0.250 g. 6.25 mmol) was added to a mixture of ethyl 4-hydroxycyclohexanoate (0.916 ml, 5.68 mmol), and 5-bromo-2-fluoropyridine (0.585 mL, 5.68 mmol) in DMF (15 mL) at room temperature under an Argon atmosphere. The reaction mixture was heated to 80°C. for 2.5 hours. Upon 30 cooling, the reaction mixture was diluted with Saturated NaHCO, (50 mL), and extracted with ethyl acetate (50 mL) and diethyl ether (50 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (hexanes/ 35 ethyl Acetate) to afford ethyl 4-(5-bromopyridin-2-yl)oxy cyclohexanecarboxylate. MS ESI calc'd, for CHBrNO, M+H 328 and 330. found 328 and 330. Preparative Example 2.3 40 A mixture of trans-4-aminocyclohexanecarboxylic acid hydrochloride (2.00 g, 11.1 mmol), 5-bromo-2-fluoropyri 2-(5-Bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol dine (2.29 mL, 22.3 mmol), potassium carbonate (3.08 g. 22.3 mmol), DIEA (3.89 mL, 22.3 mmol) in NMP (50 mL) was 45 heated to 130°C. overnight. The reaction was cooled to room temperature, filtered through a pad of CELITE, and washed PrepEx 2.3 F with NMP (50 mL). The reaction mixture was concentrated F OH under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2/MeOH, 0-10%) to afford trans-4- F n N 50 (5-bromopyridin-2-yl)aminocyclohexanecarboxylic acid as a off-white solid. MS ESI calc’d for CHBrNO. 2 M+H" 299 and 301. found 299 and 301.

Br 55 Preparative Example 2.5 Tetrabutylammonium fluoride (1.0 M in THF, 33 ul, 0.033 N-(5-bromopyridin-2-yl)-2-cyanoacetamide mmol) was added to a solution of 1-(5-bromopyridin-3-yl) ethanone (65 mg, 0.33 mmol) and trimethyl(trifluoromethyl) silane (92 mg, 0.65 mmol) in THF (1.1 mL) at ambient 60 BOP (3.07 g. 6.94 mmol) and DIEA (606 ul, 3.47 mmol) temperature. After 30 minutes, the reaction mixture was were added to a mixture of 5-bromo-2-fluoropyridine (400 diluted with water and extracted with DCM, dried over mg, 2.312 mmol) and cyanoacetic acid (201 mg, 2.358 mmol) Sodium sulfate, filtered, and concentrated under reduced pres in DMF (11.6 mL). The reaction mixture was stirred at room Sure. The residue was purified by silica gel chromatography temperature overnight, diluted with ethyl acetate and washed (0-30% ethyl acetate/hexanes, linear gradient) to afford 2-(5- 65 with water (2x). The organic layer was concentrated under bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol. MS ESI reduced pressure and the residue was purified by Silica gel calc'd, for CHsBrFNOM+H" 270 and 272. found 270 and chromatography (ethyl Acetate/hexanes) to afford N-(5-bro US 9,376,418 B2 85 86 mopyridin-2-yl)-2-cyanoacetamide. MS ESI calc’d for matography to afford an ~4.1 mixture of ethyl (2E)-3-(5- CHBrNOM+H" 240 and 242. found 240. bromopyridin-3-yl)prop-2-enoate and ethyl (2Z)-3-(5- bromopyridin-3-yl)prop-2-enoate. MS ESI calc’d. for Preparative Example 2.6 CHBrNO, M+H" 256 and 258. found 256 and 258. 'H NMR data for the major (2E) isomer: "H NMR (500 MHz, Ethyl 3-(4-bromopyridin-2-yl)propanoate DMSO-d) & 8.87 (d. J=1.7 Hz, 1H), 8.70 (d. J–2.2 Hz, 1H), 8.51 (t, J=2.0 Hz, 1H), 7.64 (d. J–16.2 Hz, 1H), 6.88 (d. J=16.2 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H). PrepEx 2.6 10 Step 2: To a solution of ethyl (2E)-3-(3-bromophenyl)prop-2- enoate and ethyl (2Z)-3-(5-bromopyridin-3-yl)prop-2-enoate r (4:1 ratio of isomers, 332 mg, 1.30 mmol) in methanol (10 mL) and water (2.5 mL) was added copper (I) chloride (257 mg, 2.59 mmol) and sodium borohydride (98 mg, 2.59 15 mmol). After 15 minutes, the reaction was diluted with ethyl acetate and filtered through CELITE. The filtrate was washed with water, dried over magnesium Sulfate, filtered and con N1 N centrated in vacuo. The residue was purified by silica gel chromatography to afford ethyl 3-(5-bromopyridin-3-yl)pro 21 panoate. MS ESI calc'd, for CHBrNO, M+H" 258 and Br 260. found 258 and 260. H NMR (500 MHz, DMSO-d) & 8.52 (d. J–2.2 Hz, 1H), 8.44 (d. J=1.8 Hz, 1H), 7.96 (t, J–2.0 Nitrogen was bubbled through a solution of 2,4-dibro HZ, 1H), 4.02 (q, J=7.1 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.67 mopyridine (0.25 g, 1.06 mmol) in THF (2 ml) for ~10 min (t, J–7.5 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H). utes. Tetrakis(triphenylphosphine)palladium(0) (0.122 g, 25 Step 3: 0.106 mmol) was added and the flask sealed with a septa. A mixture of ethyl 3-(5-bromopyridin-3-yl)propanoate Bromo (3-ethoxy-3-oxopropyl)Zinc (3.17 ml, 1.58 mmol) (1.64 g. 6.35 mmol), bis(pinacolato)diboron (1.78 g. 6.99 was added slowly via Syringe and the reaction mixture was mmol), Pd(dba) (291 mg, 0.318 mmol), tricyclohexylphos heated at 85°C. for 16 hours. Upon cooling, the reaction phine (178 mg, 0.635 mmol) and potassium acetate (998 mg, mixture was partitioned between DCM and brine. The 10.2 mmol) in degassed dioxane (64 mL) was evacuated/ organic layer was dried (Na2SO4), concentrated under 30 purged 5 times with argon. The reaction was heated to 95°C. reduced pressure and the residue was purified by silica gel for 14 hours. The reaction was then allowed to cool to room chromatography (gradient elution with EtOAc/Hexanes 7 to temperature, diluted with water, extracted with ethyl acetate, 60%) to give ethyl 3-(4-bromopyridin-2-yl)propanoate as a dried over magnesium sulfate, filtered and concentrated in pale yellow oil. MS ESI calc'd, for CHBrNO, M+H" vacuo. The residue was purified by silica gel chromatography 258 and 260. found 258 and 260." HNMR (500 MHz, CDC1) 35 to afford ethyl 3-5-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan & 8.33 (d. J=5.1 Hz, 1H), 7.39 (bs, 1H), 7.30 (dd, J=5.2, 1.7 2-yl)pyridin-3-yl)propanoate. "H NMR (500 MHz, CDC1) & HZ, 1H), 4.12 (q, J=6.7 Hz, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.79 8.85 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 4.12(q, J=7.1 Hz, 2H), (t, J=6.4 Hz, 2H), 1.23 (t, J=6.8 Hz, 3H). 3.07 (t, J–7.3 Hz, 2H), 2.70 (t, J–7.3 Hz, 2H), 1.35 (s, 12H), 1.26-1.20 (m, 3H). Preparative Example 2.7 40 Preparative Example 2.8 Ethyl 3-5-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan 2-yl)pyridin-3-ylpropanoate Ethyl 3-(5-bromopyridin-2-yl)propanoate

45

PrepEx 2.7 PrepEx 2.8

> O 50

2 closN 55 Step 1: (Carbethoxymethylene)triphenylphosphorane (1.56 g. Br 4.49 mmol) was added to a solution of 5-bromopyridine-3- carbaldehyde (0.50 mg, 2.69 mmol) in DMF (5 mL) and the Argon was bubbled through a solution of 2,5-dibromopy mixture was stirred at room temperature for one hour. The 60 ridine (3.00 g, 12.7 mmol) in THF (25.3 ml) for ~10 minutes. reaction was poured into ice water and then ethyl acetate was Palladium Tetrakis (1.46g, 1.27 mmol) was added quickly to added. The organic layer was separated, washed with brine, the reaction mixture, and then (3-ethoxy-3-oxopropyl)-a- dried over magnesium Sulfate, filtered and concentrated bromanylidenezinc (38.0 ml, 19.0 mmol) was added slowly. under reduced pressure. The residue was dissolved in ethyl The reaction mixture was heated to 85°C. overnight. The acetate and then hexanes were added until Solid crashed out. 65 cooled reaction mixture was filtered through a CELITE pad The mixture was filtered and then the filtrate was concen and washed with DCM (3x). The filtrate was diluted with trated in vacuo. The residue was purified by silica gel chro water, extracted with DCM (3x) and the combined organic US 9,376,418 B2 87 88 layers were dried under reduced pressure. The residue was cooling, the reaction mixture was diluted with Saturated purified by silica gel chromatography (ethyl acetate/hexanes) NaHCO, (50 mL), extracted with ethyl acetate (50 mL) and to afford ethyl 3-(5-bromopyridin-2-yl)propanoate. MS ESI diethyl ether (50 mL), washed with water, brine, dried over calc’d for CHBrNO, M+H" 258 and 260. found 258 and Sodium Sulfate, filtered, and concentrated in vacuo. The resi 26O. due was purified by silica gel chromatography (hexanes/ethyl acetate) to afford ethyl 4-(5-bromopyridin-2-yl)oxycyclo Preparative Example 2.9 hexanecarboxylate. MS ESI calc’d for CHBrNO 3-(6-Bromopyridin-3-yl)propanoate M+H 328 and 330. found 328 and 330. 10 Example 1

PrepEx 2.9 Preparation of Compounds of Formula (I) Using the Br General Methods Illustrated in Scheme 1 15 Example 1.1 1-6-3-(Morpholin-4-yl)-5-[4-(trifluoromethyl) pyrimidin-2-yl)amino)phenylpyridin-2- yl)cyclobutanol

O 1N 1.1 25 Palladium tetrakis (1.64 g, 1.41 mmol) was added to a solution of 2-bromo-4-iodopyridine (4.00 g, 14.1 mmol) in N OH THF (28.2 ml) under an argon atmosphere. The mixture was F cooled to 0°C., 3-ethoxy-3-oxopropylzinc bromide (36.6 F F 2 N mL, 18.3 mmol) was slowly added to the reaction mixture and stirred for 1 hour. The mixture was then allowed to warm to 30 room temperature overnight. An aqueous ammonium chlo ride was added to the reaction mixture and stirred for 5 min 21 NN utes. pH was then adjusted to ~8 with aqueous sodium bicar Sa ls bonate and product was extracted with ethyl acetate (3x). The N combined organic layers were dried over anhydrous magne 35 sium Sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford ethyl 3-(6-bromopyridin-3-yl)pro panoate. MS ESI calc’d for CHBrNO, M+H 258 and Step 1: 260. found 258 and 260. 40 Morpholine (2.53 mL, 28.1 mmol) was added to a solution of 1-fluoro-3-iodo-5-nitrobenzene (3 g, 11.2 mmol) in Preparative Example 2.10 DMSO (22.5 mL) under nitrogen. The reaction was heated at 120° C. for 2 hours, then cooled to room temperature and Ethyl diluted with a mixture of ether and ethyl acetate. The organic 4-(5-bromopyridin-2-yl)oxycyclohexanecarboxylate 45 layer was washed with water (2x) and concentrated under reduced pressure. The residue was purified by silica gel chro matography (ethyl acetate:hexanes) to afford 4-(3-iodo-5- nitrophenyl)morpholine as deep yellow solid. PrepEx 2.10 O Step 2: 50 Bis(pinacolato)diboron (2.72 g, 10.7 mmol), Pd(dppf)Cl dichloromethane adduct (397 mg, 0.486 mmol) and potas O sium acetate (2.86 g. 29.2 mmol) were added to a solution of 4-(3-iodo-5-nitrophenyl)morpholine (3.25 g, 9.73 mmol) in O N dioxane (19.5 mL) and the reaction mixture was purged and 55 flushed with N(g) (3x). The reaction mixture was heated to NN 120° C. overnight, then cooled to room temperature, diluted with ether, extracted with water (2x), dried over sodium sul fate, filtered and concentrated under reduced pressure. The 2 crude product, 4-3-nitro-5-(4.4.5.5-tetramethyl-1,3,2-diox 60 aborolan-2-yl)phenylmorpholine, which was used without Br further purification. "H NMR (500 MHz, CDC1) & 8.13 (s, 1H), 7.79 (s, 1H), 7.63 (d. J=1.9, 1H), 4.02-3.80 (m, 4H), NaH (0.250 g. 6.25 mmol) was added to a mixture of ethyl 3.46-3.17 (m, 4H), 1.38 (s, 12H). 4-hydroxycyclohexanoate (0.916 ml, 5.68 mmol), and Step 3a: 5-bromo-2-fluoropyridine (0.585 mL, 5.68 mmol) in DMF 65 Preparation of 1-(6-Bromopyridin-2-yl)cyclobutanol: (15 mL) at room temperature under an argon atmosphere. The n-Butyllithium (6.85 mL, 11.0 mmol) was added to a suspen reaction mixture was heated to 80° C. for 2.5 hours. Upon sion of 2,6-dibromopyridine (2.36 g, 9.96 mmol) in dichlo US 9,376,418 B2 89 90 romethane (60 mL) at -78° C. The reaction mixture was then cooled to room temperature. The reaction was filtered, stirred for 15 minutes and cyclobutanone (0.838 g, 12.0 diluted with water, extracted with ethyl acetate, dried over mmol) was added in one portion at -78°C. The reaction was Sodium sulfate, filtered and concentrated under reduced pres stirred for an additional 30 minutes before pouring the reac Sure. The residue was purified by silica gel chromatography (7:3 ethyl acetate:hexanes, then 100% ethyl acetate) to afford tion into a mixture of saturated aqueous NHCl and dichlo 1-6-3-amino-5-(morpholin-4-yl)phenylpyridin-2- romethane. The organic layer was concentrated to dryness yl)cyclobutanol as an off-white solid. "H NMR (500 MHz, and was purified by flash chromatography to yield 1-(6-bro CDC1,) & 7.83 (s, 1H), 7.66-7.58 (m. 1H), 7.56 (d, J–7.5, 1H), mopyridin-2-yl)cyclobutanol as a light yellow oil. MS ESI 7.36-7.23 (m, 2H), 7.01 (s, 1H), 6.90 (s, 1H), 6.34 (s, 1H), calc'd, for CH BrNOM+H" 228 and 230. found 228 and 5.81 (s, 1H), 3.90 (m, 4H), 3.23 (m, 4H), 2.64-2.54 (m, 4H), 230. 10 2.14-2.08 (m. 1H), 1.96-1.92 (m, 1H). Step 3: Step 5: Pd(dppf)C1-dichloromethane adduct (40.8 mg, 0.05 Xantphos (93 mg 0.161 mmol), palladium(II) acetate mmol) and sodium carbonate (2 N, 1.5 mL, 3.0 mmol) were (24.2 mg, 0.108 mmol), and cesium carbonate (350 mg, 1.08 added to 1-(6-bromopyridin-2-yl)cyclobutanol (228 mg, 1.0 mmol) were added to a degassed solution of 2-chloro-4- mmol) and 4-3-nitro-5-(4.4.5.5-tetramethyl-1,3,2-diox 15 (trifluoromethyl)pyrimidine (103 mg, 0.565 mmol), 1-6-3- aborolan-2-yl)phenylmorpholine (0.2 N in DMF, 5.0 mL. amino-5-(morpholin-4-yl)phenylpyridin-2-yl)cyclobutanol 1.0 mmol) and the reaction mixture was purged and flushed (175 mg, 0.538 mmol) in dioxane (45.3 mL) and the reaction with N(g)(3x). The reaction mixture was heated to 100° C. mixture was heated to 100° C. for 2 hours and then for 5 hours for 4 hours, then cooled to room temperature, diluted with at 115° C. Then, the reaction mixture was cooled to room water, extracted with diethyl ether, washed with brine, dried temperature, diluted with water, extracted with ethyl acetate, over sodium sulfate, filtered an concentrated under reduced washed with brine, dried over sodium sulfate, filtered and pressure. The crude product was purified by silica gel chro concentrated under reduced pressure. The crude product was matography (ethyl acetate:hexanes) to afford 1-6-3-(mor purified by Silica gel chromatography (ethyl acetate:hexanes) pholin-4-yl)-5-nitrophenylpyridin-2-yl)cyclobutanol. H to afford 1-6-3-(morpholin-4-yl)-5-[4-(trifluoromethyl) NMR (500 MHz, CDC1,) & 8.30-8.23 (m, 1H), 7.98-7.95 (m, 25 pyrimidin-2-yl)amino)phenylpyridin-2-yl)cyclobutanol as 1H), 7.93, (t, J=7.2 Hz 1H), 7.79 (t, J=2.2, 1H), 7.74 (d.J=7.8, an off-white solid. MS APCI calc’d for CHFNO 1H), 7.66 (d. J–7.8, 1H), 5.36 (s, 1H), 4.03-3.84 (m, 4H), M+H 472. found 472. "H NMR (NMR Hz 400 MHz, 3.46–3.29 (m, 4H), 2.82-2.47 (m, 4H), 2.27-2.09 (m, 1H), Acetone-d): 89.26 (s, 1H), 8.82 (d. J–4.8 Hz, 1H), 8.16 (s. 2.05-191 (m. 1H). 1H), 7.90 (t, J=7.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (d. J=7.8 Step 4: 30 HZ, 1H), 7.53 (s, 1H), 7.23 (d. J=4.9 HZ, 1H), 3.86 (t, J–4.4 Ammonium chloride (22.6 mg, 0.422 mmol) and iron (216 Hz, 4H), 3.30 (t, J–4.4 Hz, 4H), 2.74-2.63 (m. 2H), 2.43 (m, mg, 3.57 mmol) were added to a solution of 1-6-3-(mor 2H), 2.04 (m, 2H). pholin-4-yl)-5-nitrophenylpyridin-2-yl)cyclobutanol (250 The following examples in Table 1 were prepared in an mg, 0.703 mmol) in ethanol (4.69 mL) and water (2.36 analogous manner to that described in general scheme 1 using mmol). The reaction mixture was heated to 85°C. for 1 hour, commercially available amines in step 1. TABLE 1

RC

rsN CF 2

21 NN

M+H M + H' Ex. R3' Name Calcid Obsv'd Form(s)

1.2 —H N-(3-morpholin-4-yl-5-pyridin-2- 402 402 Free ylphenyl)-4- Base (trifluoromethyl)pyrimidin-2-amine

1.3 N-3-morpholin-4-yl-5-(6- 487 487 Free morpholin-4-ylpyridin-2-yl)phenyl- Base 4-(trifluoromethyl)pyrimidin-2- amine US 9,376,418 B2

TABLE 1-continued Rey

rsN CF 2 21 h

NullsN N N H Nul M+H M + H' Ex. R3' Name Calcid Obsv'd Form(s) 1.4 OH 2,2'-6-(3-morpholin-4-yl-5-4- 505 505 Free (trifluoromethyl)pyrimidin-2- Base yl)aminophenyl)pyridin-2- yl)imino diethanol

N-1a OH

25 Example 2 found 375. "H NMR (500 MHz, DMSO-d6) & 10.32 (s, 1H), 8.95 (s, 1H), 8.84 (d. J=5.4, 1H), 8.18 (d. J=9.6, 1H), 8.12 (d. Preparation of Compounds of Formula (I) Using the J=9.3, 1H), 8.05 (s, 1H), 7.28 (s. 2H), 2.38 (s.3H). General Methods Illustrated in Scheme 2 30 Example 2.2 Example 2.1 Methyl 3-(6-(3-((4-methoxypyrimidin-2-yl)amino)- 5-(3-Methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) 5-methylphenyl)pyridin-2-yl)propanoate amino)phenyl)pyridine-2-carboxylic acid 35

2.2 2.1 CO2H O OH 40 o1 NN F F F 21 45 r 21 NN asH

NN 1. A mixture of 4-methoxy-N-(3-methyl-5-(4.4.5.5-tetram 50 ethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (0.045 g, 0.13 mmol), ethyl 3-(6-bromopyridin-2-yl)pro A mixture of N-3-methyl-5-(4.4.5.5-tetramethyl-1,3,2- panoate (0.037g, 0.15 mmol), PdCl2(dppf)-CHCl (0.016 g. dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2- 0.020 mmol), and NaCO, (2.0 M in water, 0.13 mL, 0.26 amine (6.5 g. 17.1 mmol), 5-bromopyridine-2-carboxylic mmol) in dioxane (0.75 mL) was purged with argon and acid (3.92 g, 19.4 mmol), aqueous sodium carbonate (2M, 55 heated to 110° C. for 12 hours. Upon cooling, NaOH (1.0 M 17.1 mL, 34.3 mmol) in dioxanes (57.1 mL) was flushed and in water, 0.50 mL) and MeOH (0.50 mL) were added to the purged with Ar(g) (3x). PdCl(dppf)-dichloromethane reaction mixture and irradiated in a microwave reactor for 10 adduct (646 mg, 0.791 mmol) was then added to the reaction minutes at 110° C. Silica Supported-DMT (0.088 g., 0.13 mixture and heated at 130° C. for 10 hours. Upon cooling, the mmol. 0.57 mmol/g) was added to the reaction mixture and reaction mixture was filtered through a CELITE pad and 60 shaken for 5 hours at ambient temperature. The reaction was washed with dioxane. The crude reaction mixture was con passed through a syringe filter and the eluent was evaporated centrated under reduced pressure and diluted with 90% under reduced pressure. The residue was suspended in MeCN and 10%2M HCl (aq). The crude solid was isolated by DMSO (1.5 mL) and was purified by reverse phase prepara filtration and was recrystallized from dichloromethane to tive HPLC (0:100 to 95.5 acetonitrile:water: 0.1% v/v formic yield 5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) 65 acid modifier) to afford methyl 3-(6-(3-(4-methoxypyrimi amino)phenyl)pyridine-2-carboxylic acid as an off-white din-2-yl)amino)-5-methylphenyl)pyridin-2-yl)propanoate. powder. MS APC calc'd for C.H.F.N.O. M+H" 375. LRMS (ESI) calc’d for C.H. N.O. M+H": 365. Found: US 9,376,418 B2 93 94 365. "H NMR (600 MHz, DMSO-d) 89.54 (s, 1H), 8.33 (s, 1H), 8.18 (d. J=5.6, 1H), 7.73 (t, J=7.7, 1H), 7.64 (d. J=7.8, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.19 (d. J–7.6, 1H), 6.25 (d. J=5.6, 1H), 3.93 (s, 3H), 2.99 (t, J=7.4, 2H), 2.71 (t, J=74, 2H), 2.33 (s.3H). The following examples in Tables 2A-2D were prepared in an analogous manner to that described in general scheme 2 using known (e.g., Mallet, M., Branger, G.; Marsais, F.; Que guiner, G.J. Organometallic Chem 1990, 382, 319-32), inter mediates described above, or commercially available iodides, 10 bromides, or chlorides. In some cases, ester hydrolysis and palladium Scavenging steps were omitted. US 9,376,418 B2 95 96

UILIOJ

QUITEN

US 9,376,418 B2 101 102

UILIOJ US 9,376,418 B2 103 104

UILIOJ

HO HO HO

US 9,376,418 B2 109 110

UILIOJ

QUITEN

*HO,HOO US 9,376,418 B2 111 112

UILIOJ

HO

HO

US 9,376,418 B2 115 116

S Nº

HO

US 9,376,418 B2 123 124 TABLE 2B-continued Royl RC2 NN

2 Rey3

Ex. Revl Re32 Re33 Rev4 R4 Name Calcd Obsw'd Form methylphenyl (trifluoromethyl) pyrimidin-2- amine 2.64 1-5-(3-methyl 373 373 Free Base, (trifluoromethyl) Formate pyrimidin-2- Salt yl)amino)phenyl) pyridin-2- ylethanone 2.65 - C(O)OCH methyl 5-(3 389 389 Free methyl-5-4- Base, (trifluoromethyl) Formate pyrimidin-2- Salt aminophenyl) yridine-2- arboxylate 2.66 - CH-OH —H - H -CH 5-(3-methyl-5- 361 361 Free Base trifluoromethyl) yrimidin-2- amino)phenyl) yridin-3- methanol 2.67 - CN —H —H —CH -(3-methyl-5- 356 356 Free Base, (triflu O r O l e thyl Formate yrimidin-2- Salt amino)phenyl) yridine-3- arbonitrile 2.68 yl 5-(3- 403 403 Free hyl-5-4- Base ifluoromethyl) yrimidin-2- R p henyl) s boxylate 2.69 -(3-methy S 375 375 Free 4 Base trifluoromethyl) yrimidin-2 e ami l o p henyl) carboxylic acid

2.70 NH 4-5-(3-me hyl 443 443 Free 5-4- Base (trifluoromethyl) pyrimidin-2 yl)aminop henyl) pyridin-2-y - 1,4-diazepan-2- Ole

US 9,376,418 B2

TABLE 2D-continued Ns Rey R1 2

21 NN

NullsN N R4 H M+H M + H" Ex. RI Re3 R4 Name Calc’d ObSwd Form 2.136 O —CH ethyl 3-(4-3-(4- 403 403 Formate A cyclopropylpyrimidin-2-yl)amino- Salt O 5-methylphenylpyridin-2- yl)propanoate

2.137 —CH2CH2CO2H —CHs 3-(4-3-(4-cyclopropylpyimidin- 375 375 Formate 2-yl)amino-5- Salt methylphenylpyridin-2- yl)propanoic acid

Example 2.138 1H), 7.27 (s, 1H), 7.18 (s, 1H), 5.39 (s, 1H), 4.80-4.72 (m, 1H), 2.35 (s.3H), 1.38 (d. J=5.5 Hz, 3H). 1-5-(3-Methyl-5-4-(trifluoromethyl)pyrimidin-2- 30 yl)amino)phenyl)pyridin-2-yl)ethanol Example 3

35 2.138 Compounds of Formula (I) Using the General HO Methods Illustrated in Scheme 3

NN 40 Examples 3.1 and 3.2 21 N,N-dimethyl-2-(5-(3-methyl-5-((4-(trifluoromethyl) 45 pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetamide

Sodium borohydride (46 mg, 1.2 mmol) was added to a 50 solution of 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimi 3.1 din-2-yl)amino)phenyl)pyridin-2-yl)ethanone (45 mg, 0.12 O mmol) in tetrahydrofuran (300 ul) and methanol (300 ul) and then the reaction mixture was stirred at ambient temperature ss OH for 30 minutes. The reaction mixture was quenched with saturated aqueous potassium sodium tartrate (2 mL) and NN diluted with dichloromethane (3 mL). The mixture was stirred for 16 hours, filtered through a CELITE pad, dried over sodium sulfate, filtered, and concentrated under reduced 60 CF3 2 pressure. The residue was purified by silica gel chromatog raphy (10-40% acetone/hexanes, linear gradient) to afford NN 1-5-(3-methyl-5-4-(trifluoromethyl)pyrimidin-2-yl) aminophenyl)pyridin-2-yl)ethanol. MS ESI calc’d. for Nals N Me CHFNOM+H"375, found 375. "H NMR (500 MHz, 65 H DMSO-d) & 10.26 (s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 7.98 (d. J=7.5 Hz, 1H), 7.95 (s, 1H), 7.57 (d. J=7.5 Hz, 1H), 7.54 (s, US 9,376,418 B2 145 146 -continued by reversed phase HPLC to afford N,N-dimethyl-2-(5-(3- 3.2 methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phe O nyl)pyridin-2-yl)acetamide (8.4 mg. 0.016 mmol). MS ESI Me calc’d. for CHFNOM+H" 416. found 416. "H NMR N1 (600 MHz, CD,OD): 88.97 (s, 1H), 8.71 (d. J=4.8 Hz, 1H), 8.62 (d. J=6.0 Hz, 1H), 8.09 (s, 1H), 7.89 (d. J=6.0 Hz, 1H), 7.60 (s, 1H), 7.26 (s, 1H), 7.13 (d. J–4.8 Hz, 1H), 4.25 (s.2H), r 3.18 (s.3H), 3.00 (s.3H), 2.43 (s.3H). CF 21 10 r Example 4 Nals N Me 15 H Compounds of Formula (I) Using the General Methods Illustrated in Scheme 4 Step 1: n-Butyllithium (2.2 ml, 3.52 mmol. 1.6 M) was added dropwise to a solution of diisopropylamine (500 ul, 3.51 Example 4.1 mmol) in THF (5 ml) at -78°C. and the resulting solution was stirred at -78° C. for 30 minutes. A solution of 5-bromo-2- N-3-(2-aminopyridin-4-yl)-5-methylphenyl-4- methylpyridine (500 mg, 2.91 mmol) in THF (1 mL) was methoxypyrimidin-2-amine added dropwise to LDA solution and the mixture was stirred for 1 hour. A solution of di-tert-butyl dicarbonate (742 ul, 3.20 25 mmol) in THF (1 ml) was added to the reaction mixture and warmed to room temperature over a period of 2 hours. The mixture was quenched with Saturated ammonium chloride and extracted with ethyl acetate, washed with brine, dried, and concentrated under reduced pressure. The residue was 30 purified by silica gel chromatography (ethyl acetate/hexanes) to afford tert-butyl 2-(5-bromopyridin-2-yl)acetate (151.8 mg, 0.558 mmol). MSESI calc’d. for CHBrNO, M+H" 272 and 274. found 272 and 274. 4.1 Step 2: 35 A mixture of N-(3-methyl-5-(4.4.5.5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2- amine (110 mg, 0.290 mmol), tert-butyl 2-(5-bromopyridin 2-yl)acetate (51.3 mg, 0.189 mmol), palladium(II) chloride (dppf) (28 mg, 0.038 mmol) and sodium carbonate (0.2 ml, 40 0.400 mmol. 2 M) in DMF (2 ml) was evacuated and purged with argon (3x), and then was irradiated in a microwave reactor for 10 minutes at 100°C. The mixture was filtered and purified on reversed phase HPLC to afford tert-butyl 2-(5-(3- methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phe 45 nyl)pyridin-2-yl)acetate (49.5 mg, 0.089 mmol). MS ESI calc'd, for CHF.N.O. M+H" 445. found 445. Step 3: tert-Butyl 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimi din-2-yl)amino)phenyl)pyridin-2-yl)acetate (25 mg, 0.056 50 mmol) was added to HCl in dioxane (0.5 ml, 2.000 mmol. 4M). The mixture was stirred at room temperature for 1 hour. The solid was collected by the filtration and afforded 2-(5-(3- methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phe nyl)pyridin-2-yl)acetic acid (14.1 mg 0.033 mmol). MS ESI 55 A mixture of N-(3-bromo-5-methylphenyl)-4-methoxypy calc'd, for CHFNO, M+H 389. found 389. "H NMR rimidin-2-amine (125 mg, 0.425 mmol), 2-aminopyridine-4- (500 MHz, CDOD): 8 9.07 (d. J=1.5 Hz, 1H), 8.83 (dd, boronic acid (103 mg 0.467 mmol), PdCl2(dppf)-CH.Cl J=8.0, 1.5 Hz, 1H), 8.73 (d.J=5.0 Hz, 1H), 8.15-8.10 (m, 2H), adduct (35 mg, 0.042 mmol) and sodium carbonate (425uL. 7.66 (s, 1H), 7.34 (s, 1H), 7.18 (d. J=5.0Hz, 1H), 4.25 (s. 2H), 0.850 mmol) in dioxane (3 mL) was heated to 100° C. for 14 2.46 (s.3H). 60 hours. The reaction mixture was filtered through a CELITE Step 4: pad and washed with dioxane (3x). The filtrate was concen A mixture of 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyri trated under reduced pressure and the residue was purified by midin-2-yl)amino)phenyl)pyridin-2-yl)acetic acid (8.4 mg. silica gel chromatography (methanol/ethyl acetate) to give 0.020 mmol), dimethylamine (0.05 ml, 0.100 mmol, 2M). N-3-(2-aminopyridin-4-yl)-5-methylphenyl]-4-methoxy EDC (8.6 mg, 0.045 mmol), HOBT (7.8 mg, 0.051 mmol), 65 pyrimidin-2-amine as a tan solid. MS ESI calc’d for DIEA (10 ul, 0.057 mmol) in 1,4-dioxane (0.8 ml) was stirred CHNO IM+H 308. found 308. 'H NMR (500 MHz, at room temperature for 16 hours. The mixture was purified DMSO-d) & 9.59 (s, 1H), 8.20 (d. J=5.7 Hz, 1H), 7.95-7.88 US 9,376,418 B2 147 148 (m. 2H), 7.61 (s, 1H), 7.00 (s, 1H), 6.69 (d. J=5.4 Hz, 1H), A mixture of N-(3-bromo-5-methylphenyl)-4-(trifluorom 6.64 (s, 1H), 6.28 (d. J–5.6 Hz, 1H), 5.95 (s. 2H), 3.92 (s.3H), ethyl)pyrimidin-2-amine (70 mg, 0.211 mmol), (3-ethox 2.32 (s.3H). yphenyl)boronic acid (70.1 mg, 0.422 mmol), PdCl2(dppf)- CH2Cl adduct (34.4 mg., 0.042 mmol) and Sodium carbonate Example 4.2 5 (2 Min water) (211 uL, 0.422 mmol) in 2-methyl-tetrahydro furan (1.05 mL) was heated to 60° C. for 12 hours. Si-dimer N-3-(6-aminopyridin-3-yl)-5-methylphenyl)-4-(trif captotriazine (222 mg, 0.126 mmol) and acetonitrile (3.0 mL) luoromethyl)pyrimidin-2-amine were added to the reaction mixture and stirred for 4 hours at room temperature to Scavenge palladium. The reaction mix 10 ture was filtered, washed with DMSO (1.5 mL)) and concen 4.2 trated under reduced pressure. The reaction mixture (still in NH2 1.5 mL DMSO) was resubjected to filtration and the residue was purified by mass triggered reverse phase HPLC (57-91% NN 15 Acetonitrile/Water (0.1% Formic Acid Modifier) to afford F N-3-(6-aminopyridin-3-yl)-5-methylphenyl)-4-(trifluorom ethyl)pyrimidin-2-amine. MS APC calc’d for C.H.FNs F F 21 M+H 346. found 346. "H NMR (600 MHz, DMSO-d6) & 10.12 (s, 1H),8.78 (d. J=5.2, 1H), 8.16 (d. J=3.1, 1H), 7.79 (s. 21 2O 1H), 7.60 (dd, J=2.7, 8.8, 1H), 7.39 (s, 1H), 7.22 (d. J=5.1, 1H), 7.01 (s, 1H), 6.55-6.41 (m, 1H), 6.03 (s. 2H), 2.29 (s. 3H). N N ls N H the following examples in Tables 4A-4C were prepared in an analogous manner to that described in general scheme 4 using commercial boronic esters or acids. TABLE 4A

Reyl

RC2 n N

CF 2

21 NN

susN N CH3 H

M+H M + H' Ex. R.' Re32 Name Calcid Obsv'd Form(s)

4.3 —H —F N-3-(5-fluoropyridin-3-yl)-5- 349 349 Formate methylphenyl-4- Salt (trifluoromethyl)pyrimidin-2-amine 4.4 —F —H N-3-(6-fluoropyridin-3-yl)-5- 349 349 Formate methylphenyl-4- Salt (trifluoromethyl)pyrimidin-2-amine 4.5 —OCH —H N-3-(6-methoxypyridin-3-yl)-5- 361 361 Formate methylphenyl-4- Salt (trifluoromethyl)pyrimidin-2-amine 4.6 —CF —H N-3-methyl-5-6- 399 399 Formate (trifluoromethyl)pyridin-3- Salt yl)phenyl-4- (trifluoromethyl)pyrimidin-2-amine 4.7 - CH-OH —H 5-(3-methyl-5-4- 361 361 Formate (trifluoromethyl)pyrimidin-2- Salt yl)aminophenyl)pyridin-2- yl)methanol 4.8 - OH —H 5-(3-methyl-5-4- 347 347 Formate (trifluoromethyl)pyrimidin-2- Salt yl)amino)phenyl)pyridin-2-ol US 9,376,418 B2 150 TABLE 4B Step 1: Reyl N-3-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe nyl)-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.411 r N CF 2 mmol) and potassium fluoride (71.6 mg, 1.23 mmol) were added to 3.00 mL of a stock solution of palladium(II) acetate 21 NN (4.61 mg, 0.021 mmol) and butyl di-(3S,5S,7S)-tricyclo 10 3.3.1.1 dec-1-ylphosphane (14.7 mg, 0.04.1 mmol) in N.N l. N CH H THF (3.00 mL) under nitrogen. 5-Bromo-2-methoxypyridine M+ (0.069 mL, 0.534 mmol) and water (1.00 mL) were then H' M+H" Ex. R.' Name Calc’d Obsv'd Form(s) added to the reaction mixture and was heated to 75° C. for 17 15 4.9 —OCH N-3-(6-methoxypyridin-2- 361 361 Formate hours. Upon cooling to room temperature, the reaction mix yl)-5-methylphenyl]-4- Salt (trifluoromethyl)pyrimidin-2- ture was quenched by the addition of 25% aqueous NH.OAc. amine The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed sequentially with TABLE 4C water and brine, dried over NaSO and concentrated under N Rey reduced pressure. The residue was purified by silica gel chro

25 matography (ethyl acetate/dichloromethane) to afford N-3- s (6-methoxypyridin-3-yl)phenyl)-4-(trifluoromethyl)pyrimi CF3 21 din-2-amine as a beige solid. MS APC calc’d for 21 N CHFNOM+H"347. found 347. 30 alsN N CH3 H M + M+ H]" H]" Ex. R& Name Calc’d Obsv'd Form(s) 35 Step 2: 4.10 —OCH N-3-(2-methoxypyridin-4- 361 361 Formate Iodomethane (0.063 mL, 1.007 mmol) and sodium iodide yl)-5-methylphenyl-4- Salt (trifluoromethyl)pyrimidin (151 mg, 1.007 mmol) were added to a solution of N-3-(6- 2-amine 40 methoxypyridin-3-yl)phenyl)-4-(trifluoromethyl)pyrimidin 2-amine (109 mg, 0.315 mmol) in MeCN (3.1 mL) at room Example 5 temperature under nitrogen. The mixture was heated to 45° C. for 72 hours, then cooled to room temperature and concen Compounds of Formula (I) Using the General 45 trated in vacuo. The residue was diluted with water and Methods Illustrated in Scheme 5 extracted with ethyl acetate (2x). The combined organic lay Example 5.1 ers were washed with brine, dried over NaSO and concen 1-Methyl-5-(3-4-(trifluoromethyl)pyrimidin-2-yl) 50 trated under reduced pressure. The residue was purified by amino)phenyl)pyridin-2(1H)-one silica gel chromatography (ethyl acetate/hexanes) to afford 1-methyl-5-(3-4-(trifluoromethyl)pyrimidin-2-yl) amino)phenyl)pyridin-2(1H)-one as an off-white solid. MS 5.1 55 O APC calc'd for CHFNO IM+H" 347. found 347. N1 Check LCMS data. H NMR (400 MHz, Acetone-d): 89.31 | (s, 1H); 8.83 (d. J=4.9 Hz, 1H); 8.72 (s, 1H); 7.96 (d. J=8.2 F F 2 60 HZ, 1H); 7.84 (d. J–7.8 Hz, 1H); 7.79 (t, J–7.8 Hz, 1H); 7.54 (d. J–74 Hz, 1H); 7.48 (t, J=7.9 Hz, 1H); 7.24 (d. J=4.9 Hz, 1H); 6.76 (d. J=8.2 Hz, 1H); 4.04 (s.3H). APCI: M+H" m/z r 347.1. 1s, 65 H The following examples in Table 5 were prepared in an analogous manner to that described in general scheme 5. US 9,376,418 B2 151 152 TABLE 5 , () a NN

N N ls N CH H M+H" M+H" Ex. Cy Name Calcid ObSwd Form(s) 5.2 1-methyl-4-(3-4- 347 347 Free Base (trifluoromethyl)pyrimidin-2- N O yl)amino)phenyl)pyridin-2(1H)-one

2

5.3 O 1-methyl-6-(3-4- 347 347 Free Base N (trifluoromethyl)pyrimidin-2- yl)amino)phenyl)pyridin-2(1H)-one 1Na

Example 6 Step 2: 30 Ammonium chloride (333 mg, 6.23 mmol), ethanol (6.64 Compounds of Formula (I) Using the General mL) and water (1.66 mL) was added to N-3-nitro-5-(pyridin Methods Illustrated in Scheme 6 3-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (150 Example 6.1 mg, 0.415 mmol) and was purged and flushed with Ar(g)(3x). 35 Iron (69.6 mg, 1.25 mmol) was added to the reaction mixture and heated to 75° C. for 1.5 hours. The reaction mixture was 1-Methyl-3-3-(pyridin-3-yl)-5-[4-(trifluoromethyl) cooled to room temperature, filtered through a CELITE pad pyrimidin-2-yl)amino)phenylurea and washed with chloroform. The organic layer was washed with saturated aqueous NHCl, dried over sodium sulfate and 40 concentrating under reduced pressure. Crude 5-(pyridin-3- yl)-N-4-(trifluoromethyl)pyrimidin-2-ylbenzene-1,3-di 6.1 amine was carried forward without further purification. MS N21 APC calc’d for CHFNs M+H"332. found 332. 45 CF3 N Step 3: Triethylamine (44.2 LL, 0.317 mmol) followed by methyl isocyanate (18.1 mg, 0.317 mmol was added to a solution of NN O 5-(pyridin-3-yl)-N-4-(trifluoromethyl)pyrimidin-2-ylben 50 Zene-1,3-diamine (35 mg, 0.106 mmol) in THF (264 uL). The Nals N N l N1 reaction mixture was heated to 40°C. for 4 hours, then cooled H H H to room temperature and concentrated under reduced pres sure. The solid was diluted with diethyl ether (5.00 mL) and Step 1: was filtered to isolate 1-methyl-3-3-(pyridin-3-yl)-5-4- A mixture of N-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-di 55 (trifluoromethyl)pyrimidin-2-yl)amino)phenylurea as a tan oxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2- powder. The product was further dried under reduced pres amine (250 mg, 0.610 mmol), 2-Me-THF (1.6 mL, 0.610 sure. MS APC calc’d for CHFNOM+H" 389. found mmol), 3-bromopyridine (116 mg, 0.732 mmol) and sodium 389. "H NMR (500 MHz, DMSO-d) & 10.26 (s, 1H), 8.81 (s, carbonate (0.610 mL, 1.22 mmol) was purged and flushed 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 7.92 (d. J=8.5 Hz, with Ar(g) (3x). PdCl2(dppf)-dichloromethane adduct (24.9 60 mg, 0.030 mmol) was added to the reaction mixture and 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.26 heated to 60° C. overnight. The reaction mixture was cooled (s, 1H), 6.06 (s, 1H), 2.64 (s.3H). to room temperature, and the product was collected by filtra The following examples in Table 6 were prepared in an tion. Crude N-3-nitro-5-(pyridin-3-yl)phenyl)-4-(trifluo analogous manner to that described in general scheme 6 using romethyl)pyrimidin-2-amine was carried forward without 65 commercially available bromides in step 1 and commercially further purification. MS APC calc’d for CHFNO available acyl chlorides and isocyanates in step 3. In some M+H 362. found 362. cases, step 3 was omitted.

US 9,376,418 B2 155 156 Example 7 A mixture of N-3-(6-fluoropyridin-3-yl)-5-4-(trifluo romethyl)pyrimidin-2-yl)amino)phenyl)acetamide (75.0 Compounds of Formula (I) Using the General Methods Illustrated in Scheme 7 mg, 0.192 mmol), 2-methylalanine (39.5 mg, 0.383 mmol), and tripotassium phosphate (81.0 mg, 0.383 mmol) in DMSO Example 7.1 (479 uL) was heated to 130° C. for 1 hour. The mixture was N-5-3-(acetylamino)-5-4-(trifluoromethyl)pyri cooled to room temperature, filtered and the residue was midin-2-yl)amino)phenylpyridin-2-yl)-2-methyla purified by HPLC (10-100% acetonitrileinwater+0.5%TFA) lanine 10 to yield N-(5-3-(acetylamino)-5-[4-(trifluoromethyl)pyri midin-2-yl)amino)phenylpyridin-2-yl)-2-methylalanine as

7.1 the bis-TFA salt. MS APC calc’d for CHFNO, M+H" 15 475, found 475. 'H NMR (500 MHz, CDOD) & 8.72 (d. HN CO2H J=4.9, 1H), 8.23 (d. J=7.4, 1H),8.09 (s.1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.17-7.12 (m, 2H), 2.65 (s, 6H), 2.16 (s, NN 3H). F F F 21

21 NN O 25 s 1. N ls The following examples in Table 7A were prepared in an analogous manner to that described in general scheme 7. TABLE 7A

RC r CF3 2

a NN O

N N N H H

M+H M + H" Example Re3 Name Calc’d ObSwd Form(s)

7.2 (2S)-1-(5-3-(acetylamino)-5-4- 473.1 473.1 TFA Salt CO2H (trifluoromethyl)pyrimidin-2- N yl)amino)phenylpyridin-2- yl)azetidine-2-carboxylic acid

7.3 O NH N-(3-6-(2-oxopyrrollidin-3- 472.3 472.2 TFA Salt yl)aminolpyridin-3-yl-5-4- (trifluoromethyl)pyrimidin-2- yl)aminophenyl)acetamide HN

7.4 O N-(3-6-(5-oxo-1,4-diazepan-1- 486.2 486.2 Free Base yl)pyridin-3-yl)-5-4- (trifluoromethyl)pyrimidin-2- yl)aminophenyl)acetamide US 9,376,418 B2 158 TABLE 7A-continued Rey r CF3 2 21 h O

N N N H H M+H" M+H" Example R& Name Calc'd Obswo Form(s) 7.5 H N-(3-6-(3-oxopiperazin-1- 472.2 472.1 Free Base O N yl)pyridin-3-yl)-5-4- (trifluoromethyl)pyrimidin-2- yl)aminophenyl)acetamide N

Example 7.6 25 and the product was collected by filtration. The product was (2S)-1-(5-(3-methyl-5-4-(trifluoromethyl)pyrimi washed with cold DCM to yield N-3-(6-fluoropyridin-3-yl)- din-2-yl)amino)phenyl)pyridin-2-yllaZetidine-2- 5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine as a carboxylic acid 30 green-tinted solid. MS APC calc’d for C7HFN M-H 349. found 349. "H NMR (500 MHz, DMSO-d) & 10.27 (s, 1H), 8.82 (d. J–4.8 Hz, 1H), 8.45 (s, 1H), 8.18 (td, J=2.4 Hz, 7.6 8.2 Hz, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.31-7.24 (m, 2H), 35 7.18 (s, 1H), 3.32 (s.3H).

{)-N OH Step 2: NN N-3-(6-Fluoropyridin-3-yl)-5-methylphenyl)-4-(trifluo F 40 F F 2 romethyl)pyrimidin-2-amine (15.0 g, 43.1 mmol), (2S)-aze tidine-2-carboxylic acid (5.23 g, 51.7 mmol) and tripotas sium phosphate (18.3 g, 86.0 mmol) are flushed and purged 21 NN with N(g)(3x) and DMSO (107 mL) was added. The reac 45 Nulls tion mixture was heated to 130° C. for 6 hours, then cooled to room temperature and was stirred overnight. The CELITE was added to the reaction mixture, filtered and precipitated by Step 1: 2-Methyl-THF (123 mL), sodium carbonate (2M, 18.5 mL, 50 addition of acetonitrile (ca. 300 mL). The crude product was 36.9 mmol) and 5-bromo-2-fluoropyridine (7.15 g, 40.6 collected by filtration and purified by reverse phase chroma mmol) were added to N-3-methyl-5-(4.4.5.5-tetramethyl-1, tography to yield (2S)-1-(5-(3-methyl-5-4-(trifluorom 3.2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimi ethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)azetidine din-2-amine (14.g., 36.9 mmol) and the reaction mixture was 55 2-carboxylic acid. MS ESI calc’d for CHFNOM+H" purged and flushed with Ar(g) (3x) before adding PdCl 430. found 430. "H NMR (600 MHz, CDC1) & 8.64 (d. J=4.7 (dppf)-dichloromethane adduct (1.51 g, 1.85 mmol). The HZ, 1H), 8.29 (s, 1H), 7.85 (d. J=8.5 Hz, 1H), 7.77 (s, 1H), reaction mixture was heated to 85°C. overnight. Another 7.43 (s, 1H), 7.27 (s, 1H), 7.06-6.94 (m, 2H), 6.50 (d. J–8.6 portion of 5-bromo-2-fluoropyridine (2.00 g) and PdCl 60 HZ, 1H), 4.88 (t, J=8.1 Hz, 1H), 3.90 (dd, J=8.2 Hz, 16.3 Hz, (dppf)-dichloromethane adduct (300 mg, 0.368 mmol) were 2H), 3.03-2.88 (m, 1H), 2.49 (d. J=8.3 Hz, 1H), 2.40 (s.3H). added to the reaction mixture and heated to 85°C. overnight. The reaction mixture was cooled to room temperature and 65 The following examples in Tables 7B-7C were prepared in concentrated under reduced pressure. A hot solution of 10% an analogous manner to that described in general scheme 7 water, 20% DCM and 70% MeCN was added to the residue using known or commercially available amines in step 2.