Novel PRMT5 inhibitors

Abstract

The present invention provides compounds of formula I and their pharmaceutically acceptable salts, stereoisomers, tautomers, and pharmaceutical compositions thereof: The compounds of the present invention are useful for inhibiting PRMT5 activity and may have applications in the treatment of proliferative, metabolic and hematological disorders. Compounds of formula I have the following structure: TIFF2026041912000268.tif56167 The present invention further provides a method of treating cancer, comprising administering to a subject an effective amount of a compound of the present invention, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Description

[Background technology]

[0001] Epigenetic regulation of gene expression is a key biological determinant of protein production and cell differentiation, and plays an important pathogenetic role in many human diseases.

[0002] Epigenetic regulation involves genetic modification of genetic material without altering its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones), which control the conformational transition of chromatin between transcriptionally active and inactive states. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that can cause human disease. PRMT5 influences diseases such as proliferative, metabolic, and hematological disorders. Summary of the Invention [Problem to be solved by the invention]

[0003] Homozygous deletion of tumor suppressor genes is a major driver of cancer and often results in the concomitant loss of passenger genes located closely genomically to the tumor suppressor. These passenger gene deletions can create specific, therapeutically tractable vulnerabilities in tumor cells. Homozygous deletions of the chromosome 9p21 locus harboring the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A) are present in 15% of all tumors and frequently involve deletion of the passenger gene MTAP (methylthioadenosine phosphorylase), a key enzyme in the methionine and adenine salvage pathway. Deletion of MTAP leads to the accumulation of its substrate, methylthioadenosine (MTA). MTA shares close structural similarity with S-adenosylmethionine (SAM), the methyl donor substrate for the type II methyltransferase PRMT5. Increased MTA levels promoted by MTAP loss selectively compete with SAM for binding to PRMT5, rendering the methyltransferase in a hypomorphic state susceptible to further PRMT5 inhibition. Multiple genome-scale shRNA dropout screens performed in a large panel of tumor cell lines revealed a strong correlation between MTAP loss and cell line dependence on PRMT5, further highlighting the strength of this metabolic vulnerability. However, PRMT5 is a known cellular essential gene, and conditional PRMT5 knockout and siRNA knockdown studies suggest that inhibition of PRMT5 in normal tissues may be associated with significant drawbacks (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, etc.). Therefore, novel strategies are needed to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-null tumors while sparing PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with MTA-cooperative small molecule inhibitors allows us to preferentially target the MTA-bound state of PRMT5, which is abundant in MTAP-null tumor cells, while improving the therapeutic index against normal cells in which MTAP is intact and MTA levels are low. [Means for solving the problem]

[0004] In one aspect, the present invention provides a compound of formula I [ka] (In the formula, [ka] represents a single or double bond; X 1 and X 2 are both independently N or C; X 1 is C, C is halo or C 1~6 may be optionally substituted with alkyl; Ar is a 6-membered aromatic ring having 0-2 N atoms, and each Ar is a groups; R a In each case, cyano, halo, optionally substituted C 1~6 Alkyl, C 1~6 Haloalkyl, OR b , N.R. c R d , -C(O)NR c R d , =S, -SO2, -SO2C 1~6 Alkyl, -C(O)H, -C(O)C 1~6 Alkyl, C(O)OC 1~6 alkyl, difluoro-pyrrolidinyl, and a 4-6 membered heterocycle having 0-2 heteroatoms independently selected from O and N, and the heterocycle is independently selected from 0-2 halogen, C 1~6 Alkyl, -C(O)H, -C(O)C 1~6 may be further independently substituted with alkyl or optionally substituted cycloalkoxyl; Each R b is, in each case, H, optionally substituted C 1~6 alkyl (wherein the substituents may be selected from halo) or oxetanyl; each R c and R d is H, C 1~3 Alkyl, C 1~3independently selected from haloalkyl or -CO; R e is in each case H or C 1~6 alkyl; R f and R g In each case, H and C 1~6 independently selected from alkyl; R is H or methyl; R 1 and R 2 is, in each case, H, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkynyl, -C(OR e ), optionally substituted single and double cyclyl having 0-3 N, S or O atoms, where the substituents are halo, optionally substituted C 1~6 Alkyl, -C(O)NR f R g , OH, and an optionally substituted 5-membered ring having 0-3 N atoms; or R 1 and R 2 and the carbon atoms to which they are attached can form an optionally substituted single or double carbocyclic or heterocyclic ring which can be saturated, partially saturated, or aromatic, and further, the heterocyclic ring contains 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the substituent is an optionally substituted C 1~6 Alkyl, Halo, CN, OR e and -C(OR e ) selected from the group However, R 1 and R 2 provided that both are not simultaneously H; R 3 and R 4 is, in each case, H, halogen, alkynyl, cyano, and C optionally substituted with halo or deuterium; 1~6 alkyl) or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0005] In one aspect, the present invention provides a method for producing a compound comprising: 1 In another embodiment, the compound is provided wherein X is C. 2 can be C.

[0006] In one aspect of the invention, the compounds of the invention have formula IA: [ka] is expressed by

[0007] In another embodiment, the compound has formula IB: [ka] It can be represented by:

[0008] In one aspect of the present invention, X 2 can be N. In another aspect of the invention, X 1 can be N.

[0009] In a further aspect, the present invention provides compounds, their tautomers, their stereoisomers, or pharmaceutically acceptable salts of any of the foregoing, wherein Ar can be pyridinyl. In another aspect, Ar can be pyradazinyl. In a further aspect, Ar can be pyrazinyl. In another aspect, Ar can be phenyl.

[0010] The present invention is 1 and R 2 Further provided is a compound, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 and R 2 may each independently be selected from methyl and pyridinyl. 1 and R 2 is H, methyl, C1~6 Each of the groups may be independently selected from alkyl and optionally substituted mono- or bi-cyclyl having 0-3 N, S, or O atoms. In one aspect, cyclyl is optionally substituted thiophenyl, optionally substituted thiazolyl, or optionally substituted oxazolyl. In one aspect of the invention, R 1 and R 2 and the carbon atoms to which they are attached can form an optionally substituted single or double carbocyclic or heterocyclic ring which may be saturated, partially saturated, or aromatic, and further, the heterocyclic ring contains 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0011] In one aspect, R 4 can be methyl or halogen.

[0012] In one aspect, R a is cyano, halo or optionally substituted C 1~6 It can be alkyl.

[0013] The present invention provides 2-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-methoxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7R)-4,5,6,7-tetrahydro-1H-indazol-7-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(6-cyano-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(1,3-thiazol-4-yl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(1,2,4-oxadiazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-pyrazinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5-methyl-2-pyrazinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-(2-pyrazinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-((5-methyl-1,2-oxazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrazinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyrimidinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-pyrimidinylmethyl)-6-quinolinecarboxamide, 2-amino-N-((5-fluoro-2-pyrimidinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((3-fluoro-2-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((3-fluoro-2-pyridinyl)methyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-methyl-N-((1R)-1-(2-pyrazinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-(cyclopropylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((3,5-difluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3,5-difluoro-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((8R)-5,6,7,8-tetrahydro-8-quinolinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((8R)-5,6,7,8-tetrahydro-8-isoquinolinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(5-methyl-1,2-oxazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-cyclopropylethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-methylpropyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((4R)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(methylsulfonyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-(4-(trifluoromethyl)benzyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-(2-methyl-4-(trifluoromethyl)benzyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(cyclopropylsulfonyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-N-((1R)-1-(3-chloro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-chloro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(4-fluorophenyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-ethynyl-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((7R)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-(2-pyridinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, methyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((3-fluoro-2-pyridinyl)methyl)amino)methyl)-3-pyridinecarboxylate, 2-amino-N-((5-(difluoromethoxy)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, methyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((1R)-1-(3-fluoro-2-pyridinyl)ethyl)amino)methyl)-3-pyridinecarboxylate, 2-amino-N-((5-(dimethylcarbamoyl)-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1-(2-pyrimidinyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-1,3-thiazol-2-yl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(3-pyridinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2-amino-1,3-thiazol-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3,5-difluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5-((2H_3_)methyloxy)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(4-carbamoylbenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-3-methyl-N-((3R)-1-methyl-2-oxo-3-piperidinyl)-6-quinolinecarboxamide, 2-amino-N-((5-(dimethylcarbamoyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((4R)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-pyridinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3-methyl-2-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4-methyl-1,3-thiazol-2-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(1-piperidinyl)benzyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-(cyclobutylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1,2,3-thiadiazol-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1H-indol-3-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5-methyl-1,3-oxazol-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-3-methyl-N-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4-methyl-1,3-thiazol-5-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-fluoro-4-(hydroxymethyl)benzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-amino-3-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-3-methyl-N-((3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1,3-oxazol-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3R)-1-methyl-2-oxo-3-piperidinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3R)-2-oxo-3-piperidinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R)-1-cyclopropyl-2-oxo-3-piperidinyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-methyl-6-(trifluoromethyl)-3-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(4-cyanobenzyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-fluorophenyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-chloro-3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-cyclopropyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-7-chloro-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-methoxy-2-pyrazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyrazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-6-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-methyl-2-propanyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((1R)-1-(2-pyrimidinyl)ethyl)amino)methyl)-3',6'-dihydro[3,4'-bipyridine]-1'(2'H)-carboxylate, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3,7-dimethyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, N-((1'-acetyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl)methyl)-2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-carbamoyl-2-pyridinyl)methyl)-N-((1R)-1-(2-fluorophenyl)ethyl)-3-methyl-6-quinolinecarboxamide, 7-amino-6-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1H-indazol-5-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2,4-difluorophenyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-(~2~H_3_)methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-(2-quinolinylmethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-(3-quinolinylmethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-7-fluoro-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl))ethyl)-6-quinolinecarboxamide, 2-amino-3-(~2~H_3_)methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-(5,6-dihydro-2H-pyran-3-yl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl))ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-((1S)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,7-naphthyridine-6-carboxamide, 2-amino-3-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(2-methoxyethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-ethoxy-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-7-chloro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-2-methoxy-1-(2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-2-methoxy-1-(2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3,4-dimethyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3,4-dimethyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-3-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1H-indazol-4-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 7-amino-6-bromo-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)propyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(cyclopropyloxy)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-(2H_3_)methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-(3,3-difluoro-1-pyrrolidinyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-7-fluoro-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-(2H)methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-6-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 7-amino-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((6-(dimethylamino)-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)propyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((1R)-1-(2-pyrimidinyl)ethyl)amino)methyl)-3',6'-dihydro[3,4'-bipyridine]-1'(2'H)-carboxylate methyl, 2-amino-N-((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-(3,3-difluoro-1-azetidinyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((2S)-3,3,3-trifluoro-2-methoxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(1,3-dimethoxy-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5R)-5,6,7,8-tetrahydro-5-quinoxalinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5S)-5,6,7,8-tetrahydro-5-quinoxalinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-((2,2,2-trifluoroethyl)amino)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-chloro-2-pyridinyl)ethyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((1R,2R)-2-hydroxycyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-hydroxycyclopentyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-chloro-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-7-fluoro-3-methyl-6-quinolinecarboxamide, 2-amino-3-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-6-fluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((5-(trifluoromethyl))-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((6-(3,6-dihydro-2H-pyran-4-yl)-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl))ethyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((6-(3,6-dihydro-2H-pyran-4-yl)-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl))ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(1,3-thiazol-2-yl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(1,3-thiazol-4-yl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-(difluoromethyl)-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R,2R)-2-hydroxycyclopentyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R,2R)-2-hydroxycyclopentyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R,2R)-2-hydroxycyclopentyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-hydroxycyclopentyl)-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(1,3-thiazol-2-yl)ethyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-3-methyl-6-quinolinecarboxamide, 7-amino-6-bromo-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-6-fluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((6-(trifluoromethyl))-3-pyridazinyl)methyl)-6-quinolinecarboxamide, N-((5-(1-acetyl-4-piperidinyl)-2-pyridinyl)methyl)-2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-(3-oxetanyloxy)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((5-(3-oxetanyloxy)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5R)-5,6,7,8-tetrahydro-5-quinoxalinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-chloro-6-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((2-methoxy-6-(trifluoromethyl)-3-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((3R,4S)-4-hydroxytetrahydro-3-furanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-bromo-6-methyl-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(6-cyano-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((1S)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-1-methoxy-2-propanyl)-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-2-methyl-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-2-methyl-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, methyl 4-(6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((1R)-1-(2-pyrimidinyl)ethyl)amino)methyl)-3-pyridinyl)-1-piperidinecarboxylate, 2-amino-3-methyl-N-((8R)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-2-pyridinyl)methyl)-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((2S)-3,3,3-trifluoro-2-methoxypropyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(2-fluoro-4-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(2-fluoro-4-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-(trifluoromethoxy)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-cyano-3-pyridazinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-4,4-difluoro-2-hydroxycyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3,5-dimethyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-1-methoxy-2-propanyl)-3,5-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-2-pyridinyl)methyl)-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, N-((5-acetyl-2-pyridinyl)methyl)-2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-(2-hydroxy-2-propanyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-methoxy-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-methoxy-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-7-chloro-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1S)-1-(1,3-thiazol-4-yl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((6-methoxy-3-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((R)-cyclopropyl(2-pyrimidinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-7-fluoro-3-methyl-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-(1,2,4-oxadiazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethoxy)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethoxy)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-isoquinolinylmethyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(3-isoquinolinylmethyl)-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R,2R)-2-methoxycyclohexyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((1S,2S)-2-methoxycyclohexyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-chloro-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-bromo-3-pyridazinyl)methyl)-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-6-quinolinecarboxamide, 7-amino-6-iodo-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-(4-(3-oxetanyl)benzyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(3-oxetanyl)benzyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-cyclopropyl-2-methoxyethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-1-cyclopropyl-2-methoxyethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R,4R)-4-fluorotetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(6-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-7-fluoro-3-methyl-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 7-amino-N-((5-chloro-2-pyridinyl)methyl)-6-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((1R)-1-(6-fluoro-2-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((5-(4-morpholinyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)propyl)-6-quinolinecarboxamide, 2-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-(difluoromethoxy)cyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-2-(difluoromethoxy)cyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-chloro-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-cyano-2-methyl-3-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(2-methylpropyl)-3-phenyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-5-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-iodo-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-cyclopropyl-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((4-chloro-5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((6-(methylamino)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-cyano-2-pyridinyl)methyl)-5-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-bromo-N-((1S)-1-cyclopropyl-2-methoxyethyl)-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((4-chloro-5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1S)-2-cyano-1-cyclopropylethyl)-N-((5-cyano-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4-ethyl-1,3-thiazol-2-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-((3R)-tetrahydro-3-furanyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-((3S)-tetrahydro-3-furanyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-((3R)-tetrahydro-3-furanyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-((3S)-tetrahydro-3-furanyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-chloro-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-3-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1S,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1S,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1-cyanocyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R,2R)-2-methylcyclopentyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1R,2S)-2-methylcyclopentyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1S,2R)-2-methylcyclopentyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1S,2S)-2-methylcyclopentyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((2R,3R)-2-cyclopropyltetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((2R,3S)-2-cyclopropyltetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((2S,3R)-2-cyclopropyltetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((2S,3S)-2-cyclopropyltetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-((1S)-2-cyano-1-cyclopropylethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-chloro-5-cyano-2-pyridinyl)methyl)-3-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-iodo-N-((1R)-1-(2-pyrimidinyl)propyl)-6-quinolinecarboxamide, 2-amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-3-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-2-cyano-1-cyclopropylethyl)-N-((5-cyano-2-pyridinyl)methyl)-3-iodo-6-quinolinecarboxamide, 2-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-3-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-7-hydroxy-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-6-iodo-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4R)-4,5,6,7-tetrahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4S)-4,5,6,7-tetrahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4S)-2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R)-2,3-dihydro-1-benzofuran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3S)-2,3-dihydro-1-benzofuran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-methoxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-fluoro-3-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5S)-4,5,6,7-tetrahydro-1H-benzimidazol-5-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-hydroxybenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-6-methyl-2,3-dihydro-1H-inden-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-6-methyl-2,3-dihydro-1H-inden-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(4-(4-carbamoyl-1-piperidinyl)benzyl)-N-((2R)-2-cyclopropylpropyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-(4-(4-carbamoyl-1-piperidinyl)benzyl)-N-((2S)-2-cyclopropylpropyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((2R)-2-cyclopropylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-2-cyclopropylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, (6R)-2-amino-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-5,6,7,8-tetrahydro-6-quinolinecarboxamide, (6S)-2-amino-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-5,6,7,8-tetrahydro-6-quinolinecarboxamide, 2-amino-N-((2R)-2-ethoxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-2-ethoxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1,3-dimethyl-1H-indol-2-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-N-((5-fluoro-3-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7S)-4,5,6,7-tetrahydro-1H-indazol-7-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-N-((1R,2R)-2-cyanocyclopentyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((1R,2S)-2-cyanocyclopentyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((1S,2R)-2-cyanocyclopentyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((1S,2S)-2-cyanocyclopentyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((1R,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((1S,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((1S,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((1R,2R)-2-cyanocyclopentyl)-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2S)-2-cyanocyclopentyl)-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2R)-2-cyanocyclopentyl)-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-2-cyanocyclopentyl)-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1S,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(4-(4-carbamoyl-1-piperidinyl)benzyl)-3-methyl-N-((4-methyl-1,3-thiazol-5-yl)methyl)-6-quinolinecarboxamide, 2-amino-N-(4-(4-carbamoyl-1-piperidinyl)benzyl)-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-((1-cyanocyclopropyl)methyl)-3-methyl-N-(4-(1-piperidinyl)benzyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-(1,2,4-oxadiazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1-cyanocyclopropyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-cyclobutylethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4-chloro-1-methyl-1H-pyrrol-2-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrol-3-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-(1,2-oxazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-3-methyl-N-(cis-3-(4-(trifluoromethoxy)phenyl)cyclobutyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-3-methyl-N-(trans-3-(4-(trifluoromethoxy)phenyl)cyclobutyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-4-pyridinyl)methyl)-3-methyl-N-((2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-3,4-dihydro-1H-2-benzopyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4S)-3,4-dihydro-1H-2-benzopyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R,3R)-3-methyl-2,3-dihydro-1H-inden-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R,3S)-3-methyl-2,3-dihydro-1H-inden-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S,3R)-3-methyl-2,3-dihydro-1H-inden-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S,3S)-3-methyl-2,3-dihydro-1H-inden-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R,4R)-4-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R,4S)-4-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S,4R)-4-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S,4S)-4-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-8-methoxy-3,4-dihydro-2H-chromen-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4S)-8-methoxy-3,4-dihydro-2H-chromen-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4R)-4,5,6,7-tetrahydro-1H-indol-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4S)-4,5,6,7-tetrahydro-1H-indol-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7R)-2-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-7-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7S)-2-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-7-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4R)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4S)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R)-6,7-dimethyl-2,3-dihydro-1-benzofuran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3S)-6,7-dimethyl-2,3-dihydro-1-benzofuran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-2-methoxy-3-methylbutyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-2-methoxy-3-methylbutyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7R)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7S)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-6-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2-amino-1H-benzimidazol-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1H-indazol-6-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1-benzofuran-6-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1H-indol-5-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(5-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-oxo-1,2-dihydro-3-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-4-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,4R,7aR)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,4R,7aS)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,4S,7aR)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,4S,7aS)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,4R,7aR)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,4R,7aS)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,4S,7aR)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,4S,7aS)-octahydro-1-benzofuran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R)-4-methyl-2-pentanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-4-methyl-2-pentanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-carbamoyl-3-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(methylcarbamoyl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((3-bromo-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((2R,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R)-3-methyl-2-butanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-3-methyl-2-butanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-methylpropyl)-N-(4-(1-pyrrolidinyl)benzyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-methylpropyl)-N-(3-(1H-1,2,4-triazol-1-yl)benzyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(2-oxo-1-pyrrolidinyl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(1-pyrrolidinyl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(1H-pyrazol-3-yl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-(1H-imidazol-1-yl)benzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(3-(1H-1,2,4-triazol-1-yl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-(1H-imidazol-2-yl)benzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(3-(1H-1,2,3-triazol-1-yl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl))methyl)-6-quinolinecarboxamide, 2-amino-N-(2-(1H-imidazol-1-yl)benzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-(1H-pyrazol-1-yl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-propyn-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-3-butyn-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-3-butyn-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-butyn-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(4-hydroxy-2-butyn-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-butyn-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-((1R)-2,2,2-trifluoro-1-hydroxyethyl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-((1S)-2,2,2-trifluoro-1-hydroxyethyl)benzyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(4-hydroxybenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-fluoro-4-hydroxybenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-hydroxyphenyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(3-hydroxyphenyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-oxo-1,2-dihydro-4-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-(2-oxo-1,2-dihydro-4-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4-bromo-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((8R)-4-methoxy-5,6,7,8-tetrahydro-8-quinolinyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((8S)-4-methoxy-5,6,7,8-tetrahydro-8-quinolinyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5R)-5,6,7,8-tetrahydro-5-quinolinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5S)-5,6,7,8-tetrahydro-5-quinolinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6R)-2-amino-5,6,7,8-tetrahydro-6-quinazolinyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6S)-2-amino-5,6,7,8-tetrahydro-6-quinazolinyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,5R,7aR)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,5R,7aS)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,5S,7aR)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aR,5S,7aS)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,5R,7aR)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,5R,7aS)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,5S,7aR)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3aS,5S,7aS)-octahydro-1H-inden-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5S)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((6R)-4,5,6,7-tetrahydro-1H-indazol-6-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((6S)-4,5,6,7-tetrahydro-1H-indazol-6-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5R)-4,5,6,7-tetrahydro-1H-indazol-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5S)-4,5,6,7-tetrahydro-1H-indazol-5-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-1-ethyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4S)-1-ethyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-1-hydroxy-2,3-dihydro-1H-inden-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2S)-1-hydroxy-2,3-dihydro-1H-inden-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2R)-1-hydroxy-2,3-dihydro-1H-inden-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S,2S)-1-hydroxy-2,3-dihydro-1H-inden-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1R,3R)-3-hydroxycyclopentyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1R,3S)-3-hydroxycyclopentyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1S,3R)-3-hydroxycyclopentyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1S,3S)-3-hydroxycyclopentyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1R,3R)-3-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1R,3S)-3-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1S,3R)-3-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(((1S,3S)-3-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R,3R)-3-(1H-pyrazol-1-yl)-2-butanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R,3S)-3-(1H-pyrazol-1-yl)-2-butanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S,3R)-3-(1H-pyrazol-1-yl)-2-butanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S,3S)-3-(1H-pyrazol-1-yl)-2-butanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(4-(2-amino-2-oxoethyl)benzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-3-amino-3-oxo-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-3-amino-3-oxo-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((3,5-difluoro-4-pyridinyl)methyl)-3-methyl-N-(4-(trifluoromethyl)benzyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-(4-hydroxybenzyl)-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-(1H-pyrrol-2-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-(2-hydroxybenzyl)-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-((5-amino-2-pyridinyl)methyl)-N-(1H-indol-3-ylmethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-pentyn-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-1-cyano-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-1-cyano-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-cyclopropylethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2R)-1-cyclopropyl-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2S)-1-cyclopropyl-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(cis-3-cyanocyclobutyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(trans-3-cyanocyclobutyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, and 2-Amino-N-(6,6-difluorospiro[3.3]heptan-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide Further provided is a compound selected from: a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0014] The present invention further provides a method of treating cancer, comprising administering to a subject an effective amount of a compound of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer is selected from ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0015] The present invention further provides a pharmaceutical composition comprising a compound of the present invention, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable excipient.

[0016] The present invention also provides a method of treating cancer, comprising administering to a subject an effective amount of a compound of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer can be ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0017] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition As used herein, when any variable occurs more than once in a chemical formula, its definition at each occurrence is independent of its definition at all other occurrences. When the chemical structure and chemical name conflict, the chemical structure determines the identity of the compound. The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, any chemical structure depicted in its relative configuration within all or part of this specification encompasses all possible enantiomers and stereoisomers of the exemplified compound, including stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be separated into their constituent enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art.

[0019] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds; racemates, enantiomers, diastereomers, geometric isomers, and individual isomers are all intended to be encompassed within the scope of the present invention. Furthermore, atropisomers and mixtures thereof resulting from restricted rotation around two aromatic or heteroaromatic rings bonded to each other are also intended to be encompassed within the scope of the present invention. For example, if a phenyl group is substituted with two groups bonded to the C atom adjacent to the point of attachment to the N atom of a triazole, the rotation of the phenyl may be restricted. In some cases, this rotational barrier is high enough to allow the different atropisomers to be separated and isolated.

[0020] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound, i.e., the compound is substantially free of other stereoisomers. For example, a stereoisomerically pure compound having one chiral center will be substantially free of mirror image enantiomers. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers. A typical stereoisomerically pure compound will contain more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer, more preferably more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer, even more preferably more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer, and most preferably more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer.

[0013] Where the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates where a group is attached to the rest of the molecule.

[0021] As known to those skilled in the art, certain compounds of the present invention may exist in one or more tautomeric forms. Because a chemical structure may only be used to represent one tautomeric form, for convenience, reference to a compound of a given structural formula will be understood to include all tautomers of the structure represented by the structural formula. Depending on the compound, some compounds may exist predominantly in one form rather than another. Also, depending on the compound and the energy required to convert one tautomer to the other, some compounds may exist as a mixture at room temperature, while others may be isolated in one or the other tautomeric form. Other examples of tautomers related to the compounds of the present invention are those with a pyridone group (pyridinyl), of which hydroxypyridine is a tautomer, and compounds with a ketone group, which have enol tautomers. Examples of these are shown below. [ka]

[0022] Compounds of the present disclosure include, but are not limited to, compounds of Formula I and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds listed herein include pharmaceutically acceptable salts, solvates, crystalline forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term "compound" encompasses not only the compound itself, but also its pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures of any of the foregoing. In some embodiments, the term "compound" encompasses the compound itself, pharmaceutically acceptable salts, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs, such as (C1-C4) alkyl esters. In other embodiments, the term "compound" encompasses the compound itself, pharmaceutically acceptable salts, tautomers of the compound, and pharmaceutically acceptable salts of the tautomers.

[0023] The term "solvate" refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0024] The compounds of the present invention may also contain naturally occurring or unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon 14 ( 14 Radiolabeled compounds may be radiolabeled with radioactive isotopes such as HCl (H), ...

[0025] "Alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, such as propan-1-yl and propan-2-yl, butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, butyl, such as tert-butyl, and the like. In certain embodiments, an alkyl group contains 1 to 20 carbon atoms. In some embodiments, an alkyl group contains 1 to 10 carbon atoms or 1 to 6 carbon atoms, while in other embodiments, an alkyl group contains 1 to 4 carbon atoms. In still other embodiments, an alkyl group contains 1 or 2 carbon atoms. Branched-chain alkyl groups contain at least 3 carbon atoms, typically 3 to 7, or in some embodiments, 3 to 6 carbon atoms. Alkyl groups having 1 to 6 carbon atoms may be referred to as (C1-C6) alkyl groups, and alkyl groups having 1 to 4 carbon atoms may be referred to as (C1-C4) alkyl groups. This nomenclature can also be used for alkyl groups with different numbers of carbon atoms. "Alkyl" also includes cycloalkyl.

[0026] "Alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z or E configuration (cis or trans) about the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl. In certain embodiments, alkenyl groups have 2 to 20 carbon atoms, and in other embodiments, 2 to 6 carbon atoms. Alkenyl groups having 2 to 6 carbon atoms are sometimes referred to as (C2-C6) alkenyl groups. "Alkenyl" also includes cycloalkenyl.

[0027] "Alkynyl" refers to an unsaturated branched or straight chain hydrocarbon having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, and the like. In certain embodiments, alkynyl groups have 2 to 20 carbon atoms, and in other embodiments, 2 to 6 carbon atoms. Alkynyl groups having 2 to 6 carbon atoms are sometimes referred to as -(C2-C6)alkynyl groups.

[0028] "Alkoxy" refers to the group -OR, where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groups contain 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms within the R group. Alkoxy groups containing 1 to 6 carbon atoms may be referred to as -O-(C1-C6)alkyl or -O-(C1-C6 alkyl) groups. In some embodiments, alkoxy groups may contain 1 to 4 carbon atoms and may be referred to as -O-(C1-C4)alkyl or -O-(C1-C4 alkyl) groups.

[0029] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes monocyclic carbocyclic aromatic rings, such as benzene. Aryl also includes bicyclic carbocyclic aromatic ring systems in which each ring is aromatic, such as naphthalene. Thus, aryl groups can include fused ring systems in which each ring is a carbocyclic aromatic ring. In certain embodiments, aryl groups contain 6 to 10 carbon atoms. Such groups include C6 to C8 10 They are sometimes referred to as aryl groups. However, aryl does not in any way encompass or overlap with heteroaryl, as defined separately below. Thus, when one or more carbocyclic aromatic rings are fused with an aromatic ring containing at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group as defined herein.

[0030] "Carbonyl" refers to the group -C(O), which may also be referred to as the -C(=O) group.

[0031] "Carboxy" refers to the group -C(O)OH, which may also be referred to as -C(=O)OH.

[0032] "Cyano" refers to the group --CN.

[0033] "Cycloalkyl" refers to a saturated cyclic alkyl group derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 3 to 8 ring members may be referred to as a (C3-C8)cycloalkyl, a cycloalkyl group having 3 to 7 ring members may be referred to as a (C3-C7)cycloalkyl, and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C4-C7)cycloalkyl. In certain embodiments, a cycloalkyl group is a (C3-C8)cycloalkyl group. 10 )cycloalkyl, (C3-C8)cycloalkyl, (C3-C7)cycloalkyl, (C3-C6)cycloalkyl or (C4-C7)cycloalkyl groups, which may be, using alternative terms, C3-C 10 It may be referred to as cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl or C4-C7 cycloalkyl group.

[0034] "Heterocyclyl" refers to a cyclic group containing at least one saturated (partially unsaturated) cyclic ring. A heterocyclyl group contains at least one heteroatom as a ring member. Typical heteroatoms include O, S, and N, which are independently selected. Heterocyclyl groups include monocyclic and bicyclic ring systems. Bicyclic heterocyclyl groups contain at least one non-aromatic ring with at least one heteroatom ring member, which may be fused to a cycloalkyl ring or to an aromatic ring (which may be carbocyclic or may contain one or more heteroatoms). The point of attachment of a bicyclic heterocyclyl group may be to the non-aromatic ring containing at least one heteroatom, or to another ring in the heterocyclyl group. For example, a heterocyclyl group derived by removing a hydrogen atom from one of the nine-membered heterocyclic compounds shown below may be attached to the remainder of a five- or six-membered molecule. [ka]

[0035] In some embodiments, heterocyclyl groups contain 5 to 10 ring members, of which 1, 2, 3, or 4, or 1, 2, or 3, are heteroatoms independently selected from O, S, or N. In other embodiments, heterocyclyl groups contain 3 to 7 ring members, of which 1, 2, or 3 heteroatoms are independently selected from O, S, or N. In such 3- to 7-membered heterocyclyl groups, when the ring contains only 3 ring members, only one of the ring atoms is a heteroatom, and when the ring contains 4 ring members, one or two heteroatoms are included. In some embodiments, heterocyclyl groups contain 3 or 4 ring members, one of which is a heteroatom selected from O, S, or N. In other embodiments, heterocyclyl groups contain 5 to 7 ring members, of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Heterocyclyl groups can be fully saturated or can contain one or more double bonds. Examples of such heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like. A substituted heterocyclyl may include one or more oxo (=O) or oxide (-O -) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-onyl, 3,4-dihydroisoquinolin-1(2H)-onyl, indolin-onyl, 1H-imidazo[4,5-c]pyridin-2(3H)-onyl, 7H-purin-8(9H)-onyl, imidazolidin-2-onyl, 1H-imidazol-2(3H)-onyl, 1,1-dioxo-1-thiomorpholinyl, and the like.

[0036] The term "comprising" is meant to be open-ended, i.e., all-inclusive and non-limiting. This term may be used interchangeably herein with "having" or "including." Comprising is intended to include any components or elements shown or listed, but not to exclude other components or elements.

[0037] "Disease" refers to any disease, disorder, condition, symptom, or manifestation.

[0038] "Halo" or "halogen" refers to a fluoro, chloro, bromo, or iodo group.

[0039] "Haloalkyl" refers to an alkyl group in which at least one hydrogen has been replaced with a halogen atom. Thus, the term "haloalkyl" includes monohaloalkyl (an alkyl substituted with one halogen atom) and polyhaloalkyl (an alkyl substituted with two or more halogen atoms). Representative "haloalkyl" groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. The term "perhaloalkyl," unless otherwise specified, refers to an alkyl group in which each of the hydrogen atoms has been replaced with a halogen atom. For example, the term "perhaloalkyl" includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

[0040] "Heteroaryl" refers to a monovalent aromatic heterocyclic group derived by removing one hydrogen atom from a single carbon atom of a parent heteroaromatic ring system. Heteroaryl groups typically contain 5 to 14 ring members, but more typically include 5-10 membered aromatic monocyclic, bicyclic, and tricyclic rings containing one or more, e.g., 1, 2, 3, or 4 (or in certain embodiments, 1, 2, or 3) heteroatoms selected from O, S, or N (the remaining ring atoms are carbon). In monocyclic heteroaryl groups, the single ring is aromatic and contains at least one heteroatom. In some embodiments, monocyclic heteroaryl groups can contain 5 or 6 ring members and can contain 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom, where the heteroatoms are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must contain a heteroatom, but both rings do not have to, although it is permissible. For example, the term "heteroaryl" includes a 5- to 7-membered aromatic heterocycle fused to a carbocyclic aromatic ring or to another aromatic heterocycle. In tricyclic aromatic rings, all three rings are aromatic and at least one of the rings contains at least one heteroatom. For fused, bicyclic, and tricyclic heteroaryl ring systems in which only one ring contains one or more heteroatoms, the point of attachment can be to the ring containing at least one heteroatom or to a carbocyclic ring. When the total number of S and O atoms in a heteroaryl group exceeds one, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in a heteroaryl group is two or less. In certain embodiments, the total number of S and O atoms in an aromatic heterocycle is one or less. Heteroaryl does not encompass or overlap with aryl, as defined above.Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, etc. In certain embodiments, the heteroaryl group can be a 5- to 20-membered heteroaryl, such as a 5- to 14-membered or 5- to 10-membered heteroaryl. In certain embodiments, heteroaryl groups can be derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole, benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

[0041] "Pharmaceutically acceptable" refers to something generally recognized for use in animals, and more specifically, humans.

[0042] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.

[0043] "Pharmaceutically acceptable excipients" refers to a wide variety of ingredients that can be combined with the compounds or salts of the present invention to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0044] "Stereoisomers" refer to isomers that differ in the arrangement of their atoms in space. Stereoisomers that are mirror images of each other and are optically active are termed "enantiomers" and those that are not mirror images of each other and are optically active are termed "diastereomers."

[0045] A "subject" includes mammals and humans. The terms "human" and "subject" are used interchangeably herein.

[0046] A "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment of the disease, disorder, or symptom. As one skilled in the art will recognize, this amount is typically not limited to a single dose but can include multiple doses over a significant period of time required to produce a therapeutic or prophylactic response in a subject. Thus, a "therapeutically effective amount" is not limited to the amount in a single capsule or tablet but can include multiple capsules or tablets, the dosage prescribed by a qualified physician or healthcare provider. A "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age and / or weight of the subject being treated. The appropriate amount in any given instance will be readily apparent to one skilled in the art or may be determined by routine experimentation.

[0047] "Treating" or "treatment" of any disease or disorder refers to arresting or ameliorating the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the risk of contracting the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the onset of the disease, disorder, or at least one clinical symptom of the disease or disorder, or reducing the risk of developing the disease, disorder, or at least one clinical symptom of the disease or disorder. "Treating" or "treatment" refers to inhibiting the disease or disorder physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both, or inhibiting at least one physical parameter, which may be imperceptible to the subject. Furthermore, "treating" or "treatment" refers to delaying the onset of the disease or disorder, or at least a symptom thereof, in a subject who may be exposed to or susceptible to the disease or disorder, even if the subject does not yet experience or show symptoms of the disease or disorder.

[0048] In some aspects, the compounds may be in the form of salts. Such salts may be anhydrous or associated with water as hydrates. In some embodiments, the compounds may be in neutral form as bases or acids.

[0049] Also provided are pharmaceutical compositions comprising a compound according to any one of the Examples, or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a stereoisomer of any of the foregoing, or a mixture thereof, and at least one pharmaceutically acceptable excipient, carrier, or diluent. In some such examples, the compound according to any one of the Examples, or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a stereoisomer of any of the foregoing, or a mixture thereof, is present in an amount effective to treat PRMT5-dependent cancer. In some embodiments, the pharmaceutical composition is formulated for oral delivery, while in other embodiments, the pharmaceutical composition is formulated for intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for once-daily, i.e., QD, oral administration; some such formulations are tablets in which the effective amount of active ingredient ranges from 1 mg to 100 mg, 5 mg to 80 mg, 10 mg to 50 mg, or 15 to 30 mg.

[0050] In some aspects, the subject is a mammal. In some such aspects, the mammal is a rodent. In other aspects, the mammal is a dog. In still other embodiments, the subject is a primate, and in some such embodiments, the subject is a human.

[0051] Pharmaceutical compositions or formulations for administering the compounds of the present invention can be conveniently provided in unit dosage form and can be prepared by any method known in the art.All methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more accessory ingredients.In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.In the pharmaceutical composition, the desired active compound is contained in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0052] The compounds of the present invention may be administered orally, mucosally (including sublingually, bucally, rectally, nasally, or vaginally), parenterally (including subcutaneously, intramuscularly, bolus injection, intraarterially, or intravenously), transdermally, or topically. In some aspects, the compounds of the present invention are administered mucosally (including sublingually, buccally, rectally, nasally, or vaginally), parenterally (including subcutaneously, intramuscularly, bolus injection, intraarterially, or intravenously), transdermally, or topically. In other aspects, the compounds of the present invention are administered orally. In yet other embodiments, the compounds of the present invention are not administered orally.

[0053] The compounds of the present invention, their pharmaceutically acceptable salts, their tautomers, their pharmaceutically acceptable salts of their tautomers, stereoisomers of any of the foregoing, or mixtures thereof, can be used in treating a number of conditions.

[0054] The compounds and compositions described herein are generally useful for inhibiting PRMT5. In some embodiments, provided are methods for treating a PRMT5-mediated disorder in a subject, comprising administering an effective amount of a compound described herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in need of treatment. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the subject is suffering from a PRMT5-mediated disorder (e.g., cancer, e.g., lymphoma, breast cancer, or pancreatic cancer). In other embodiments, the subject is susceptible to a PRMT5-mediated disorder (e.g., cancer, e.g., lymphoma, breast cancer, or pancreatic cancer).

[0055] As used herein, the term "PRMT5-mediated disorder" refers to any disease, disorder, or other condition that PRMT5 is known to affect. Accordingly, in some aspects, the present disclosure relates to treating or reducing the severity of one or more diseases that PRMT5 is known to affect.

[0056] In some aspects, provided herein are methods for inhibiting PRMT5 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition thereof.

[0057] In further aspects, compounds contemplated by the present invention are useful for treating proliferative disorders such as cancer. In certain aspects, compounds described herein are useful for treating lymphoma. In some embodiments, the lymphoma is mantle cell lymphoma (MCL). In some embodiments, the lymphoma is acute myeloid lymphoma (AML). In some aspects, cancer compounds described herein are useful for treating pancreatic cancer. In some aspects, cancer compounds described herein are useful for treating multiple myeloma (MM). In a further aspect, cancer compounds described herein are useful for treating breast cancer. The breast cancer can be estrogen receptor negative (ER-), or the breast cancer can be progesterone receptor negative (PR-). In a further embodiment, the breast cancer can be HER2-negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative, and HER2-negative, also referred to herein as "triple-negative breast cancer."

[0058] In further aspects, the breast cancer can be lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer (including, but not limited to, triple negative, HER-positive, estrogen receptor-positive, progesterone receptor-positive, HER and estrogen receptor-positive, HER and progesterone receptor-positive, estrogen and progesterone receptor-positive, and HER and estrogen and progesterone receptor-positive).

[0059] In one aspect, the compounds of the present invention are useful in the treatment of pancreatic cancer.

[0060] In another aspect, the compounds of the present invention are useful for treating NSCLC (non-small cell lung cancer). In one embodiment, the NSCLC can be squamous cell NSCLC. In another embodiment, the NSCLC can be adenocarcinoma.

[0061] In a further aspect, the cancer can be GBM. In a further aspect, the cancer can be mesothelioma. In one aspect, the cancer can be bladder cancer. In another aspect, the cancer can be esophageal cancer. In a further aspect, the cancer can be melanoma. In one aspect, the cancer can be DLBCL, HNSCC, or cholangiocarcinoma.

[0062] In some aspects, one or more compounds described herein are useful for treating any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, for example, a cancer that is PRMT5-responsive.

[0063] In one aspect, cancers that lack p53 (e.g., p53-null cancers) are less sensitive to PRMT5 inhibition than p53-positive cancers. Thus, a PRMT5-responsive cancer can be a p53-positive cancer. The term "p53-positive" refers to a cancer that does not lack p53 expression and / or activity. In some embodiments, one or more compounds described herein are useful for treating p53-positive cancers. In some aspects, a larger amount of one or more compounds described herein may be required to treat a p53-negative cancer (e.g., a p53-null cancer) than a p53-positive cancer.

[0064] In some aspects, the present disclosure provides methods for identifying a subject having a cancer that is susceptible to treatment with a PRMT5 inhibitor. In some embodiments, the method includes obtaining a sample from the subject; detecting the presence or absence of p53; and identifying the subject as having a cancer that is susceptible to treatment with a PRMT5 inhibitor if p53 is present in the sample. Thus, in some embodiments, a subject having a p53-positive cancer is identified as a subject for treatment with a PRMT5 inhibitor. In some embodiments, the method further includes administering to the subject a composition comprising a PRMT5 inhibitor.

[0065] In some embodiments, aspects of the present disclosure relate to methods for identifying a subject having a cancer that is insensitive (or less sensitive) to treatment with a PRMT5 inhibitor. In some embodiments, the method includes obtaining a sample from a subject; detecting the presence or absence of p53; and if p53 is not present in the sample (e.g., the cancer is a p53-null cancer), identifying the subject as having a cancer that is not sensitive to treatment with a PRMT5 inhibitor (e.g., a cancer that is less sensitive than a p53-positive cancer). In some embodiments, p53-negative cancers (e.g., p53-null cancers) are treated with a PRMT5 inhibitor, although a larger amount of a PRMT5 inhibitor may be required to treat a p53-negative cancer than a p53-positive cancer. However, in some embodiments, a subject having a p53-negative cancer (e.g., a p53-null cancer) is treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0066] "Sample" refers to any biological sample derived from a subject, including, but not limited to, cells, tissue samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cells, and cancer tissues. Detection of the presence or absence of p53 in a sample can be performed by any suitable method for detecting p53 nucleic acid or protein, such as nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, etc., or any combination thereof.

[0067] In some embodiments, one or more of the compounds described herein may be used to treat other types of cancer (including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, intravascular sarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, brain cancer (e.g., meningioma; glioma (e.g., astrocytoma, oligodendroglioma); medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, and the like). , colorectal cancer (e.g., colon cancer, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine carcinoma, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma, Ewing's sarcoma), eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), throat cancer (e.g., laryngeal cancer, pharyngeal cancer), nasopharyngeal cancer, oropharyngeal cancer), hematopoietic cancer (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenström's macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixed leukemia / lymphoma of one or more of the above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic leukemia, Alveolar tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), myelofibrosis (MF), myeloid metaplasia of unknown etiology (AMM), Chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis), neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer It will be appreciated that the compounds may be useful in the treatment of skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovium, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva).

[0068] In some aspects, a method of treating cancer in a subject comprises administering to the subject a composition comprising a PRMT5 inhibitor, wherein treatment with the PRMT5 inhibitor inhibits tumor growth of the cancer by more than about 25%, more than about 50%, more than about 75%, or more than about 90% (e.g., 25% to 50%, 50% to 75%, 75% to 90%, or 90% to 100%). In some embodiments, a method of treating cancer in a subject comprises administering to the subject a composition comprising a PRMT5 inhibitor, wherein methyl marks in the cancer are reduced by more than about 50%, more than about 75%, or more than about 80% (e.g., 50% to 75%, 50% to 80%, 80% to 90%, 80% to 100%, or 90% to 100%). Methyl marks refer to protein methylation, e.g., histone methylation (e.g., methylation of one or more lysine and / or arginine residues of a histone protein) or DNA methylation (e.g., epigenetic DNA methylation, e.g., methylated CpG sites). In some embodiments, the methyl mark level of a cell is a measure of the extent to which histones are methylated in the cell (e.g., at one or more specific lysine and / or arginine residues).

[0069] The invention will now be further described with reference to the following examples, which are intended to illustrate, but not in any way limit, the claimed invention. [Example]

[0070] Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification.

[0071] The following abbreviations are used to refer to the various reagents and solvents:

[0072] [Table 1]

[0073] [Table 2]

[0074] [Table 3]

[0075] General synthetic scheme Method A-1 [ka] Method A-2 [ka] Method B-1 [ka] Method B-2 [ka] Method C: One-pot, two-step synthesis [ka] Method D: One-step synthesis [ka] Method A: Compound I can be prepared from the reaction of acid IA with secondary amine IB-1 in the presence of a base such as EtN or DIPEA, an activating reagent such as HATU or PyBroP, in a solvent such as DMF or DMAc.

[0076] Method B: Compound I can be prepared from the reaction of an acid chloride IC with a secondary amine IB in the presence of a base such as EtN or DIPEA or pyridine in a solvent such as THF or dioxane or DCM. 2 If is not H, then Method A-PyBroP and Method B are preferred over Method A-HATU. 2If is not H, compound I can be subjected to chiral SFC to obtain a single enantiomer. Alternatively, chiral amine 1B-2 can be used in an amide coupling reaction (method A-2 or B-2) to obtain the final product as a single enantiomer. The more potent (IC in the HCT116 MTAP null cell viability assay) 50 (measured by ) enantiomer was assigned as (R)- and the less potent (IC in HCT116 MTAP null cell viability assay) 50 (measured by) was assigned to (S)-.

[0077] Method C: Compound I can be prepared by a variety of small-scale, one-pot, two-step protocols, as illustrated in general scheme Method C. Primary amine 1D can be combined with aldehyde 1E in a solvent specified in this method to give secondary amine (Int-1) as the crude product after imine formation and reduction. Secondary amine (Int-1) was reacted with acid IA using coupling reagents specific to this method to give product I after HPLC purification.

[0078] Method D: Compounds were synthesized by a variety of small-scale one-step protocols as illustrated in general Scheme D. A secondary amine (IB) was combined with an acid (IA) and treated with coupling reagents and solvent mixtures specific to this method to afford product I after HPLC purification.

[0079] Analytical U / HPLC The following equipment was used for analytical UHPLC: a Waters Acquity system equipped with an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) with a linear gradient of the binary solvent system (HO / CH3CN / HC02H (95 / 5 / 0.1% to 0 / 100 / 0.1%)) at ambient temperature, coupled with MS detection SQD I and a DAD; an Agilent Infinity I / II - TOF6230B / CLND Antek 8060 equipped with an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) with a linear gradient of the binary solvent system (HO / MeOH / HC02H (95 / 5 / 0.1% to 0 / 100 / 0.1%)) at a flow rate of 0.75 mL / min, coupled with a DAD;

[0080] Preparative HPLC The following equipment was used for preparative HPLC: Shimadzu equipped with a Merck Chromolith SpeedROD RP-18E (5 μm, 10 × 100 mm) with a linear gradient of the binary solvent system using a flow rate of 4-7 mL / min and UV detection at 254 nm, coupled with MS detection on a Shimadzu LCMS-2020. Nexera X2. A linear gradient was used (H2O / MeOH / HCO2H (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0081] Intermediates Intermediate 1: 2-amino-3-methylquinoline-6-carboxylic acid. [ka] To a stirred solution of propionitrile (59.9 mL, 837 mmol, Loba Chem) in DMSO (750 mL) in a round-bottom flask under a N atmosphere was added potassium tert-butoxide (1.0 M in THF, 837 mL, 837 mmol) at 0 °C. The mixture was then stirred for 15 minutes before being treated portionwise with methyl 4-amino-3-formylbenzoate (75 g, 419 mmol, Abovchem) and then heated at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (1000 mL), and extracted with ethyl acetate (2 × 1000 mL). The pH of the aqueous layer was adjusted to around 6.5 using 1.5 N HCl solution. The resulting solid was filtered, washed with water (2 × 1000 mL), followed by acetone (2 × 1000 mL), and dried under vacuum overnight. The solid was stirred in MTBE (1000 mL) for 12 h, filtered, and dried under vacuum to give acid 1 (52.3 g, 259 mmol, 61.8% yield). m / z (ESI): 203.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6):δ ppm 10.01(br s,1H),8.24(d,J=2.0Hz,1H),7.91(dd,J=8.7,2.0Hz,1H),7.86(s,1H),7.46(d,J=8.7Hz,1H),6.67(s,2H),2.22(s,3H).

[0082] Intermediate 1a: 2-amino-3-methyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid [ka] Methyl 2-acetamido-3-methylquinoline-6-carboxylate (1b). Methyl 2-amino-3-methylquinoline-6-carboxylate (1.00 g, 4.62 mmol) and triethylamine (1.3 mL, 9.25 mmol, Sigma-Aldrich Corporation) in DCM (23 mL) were added to a 150 mL round-bottom flask. Acetic anhydride (0.5 mL, 5.78 mmol, Sigma-Aldrich Corporation) was then added dropwise to the reaction mixture. The resulting reaction mixture was stirred overnight at room temperature under an inert (N2) atmosphere. The reaction mixture was concentrated in vacuo. The residue was triturated from EtOAc and heptane. The precipitate was collected, and the solid was washed with heptane to give the title compound (1b, 1.02 g, 3.96 mmol, 86% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.31(br s,1H),8.57(br s,1H),8.37(br s,1H),8.13(br d,J=8.2Hz,1H),7.92(br d,J=8.4Hz,1H),3.92(br s,3H),2.32-2.38(m,3H),2.18(br s,3H).m / z(ESI):259.1(M+H) + .

[0083] Methyl 2-acetamido-3-methyl-5,6,7,8-tetrahydroquinoline-6-carboxylate (1c). Methyl 2-acetamido-3-methylquinoline-6-carboxylate (0.35 g, 1.36 mmol) and platinum(IV) oxide (0.062 g, 0.271 mmol, Sigma-Aldrich) in TFA (3.3 mL) were placed in a glass reaction vessel. The reaction chamber was closed and sealed. The vessel was then purged with argon (3 times) and then with H (3 times). H (175 psi) was then added, and the vial was stirred at 6 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with DCM:CHCl:MeOH (1:1:0.1). The mixture was then treated with saturated aqueous NaHCO to adjust the pH to approximately 10. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extracts were filtered through a pad of Celite, and the Celite was then rinsed with 1:1 DCM:MeOH (3 times). The collected filtrate was dried over MgSO, filtered, and concentrated in vacuo to give the title compound (1c, 0.21 g, 0.80 mmol, 59% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.85(br s,1H),7.36(s,1H),3.63-3.66(m,3H),2.74-2.96(m,5H),2.09-2.18(m, 1H),2.07(s,3H),2.00(s,3H),1.78-1.92(m,1H).m / z(ESI):263.1(M+H) + Note: This reaction was carried out using the Biotage® Endeavor™ Catalyst Screening System.

[0084] 2-Amino-3-methyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (1a). To a 150 mL round-bottom flask were added methyl 2-acetamido-3-methyl-5,6,7,8-tetrahydroquinoline-6-carboxylate (0.630 g, 2.402 mmol) and 1,4-dioxane (4.8 mL). Lithium hydroxide (1.0 M in HO) (12 mL, 12.01 mmol, Sigma-Aldrich) was then added to the reaction mixture. The reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was partially concentrated in vacuo (to remove 1,4-dioxane). The residue was treated with 1 N HCl to adjust the pH to approximately 7-8. The precipitate was collected by filtration, and the solid was washed with water. The solid was dried in a vacuum oven (40 °C) for 3 h. This gave 2-amino-3-methyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (1a, 0.25 g, 1.21 mmol, 51% yield) as a tan solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.84(br s,1H),5.27(br s,2H),2.53-2.59(m,2H),2.49-2.53(m,1H),2.27-2.36(m,1H),1.90(br s,4H),1.73(br s,2H),1.59(br s,1H).m / z(ESI):207.2(M+H) + .

[0085] Intermediate 2: 2-amino-3-(methyl-D3)quinoline-6-carboxylic acid. This acid was prepared from propionitrile-3,3,3-D3 (C / D / N Isotopes Inc.) according to the procedure described for acid 1. m / z (ESI): 206.1 (M+H). + . 1 H NMR (methanol-D4,400MHz)δ 8.52(d,1H,J=1.9Hz),8.3-8.4(m,2H),7.72(d,1H,J=8.8Hz). [ka]

[0086] Intermediate 3: 2-amino-3-chloroquinoline-6-carboxylic acid. [ka] Methyl 2,3-dichloroquinoline-6-carboxylate (3a). To a solution of methyl 3-chloroquinoline-6-carboxylate (25.0 g, 113 mmol, PharmaBlock) in DCM (500 mL) was added mCPBA (64.9 g, 226 mmol) at 0 °C, followed by stirring at room temperature for 16 h. The reaction was quenched with saturated sodium bicarbonate (1500 mL) and extracted with DCM (2 × 1000 mL). The organic extract was washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated. The residue was stirred with diethyl ether (2 × 500 mL) for 10 min, and the diethyl ether was decanted. The resulting solid was dried under reduced pressure to give 3-chloro-6-(methoxycarbonyl)quinoline 1-oxide (23 g, 97 mmol, 86% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 8.95(d,J=1.7Hz,1H),8.76(d,J=1.9Hz,1H),8.58(d,J=9.1Hz,1H),8.39(t,J=1.3Hz,1H),8.26(dd,J=9.1,1.9Hz,1H),3.96(s,3H).

[0087] A mixture of 3-chloro-6-(methoxycarbonyl)quinoline 1-oxide (8.0 g, 33.7 mmol) and POCl (30 mL) was stirred at 80 °C for 2 hours and then concentrated under reduced pressure. The residue was treated with saturated sodium bicarbonate (500 mL) and extracted with ethyl acetate (2 × 1000 mL). The organic extract was washed with brine (NaCl) (500 mL), dried over NaSO, filtered, and concentrated. The crude material was absorbed onto a silica gel plug and purified by chromatography (7% EtOAc in hexanes) to give methyl 2,3-dichloroquinoline-6-carboxylate (3a, 6.5 g, 25.6 mmol, 76% yield) as a brown solid. m / z (ESI): 256.2 (M+H). + . 1H NMR (400 MHz, chloroform-d): δ ppm 8.53 (d, J = 1.9 Hz, 1H), 8.29-8.40 (m, 2H), 8.07 (dt, J = 8.8, 0.7 Hz, 1H), 4.02 (s, 3H).

[0088] Methyl 3-chloro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (3b). A mixture of methyl 2,3-dichloroquinoline-6-carboxylate (3a, 9.0 g, 35.1 mmol) and 4-methoxybenzylamine (9.18 mL, 70.3 mmol) in N-methyl-2-pyrrolidinone (100 mL) was stirred at 120 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with water (500 mL), and extracted with EtOAc (2 × 400 mL). The organic extract was washed with brine (500 mL) and dried over NaSO. The mixture was filtered and concentrated. The crude material was absorbed onto a silica gel plug and purified by chromatography (15–17% EtOAc in hexanes) to give compound 3b (11.9 g, 33.3 mmol, 95% yield) as a white solid. m / z (ESI): 357.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6):δ ppm 8.39(dd,J=9.4,1.3Hz,2H),8.00(dd,J=8.8,2.1Hz,1H),7.91(t,J=6.1Hz,1H),7.58(d,J=8.8 Hz,1H),7.30-7.40(m,2H),6.83-6.92(m,2H),4.66(d,J=6.0Hz,2H),3.87(s,3H),3.81(s,3H).

[0089] Methyl 2-amino-3-chloroquinoline-6-carboxylate 2,2,2-trifluoroacetate (3c). Methyl 3-chloro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (3b, 12.0 g, 28.9 mmol) was treated with TFA (22.28 mL, 289 mmol) at room temperature. The mixture was stirred at 60° C. for 16 hours and then concentrated under reduced pressure. The residue was triturated with diethyl ether, and the diethyl ether was decanted. The resulting white solid was dried under high vacuum to give compound 3c (5.45 g, 23.1 mmol, 80%). m / z (ESI): 237.1 (M+H). + .

[0090] 2-Amino-3-chloroquinoline-6-carboxylic acid (3). To a stirred solution of methyl 2,2,2-trifluoroacetate (3c, 18.0 g, 51.3 mmol) in MeOH and THF (4:1, 250 mL) was added a solution of lithium hydroxide (6.15 g, 257 mmol) in water (50 mL). After 16 h, the reaction mixture was concentrated under reduced pressure. The residue was cooled in an ice bath and acidified to pH 6.5 by the addition of 1.5 N HCl. The resulting off-white solid was filtered and dried under vacuum to give acid 3 (13.1 g, 49.4 mmol, 96% yield). m / z (ESI): 223.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.33-8.39(m,2H),7.99(dd,J=8.8,2.1Hz,1H),7.52(d,J=8.8Hz,1H),7.06-7.18(m,2H),6.73(br s,1H).

[0091] Intermediate 4: 2-amino-3-bromoquinoline-6-carboxylic acid. [ka] Diethyl (bromo(cyano)methyl)phosphonate (4a). To a stirred solution of diethyl (cyanomethyl)phosphonate (100.0 g, 565 mmol) in THF (3 L) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 621 mL, 621 mmol) at 0 °C, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was cooled to -78 °C, and 1-bromopyrrolidine-2,5-dione (121.0 g, 677 mmol) was added. The reaction mixture was slowly warmed to -10 °C and stirred at -10 °C to 0 °C for 3 h. The reaction mixture was quenched with 1.5 N HCl solution (2 L) and extracted with DCM (2 × 2 L). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (80 g) eluting with 20% to 25% ethyl acetate in hexane to give diethyl (bromo(cyano)methyl)phosphonate (4a, 100.0 g, 392 mmol, 69% yield) as a brown oil. m / z (ESI): 256.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6):δ ppm 5.92(d,J=16.3Hz,1H),4.30-4.21(m,4H),1.33-1.31(m,6H).

[0092] Methyl 2-amino-3-bromoquinoline-6-carboxylate (4b). To a suspension of sodium hydride (60% in mineral oil, 1.674 g, 41.9 mmol) in THF (75 mL) was added a solution of compound 4a (10.0 g, 39.1 mmol) in THF (75 mL) at 0 °C under N2. The resulting mixture was stirred for 30 min and then treated with a solution of methyl 4-amino-3-formylbenzoate (5.0 g, 27.9 mmol, Abovchem) in THF (15 mL). The reaction mixture was stirred at room temperature for 4 h and then quenched with water (100 mL). The resulting pale yellow solid was filtered and dried under vacuum to give 4b (4.7 g, 16.7 mmol, 60% yield). m / z (ESI): 280.9 (M+H). + . 1H NMR (400MHz, DMSO-d6): δ 8.59(s,1H),8.39(d,J=2.0Hz,1H),8.02(dd,J=8.8,2.1Hz,1H),7.54(d,J=8.8Hz,1H),7.11(s,2H),3.88(s,3H).

[0093] 2-Amino-3-bromoquinoline-6-carboxylic acid (4). To a stirred solution of compound 4b (4.7 g, 16.0 mmol) in THF (30 mL), water (15 mL), and MeOH (15 mL) was added lithium hydroxide (2.68 g, 64.0 mmol). After stirring for 4 h, the reaction mixture was concentrated, and the residue was acidified with 1.5 N HCl solution to a pH of approximately 6.0-6.5. The off-white solid was filtered and dried under high vacuum to give acid 4 (4.5 g, 100% yield). m / z (ESI): 266.9 (M+H). + . 1 H NMR (400MHz, DMSO-d6): δ 12.87(s,1H),8.57(s,1H),8.35(d,J=2.0Hz,1H),8.01(dd,J=8.8,2.0Hz,1H),7.50(d,J=2.0Hz,1H),7.05(s,2H).

[0094] Intermediate 5: 2-amino-7-fluoro-3-methylquinoline-6-carboxylic acid. [ka] 6-Bromo-7-fluoro-3-methylquinolin-2-amine (5a). Propionitrile (19.69 mL, 275 mmol, Loba Chemie), potassium tert-butoxide (1 M in THF, 275 mL, 275 mmol, Spectrochem), and DMSO (300 mL) were added to a round-bottom flask. The mixture was cooled in an ice bath and treated portionwise with 2-amino-5-bromo-4-fluorobenzaldehyde (30 g, 138 mmol, Biogene). The mixture was heated at 50° C. for 12 hours, then cooled to room temperature and slowly quenched with water (1 L). The precipitated white solid was filtered, washed with water (500 mL), and dried under vacuum. The white solid was triturated with diethyl ether (500 mL) and filtered to give compound 5a (25 g, 98 mmol, 71% yield). m / z(ESI):255.0(M+H) + . 1 H NMR (400MHz, DMSO-d6): δ ppm 7.97(d,J=8.0Hz,1H),7.73(s,1H),7.29(d,J=10.9Hz,1H),6.60(s,2H),2.19(s,3H).

[0095] Methyl 2-amino-7-fluoro-3-methylquinoline-6-carboxylate (5b). Compound 5a (10 g, 39.2 mmol), dppf (6.52 g, 11.76 mmol), triethylamine (13.6 mL, 98 mmol), and palladium(II) acetate (1.76 g, 7.84 mmol) in MeOH (60 mL) and dimethyl sulfoxide (60 mL) were added to a 250 mL autoclave pressure reactor. The reaction mixture was stirred at 80 °C under a CO atmosphere (100 psi) for 36 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 × 100 mL). The organic layer was concentrated under reduced pressure, and the crude material was absorbed onto a silica gel plug and purified by chromatography eluting with a gradient of 70 to 100% EtOAc in hexane to give compound 5b (6.0 g, 25.6 mmol, 65% yield) as an off-white solid. m / z(ESI):235.1(M+H) + . 1H NMR (400MHz, DMSO-d6): δ ppm 8.24(d,J=8.4Hz,1H),7.87(s,1H),7.17(dd,J=13.4,0.7Hz,1H),6.90(s,2H),3.86(s,3H),2.19(s,3H).

[0096] 2-Amino-7-fluoro-3-methylquinoline-6-carboxylic acid (5). To a stirred solution of compound 5b (6.0 g, 25.6 mmol) in THF (60 mL), MeOH (30 mL), and water (30 mL) was added lithium hydroxide monohydrate (3.22 g, 77 mmol). After stirring at room temperature for 12 h, the mixture was concentrated, and the residue was acidified to pH = 6 with 1.5 N HCl solution. The precipitated brown solid was filtered, washed with MeOH (50 mL), and azeotroped twice with toluene (30 mL) to give acid 5 (5 g, 19.04 mmol, 89% yield). m / z (ESI): 221.1 (M+H). + . 1 H NMR (400MHz, DMSO-d6): δ ppm 8.35(d,J=8.0Hz,1H),8.13(s,1H),7.99(br s,2H),7.42(d,J=12.1Hz,1H),2.22(s,3H).

[0097] Intermediate 6: 2-amino-7-chloro-3-methylquinoline-6-carboxylic acid. [ka] Methyl 4-amino-2-chloro-5-formylbenzoate (6a). Methyl 4-amino-2-chloro-5-iodobenzoate (398 mg, 1.28 mmol, Combi-Blocks Inc.), N-formylsaccharin (809 mg, 3.83 mmol, Combi-Blocks Inc.), palladium(II) acetate (28.7 mg, 0.128 mmol, Umicore AG & Co. KG.), 1,4-bis(diphenylphosphino)butane (109 mg, 0.256 mmol, Sigma-Aldrich Corporation), and triethylsilane (193 mg, 0.265 mL, 1.661 mmol, Sigma-Aldrich Corporation) were mixed with N,N-dimethylformamide (3 mL) in a sealed vial under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 minutes. Stirring was stopped, and triethylamine (388 mg, 0.539 mL, 3.83 mmol) was added carefully to minimize mixing (bubbles were observed). The reaction mixture was heated at 115 °C for 1 h, then cooled to room temperature and partitioned between EtOAc (80 mL) and saturated NH₄Cl (60 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0–30% EtOAc in heptane) afforded 6a (122 mg, 0.571 mmol, 45% yield) as a yellow solid. MS (ESI, +ve) m / z: 213.9 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 9.86 (1H, s) 8.21 (1H, s) 6.73 (1H, s) 3.90 (3H, s).

[0098] 2-Amino-7-chloro-3-methylquinoline-6-carboxylic acid (6). This acid was prepared from 6a according to the procedure described for acid 1. MS (ESI, +ve) m / z: 236.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.32(1H,s)8.19(1H,s)7.71(1H,s)2.28(3H,s).

[0099] Intermediates 7 and 8: 2-amino-4-methylquinoline-6-carboxylic acid and 2-amino-4-chloroquinoline-6-carboxylic acid. These acids were purchased from Labnetwork. [ka]

[0100] Intermediate 9: 2-((4-methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylic acid. [ka] Methyl 2,4-dichloro-3-methylquinoline-6-carboxylate (9a): A mixture of 4-aminomethylbenzoic acid (5.0 g, 33.1 mmol) and methylmalonic acid (4.3 g, 36.4 mmol) in phosphorus oxychloride (15.41 mL, 165 mmol) was heated at 90 °C for 5 h. It was cooled to room temperature and slowly transferred (using a pipette) to ice-cold saturated aqueous KOAc (100 mL). Once the entire reaction was quenched, the pH of the aqueous solution was adjusted to 10 by adding solid NaOH (exothermic). The mixture was extracted with DCM (4 × 70 mL). The organics were dried over MgSO, filtered, and concentrated in vacuo to give a yellow residue. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give methyl 2,4-dichloro-3-methylquinoline-6-carboxylate (9a, 5.45 g, 20.18 mmol, 61% yield) as a white solid. m / z (ESI): 270.0 (M+H). + .

[0101] Methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (9b): A mixture of methyl 2,4-dichloro-3-methylquinoline-6-carboxylate (9a, 3.0 g, 11.1 mmol) and 4-methoxybenzylamine (2.93 mL, 22.21 mmol) in NMP (37 mL) was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and then diluted with saturated NaHCO (50 mL) and extracted with EtOAc (3×50 mL). The organics were dried over MgSO, filtered, and concentrated in vacuo to give the crude material as a yellow oil (contains NMP). The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane) to give methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (9b, 3.6 g, 9.71 mmol, 87% yield) as a white solid. m / z (ESI): 371.0 (M+H). + .

[0102] Methyl 2-((4-methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylate (9c): Methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (9b, 0.80 g, 2.1 mmol) and Pd(PPh) (0.25 g, 0.22 mmol) in 1,4-dioxane (13 mL) were added to a 20 mL microwave vial. Trimethylaluminum (2.1 mL of a 2.0 M solution in toluene, 4.2 mmol) was then added to the solution. The vial was sealed and then heated in a microwave reactor at 130 °C for 3 h. The reaction mixture was carefully poured into saturated aqueous NaHCO (50 mL). The resulting solid was filtered and washed with EtOAc. The filtrate was extracted with EtOAc (3 × 30 mL). The organics were concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give methyl 2-((4-methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylate (9c, 396 mg, 1.13 mmol, 52% yield) as a pale yellow solid. m / z (ESI): 351.2 (M+H). + .

[0103] 2-((4-Methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylic acid hydrochloride (9): A mixture of methyl 2-((4-methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylate (9c, 150 mg, 0.43 mmol) in water / MeOH / THF (1:1:1, 8.56 mL) was treated with lithium hydroxide monohydrate (90 mg, 2.14 mmol) and then heated at 60 °C for 2 h. The solvent was concentrated in vacuo. The residue was adjusted to pH 2-3 by adding HCl (2N) and then evaporated (with toluene) to give 2-((4-methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylic acid hydrochloride (9, contaminated with 5 equivalents of LiCl) as an off-white solid. This product was used in the next step without further purification. The theoretical yield was taken into account. m / z (ESI): 337.1 (M+H). + .

[0104] Intermediate 10: 7-amino-6-methyl-1,8-naphthyridine-3-carboxylic acid hydrochloride. [ka] 7-Amino-6-methyl-1,8-naphthyridine-3-carbonitrile (10a). This molecule was prepared in a similar manner as described for 5a. m / z (ESI): 185.1 (M+H). + . 1 H NMR (400MHz, DMSO-d6): δ ppm 8.91(d,J=2.4Hz,1H),8.55(d,J=2.4Hz,1H),7.82(d,J=1.3Hz,1H),7.42(s,2H),2.24(s,3H).

[0105] 7-Amino-6-methyl-1,8-naphthyridine-3-carboxylic acid hydrochloride (10). A mixture of compound 10a (6.6 g, 35.8 mmol) and concentrated hydrochloric acid (66 mL) was heated at 80° C. for 16 hours, then cooled to room temperature and diluted with water (60 mL). The resulting solid was filtered and dried under vacuum to give acid 10 (2.5 g, 12.2 mmol, 34% yield). m / z (ESI): 204.1 (M+H). +. 1 H NMR (400MHz, DMSO-d6): δ ppm 13.72(s,1H),9.12(d,J=2.2Hz,1H),8.88(d,J=2.2Hz,1H),8.75(s,2H),8.31(s,1H),2.32(s,3H).

[0106] Intermediate 11: 7-amino-6-chloro-1,8-naphthyridine-3-carboxylic acid. [ka] Diethyl (chloro(cyano)methyl)phosphonate (11a). This molecule was prepared in a similar manner as described for 4a. m / z (ESI): 212.1 (MH). + . 1 H NMR (400MHz, DMSO-d6): δ ppm 6.20(d,J=17.3Hz,1H),4.29-4.22(m,4H),1.33-1.30(m,6H).

[0107] 6-Bromo-3-chloro-1,8-naphthyridin-2-amine (11b). To a 500 mL three-necked RB flask containing THF (300 mL) was added sodium hydride (2.98 g, 74.6 mmol). A solution of compound 11a (15.79 g, 74.6 mmol) in THF (75 mL) was added at 0 °C and stirred at the same temperature for 30 min. The mixture was treated with 2-amino-5-bromonicotinaldehyde (10 g, 49.7 mmol) and then stirred at room temperature for 4 h. The mixture was diluted with water (400 mL). The resulting yellow solid was filtered and azeotroped with toluene to give compound 11b (7.0 g, 27.1 mmol, 54% yield). m / z (ESI): 258.0 (M+H). + . 1 H NMR (400MHz, DMSO): δ ppm 8.77(d,J=2.6Hz,1H),8.38(d,J=2.6Hz,1H),8.24(s,1H),7.36(s,2H).

[0108] 7-Amino-6-chloro-1,8-naphthyridine-3-carboxylic acid (11). This molecule was prepared from 11b following the procedure described for acid 5 (carbonylation followed by saponification). m / z (ESI): 224.0 (M+H). + . 1 H NMR (400MHz, DMSO d6): δ ppm 13.19(s,1H),9.16(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.44(s,1H),7.60(s,2H).

[0109] Intermediate 12: 7-amino-6-bromo-1,8-naphthyridine-3-carboxylic acid. [ka] 7-Amino-6-bromo-1,8-naphthyridine-3-carbonitrile (12a). To a suspension of sodium hydride (60% in mineral oil, 1.63 g, 68 mmol) in THF (150 mL) was added a solution of diethyl (bromo(cyano)methyl)phosphonate (17.4 g, 68 mmol) in THF (100 mL) at 0 °C. The resulting mixture was stirred under a N atmosphere for 30 minutes. 6-Amino-5-formylnicotinonitrile (5.0 g, 34 mmol) was added portionwise to the reaction mixture. The mixture was stirred at room temperature for 4 hours and then quenched with water (50 mL). The brown solid was filtered and dried under vacuum to give 7-amino-6-bromo-1,8-naphthyridine-3-carbonitrile (12a, 5.5 g, 22.08 mmol, 65% yield). m / z(ESI):249.1(M+H) + . 1 H NMR (400MHz, DMSO-d6): δ ppm 9.03(d,J=2.4Hz,1H),8.63(d,J=2.5Hz,1H),8.50(s,1H).

[0110] Methyl 7-amino-6-bromo-1,8-naphthyridine-3-carboxylate (12b). A stirred solution of 7-amino-6-bromo-1,8-naphthyridine-3-carbonitrile (12a, 5.0 g, 20.07 mmol) in MeOH (60 mL) was treated with sulfuric acid (60 mL) at room temperature and stirred at 80 °C for 4 h. The reaction mixture was concentrated in vacuo and diluted with water (160 mL). The product was precipitated by adding NaOH solution (pH approximately 7.5-8.5). The solid was filtered, washed with MTBE, and dried under vacuum to give methyl 7-amino-6-bromo-1,8-naphthyridine-3-carboxylate (12c, 4.6 g, 16.3 mmol, 81% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 9.18(d,J=2.5Hz,1H),8.70(d,J=2.5Hz,1H),8.64(s,1H),3.90(s,3H).m / z(ESI):282.0(M+H) + .

[0111] 7-Amino-6-bromo-1,8-naphthyridine-3-carboxylic acid (12). To a stirred solution of 7-amino-6-bromo-1,8-naphthyridine-3-carboxylate (12b, 4.7 g, 16.7 mmol) in THF (50 mL), MeOH (50 mL), and water (50 mL) was added lithium hydroxide monohydrate (2.09 g, 50.0 mmol) at room temperature and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water (50 mL) and acidified to pH 6-6.5 with 1N HCl solution. The precipitated solid was filtered and dried under vacuum to give 7-amino-6-bromo-1,8-naphthyridine-3-carboxylic acid (12, 3.1 g, 11.5 mmol, 69% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 9.17(d,J=2.5Hz,1H),8.65(d,J=2.4Hz,1H),8.62(s,1H),7.43(br s,2H).m / z(ESI):267.9(M+H) +

[0112] Intermediate 13: 2-amino-3-methyl-1,7-naphthyridine-6-carboxylic acid. [ka] This molecule was prepared according to the procedure described for acid 1. m / z (ESI): 204.1 (M+H) + . 1 H NMR (400MHz, TFA d): δ ppm 9.74(s,1H),9.17(s,1H),8.61(s,1H),2.81(s,3H).

[0113] Intermediate 14: 2-amino-3-chloro-1,7-naphthyridine-6-carboxylic acid. [ka] This molecule was prepared according to the procedure described for acid 4. m / z (ESI): 224.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6): δ 11.01(s,1H),8.68(s,1H),8.41(s,1H),8.22(s,1H),7.23(s,2H).

[0114] Intermediate 15: 2-amino-3-bromo-1,7-naphthyridine-6-carboxylic acid. [ka] This molecule was prepared according to the procedure described for acid 4. m / z (ESI): 268.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6): δ ppm 8.71(s,1H),8.61(s,1H),8.24(s,1H),7.18(s,2H).

[0115] Intermediate 16: 2-amino-3-methylquinoline-6-carbonyl chloride hydrochloride. [ka] To a suspension of 2-amino-3-methylquinoline-6-carboxylic acid (1, 10.29 g, 50.9 mmol) in DCM (200 mL) was added HCl (14 mL of 4.0 M in dioxane, 56.0 mmol, Sigma-Aldrich) under nitrogen. The mixture was stirred for 10 minutes and then evaporated to dryness under reduced pressure. The resulting yellow solid was treated with thionyl chloride (91 g, 55.7 mL, 763 mmol, Sigma-Aldrich) followed by DMF (25 μL) and then heated at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with DCM (100 mL), and filtered through a fritted funnel. The solid was rinsed with 1:1 DCM:heptane (10 mL) and briefly dried under a stream of nitrogen to give intermediate 16 (12.86 g, 98% yield) as a free-flowing yellow powder. This material was used without further manipulation.

[0116] [Table 4]

[0117] Intermediate 18: 6-Bromo-N,N-bis-Boc-3-methyl-1,8-naphthyridin-2-amine. [ka] 6-Bromo-3-methyl-1,8-naphthyridin-2-amine (18a): 2-Amino-5-bromo-3-formylpyridine (1.79 g, 8.93 mmol, Combi-Blocks Inc.), propiononitrile (0.96 mL, 13.39 mmol, Aldrich), and potassium t-butoxide (150 g, 13.39 mmol) were added to a 25 mL glass vial. The mixture was heated at 70 °C for 2 h, then cooled to room temperature and added to water. The precipitated orange solid was collected by filtration. This was suspended in EtOAc, sonicated for several minutes, filtered, and dried in an oven to give 6-bromo-3-methyl-1,8-naphthyridin-2-amine (18a, 1.19 g, 5.00 mmol, 56% yield) as a light tan solid. m / z(ESI):238 / 240(M+H) + . 1H NMR(400MHz,DMSO-d6)δ ppm 8.66(d,J=2.51Hz,1H),8.27(d,J=2.72Hz,1H),7.75(d,J=0.84Hz,1H),6.86(br s,2H),2.23(d,J=1.05Hz,3H).

[0118] 6-Bromo-N,N-bis-Boc-3-methyl-1,8-naphthyridin-2-amine (18): A mixture of 6-bromo-3-methyl-1,8-naphthyridin-2-amine (18a, 890 mg, 3.74 mmol) in THF (15 mL) was treated with sodium hydride (299 mg, 7.48 mmol, 60% by weight in mineral oil) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and then treated with di-tert-butyl dicarbonate (1.71 g, 7.85 mmol) in THF (2 mL). The mixture was stirred at room temperature for 90 minutes and then heated at 60° C. for 18 hours. The mixture was cooled to room temperature, diluted with saturated aqueous NH4Cl, and extracted with EtOAc. The organic extract was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography through a Redi-Sep packed silica gel column (40 g) eluting with a gradient of 0–3% 2M NH3·MeOH in DCM to give intermediate 18 (0.61 g, 50% yield) as a tan solid. m / z (ESI): 438 / 440 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ ppm 9.11(d,J=2.51Hz,1H),8.81(d,J=2.51Hz,1H),8.39(d,J=0.84Hz,1H),2.37(d,J=0.63Hz,3H),1.36(s,18H).

[0119] Intermediate 19: 2-amino-3-ethylquinoline-6-carboxylic acid. [ka] This acid was prepared in a similar manner as described for Intermediate 1. m / z (ESI): 217.0 (M+H) + .

[0120] Intermediate 20: 2-(bis(4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylic acid. [ka] 6-Bromo-3-methylquinolin-2-amine (25 g, 105 mmol, PharmaBlock), 1-(chloromethyl)-4-methoxybenzene (49.5 g, 316 mmol), sodium iodide (7.90 g, 52.7 mmol), and THF (250 mL) were placed in a 500 mL round-bottom flask, and the reaction mixture was stirred at 0 °C for 30 minutes. To the reaction mixture, KHMDS (316 mL of 1 M in THF, 316 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 hours, then quenched with ice-cold water (250 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine solution (2 × 50 mL), dried (Na SO ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1% EtOAc in petroleum ether) to give 6-bromo-N,N-bis(4-methoxybenzyl)-3-methylquinolin-2-amine (20a, 25 g, 52.4 mmol, 50% yield) as a white solid. m / z (ESI): 477 / 479 (M+H). + .

[0121] THF (50 mL) was cooled to −78° C. and then treated with n-butyllithium solution (2.5 M in hexane, 25.1 mL, 62.8 mmol). The resulting mixture was stirred at −78° C. for 10 minutes and then slowly treated with 6-bromo-N,N-bis(4-methoxybenzyl)-3-methylquinolin-2-amine (20a, 25 g, 52.4 mmol) in THF (10 mL). The mixture was stirred at −78° C. for 10 minutes and then treated with crushed solid CO. The reaction mixture was stirred at room temperature for 30 minutes, then quenched with ice water and extracted with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1.5 N HCl solution to adjust the pH to 6. The precipitated tan solid was filtered and dried to give 2-(bis(4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylic acid (20, 24 g). m / z(ESI):443.2(M+H) + .

[0122] Intermediate 22: 7-amino-6-bromo-5-methyl-1,8-naphthyridine-3-carboxylic acid. [ka] Sodium hydride (1.40 g, 34.9 mmol) in tetrahydrofuran (80 mL) was added to a 100 mL RBF, and the mixture was then cooled to 0 °C. Next, diethyl (cyanomethyl)phosphonate (4.94 g, 27.9 mmol; GLR Innovations Chemicals) was added to the mixture, and the mixture was stirred for 1 h while maintaining the temperature at 0 °C. A solution of 1-(2-amino-5-bromopyridin-3-yl)ethan-1-one (5 g, 23.25 mmol) in THF was added to the mixture at 0 °C, and the whole mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH4Cl (100 mL), and the mixture was filtered through a Celite pad. The filtrate was collected, and the aqueous layer was then extracted with EtOAc (2 × 200 mL). The organic extract was washed with saturated aqueous NaCl (100 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give 6-bromo-4-methyl-1,8-naphthyridin-2-amine (3.0 g, 12.60 mmol, 54.2% yield) as a brown solid. m / z (ESI): 240.1 (M+H). + .

[0123] 6-Bromo-4-methyl-1,8-naphthyridin-2-amine (2 g, 8.40 mmol), PdOAc (0.38 g, 1.68 mmol), dppf (1.40 g, 2.52 mmol), and triethylamine (2.9 mL, 21.00 mmol) in dimethyl sulfoxide (12 mL) and methanol (12 mL) were added to a 100 mL TiNiClave. This was purged with CO (gas) under 10 kg pressure. The reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with CHCl (2 × 200 mL). The organic extract was dried over NaSO. The solution was filtered and concentrated in vacuo to give the crude material as a tan solid. The crude material was absorbed onto a silica gel plug and purified by chromatography through a SiO2 column eluting with a gradient of 60% to 100% EtOAc in hexanes to afford methyl 7-amino-5-methyl-1,8-naphthyridine-3-carboxylate (0.7 g, 3.22 mmol, 38% yield) as a brown solid. 1 H NMR(400MHz,DMSO):δ ppm 8.52(d,J=2.3Hz,1H),7.73(d,J=2.2Hz,1H),6.93(s,2H),5.82(q,J=1.1Hz,1H),3.78(s,3H),2.29(d,J=1.1Hz,3H).m / z(ESI):218.3(M+H) + .

[0124] Methyl 7-amino-5-methyl-1,8-naphthyridine-3-carboxylate (1 g, 4.60 mmol) in sulfuric acid (0.25 mL, 4.69 mmol) was added to a 50 mL RBF. Next, NBS (1.64 g, 9.21 mmol) was added to the mixture, which was then heated and stirred at 90 °C for 3 h. The reaction mixture was diluted with water and quenched with solid NaOH to adjust the pH to approximately 10, and the mixture was then stirred for 1 h. The reaction mixture was acidified with concentrated HCl solution to adjust the pH to 6-6.5, resulting in a precipitate. The solid was collected by filtration and dried to give methyl 7-amino-6-bromo-5-methyl-1,8-naphthyridine-3-carboxylate (1.3 g, 4.39 mmol, 95% yield) as an off-white solid. m / z (ESI): 282.0 / 284.0 (M+H). + .

[0125] Intermediate 23: 2-Amino-3-iodoquinoline-6-carboxylic acid-lithium chloride [ka] To a solution of diethyl (cyanomethyl)phosphonate (1.09 g, 6.15 mmol, Combi-Blocks Inc.) in THF (25 mL) was added LHMDS (6.15 mL of 1 M in THF, 6.15 mmol, Aldrich) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then cooled to -78 °C and treated with NIS (1.38 g, 6.15 mmol, Aldrich) as a solid. The reaction mixture was warmed to -10 °C and stirred at -10 °C to -5 °C for 2 h. It was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 × 50 mL). The organic extract was washed with 5 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep packed silica gel column (40 g) eluting with 20% to 75% EtOAc in heptane to give diethyl (cyanoiodomethyl)phosphonate (0.80 g, 2.64 mmol, 42.9% yield) as a brown oil. m / z (ESI): 304 (M+H). + .

[0126] Sodium hydride (110 mg, 2.76 mmol, 60 wt% in mineral oil) was added to a solution of diethyl (cyanoiodomethyl)phosphonate (781 mg, 2.58 mmol) in THF (10 mL) at 0 °C. The resulting yellow mixture was stirred at 0 °C for 30 min and then treated with a solution of methyl 4-amino-3-formylbenzoate (330 mg, 1.842 mmol) in THF (5 mL). The mixture was stirred at room temperature for 30 min, then treated with sodium hydride (20 mg, 60 wt% in mineral oil) and stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with 2 × 25 mL of EtOAc. The organic layers were combined, washed with 5 mL of water, and concentrated. The residue was purified on a silica gel column (10% to 75% EtOAc in DCM) to give a brown sticky solid (32 mg). This material was stirred in 2 mL of heptane and the liquid was decanted. The resulting brown solid was dried to give methyl 2-amino-3-iodoquinoline-6-carboxylate (24 mg, 0.073 mmol, 4% yield). m / z (ESI): 328.5 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 8.80(s,1H),8.35(d,J=2.0Hz,1H),8.02(d,J=9.41Hz,1H),7.52(d,J=8.99Hz,1H),6.87-7.14(m,2H),3.88(s,3H).

[0127] Methyl 2-amino-3-iodoquinoline-6-carboxylate (24 mg, 0.073 mmol) in 1 mL of THF, 1 mL of MeOH, and 0.5 mL of water was treated with LiOH—HO (6 mg, 0.14 mmol) and heated at 45° C. for 1 h. The mixture was diluted with 0.08 mL of 2N The residue was treated with HCl and concentrated to dryness. The residue was co-evaporated twice with 2 mL of toluene to give 2-amino-3-iodoquinoline-6-carboxylic acid-lithium chloride (23) (30 mg) as a brown solid, which was used crude. m / z (ESI): 315 (M+H). + .

[0128] Intermediate 24: 7-Amino-6-iodo-1,8-naphthyridine-3-carboxylic acid hydrochloride [ka] To a mixture of methyl 7-amino-1,8-naphthyridine-3-carboxylate (1.20 g, 5.91 mmol) in acetic acid (35 mL) was added NIS (4.65 g, 20.67 mmol, Aldrich) at room temperature. The mixture was stirred at room temperature for 30 minutes and then heated at 120 °C for 4 hours. The acetic acid was evaporated under high vacuum. The residue was basified with saturated aqueous sodium carbonate. The insoluble solid was filtered and washed with 3 × 10 mL of water, followed by 3 × 10 mL of EtOAc. The black solid was dried to give methyl 7-amino-6-iodo-1,8-naphthyridine-3-carboxylate (1.30 g, 3.95 mmol, 67% yield). The filtrate was extracted with 50 mL of 4:1 EtOAc / EtOH, and the organic solution was concentrated and purified on a silica gel column (1% to 10% MeOH in EtOAc) to give methyl 7-amino-6-iodo-1,8-naphthyridine-3-carboxylate (200 mg). m / z (ESI): 330 (M+H). + .

[0129] To a mixture of methyl 7-amino-6-iodo-1,8-naphthyridine-3-carboxylate (1.30 g, 3.95 mmol) in 3 mL of THF, 3 mL of MeOH, and 3 mL of water was added lithium hydroxide hydrate (0.365 g, 8.69 mmol). The mixture was heated at 45° C. for 1 hour and then concentrated. The residue was treated with 4 N HCl and stirred at room temperature for 10 minutes. The brown solid was filtered, washed with 2×5 mL of water, followed by 2×3 mL of ether, collected, and dried to give 7-amino-6-iodo-1,8-naphthyridine-3-carboxylic acid hydrochloride (1.51 g, 4.30 mmol, 109% yield), which was used crude. m / z (ESI): 315.8 (M+H). + . 1 H NMR(DMSO-d6,400MHz)δ10.1(brs,1H),9.14(d,1H,J=2.1Hz),8.91(s,1H,J=2.1Hz),8.76(s,1H),7.78(brs,1H),6.81(brs,1H).

[0130] Intermediate 25: 2-amino-3,5-dimethylquinoline-6-carboxylic acid. [ka] Methyl 4-amino-3-bromo-2-methylbenzoate (1.74 g, 7.13 mmol) and bis(pinacolato)diboron (3.62 g, 14.26 mmol) in 1,4-dioxane (23.76 mL) were added to a 150 mL round-bottom flask. Potassium acetate (2.099 g, 21.39 mmol) was then added to the solution. The mixture was degassed by bubbling Ar for 5 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.582 g, 0.713 mmol) in dichloromethane complex was added. The reaction was then continued to stir at 100 °C. After 5 h, LCMS indicated the formation of the desired product along with the dehalogenated compound. Water (30 mL) was added to the mixture, which was extracted with DCM (3 × 25 mL), dried over MgSO, filtered, and concentrated to give a black oil / solid. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (120 g) eluting with a gradient of 0% to 30% (3:1 EtOAc:EtOH) in DCM (desired product eluting at 5%) to give methyl 4-amino-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (830 mg, 2.85 mmol, 40.0% yield) as a pale yellow solid. m / z (ESI): 292.3 (M+H). + .

[0131] Methyl 4-amino-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, 2.404 mmol), 3-bromo-2-methylacrylonitrile (mixture of isomers) (351 mg, 2.404 mmol), tribasic potassium phosphate (1021 mg, 4.81 mmol), and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (204 mg, 0.240 mmol) in 1,4-dioxane (6011 μL) and water (6011 μL) were added to a red-capped vial. The solution was heated to 90°C and stirred for 2 hours. Water (15 mL) was added and the solid formed was filtered and washed with DCM to give methyl 2-amino-3,5-dimethylquinoline-6-carboxylate (160 mg, 0.695 mmol, 28.9% yield) as a pale yellow solid. m / z (ESI): 231.1 (M+H). + .

[0132] Methyl 2-amino-3,5-dimethylquinoline-6-carboxylate (0.092 g, 0.4 mmol) in water (2.67 mL), methanol (2.67 mL), and tetrahydrofuran (2.67 mL) was added to a 150 mL round-bottom flask. Lithium hydroxide monohydrate (0.084 g, 2.000 mmol) was then added, and the mixture was stirred at 70 °C for 4 h. The solvent was concentrated in vacuo, and the resulting aqueous layer was adjusted to pH 3 by adding 2 N HCl. The water was then evaporated (using toluene) to give 2-amino-3,5-dimethylquinoline-6-carboxylic acid hydrochloride (25) (contaminated with 5 equivalents of LiCl) as an off-white solid. This product was used in the next step without further purification. m / z (ESI): 217.1 (M+H). + .

[0133] Intermediate 26: 2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine. [ka] To a mixture of 5-(trifluoromethyl)picolinaldehyde (3.02 g, 17.27 mmol, AstaTech Inc.) and isobutylamine (1.48 g, 20.21 mmol, Combi-Blocks Inc.) in DCM (50 mL) was added acetic acid (1.11 g, 18.48 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes and then treated with sodium triacetoxyborohydride (5.49 g, 25.9 mmol, Aldrich). The mixture was stirred at room temperature for 1 hour and then neutralized with saturated aqueous Na2CO3. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0–100% EtOAc / EtOH (3 / 1) in heptane) to afford the title compound (26, 2.81 g, 70% yield) as a brown oil. m / z(ESI):233.0(M+H) + . 1 H NMR(400MHz,chloroform-d)δ ppm 8.81(s,1H),7.88(dd,J=8.1,2.1Hz,1H),7.50(d,J=8.1Hz,1H),3.98(s,2H),2.46(d,J=6.6Hz,2H),1.73-1.84(m,2H),0.94(d,J=6.6Hz,6H). 19 F NMR (376 MHz, chloroform-d) δ ppm −62.26 (s, 3F).

[0134] [Table 5]

[0135] [Table 6]

[0136] [Table 7]

[0137] [Table 8]

[0138] Intermediate 65: 6-((((3-fluoropyridin-2-yl)methyl)amino)methyl)nicotinonitrile. [ka] A mixture of 6-formylnicotinonitrile (0.198 g, 1.49 mmol, Enamine), 1,2-dichloroethane (7 mL), (3-fluoropyridin-2-yl)methanamine dihydrochloride (0.328 g, 1.64 mmol, Aurum Pharmatech), and TEA (0.47 mL, 3.37 mmol) was stirred at room temperature for 2 minutes, and then acetic acid (0.10 mL, 1.72 mmol) was added. After 10 minutes, sodium triacetoxyborohydride (0.41 g, 1.94 mmol) was added. The mixture was stirred at room temperature for 2.5 hours and then neutralized with saturated aqueous Na2CO3. The mixture was extracted three times with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / EtOH (3:1) in heptane) to give the title compound (65, 0.24 g, 66% yield) as an orange oil. MS: m / z (ESI): 243 (M+H). + .

[0139] [Table 9]

[0140] Intermediate 76: 6-(1-(((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)ethyl)picolinonitrile. [ka] 6-Acetyl-2-cyanopyridine (0.500 g, 0.50 mL, 3.42 mmol, AstaTech, Inc.) and (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (0.73 g, 3.42 mmol, PharmaBlock Sciences, Inc.) in methanol (17 mL) were added to a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C, and then N,N'-diisopropylethylamine (0.66 g, 0.9 mL, 5.13 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture, followed by acetic acid (0.2 mL, 3.42 mmol, Sigma-Aldrich Corporation) and sodium cyanoborohydride (0.65 g, 10.26 mmol, Oakwood Products, Inc.). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3, and then the mixture was diluted with DCM. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (80 g) eluting with a gradient of 0% to 80% EtOAc:EtOH (3:1) in heptane to afford 6-(1-(((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)ethyl)picolinonitrile (0.26 g, 0.86 mmol, 25% yield) as a tan oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.83(s,1H),8.14(dd,J=8.4,2.1Hz,1H),8.01(t,J=7.5Hz,1H),7.89(dd,J=7.6,0.9Hz,1H),7.83(dd,J=7.9,0.8Hz,1H),7 .68(d,J=8.2Hz,1H),3.85-3.93(m,1H),3.75-3.79(m,2H),3.06-3.17(m,1H),1.33(d,J=6.9Hz,3H).m / z(ESI):307.0(M+H) + .

[0141] Intermediate 77: (R)-1-(pyrimidin-2-yl)-N-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)ethan-1-amine. [ka] 1-(Pyrimidin-2-yl)ethan-1-amine dihydrochloride (2.79 g, 14.23 mmol, Enamine) in a 1:1 mixture of methanol (22 mL) and dichloromethane (22 mL) was added to a 150 mL round-bottom flask. The reaction mixture was cooled to 0 °C, and N,N'-diisopropylethylamine (3.51 g, 4.7 mL, 27.2 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture and stirred for 10 minutes. Next, 3-formyl-6-hydroxypyridazine (1.6 g, 12.93 mmol, Aurum Pharmatech LLC) and acetic acid (0.78 g, 0.8 mL, 12.93 mmol, Sigma-Aldrich Corporation) were added to the mixture, followed by sodium triacetoxyborohydride (12.93 mmol, Sigma-Aldrich Corporation). The reaction mixture was allowed to warm to room temperature over 15 minutes, then sodium triacetoxyborohydride (6.85 g, 32.3 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture, and the entire mixture was stirred for 16 hours under an inert (N2) atmosphere. Another aliquot of sodium triacetoxyborohydride (6.85 g, 32.3 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture, and the mixture was stirred for an additional 16 hours. The reaction mixture was filtered through a pad of Celite, and the filter cake was then rinsed with 1:1 MeOH:DCM (3 times). The filtrate was collected and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (120 g) eluting with a gradient of 0% to 35% MeOH in CHCl to afford 6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)pyridazin-3-ol (1.12 g, 4.84 mmol, 37% yield) as a pale yellow solid. 1H NMR(400MHz, methanol-d4)δ ppm 8.78(d,J=5.0Hz,2H),7.54(d,J=9.6Hz,1H),7.38(t,J=4.9Hz,1H),6.92(d,J=9.6Hz,1H),4.07( q,J=6.8Hz,1H),3.72(d,J=2.3Hz,2H),1.98(s,1H),1.48(d,J=6.9Hz,3H).m / z(ESI):232.1(M+H) + .

[0142] 6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)pyridazin-3-ol (1.11 g, 4.80 mmol) and triethylamine (2 mL, 14.40 mmol, Sigma-Aldrich Corporation) in 1,2-dichloroethane (24 mL) were added to a 150 mL round-bottom flask. Di-tert-butyl dicarbonate (1.57 g, 7.20 mmol, Sigma-Aldrich Corporation) was then added to the reaction mixture. The entire reaction mixture was stirred and heated at 70 °C for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and then the mixture was diluted with DCM. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (120 g) eluting with a gradient of 0% to 80% EtOAc:EtOH (3:1) in heptane to afford tert-butyl ((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (1.04 g, 3.15 mmol, 66% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.77(s,1H),8.75(d,J=4.8Hz,2H),7.37(t,J=4.8Hz,2H),6.85(d,J=9.6Hz,1H),4.88-5.05(m,1H),4.42(br s,2H),1.54(d,J=7.3Hz,3H),1.15-1.34(m,9H).m / z332.1(ESI):(M+H) + .

[0143] Racemic tert-butyl ((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (1.0 g) was purified by preparative SFC using a Chiral Technologies AD column (250 × 30 mm, 5 mm) with 80% liquid CO and 20% EtOH (with 0.2% TEA) as the mobile phase using a flow rate of 150 mL / min to yield peak 1 (R)-((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.436 g, ee >99%) and peak 2 (S)-tert-butyl ((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.455 g, ee 98.8%). Peak assignments were determined by SFC on an AD column using 10% EtOH containing 0.2% TEA.

[0144] (R)-tert-Butyl ((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.075 g, 0.23 mmol), 2,2,2-trifluoroethyl triflate (0.07 g, 0.04 mL, 0.28 mmol, Combi-Blocks Inc.), and cesium carbonate (0.09 g, 0.28 mmol, Sigma-Aldrich Corporation) in N,N-dimethylformamide (2.3 mL) were placed in a resealable vial. The vial was sealed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (12 g) eluting with a gradient of 0% to 60% MeOH in CHCl to give tert-butyl (S)-(1-(pyrimidin-2-yl)ethyl)((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)carbamate (0.075 g, 0.18 mmol, 80% yield) as a pale yellow solid. m / z 414.2 (ESI):(M+H) + .

[0145] (R)-(1-(pyrimidin-2-yl)ethyl)((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)tert-butylcarbamate (0.075 g, 0.18 mmol) and trifluoroacetic acid (0.47 mL, 6.35 mmol, Sigma-Aldrich Corporation) in 1,2-dichloroethane (1.8 mL) were added to a 50 mL round-bottom flask. The reaction mixture was stirred at 70° C. for 6 hours. The reaction mixture was concentrated in vacuo. This gave (R)-1-(pyrimidin-2-yl)-N-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)ethan-1-amine as a crude residue, which was used directly in the next step of the synthesis. m / z 314.0 (ESI):(M+H) + .

[0146] Intermediate 78: N-((6-(difluoromethoxy)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] tert-Butyl ((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.40 g, 1.21 mmol) and potassium bifluoride (0.75 g, 9.66 mmol, Sigma-Aldrich Corporation) in dichloromethane (2.8 mL) / water (1.21 mL) were added to a 50 mL round-bottom flask. The reaction mixture was sparged with argon (gas) for 5 minutes. Next, trimethyl(bromodifluoromethyl)silane (0.98 g, 4.83 mmol, Combi-Blocks Inc.) was added to the reaction mixture. The entire reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and then the mixture was treated with saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The organic extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo. This gave tert-butyl ((6-(difluoromethoxy)pyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate as a crude oil, which was used directly in the next step of the synthesis without further purification. m / z 382.1 (ESI):(M+H). + .

[0147] The residue from above was diluted with dichloromethane (2.8 mL) and then treated with trifluoroacetic acid (4.8 g, 3.2 mL, 42.2 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and treated with saturated aqueous NaHCO. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (40 g) eluting with a gradient of 0 to 100% EtOAc:EtOH (3:1) in heptane to afford N-((6-(difluoromethoxy)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (0.100 g, 0.356 mmol, 30% yield) as a tan solid. m / z(ESI):282.2(M+H) + .

[0148] Intermediate 79: 1-(pyrimidin-2-yl)-N-((6-(trifluoromethoxy)pyridazin-3-yl)methyl)ethan-1-amine. [ka] tert-Butyl ((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.20 g, 0.60 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3(1h)-one (Togni's reagent 1) (1.59 g, 3.02 mmol, Sigma-Aldrich Corporation) in chloroform (6 mL) were added to a 50 mL round-bottom flask. The reaction mixture was stirred and heated at 70 °C for 2 days. The reaction mixture was filtered through a Celite pad, and the filtrate was then collected and treated with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (3 times). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (12 g) eluting with a gradient of 0% to 75% EtOAc:EtOH (3:1) in heptane to afford tert-butyl (1-(pyrimidin-2-yl)ethyl)((6-(trifluoromethoxy)pyridazin-3-yl)methyl)carbamate (0.040 g, 0.100 mmol, 17% yield) as a tan solid. m / z (ESI): 400.1 (M+H). + .

[0149] tert-Butyl (1-(pyrimidin-2-yl)ethyl)((6-(trifluoromethoxy)pyridazin-3-yl)methyl)carbamate (0.040 g, 0.100 mmol) and trifluoroacetic acid (0.3 mL, 3.51 mmol, Sigma-Aldrich Corporation) in dichloromethane (1 mL) were added to a 50 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The crude material was used directly in the next step of the synthesis without further purification. m / z (ESI): 300.1 (M+H). + .

[0150] Intermediate 80: 6-Fluoro-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine. [ka] Triphenylphosphine (1.37 g, 5.21 mmol, Sigma-Aldrich) and DIAD (1.05 g, 1.03 mL, 5.21 mmol, Sigma-Aldrich) were added to a solution of 3-buten-1-ol (0.38 g, 0.45 mL, 5.21 mmol, Sigma-Aldrich) and 2-bromo-6-fluoro-3-hydroxypyridine (1.0 g, 5.21 mmol, Combi-Blocks Inc.) in THF (20 mL) under argon at 0° C. The ice bath was removed and the mixture was stirred at 55° C. for 18 h and then cooled to room temperature. The organic material was fused to silica gel and then purified by chromatography (0-40% EtOAc / heptane) through a Redi-Sep packed silica gel column to give 2-bromo-3-(but-3-en-1-yloxy-6-fluoropyridine) (1.12 g, 4.55 mmol, 87% yield) as a colorless oil. m / z (ESI): 245.9 / 247.9 (M+H). + .

[0151] 2-Bromo-3-(but-3-en-1-yloxy-6-fluoropyridine) (1.12 g, 4.55 mmol), palladium acetate (0.102 g, 0.46 mmol), triphenylphosphine (0.36 g, 1.37 mmol, Sigma-Aldrich), potassium acetate (2.23 g, 22.8 mmol, Sigma-Aldrich Corporation), and tetraethylammonium chloride (1.51 g, 9.10 mmol, Sigma-Aldrich Corporation) were dissolved in 100 ml of ... A mixture of (Agilent Technologies, Inc.) and water (0.16 g, 0.16 mL, 9.10 mmol) in DMF (20 mL) was stirred at 100° C. for 6 hours under argon and then cooled to room temperature. The resulting mixture was filtered through Celite, and the filtrate was diluted with EtOAc (50 mL). The mixture was washed with water (3×20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 6-fluoro-4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine as an oil, which was used directly in the next step without further purification. m / z (ESI): 166.2 (M+H). + .

[0152] Osmium tetroxide solution (0.46 g, 0.57 mL, 0.046 mmol, Sigma-Aldrich) was added to a solution of 6-fluoro-4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (4.55 mmol) and 4-methylmorpholine N-oxide (0.64 g, 5.46 mmol, Sigma-Aldrich) in acetone (20 mL) and water (2.9 mL). The mixture was stirred at room temperature for 6 hours, after which sodium (meta)periodate (2.44 g, 11.4 mmol, Sigma-Aldrich) was added. The mixture was stirred at room temperature for 18 hours, after which EtOAc (50 mL) and saturated sodium thiosulfate (50 mL) were added. The mixture was stirred vigorously for 5 minutes, and the layers were then separated. The organic layer was then dried over anhydrous MgSO, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography (0-100% EtOAc / heptane) to afford 6-fluoro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one (0.58 g, 3.47 mmol, 76% yield over two steps) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.78(dd,J=8.9,6.6Hz,1H),7.41(dd,J=8.9,3.7Hz,1H),4.59-4.65(m,2H),2.85-2.92(m,2H).m / z(ESI):168.2(M+H) +

[0153] Titanium isopropoxide (0.34 g, 0.35 mL, 1.20 mmol, Sigma-Aldrich) was added to a solution of 6-fluoro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one (0.20 g, 1.2 mmol) and (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (254 mg, 1.20 mmol, PharmaBlock) in THF (4 mL). The mixture was stirred under an argon atmosphere for 18 hours, and then sodium triacetoxyborohydride (507 mg, 2.39 mmol, Sigma-Aldrich) was added. The mixture was stirred at room temperature for 4 hours, and then 1 mL of NH4OH (aq) was added. The resulting suspension was filtered, and the filtrate was concentrated in vacuo and then purified by silica gel chromatography (0-10% 2N NH3-MeOH / DCM gradient) to afford 6-fluoro-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine (246 mg, 0.75 mmol, 63% yield) as a pale yellow oil. m / z (ESI): 328.0 (M+H). + .

[0154] Intermediate 81: 6-Fluoro-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine. [ka] This amine was prepared in a similar manner as described for amine 80. m / z (ESI): 329.2 (M+H) + .

[0155] Intermediate 82: rac-2-methyl-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine. [ka] Isopropylmagnesium bromide (15.22 mL, 11.42 mmol) was added dropwise to a solution of pyrimidine-2-carbonitrile (1 g, 9.51 mmol, Combi-Blocks Inc.) in diethyl ether (15 mL) at −15 °C, and the resulting mixture was stirred at −15 °C for 1 h and then at ambient temperature for 2 h. The reaction mixture was poured into ice water, and saturated sodium bicarbonate solution was added to a final pH of 8. The resulting mixture was extracted with DCM (2 × 25 mL), and the combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was absorbed onto silica gel and purified by silica gel chromatography (0–30% ethyl acetate / petroleum ether) to afford 2-methyl-1-(pyrimidin-2-yl)propan-1-one (0.7 g, 4.47 mmol, 47% yield) as a yellow oil. 1 H NMR (400MHz, chloroform-d): δ ppm 8.95(d,J=4.9Hz,2H),7.47(t,J=4.9Hz,1H),3.98-4.09(m,1H),1.28(s,3H),1.26(s,3H).m / z(ESI):151.1(M+H) + .

[0156] Intermediate 82 was prepared from 2-methyl-1-(pyrimidin-2-yl)propan-1-one and (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Shanghai Arbor Chemical Co., Ltd.) in a similar manner as described for amine 80. m / z (ESI): 311.1 (M+H) + .

[0157] Intermediate 83: N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine [ka] To a stirred mixture of 5-(trifluoromethyl)picolinaldehyde (554 mg, 3.16 mmol) and 2H,3H,4H-pyrano[3,2-b]pyridin-4-amine (500 mg, 3.33 mmol, AstaTech, Inc.) in DCM (6 mL) in a 25 mL single-neck round-bottom flask at room temperature, acetic acid (0.19 mL, 3.33 mmol) was added, followed 10 min later by the addition of sodium triacetoxyborohydride (1.05 g, 4.99 mmol) as a solid in one portion. The resulting mixture was stirred at room temperature for 3.5 h, then poured onto ice and saturated aqueous sodium carbonate and extracted with DCM (3 times). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (1–10% 2M NH3 in MeOH in DCM) to afford the title amine (275 mg, 27% yield) as a colorless solid. m / z(ESI):310.1(M+H) + . 1 H NMR (chloroform-d, 400 MHz) δ 8.8-8.9 (m, 1H), 8.18 (dd, 1H, J = 1.9, 4.0 Hz), 7.91 (dd, 1H, J = 2.0, 8.3 Hz), 7.61 (d, 1H, J = 8.4 Hz), 7.1-7.2 (m, 2H), 4.41 (m, 1H), 4.2-4.3 (m, 3H), 4.03 (t, 1H, J = 5.7 Hz), 2.2-2.3 (m, 1H), 2.1-2.2 (m, 1H).

[0158] [Table 10]

[0159] [Table 11]

[0160] Intermediate 100: N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoxalin-5-amine. This amine was prepared from 7,8-dihydroquinoxalin-5(6H)-one (purchased from Enamine) in a manner similar to that described for amine 65. m / z (ESI): 309.2 (M+H). + . [ka]

[0161] Intermediate 102: (R)-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine. [ka] To a stirred solution of (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (115 g, 541 mmol) and 1-(pyrimidin-2-yl)ethan-1-one (76 g, 622 mmol) in DCM (3.5 L) was added potassium acetate (63.7 g, 649 mmol). The mixture was stirred at room temperature for 30 minutes and then treated with sodium triacetoxyborohydride (149 g, 703 mmol). After stirring for 1.5 hours, the reaction mixture was diluted with water (2 L), treated with 1 N HCl (2 L), and extracted with DCM (1 L). The layers were separated. The aqueous layer was treated with 10% sodium hydroxide to adjust the pH to 12 and extracted with DCM (3 × 2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (2% MeOH in DCM) to give 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (97 g, 344 mmol, 63% yield) as a brown oil. m / z (ESI): 283.0 (M+H) + . 1H NMR (400MHz, chloroform-d): δ ppm 8.81(dt,J=2.2,1.0Hz,1H),8.74(d,J=4.9Hz,2H),7.88(dd,J=8.2,2.3Hz,1H),7.54(d,J=8.2Hz ,1H),7.20(t,J=4.9Hz,1H),4.10(q,J=6.8Hz,1H),3.94(d,J=2.9Hz,2H),1.53(d,J=6.8Hz,3H).

[0162] Racemic secondary amine (44 g) was dissolved in 200 mL of MeOH and subjected to chiral SFC using the following conditions: The first eluting peak was (S)-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (101, 18 g, ee >99%), and the second eluting peak was (R)-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (102, 19 g, ee >99%). Column temperature = 40 °C. Column = [Chiralpak AD-H (250 × 30 mm, 5 μ)]. Mobile phase = [liquid CO2:0.5% DEA in EtOH (90:10)]. Flow rate = 100 mL / min. Wavelength = 245 nm.

[0163] [Table 12]

[0164] Intermediate 115: (R)-N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] A mixture of 6-methoxy-pyridazine-3-carbaldehyde (0.49 g, 3.54 mmol, Princeton BioMolecular Research, Inc.), 1-(pyrimidin-2-yl)ethan-1-amine dihydrochloride (0.73 g, 3.72 mmol, Enamine), 1,2-dichloroethane (30 mL), and acetic acid (0.22 mL, 3.90 mmol) was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (1.013 g, 4.78 mmol) was added. The mixture was stirred at room temperature for 30 minutes and then neutralized with saturated aqueous Na2CO3. The crude product was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (30-100% EtOAc / EtOH (3 / 1) in heptane) to give N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (0.84 g, 96% yield) as an orange oil. m / z (ESI): 246 (M+H). + .

[0165] The racemic amine was subjected to chiral SFC using a Chiral Technologies IC column (250 × 30 mm, 5 μm) with a mobile phase of 70% liquid CO and 30% MeOH (with 0.2% TEA) at a flow rate of 150 mL / min. The first eluting peak was (R)-N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (115, 369 mg, ee > 99%). The second eluting peak was (S)-N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (116, 374 mg, ee > 99%).

[0166] [Table 13]

[0167] [Table 14]

[0168] [Table 15]

[0169] [Table 16]

[0170] [Table 17]

[0171] [Table 18]

[0172] [Table 19]

[0173] [Table 20]

[0174] [Table 21]

[0175] [Table 22]

[0176] [Table 23]

[0177] Intermediate 222: (R)-N-((6-ethoxypyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] To a solution of 1-(pyrimidin-2-yl)-N-((6-bromopyridizin-3-yl)methyl)propan-1-amine (0.84 g, 3.47 mmol) and DIPEA (0.89 g, 1.212 mL, 6.94 mmol) in DCM (17 mL) was added di-tert-butyl dicarbonate (1.21 g, 5.55 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then partitioned between DCM and water. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (0 to 100% EtOAc in heptane) to give tert-butyl (R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (1.61 g, 4.70 mmol, 136% yield) as a solid containing some residual solvent. m / z(ESI):394.1 / 396.1(M+H) + .

[0178] To a mixture of t-butyl BrettPhos Pd G3 (98 mg, 0.11 mmol, Aldrich), EtOH (0.33 mL), (R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (300 mg, 0.76 mmol), and cesium carbonate (350 mg, 1.1 mmol) in dioxane (2.5 mL) was added a solution of t-butyl BrettPhos (55 mg, 0.11 mmol, Aldrich) in dioxane (1.0 mL). The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (R)-((6-ethoxypyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (231 mg, 0.643 mmol, 84% yield) as a brown solid. m / z (ESI): 360.0 (M+H). +This material was treated with TFA (10 mL), stirred for 15 minutes, and then concentrated under reduced pressure. The residue was dissolved in MeOH and free-based by eluting through an SCX column with MeOH followed by 2M ammonia in MeOH to afford (R)-N-((6-ethoxypyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (222, 166 mg, 0.64 mmol, 84% yield) as a brown oil. m / z (ESI): 260.0 (M+H). + .

[0179] Intermediates 224 and 225. (R)—N-((5-ethoxypyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (224, m / z (ESI): 259.0 (M+H) + ) and (R)—N-((5-cyclopropoxypyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (225, m / z (ESI): 271.1 (M+H) + ) was prepared from intermediate 108 in a similar manner as described for amine 222. [ka]

[0180] Intermediate 226: (R)-6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine. [ka] 4,4'-di-tert-butyl-2,2'-bipyridinebis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)iridium hexafluorophosphate(V) salt (1 M in DMAc solution) (0.05 mL, 0.050 μmol, Aldrich) (approximate weight), nickel(II) bromide ethylene glycol dimethyl ether complex (5.9 mg, 0.019 mmol, Sigma-Aldrich), 2,2,2-trifluoroethane- 1-Amine (38 mg, 0.030 mL, 0.38 mmol, Enamine), (R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl) tert-butylcarbamate (221, 150 mg, 0.38 mmol), DMAc (1 mL), and 1,3,4,6,7,8-hexahydro-1-methyl-2h-pyrimido[1,2-a]pyrimidine (150 mg, 0.14 mL, 0.95 mmol) were placed in a 4 mL glass vial. The vial was sealed and irradiated in a Penn photoreactor (450 nm, 100% LED power, fan 1500 RPM, full stirring) for 18 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (40 mL), followed by brine (20 mL), and dried over MgSO. The crude product was purified by silica gel chromatography (0 to 100% EtOAc in heptane) to give tert-butyl (R)-(1-(pyrimidin-2-yl)ethyl)((6-((2,2,2-trifluoroethyl)amino)pyridazin-3-yl)methyl)carbamate (12 mg, 0.028 mmol, 7% yield). This Boc-protected material was dissolved in TFA (5 mL) and stirred for 30 min. The reaction mixture was concentrated and the residue was eluted through an SCX column with MeOH followed by 2M ammonia in MeOH to give (R)-6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (226, 8.6 mg, 0.028 mmol, 7% yield over two steps) as a brown oil. m / z (ESI): 313.1 (M+H). + .

[0181] Intermediate 227: (R)-N-((6-(difluoromethyl)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] (R)-tert-Butyl ((6-bromopyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (221, 0.20 g, 0.51 mmol), potassium trifluoro(vinyl)borate (0.14 g, 1.0 mmol, Oakwood Products), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane adduct (10 mg, 0.013 mmol, Strem Chemicals), KCO (0.280 g, 2.0 mmol), 1,4-dioxane (1.9 mL), and water (0.63 mL) were added to a 20 mL glass vial. The vial was evacuated and refilled with nitrogen three times before being sealed and heated to 80 °C. After 2 h, approximately 60% conversion was observed. Additional vinyl borate was added (approximately 50 mg), and the reaction was stirred at 80 °C for 2 h. Purification of the reaction mixture by silica gel column (10-100% EtOAc in heptane) afforded tert-butyl (R)-(1-(pyrimidin-2-yl)ethyl)((6-vinylpyridazin-3-yl)methyl)carbamate (0.11 g, 0.33 mmol, 65% yield) as a white solid. m / z (ESI): 342.0 (M+H). + .

[0182] To a mixture of tert-butyl (R)-(1-(pyrimidin-2-yl)ethyl)((6-vinylpyridazin-3-yl)methyl)carbamate (110 mg, 0.33 mmol) in 4:1 THF-HO (1.7 mL) was added osmium(VIII) oxide (110 mg, 100 μL, 0.017 mmol, Sigma-Aldrich), followed by sodium periodate (210 mg, 0.99 mmol, Sigma-Aldrich). The resulting reddish-brown slurry was stirred at room temperature for 7 days to near completion (ca. 85%). The reaction mixture was then diluted with EtOAc (30 mL) and washed with saturated sodium bicarbonate (20 mL). The layers were separated, and the organic layer was washed again with saturated aqueous sodium bicarbonate (20 mL), followed by brine (15 mL), and dried over MgSO. The filtrate was concentrated to give tert-butyl (R)-((6-formylpyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (70 mg, 0.20 mmol, 62% yield) (approximately 60% purity) as a brown oil, which was used directly in the next reaction. m / z (ESI): 344.1 (M+H). + .

[0183] To a solution of tert-butyl (R)-((6-formylpyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (70 mg, 0.20 mmol) in DCM (2.0 mL) was added DAST (160 mg, 1.0 mmol, Aldrich) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature over 1.5 h and then quenched by the dropwise addition of saturated sodium bicarbonate (15 mL). This mixture was then extracted with DCM (2 × 30 mL). The combined organic layers were then dried over MgSO and concentrated. The crude product was purified by silica gel chromatography (0–100% EtOAc in heptane) to give tert-butyl (R)-((6-(difluoromethyl)pyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (11.1 mg). This material was treated with 3.0 mL of TFA and stirred for 45 minutes. The reaction mixture was concentrated, and the residue was dissolved in MeOH and eluted through an SCX column with MeOH followed by 2 M ammonia in MeOH to give (R)—N-((6-(difluoromethyl)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (227, 9.2 mg, 0.035 mmol, 17% yield over three steps). m / z (ESI): 266.1 (M+H). + .

[0184] Intermediates 228 and 229. (R)—N-((6-(3,3-difluoropyrrolidin-1-yl)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (228, m / z (ESI): 321.0 (M+H) + ) and (R)—N-((6-(3,3-difluoroazetidin-1-yl)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (229, m / z (ESI): 307.0 (M+H) + ) was prepared from intermediate 222 in a similar manner as described for amine 226. [ka]

[0185] Intermediate 230. (R)-6-(((1-(3-fluoropyridin-2-yl)ethyl)amino)methyl)pyridazine-3-carbonitrile (230, m / z (ESI): 258.0 (M+H) + ) was prepared from intermediate 205 in a similar manner as described in Example 549. [ka]

[0186] Intermediate 231. (R)-1-(3-fluoropyridin-2-yl)-N-((6-morpholinopyridazin-3-yl)methyl)ethan-1-amine (231, m / z (ESI): 318.0 (M+H) + ) was prepared from intermediate 205 in a similar manner as described in Example 554. [ka]

[0187] Intermediate 234: (R)—N-((6-bromopyridazin-3-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-amine. Racemic amine 232 was prepared in a similar manner as described above for amine 115a. m / z (ESI): 309 / 311 (M+H). + The racemic amine was subjected to chiral SFC to give the enantiomerically pure amines 233 (ee > 90%) and 234 (ee > 96%). SFC conditions: Chiral Technologies AS column (250 × 21 mm, 5 μm) with a mobile phase of 80% liquid CO and 20% EtOH (with 0.2% TEA) using a flow rate of 80 mL / min. [ka]

[0188] Intermediate 236: (R)—N-((6-(3,6-dihydro-2H-pyran-4-yl)pyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine hydrochloride. [ka] 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 mg, 0.571 mmol, Combi Blocks), (R)-tert-butyl((6-bromopyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (221, 150 mg, 0.380 mmol), potassium phosphate tribasic (242 mg, 1.141 mmol), palladium acetate (12.81 mg, 0.057 mmol), tricyclohexylphosphine (32.0 mg, 0.114 mmol), toluene (3.4 mL), and HO (0.38 mL) were placed in a scintillation vial. The mixture was purged with nitrogen for 10 minutes and then heated at 90 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0% to 100% in heptane (EtOAc:EtOH, 3:1)) to give tert-butyl (R)-((6-(3,6-dihydro-2H-pyran-4-yl)pyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (235, 130 mg, 0.32 mmol, 86% yield) as a white solid. m / z (ESI): 398.0 (M+H). + The white solid (130 mg, 0.327 mmol) was suspended in DCM (3.3 mL) and treated with HCl (0.050 mL of 4 M in dioxane). The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to give the title compound (236) as a brown solid, which was used in the subsequent step without further purification. m / z (ESI): 298.1 (M+H). + .

[0189] Intermediate 238: (R)-N-((5-(oxetan-3-yloxy)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] CsCO (1.243 g, 3.81 mmol), allylpalladium(II) chloride dimer (0.093 g, 0.254 mmol), 2-(di-t-butylphosphono)-3-methoxy-6-methyl-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (0.143 g, 0.305 mmol), oxetan-3-ol (0.471 g, 6.36 mmol), and toluene (5.09 mL) were placed in a scintillation vial. The mixture was purged with N for 10 min, heated at 90 °C for 3 min, and then treated with (R)-((5-bromopyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl) tert-butylcarbamate (223, 1.00 g, 2.54 mmol). The mixture was stirred at 90°C for 18 hours, then cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (0-100% (EtOAc:EtOH 3:1) in heptane) to afford tert-butyl (R)-((5-(oxetan-3-yloxy)pyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (237, 1.00 g, 2.59 mmol, 100% yield) as a yellow oil. m / z (ESI): 387.2 (M+H). + The yellow oil in DCM (25.9 mL) was treated with TFA (4 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-100% in heptane (89:9:1 = DCM:MeOH:NH)) to afford (R)-N-((5-(oxetan-3-yloxy)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (238, 677 mg, 2.36 mmol, 91% yield) as a white solid. m / z (ESI): 287.2 (M+H). + .

[0190] Intermediate 239: (1R,2R)-2-Methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-amine. [ka] 5-(Trifluoromethyl)picolinaldehyde (200 mg, 1.142 mmol), (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (170 mg, 1.142 mmol, Sigma-Aldrich), triethylamine (289 mg, 0.398 mL, 2.86 mmol), and DCM (11.4 mL) were added to a 25 mL scintillation vial. The mixture was stirred at room temperature for 10 minutes, after which acetic acid (82 mg, 0.078 mL, 1.371 mmol) was added. The mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (363 mg, 1.713 mmol) was added. The mixture was stirred at room temperature overnight. Upon completion, the reaction was concentrated and loaded directly onto a redisep cartridge for chromatography using 0-100% (DCM:MeOH:NH3 89:9:1) in heptane to give (1R,2R)-1-(((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-2,3-dihydro-1H-inden-2-ol (298 mg, 0.967 mmol, 85% yield). m / z (ESI): 309.2 (M+H). + .

[0191] To a solution of (1R,2R)-1-(((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-2,3-dihydro-1H-inden-2-ol (298 mg, 0.967 mmol) and THF (10 mL) at 0 °C, potassium t-butoxide (130 mg, 1.160 mmol) was added in one portion. The reaction was stirred for 15 minutes and then treated dropwise with methyl iodide (206 mg, 0.090 mL, 1.45 mmol). The reaction was stirred overnight. Upon completion, the reaction was concentrated and purified by silica gel chromatography using 0-40% (EtOAc:EtOH 3:1) in heptane to give intermediate 239 (37 mg, 0.114 mmol, 12% yield). m / z (ESI): 323.2 (M+H). + .

[0192] Intermediate 240: (1S,2S)-2-Methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-amine. [ka] (1S,2S)-2-Methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-amine was prepared similarly to 239. m / z (ESI): 323.2 (M+H) + .

[0193] Intermediate 242: (R)-1-(6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)pyridin-3-yl)ethan-1-one hydrochloride. [ka] (R)-tert-Butyl ((5-bromopyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (223, 200 mg, 0.509 mmol), Pd(PPh3)4 (58.8 mg, 0.051 mmol), and cesium fluoride (309 mg, 2.034 mmol) were added to a 25 mL round-bottom flask. The vial was evacuated and backfilled with nitrogen three times. DCE (509 μL) and 1-(trimethylsilyl)ethan-1-one (118 mg, 118 μL, 1.017 mmol, Sigma-Aldrich) were then added. The reaction was purged with nitrogen for 10 minutes and placed in a heating block maintained at 75 °C for 8 hours. Upon completion, the mixture was loaded directly onto a redisep cartridge for chromatography. Compound 241 was prepared by elution of 0 to 50% (DCM:MeOH:NH3 Eluted as a yellow oil with a HPLC ratio of 89:9:1. m / z (ESI): 357.2 (M+H). + .

[0194] (R)-tert-Butyl ((5-acetylpyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (241, 50 mg, 0.140 mmol), DCM (1.4 mL), and hydrochloric acid (0.015 mL, 0.421 mmol) were added to a 25 mL vial. The reaction was stirred at room temperature overnight. Upon completion, the reaction was concentrated and used directly in the next step, assuming quantitative yield. m / z (ESI): 257.2 (M+H). + .

[0195] Intermediate 244: (R)-2-(6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)pyridin-3-yl)propan-2-ol. [ka] Trimethylsulfoxonium iodide (309 mg, 1.403 mmol), potassium tert-butoxide (157 mg, 1.403 mmol), and THF (3.5 mL) were added to a 25 mL scintillation vial. The mixture was stirred under nitrogen at 50 °C for 30 min. Next, (R)-((5-acetylpyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl) tert-butylcarbamate (241, 125 mg, 0.351 mmol) was added, and the mixture was stirred at 50 °C overnight. Upon completion, the mixture was directly loaded onto a redisep cartridge for chromatography using 0-50% DCM:MeOH:NH3 in heptane (89:9:1) to afford 243 (57 mg, 0.154 mmol, 44% yield) as a yellow oil. m / z (ESI): 371.2 (M+H). + .

[0196] tert-Butyl ((5-(2-methyloxiran-2-yl)pyridin-2-yl)methyl)((R)-1-(pyrimidin-2-yl)ethyl)carbamate (243, 57 mg, 0.154 mmol) and EtOH (1.5 mL) were added to a 25 mL scintillation vial. The mixture was cooled to 0 °C and NaBH (14.55 mg, 0.385 mmol) was added in one portion. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. Upon completion, the reaction was concentrated to dryness and redissolved in DCM (1 mL) and TFA (1754 mg, 1.185 mL, 15.39 mmol). The reaction was stirred at room temperature for 2 h. Upon removal of the Boc group, the reaction was concentrated and used directly in the next step, assuming quantitative yield. m / z (ESI): 273.3 (M+H). + .

[0197] Intermediate 246: (R)-N-((6-cyclopropylpyridazin-3-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] A mixture of (R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)tert-butylcarbamate (0.2 g, 0.507 mmol, 221), cyclopropylboronic acid (0.218 g, 2.54 mmol, Combi-Blocks), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(ii) dichloromethane complex (0.041 g, 0.051 mmol, Oakwood Products, Inc.), silver(i) oxide (0.223 g, 0.964 mmol, Sigma-Aldrich Corporation), potassium carbonate (0.210 g, 1.522 mmol, Acros), and 1,4-dioxane (5 mL) was purged with Ar and then stirred at 80° C. for 4.5 h in a sealed vial. LCMS showed the desired product. The mixture was filtered through Celite and concentrated in vacuo. The crude material was purified by chromatography through a silica gel column eluting with 0-100% (EtOAc / EtOH 3 / 1) in heptane. The product was obtained as an off-white solid (0.149 g, 83%). MS: m / z (ESI): 356.3 (M+H)+.

[0198] To a solution of tert-butyl (R)-((6-cyclopropylpyridazin-3-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.14 g, 0.394 mmol) in dichloromethane (4 mL) was added 4.0 M HCl in dioxane (0.788 mL, 3.15 mmol, Aldrich). The solution became a suspension. MeOH was added to reconstitute the suspension. The mixture was stirred at room temperature overnight. LCMS showed the product. The mixture was concentrated in vacuo. The product was obtained as an orange solid. MS: m / z (ESI): 256 (M+H)+.

[0199] Intermediate 247: (R)-N-((5-morpholinopyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine. [ka] (R)-((5-bromopyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl) tert-butyl carbamate (0.350 g, 0.890 mmol, 223), morpholine (0.233 g, 0.234 mL, 2.67 mmol, Aldrich), 2-methyltetrahydrofuran (5.5 mL), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (RuPhos) (0.145 g, 0.311 mmol, Aldrich), and RuPhos Pd A mixture of G1 methyl t-butyl ether adduct (0.254 g, 0.311 mmol, Strem) and sodium tert-butoxide (0.257 g, 2.67 mmol, Aldrich) was purged with Ar for 5 minutes, and then the mixture was heated at 80 °C overnight. LCMS showed the product. The reaction mixture was filtered through a pad of diatomaceous earth and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (0-100% EtOAc / EtOH (3 / 1) in DCM). The product was obtained as an orange solid (0.163 g, 46%). MS: m / z (ESI): 400 (M+H)+.

[0200] To a solution of tert-butyl (R)-((5-morpholinopyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamate (0.163 g, 0.408 mmol) in dichloromethane (4 mL) was added 4.0 M HCl in dioxane (0.918 mL, 3.67 mmol, Aldrich). The solution became a suspension. MeOH was added to turn the suspension into a solution. The mixture was stirred at room temperature overnight. LCMS showed the product. The mixture was concentrated in vacuo. The product was obtained as an orange solid. MS: m / z (ESI): 300 (M+H) + .

[0201] Example Example 300: 2-amino-N-isobutyl-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide. (Method A-HATU) [ka] To a mixture of 2-amino-3-methylquinoline-6-carboxylic acid (1, 105 mg, 0.52 mmol), 2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine (26, 133 mg, 0.57 mmol), and triethylamine (0.15 mL, 1.04 mmol) in DMF (2 mL) was added HATU (217 mg, 0.57 mmol, ChemPep) at room temperature. The mixture was stirred at room temperature for 4 h and then partitioned between 50 mL of EtOAc and 5 mL of water. The layers were separated. The organic layer was washed with 5 mL of 1N NaOH and concentrated. The residue was purified on a silica gel column (20-90% EtOAc in heptane) to give the title compound (300, 177 mg, 0.43 mmol, 82% yield) as a pale yellow solid. m / z (ESI): 417.0 (M+H). + . 1 H NMR (chloroform-d, 400 MHz) δ 8.84 (br s, 1H), 7.92 (br s, 1H), 7.5-7.8 (m, 5H), 5.20 (br s, 2H), 4.94 (m, 1H), 4.75 (m, 1H), 3.31 (m, 2H), 2.31 (s, 3H), 2.04 (m, 1H), 0.58-1.10 (m, 6H).

[0202] [Table 24]

[0203] [Table 25]

[0204] [Table 26]

[0205] [Table 27]

[0206] [Table 28]

[0207] [Table 29]

[0208] [Table 30]

[0209] [Table 31]

[0210] [Table 32]

[0211] Example 345: (R)-2-Amino-3-bromo-N-((5-chloropyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. (Method A-PyBroP) [ka] To a mixture of 2-amino-3-bromoquinoline-6-carboxylic acid (4, 64 mg, 0.24 mmol), (R)-N-((5-chloropyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethan-1-amine (105, 50 mg, 0.20 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) (112 mg, 0.24 mmol, Sigma-Aldrich Corporation), and N,N-dimethylacetamide (DMAc) (2 mL) was added triethylamine (0.07 mL, 0.50 mmol). The resulting mixture was stirred at room temperature for 18 hours and then filtered through a fritted funnel. The solid was rinsed with 1 mL of DMAc. The filtrate was purified by reverse-phase preparative HPLC (10-70% water in MeCN containing 0.1% TFA) to give (R)-2-amino-3-bromo-N-((5-chloropyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide 2,2,2-trifluoroacetate (345, 83 mg, 63% yield) as an off-white solid. m / z (ESI): 497 / 499 (M+H). + . 1 H NMR (400 MHz, methanol-d4) δ ppm 8.74(br d,J=3.7Hz,2H),8.31-8.44(m,2H),7.56-7.96(m,4H),7.27-7.45(m,2H),5. 36-5.52(m,1H),4.90-5.01(m,1H),4.55-4.68(m,1H),1.67(d,J=7.0Hz,3H).

[0212] [Table 33]

[0213] [Table 34]

[0214] [Table 35]

[0215] Table 36

[0216] Table 37

[0217] Table 38

[0218] Table 39

[0219] Table 40

[0220] Table 41

[0221] Table 42

[0222] Table 43

[0223] Table 44

[0224] Table 45

[0225] Table 46

[0226] Table 47

[0227] Table 48

[0228] Table 49

[0229] Table 50

[0230] Table 51

[0231] Table 52

[0232] Table 53

[0233] Table 54

[0234] Table 55

[0235] Table 56

[0236] [Table 57]

[0237] [Table 58]

[0238] [Table 59]

[0239] [Table 60]

[0240] [Table 61]

[0241] [Table 62]

[0242] [Table 63]

[0243] [Table 64]

[0244] Example 443: (R)-7-Amino-6-bromo-N-(1-(pyrimidin-2-yl)propyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide. (Method A-PyBroP-SFC) [ka] To a mixture of 7-amino-6-bromo-1,8-naphthyridine-3-carboxylic acid (12, 249 mg, 0.93 mmol), 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine (133, 250 mg, 0.84 mmol), and triethylamine (0.35 mL, 2.53 mmol) in DMAc (2 mL) was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) (413 mg, 0.88 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours and then partitioned between 50 mL of EtOAc and 5 mL of water. The layers were separated. The organic layer was washed with 5 mL of 1N NaOH and concentrated. The residue was purified on a silica gel column (50% EtOAc in DCM followed by 5-8% MeOH in DCM) to give 7-amino-6-bromo-N-(1-(pyrimidin-2-yl)propyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide (443a, m / z (ESI): 546 / 548 (M+H)). + ) and tri(pyrrolidin-1-yl)phosphine oxide (m / z (ESI): 258.1 (M+H) + ) to give a brown solid.

[0245] The racemic material was subjected to chiral SFC under the conditions shown below, yielding two eluents. Chiral SFC: Chiralcel OD-H SFC column (5 μm, 21 × 250 mm column) using 20% ​​EtOH (with 0.2% TEA) as a modifier, using a flow rate of 80 mL / min. The stronger eluent (IC in HCT116 MTAP null cell viability assay) yielded 1.25% elution yield. 50 (measured by ) enantiomer was assigned to (R)- and the less potent (IC in HCT116 MTAP null cell viability assay) 50The enantiomer was assigned to (S-). The first eluting peak was (R)-7-amino-6-bromo-N-(1-(pyrimidin-2-yl)propyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide (443, 82 mg). The second eluting peak was (S)-7-amino-6-bromo-N-(1-(pyrimidin-2-yl)propyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide (55 mg). m / z (ESI): 546 / 548 (M+H). + . 1 H NMR (methanol-d4,400MHz)δ 9.10(s,1H),8.73(d,2H,J=4.4Hz),8.67(s,1H),8.5-8.6(m,2H),7.9-8.0(m,1H),7.4-7.5(m ,1H),7.32(t,1H,J=4.9Hz),5.25(m,1H),5.05(m,1H),4.94(m,1H),2.27(m,2H),1.25(m,3H).

[0246] [Table 65]

[0247] [Table 66]

[0248] [Table 67]

[0249] [Table 68]

[0250] [Table 69]

[0251] Table 70

[0252] Table 71

[0253] Table 72

[0254] Table 73

[0255] Table 74

[0256] Table 75

[0257] Table 76

[0258] Table 77

[0259] Table 78

[0260] Table 79

[0261] Table 80

[0262] [Table 81]

[0263] [Table 82]

[0264] [Table 83]

[0265] Example 502. (R)-2-Amino-N-((5-cyanopyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. (Method B) [ka] (R)-6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)nicotinonitrile (111, 1.00 g, 4.18 mmol) and 2-amino-3-methylquinoline-6-carbonyl chloride hydrochloride (16, 1.34 g, 5.22 mmol) in 1,2-dichloroethane (41.8 mL) were added to a 150 mL round-bottom flask. Pyridine (3.55 mL, 41.8 mmol) was then added to the reaction mixture. The reaction mixture was heated to 60 °C, then cooled to room temperature and treated with saturated NaHCO and a small amount of MeOH. The mixture was diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM (3 times). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH 3:1 in heptane) to afford the title compound (502, 1.35 g, 3.19 mmol, 76% yield) as a pale yellow solid. m / z (ESI): 424.1 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ ppm 8.89(d,J=1.5Hz,1H),8.77(d,J=4.8Hz,2H),8.20(br d,J=7.7Hz,1H),7.82(s,1H),7.79(s,1H),7.59(br s,1H),7.53(br d,J=8.4Hz,2H),7.39(t,J=4.9Hz,1H),6.48(br s,2H),5.43(br s,1H),4.89(br d,J=17.3Hz,1H),4.51(br d,J=15.7Hz,1H),2.21(br s,3H),1.61(br d,J=6.7Hz,3H).

[0266] Table 84

[0267] Table 85

[0268] Table 86

[0269] Table 87

[0270] Table 88

[0271] Table 89

[0272] Table 90

[0273] [Table 91]

[0274] Example 515: (R)-2-amino-N-(6-fluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((6-(trifluoromethyl))pyridazin-3-yl)methyl)quinoline-6-carboxamide. (Method B-SFC) [ka] A mixture of triethylamine (0.52 mL, 3.77 mmol) and 6-fluoro-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine (81, 206 mg, 0.62 mmol) in THF (2.5 mL) was treated as a solid with 2-amino-3-methylquinoline-6-carbonyl chloride hydrochloride (16, 161 mg, 0.62 mmol) at room temperature. The mixture was stirred for 30 minutes and then concentrated in vacuo. The residue containing racemic 515a was subjected to chiral SFC under the conditions shown below to obtain two eluents. Chiral SFC: Chiral Technologies OJ column (250 × 21 mm, 5 μm) using a flow rate of 80 mL / min with 75% liquid CO and 25% MeOH (with 0.2% TEA) as the mobile phase. Potent (IC in HCT116 MTAP-null cell viability assay) 50 (measured by ) enantiomer was assigned to (R)- and the less potent (IC in HCT116 MTAP null cell viability assay) 50 The enantiomer was assigned to (S)- (as determined by HPLC). The first eluting peak was assigned to (R)-2-amino-N-(6-fluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((6-(trifluoromethyl))pyridazin-3-yl)methyl)quinoline-6-carboxamide (515, 53 mg, 0.10 mmol, 16% yield) as an off-white solid. m / z (ESI): 513.0 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ ppm 8.23(br d,J=8.57Hz,1H)8.02-8.19(m,1H)7.85-8.00(m,1H)7.73-7.85(m,1H)7.66(br d,J=7.73Hz,1H)7.35-7.58(m,2H)7.00(br dd,J=8.57,2.72Hz,1H)6.52(br s,2H)5.38-5.45(m,1H)4.93(br d,J=16.10Hz,1H)4.48(br d,J=16.51Hz,1H)4.32(br d, J = 11.29 Hz, 1H) 4.10-4.23 (m, 1H) 2.32-2.47 (m, 2H) 2.22 (s, 3H). The second eluting peak was assigned to (S)-2-amino-N-(6-fluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((6-(trifluoromethyl))pyridazin-3-yl)methyl)quinoline-6-carboxamide (55 mg, 0.107 mmol, 17% yield). m / z (ESI): 513.1 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ ppm 8.23(br d,J=8.57Hz,1H)8.12(br d,J=8.78Hz,1H)7.88(br s,1H)7.81(br s,1H)7.66(br d,J=7.73Hz,1H)7.51(br d,J=8.36Hz,1H)7.43(dd,J=8.57,6.69Hz,1H)7.00(br dd,J=8.47,2.61Hz,1H)6.50(br s,2H)5.37-5.45(m,1H)4.93(br d,J=16.30Hz,1H)4.48(br d,J=16.72Hz,1H)4.25-4.39(m,1H)4.10-4.23(m,1H)2.32-2.47(m,2H)2.22(s,3H).

[0275] [Table 92]

[0276] [Table 93]

[0277] [Table 94]

[0278] [Table 95]

[0279] [Table 96]

[0280] [Table 97]

[0281] [Table 98]

[0282] [Table 99]

[0283] [Table 100]

[0284] [Table 101]

[0285] [Table 102]

[0286] Example 537: 7-amino-N-((3-fluoropyridin-2-yl)methyl)-6-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide. [ka] A COware system (Sigma-Aldrich) was used for this reaction. Chamber 1 was charged with formic acid (33 mg, 0.72 mmol), methanesulfonyl chloride (83 mg, 0.72 mmol), and triethylamine (0.20 mL, 1.44 mmol) in toluene (1 mL). Chamber 2 was charged with methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(ii) (xanthophospalladacycle G4) (17 mg, 0.018 mmol, Strem), 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methanamine (28, 134 mg, 0.47 mmol), Intermediate 18 (158 mg, 0.36 mmol), triethylamine (0.20 mL, 1.44 mmol), and dioxane (2 mL). The COware system was heated at 60 °C for 18 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad, rinsing the solid with 5 mL of EtOAc. The filtrate was concentrated to give m / z(ESI): 671.3(M+H) + A brown solid containing 537 was obtained. This brown solid was suspended in DCM (2 mL) and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The crude material was purified by reverse-phase preparative HPLC (0.1% TFA in CHCN / HO using a gradient from 10% to 100%) to give 7-amino-N-((3-fluoropyridin-2-yl)methyl)-6-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide 2,2,2-trifluoroacetate (537, 148 mg, 0.253 mmol, 70% yield) as an off-white solid. MS (ESI, +ve) m / z: 471 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm 8.74-9.06(m,2H),8.38-8.65(m,4H),8.18(br d,J=5.23Hz,2H),7.54-7.79(m,2H),7.43(dt,J=8.47,4.34Hz,1H),4.87(br d,J=5.43Hz,3H),3.44-4.21(m,2H),2.31(s,3H).

[0287] Example 538: 7-amino-6-methyl-N-((1R)-1-(2-pyrazinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide. [ka] The title compound (538) was prepared from amine 145 in a similar manner as described in Example 537, followed by chiral SFC (first eluting peak). MS (ESI, +ve) m / z: 468.1 [M+H] + . SFC conditions: Chiral Technology AD (250 × 21 mm, 5 μm). Mobile phase: 80:20. B: 0.2% TEA in MeOH.

[0288] Example 539: 2-amino-N-isobutyl-3,7-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide. [ka] To a stirred mixture of 2-amino-7-chloro-N-isobutyl-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (436, 77 mg, 0.17 mmol) and tetrakis(triphenylphosphine)palladium (39.5 mg, 0.034 mmol, Sigma-Aldrich) in 1,4-dioxane (0.5 mL) in a microwave vial was added trimethylaluminum (0.17 mL of a 2.0 M solution in toluene, 0.34 mmol, Sigma-Aldrich) under a nitrogen atmosphere. The reaction mixture was heated in a microwave at 130° C. for 6 hours, then cooled to room temperature and partitioned between EtOAc (40 mL) and saturated NaHCO (40 mL). The organic layer was separated, washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) afforded the title compound (539, 4 mg, 5% yield) as a pale yellow solid. MS (ESI, +ve) m / z: 431.1 [M+H] + .

[0289] Example 540: (R)-2-amino-N-((5-(cyclopropylsulfonyl)pyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide. [ka] To a mixture of (R)-2-amino-N-((5-bromopyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide (400, 45 mg, 0.09 mmol), sodium cyclopropanesulfinate (46 mg, 0.36 mmol, Accela ChemBio Inc.), (S)-pyrrolidine-2-carboxylic acid sodium salt (10 mg, 0.07 mmol, Combi-Blocks), and copper(i) iodide (7 mg, 0.03 mmol, Sigma-Aldrich) in a 5 mL microwave vessel was added dimethyl sulfoxide (3.0 mL). The resulting solution was purged with nitrogen for 10 minutes, then sealed and heated in a microwave at 95 °C for 3 hours. The mixture was purified by reverse-phase HPLC (10% to 85% MeCN in water with 0.1% TFA) to give, after lyophilization, (R)-2-amino-N-((5-(cyclopropylsulfonyl)pyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide TFA salt (26 mg, 0.041 mmol, 45% yield) as a white solid. m / z (ESI): 520.0 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ 8.82(dd,J=0.63,2.30Hz,1H),7.88-8.39(m,5H),7.73-7.87(m,1H),7.36-7.66(m ,2H),7.28(td,J=4.34,8.47Hz,1H),5.02-5.57(m,1H),4.88-4.95(m,2H),2.72(br s,1H),2.28-2.51(m,3H),1.60-1.80(m,3H),1.22-1.31(m,2H),1.05-1.15(m,2H). 19 F NMR (376 MHz, methanol-d4) δ -77.09 (s, 3F from TFA), -125.00 (s, 1F). m / z (ESI): 520.0 (M+H) + .

[0290] Example 541: (R)-2-amino-N-((5-(methylsulfonyl)pyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide. This molecule was prepared in a similar manner as described for Example 540. m / z (ESI): 494.1 (M+H) + . [ka]

[0291] Example 542: (R)-2-amino-N-((5-cyanopyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide. [ka] A mixture of (R)-2-amino-N-((5-bromopyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide (400, 100 mg, 0.20 mmol), L-(-)-proline (23 mg, 0.20 mmol), and copper(i) cyanide (45 mg, 0.50 mmol) in NMP (2.0 mL) in a 5 mL microwave vessel was purged with nitrogen for 10 minutes, then sealed and subjected to microwave heating (140° C. for 2 hours). The mixture was treated with CuCN (approximately 25 mg) and then heated in a microwave (140° C. for 16 hours). The crude reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (10% to 85% MeCN in water with 0.1% TFA) to give, after lyophilization, (R)-2-amino-N-((5-cyanopyridin-2-yl)methyl)-N-(1-(3-fluoropyridin-2-yl)ethyl)-3-methylquinoline-6-carboxamide (10 mg) as the free base as an off-white solid (Note: 19 F No TFA signal was observed in NMR. m / z (ESI): 441.2 (M+H) + . 1H NMR(400MHz, methanol-d4)δ 8.72(br s,1H),8.15-8.33(m,2H),7.69-8.10(m,4H),7.23-7.51(m,3H),5.40-6.51(m,1H),4.88-4.94(m,2H),2.40(br s,3H),1.70(br s,3H). 19 F NMR (376 MHz, methanol-d4) δ -125.09 (s, 1F).

[0292] Example 543: (R)-7-amino-6-ethynyl-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide. [ka] A mixture of (R)-7-amino-6-bromo-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide 2,2,2-trifluoroacetic acid (388, 100 mg, 0.15 mmol), Pd(PPh) (35 mg, 0.03 mmol, Combi Blocks), copper(i) iodide (11 mg, 0.06 mmol), and 1,1′-dimethyltriethylamine (0.10 mL, 0.60 mmol) in NMP (2.5 mL) in a 5 mL microwave reaction vessel was purged with nitrogen for 10 minutes before introducing (trimethylsilyl)acetylene (0.11 mL, 0.75 mmol, Matrix Scientific). The vessel was sealed and subjected to microwave heating (70° C. for 15 hours). The crude material was directly loaded onto a silica gel column and eluted with MeOH (containing 0.5% ammonium hydroxide) / DCM to give an impure mixture of (R)-7-amino-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-6-((trimethylsilyl)ethynyl)-1,8-naphthyridine-3-carboxamide and (R)-7-amino-6-ethynyl-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,8-naphthyridine-3-carboxamide. To this was added MeOH (5 mL), followed by potassium carbonate (98 mg, 0.70 mmol), and the resulting mixture was stirred at room temperature for 20 minutes. The crude material was loaded directly onto a silica gel column and eluted with MeOH (containing 0.5% ammonium hydroxide) / DCM to give impure desired product, which was dissolved in MeOH and subjected to preparative reverse-phase HPLC (10% to 85% MeCN in water with 0.1% TFA) to give the title compound as a TFA salt (543, 9.5 mg) as a white solid. m / z (ESI): 495.0 (M+H). + . 1H NMR(400MHz, methanol-d4)δ 8.97(br s,1H),8.25-8.81(m,3H),7.73-8.08(m,1H),7.08-7.53(m,3H),5.43-6.49(m,1H),4.89-5.00(m,3H),4.34(br s,1H),1.53-1.87(m,3H).

[0293] Example 544: (R)-2-amino-3-iodo-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide. [ka] A mixture of trans-(-)-N,N''-dimethylcyclohexane-1,2-diamine (4.02 mg, 0.028 mmol, Sigma-Aldrich), copper(i) iodide (2.69 mg, 0.014 mmol, Acros Organics), sodium iodide (52.9 mg, 0.353 mmol, Sigma-Aldrich), and (R)-2-amino-3-bromo-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (434, 75 mg, 0.14 mmol) in 2 mL of dioxane was heated at 125 °C for 8 h. The mixture was diluted with 50 mL of EtOAc and filtered through a Celite pad. The filtrate was washed with 5 mL of water. The organic solution was concentrated, and the residue was purified on a silica gel column (1% to 5% MeOH in EtOAc) to give a brown solid containing a 2:3 mixture of 434:544. This material (80 mg) was purified by SFC using a Regis (S,S) Whelk-01 column (250 × 21 mm, 5 μm) with a mobile phase of 50% liquid CO and 50% MeOH (with 0.2% TEA) using a flow rate of 60 mL / min to give 14 mg of peak 1 (434, m / z (ESI): 531 / 533 (M+H)). + ) and 20 mg of peak 2 (544, m / z (ESI): 578.9 (M+H) +(R)-2-amino-3-iodo-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (544, 20 mg, 24% yield) was obtained as a brown solid. 1 H NMR (methanol-d4,400MHz)δ 8.75(m,3H),8.63(s,1H),8.0-8.1(m,1H),7.92(m,1H),7.7-7.8(m,1H),7.5-7.7(m,2H),7.34(t,1 H,J=4.9Hz),5.91(m,0.3H),5.49(m,0.7H),4.9-5.1(m,1H),4.7-4.8(m,1H),1.71(d,3H,J=7.0Hz).

[0294] Example 545: 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3,4-dimethyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide. [ka] A mixture of (R)-6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)nicotinonitrile (111, 88 mg, 0.368 mmol) and 2-((4-methoxybenzyl)amino)-3,4-dimethylquinoline-6-carboxylic acid hydrochloride (9, 91 mg, 0.245 mmol) in DMF (2.5 mL) was treated with diisopropylethylamine (0.43 mL, 2.45 mmol) followed by PyBroP (286 mg, 0.61 mmol) at room temperature. The reaction mixture was heated at 70° C. for 3 h. It was cooled to room temperature, quenched with saturated NaHCO (15 mL), and extracted with EtOAc (3×15 mL). The organic solution was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give 545a (m / z (ESI): 558.2 (M+H) + ) and tri(pyrrolidin-1-yl)phosphine oxide (m / z (ESI): 258.1 (M+H) +), yielding 176 mg of a brown oil. The resulting brown oil was treated with trifluoroacetic acid (1.8 mL) and then heated at 70° C. for 2.5 hours. The mixture was concentrated in vacuo. The remaining orange solid was purified by silica gel chromatography to give m / z (ESI): 438.2 (M+H). + 30 mg of an off-white solid having the formula: 1 H NMR (400 MHz, methanol-d4) δ ppm 8.78 (d, J = 5.0 Hz, 3H), 8.23-8.48 (m, 1H), 8.09 (br d, J = 7.9 Hz, 1H), 7.47-7.98 (m, 3H), 7.38 (t, J = 4.9 Hz, 1H), 5.33-5.95 (m, 1H), 4.90-5.20 (m, 2H), 2.46-2.78 (m, 3H), 2.36 (br s, 3H), 1.70 (d, J = 7.1 Hz, 3H). The ee of the isolated product was then evaluated, revealing that the compound underwent epimerization during deprotection with TFA. This material was subjected to chiral SFC to give 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3,4-dimethyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide (545, 9 mg, m / z (ESI): 438.2 (M+H) + ) was obtained as the first eluting peak. SFC conditions: The sample was purified by preparative SFC using a Chiral Technologies OD column (250 × 21 mm, 5 mm) with a mobile phase of 80% liquid CO2 and 20% MeOH (with 0.2% TEA) using a flow rate of 80 mL / min, yielding 9 mg of peak 1 (ee >99%) and 16.5 mg of peak 2 (ee >96.74%). Peak assignments were determined by SFC on the OD column using 20% ​​EtOH with 0.2% TEA.

[0295] Example 546: 2-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide. [ka] A mixture of 2-amino-N-((5-bromopyridin-2-yl)methyl)-N-isobutyl-3-methylquinoline-6-carboxamide (357, 23 mg, 0.054 mmol), cyclopropylboronic acid (23 mg, 0.269 mmol, Oakwood), and toluene (2 mL) was purged with argon, followed by the addition of potassium phosphate hydrate (37 mg, 0.161 mmol, Aldrich) and water (0.22 mL). The mixture was stirred at room temperature for 10 minutes, followed by the addition of tricyclohexylphosphine (2 mg, 5.4 μmol, Strem) and palladium(II) acetate (0.6 mg, 2.7 μmol, Aldrich). The mixture was stirred in a sealed vial at 90° C. overnight and then filtered through Celite. The filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0% to 100% (EtOAc / EtOH 3 / 1) in heptane) to give the title compound (546, 11 mg, 52% yield) as an off-white solid. MS: m / z (ESI): 389.1 (M+H). + . 1 H NMR(400MHz,chloroform-d)δ ppm 8.27-8.43(m,1H),7.26(s,6H),5.04(br s,2H),4.56-4.92(m,2H),3.07-3.44(m,2H),2.29(br s,3H),1.82-1.99(m,2H),0.90-1.08(m,5H),0.71(br s,5H).

[0296] Example 821: (R)-2-amino-N-((5-cyclopropylpyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. [ka] This molecule was prepared from Example 402 in a similar manner as described for Example 546. m / z (ESI): 439 (M+H) + .

[0297] Example 548. N-((1'-acetyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl)methyl)-2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide. [ka] (R)-tert-butyl 6-((2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamido)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (547, MS: m / z (ESI): 580 (M+H) + ) was prepared from Example 402 in a manner similar to that described for Example 546.

[0298] A mixture of (R)-tert-butyl 6-((2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamido)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (547, 34 mg, 0.059 mmol), DCM (1 mL), and TFA (0.5 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo to give 548a as an off-white solid, which was used in the next step without purification. MS: m / z (ESI): 480 (M+H). + .

[0299] A mixture of 548a (0.031 g, 0.052 mmol), dichloromethane (2 mL), TEA (0.102 mL, 0.731 mmol), and acetic anhydride (0.044 mL, 0.470 mmol) was stirred at room temperature for 18 hours. The mixture was purified by silica gel chromatography (0% to 100% in heptane, then 100% EtOAc / EtOH (3 / 1)) to give (R)-2-acetamido-N-((1'-acetyl-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (548b, 29 mg) as an off-white solid. MS: m / z (ESI): 564 (M+H). + .

[0300] A mixture of 548b (0.029 g, 0.051 mmol), lithium hydroxide hydrate (0.017 g, 0.412 mmol), MeOH (3 mL), and water (1 mL) was stirred at room temperature for 18 h. The mixture was purified by reverse-phase HPLC (10–70% water in MeCN containing 0.1% TFA) to give N-((1'-acetyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl)methyl)-2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide TFA salt (548, 30 mg, 925% yield) as a white solid. MS: m / z (ESI): 522 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.80(d,J=5.0Hz,2H),8.63-8.72(m,1H),7.54-8.28(m,6H),7.39(t,J=5.0Hz,1H),6.32-6.42(m,1H),5.35-5.44(m,1H),5.02(br d,J=15.1Hz,1H),4.79(br d,J=3.7Hz,1H),4.26(br s,2H),3.81(dt,J=20.0,5.7Hz,2H),2.52-2.71(m,2H),2.40(br s,3H),2.17(d,J=15.3Hz,3H),1.73(br d, J = 7.0 Hz, 3H).

[0301] Example 549: 2-amino-N-((5-cyano-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide. [ka] 2-amino-N-((5-bromo-3-methylpyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (549a, MS: m / z (ESI): 491 / 493 (M+H) + ) was prepared from amine 179 and acid chloride 16 according to Method B.

[0302] A mixture of 2-amino-N-((5-bromo-3-methylpyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide hydrochloride (549a, 0.14 g, 0.26 mmol), sodium carbonate (0.10 g, 0.92 mmol), N,N-dimethylacetamide (2 mL), potassium ferrocyanide trihydrate (0.11 g, 0.26 mmol, Toronto Research Chemicals), and palladium acetate (6 mg, 0.026 mmol, Strem) was purged with Ar and then stirred at 120 °C overnight. The mixture was filtered through Celite. The filtrate was purified by reverse-phase HPLC (10-70% water in MeCN containing 0.1% TFA) to give 2-amino-N-((5-cyano-3-methylpyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (59 mg) as the TFA salt as a gray solid. MS: m / z (ESI): 438 (M+H). + .

[0303] The racemic material (59 mg) was subjected to chiral SFC using a Chiral Technologies OD column (250 x 21 mm, 5 μm) with a mobile phase of 70% liquid CO2 and 30% EtOH (with 0.2% TEA) using a flow rate of 70 mL / min. The stronger (IC in the HCT116 MTAP null cell viability assay) 50 (measured by ) enantiomer was assigned to (R)- and the less potent (IC in HCT116 MTAP null cell viability assay) 50 The enantiomer was assigned to (S)-. The first eluting peak was 2-amino-N-((5-cyano-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide (549, 20 mg, ee >99%). MS: m / z (ESI): 438 (M+H). + . 1 H NMR (400 MHz, methanol-d₄) δ ppm 8.52-8.80 (m, 3H), 7.20-7.98 (m, 6H), 5.40-5.56 (m, 1H), 5.01-5.17 (m, 1H), 4.65-4.76 (m, 1H), 1.94-2.49 (m, 6H), 1.63-1.70 (m, 3H). The second eluting peak was 2-amino-N-((5-cyano-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide (31 mg, ee >99%).

[0304] Example 550: 2-amino-N-((5-carbamoyl-2-pyridinyl)methyl)-N-((1R)-1-(2-fluorophenyl)ethyl)-3-methyl-6-quinolinecarboxamide. [ka] A mixture of (R)-2-amino-N-((5-cyanopyridin-2-yl)methyl)-N-(1-(2-fluorophenyl)ethyl)-3-methylquinoline-6-carboxamide 2,2,2-trifluoroacetic acid (405, 6 mg), tert-butanol (1 mL), and KOH (5 mg) was stirred at 85 °C for 55 min. The mixture was dissolved in MeOH / DMF, filtered, and purified by reverse-phase HPLC (10-70% water in MeCN with 0.1% TFA) to give the title compound as the TFA salt (3.2 mg, 51% yield) as a white solid. MS: m / z (ESI): 458 (M+H). + . 1 H NMR (400 MHz, methanol-d₄) δ ppm 8.85 (d, J = 1.7 Hz, 1H), 6.84-8.38 (m, 10H), 5.32-5.44 (m, 1H), 4.93 (s, 1H), 4.78 (s, 1H), 2.31-2.50 (m, 3H), 1.59-1.79 (m, 3H).

[0305] Example 551: Methyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((1R)-1-(2-pyrimidinyl)ethyl)amino)methyl)-3',6'-dihydro[3,4'-bipyridine]-1'(2'H)-carboxylate. [ka] A mixture of 547 (0.50 g, 0.85 mmol), dichloromethane (5 mL), N,N-diisopropylethylamine (0.60 mL, 3.42 mmol), and acetic anhydride (0.16 mL, 1.71 mmol) was stirred at room temperature for 18 h. The mixture was purified by silica gel chromatography (0% to 100% EtOAc / EtOH (3 / 1) in DCM) to give (R)-6-((2-acetamido-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamido)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.53 g) as an off-white solid. MS: m / z (ESI): 622 (M+H). +To the off-white solid (0.53 g, 0.86 mmol) in DCM (10 mL) and MeOH (1 mL) was added HCl (4.0 M in dioxane, 1.93 mL). After stirring at room temperature for 18 h, the mixture was concentrated in vacuo to give 551a as an orange solid, which was used crude in the next step. MS: m / z (ESI): 522 (M+H). + .

[0306] To a mixture of (R)-2-acetamido-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)quinoline-6-carboxamide trihydrochloride (551a, 0.094 g, 0.15 mmol) in dichloromethane (2 mL) was added DIPEA (0.21 mL, 1.19 mmol) and methyl chloroformate (0.015 mL, 0.194 mmol, Aldrich). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / EtOH (3 / 1) in DCM) to give (R)-methyl 6-((2-acetamido-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamido)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (90 mg) as an orange solid. MS: m / z (ESI): 580 (M+H). + The orange solid (90 mg) was dissolved in MeOH (3 mL) and water (1 mL) and treated with lithium hydroxide hydrate (62 mg). After stirring at room temperature for 18 h, the mixture was purified by silica gel chromatography (5-100% in DCM, then 100% EtOAc / EtOH (3 / 1)) to give (R)-6-((2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamido)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (551, 24 mg, 30% yield) as a white solid. MS: m / z (ESI): 538 (M+H). + . 1H NMR (400MHz, methanol-d4) δ ppm 8.73(br s,2H),8.43-8.48(m,1H),7.46-7.95(m,5H),7.39(br d,J=8.2Hz,1H),7.31(br t,J=4.5Hz,1H),6.11-6.25(m,1H),5.44-5.54(m,1H),4.94-5.05(m,1H),4.5 4-4.67(m,1H),4.11-4.17(m,2H),3.74(s,3H),3.70(t,J=5.7Hz,2H),2.54(br s,2H),2.30(br s,3H),1.67(br d,J=6.1Hz,3H).

[0307] Example 552: N-((5-(1-acetyl-4-piperidinyl)-2-pyridinyl)methyl)-2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide. [ka] A mixture of 10% palladium on carbon (0.024 g, 0.023 mmol, Aldrich), 548 (0.059 g, 0.11 mmol), and EtOH (3 mL) was hydrogenated at 40 psi of H for 18 h. The mixture was filtered through Celite. The Celite was washed with 3 / 1 EtOAc / EtOH. The filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (1% to 10% MeOH / DCM with 1% concentrated NHOH in water) to give the title compound (552, 22 mg, 37% yield) as a white solid. MS: m / z (ESI): 524 (M+H). + H-NMR (MeOH-d4): 31H was observed. 1H NMR (400MHz, methanol-d4) δ ppm 8.65-8.81(m,2H),8.30(s,1H),7.24-7.99(m,7H),5.49(s,1H),4.91-5.04(m,1H),4.69(br d,J=12.6Hz,1H),3.95-4.10(m,1H),3.88(s,1H),3.59(s,1H),3.19-3.28(m,1H),2.82-2.93(m ,1H),2.66-2.76(m,1H),2.23-2.36(m,3H),2.14(s,3H),1.79-1.96(m,2H),1.54-1.75(m,4H).

[0308] Example 822: (R)-4-(6-((2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamido)methyl)pyridin-3-yl)piperidine-1-carboxylate was prepared in a similar manner as described for Example 552 using Example 551 as the starting material. m / z (ESI): 540 (M+H) + . [ka]

[0309] Example 553: 2-amino-N-((5-cyano-2-pyrazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide. [ka] 2-amino-N-((5-bromopyrazin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (553a, m / z (ESI): 478 / 480 (M+H) + ) was prepared from amine 143 and acid chloride 16 according to Method B.

[0310] 2-Amino-N-((5-cyano-2-pyrazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide (553, m / z (ESI): 425.1 (M+H) + ) was prepared from amine 553a in a manner similar to that described for Example 549. Chiral SFC conditions: Chiral Technologies OD column (250 x 21 mm, 5 μm); mobile phase: 65:35; B: 0.2% TEA in MeOH. The first eluting peak was Example 553 (ee > 99%). 1 H NMR (400MHz, methanol-d4) δ ppm 8.90(d,J=1.5Hz,1H),8.84(br s,1H),8.76(d,J=4.8Hz,2H),7.85(br s,2H),7.67(br s,1H),7.50-7.64(m,1H),7.37(t,J=4.9Hz,1H),5.51(br s,1H),4.91-5.14(m,2H),2.32(s,3H),2.00(s,2H),1.76(d,J=7.1Hz,3H).

[0311] Example 554: (R)-2-amino-N-((6-(dimethylamino)pyridazin-3-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. [ka] (R)-2-(bis(4-methoxybenzyl)amino)-N-((6-bromopyridazin-3-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (554a, m / z (ESI): 718.0, 720.0 (M+H) + ) was prepared from amine 126 and acid 20 according to the procedure described in Method A-PyBroP.

[0312] RuPhos (18mg, 0.039mmol, Strem) and RuPhos Pd A mixture of G1 (32 mg, 0.39 mmol, Aldrich), (R)-2-(bis(4-methoxybenzyl)amino)-N-((6-bromopyridazin)-3-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (554a, 110 mg, 0.15 mmol), dimethylamine (2.0 M in THF, 230 μL, 0.46 mmol, Aldrich), and cesium carbonate (200 mg, 0.62 mmol, Aldrich) in THF (1.0 mL) was heated at 85° C. for 2.5 h. The reaction mixture was filtered through a pad of diatomaceous earth and washed with EtOAc. The filtrate was concentrated and the crude product was purified by silica gel chromatography (0% to 100% EtOAc in heptane, followed by 30% to 100% in heptane (EtOAc:EtOH 3:1)) to afford (R)-2-(bis(4-methoxybenzyl)amino)-N-((6-(dimethylamino)pyridazin-3-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (48 mg, 0.07 mmol, 45% yield). This material was dissolved in TFA (6.0 mL), heated to 60° C. for 18 hours, and concentrated. The crude product was purified on an SCX column eluting with MeOH followed by 2M ammonia in MeOH to afford the title compound (554, 30 mg, 0.068 mmol, 44% yield) as a brown solid. m / z (ESI): 443.1 (M+H). + . 1 H NMR (400 MHz, methanol-d4) δ ppm 8.71 (br d, J = 4.2 Hz, 2H), 7.82 (br s, 1H), 7.75 (br s, 1H), 7.64 (br s,1H),7.54(br d,J=7.5Hz,2H),7.29(br t,J=4.8Hz,1H),7.02(br d,J=8.2Hz,1H),5.26-5.77(m,1H),4.98(br d,J=15.0Hz,1H),4.69(br d,J=9.4Hz,1H),3.11(s,6H),2.27(s,3H),1.68(br d,J=7.1Hz,3H).

[0313] Example 555: (R)-2-amino-3-methyl-N-((6-morpholinopyridazin-3-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. This molecule was prepared in a similar manner as described for Example 554. m / z (ESI): 485.1 (M+H). + . [ka]

[0314] Example 823: 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide. This molecule was prepared from 205 in a similar manner as described for Example 554. m / z (ESI): 502.2 (M+H). + . [ka]

[0315] Example 824: 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((6-(methylamino)-3-pyridazinyl)methyl)-6-quinolinecarboxamide. This molecule was prepared from 205 in a similar manner as described for Example 554, except that BrettPhos was used instead of RuPhos. m / z (ESI): 446.1 (M+H). + . [ka]

[0316] Example 556: (R)—N-((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. [ka] 2-amino-N-((5-bromopyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (556a, m / z (ESI): 477 / 479 (M+H) + ) was prepared from amine 106 and acid chloride 16 according to Method B.

[0317] Dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (26 mg, 0.057 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl t-butyl ether (46 mg, 0.057 mmol), and sodium tetrahydrofuran (Te) To a stirred solution of rt-butoxide (91 mg, 0.94 mmol) and 2-amino-N-((5-bromopyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (556a, 180 mg, 0.37 mmol) in THF (3.8 mL) was added 2-oxa-6-azaspiro[3.3]heptane (37 mg, 0.37 mmol, Combi Blocks). The mixture was purged with N for 10 minutes and then heated to 60° C. for 24 hours. The reaction was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (3×10 mL). The combined organics were concentrated and the residue was chromatographed on silica gel (0% to 100% in heptane (EtOAc / EtOH 3:1)) to give N-((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (42 mg, 0.085 mmol, 22.5% yield) as a brown solid. m / z (ESI): 496.3 (M+H). +The racemic material was subjected to chiral SFC under the conditions shown below, giving two eluates. Chiral SFC: Chiral Technologies OJ column (250 × 21 mm, 5 μm) using a mobile phase of 85% liquid CO₂ and 15% EtOH (with 0.2% TEA) at a flow rate of 80 mL / min. The first eluting peak was (R)-N-((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (556, 18 mg, ee >99%) as a brown solid. m / z (ESI): 496.3 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 8.75(br s,2H),7.54-7.97(m,5H),7.20-7.39(m,2H),6.89(br d,J=6.7Hz,1H),5.37-5.71(m,1H),4.89-5.07(m,2H),4.86(s,4H),4.08(s,4H),2.33(s,3H),1.64(br d, J = 5.6 Hz, 3H). The second eluting peak was (S)-N-((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (18 mg, ee > 99%) as a brown solid. m / z (ESI): 496.3 (M+H). + .

[0318] Example 557: (R)-2-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide. [ka] 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (726 mg, 3.46 mmol), 556a (550 mg, 1.15 mmol), tribasic potassium phosphate (734 mg, 3.46 mmol), palladium(II) acetate (39 mg, 0.17 mmol), tricyclohexylphosphine (97 mg, 0.34 mmol), toluene (5.2 mmol), and water (0.6 mL) were placed in a 50 mL RBF. The mixture was purged with N for 10 minutes and then heated at 90 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% in heptane (EtOAc:EtOH 3:1)) to afford 2-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (557a, 135 mg, 0.28 mmol, 24% yield) as a white solid. m / z (ESI): 481.3 (M+H). + .

[0319] The racemic material was subjected to chiral SFC under the conditions shown below, giving two eluents. Chiral SFC: Chiral Technologies OJ column (250 × 21 mm, 5 μm) using a flow rate of 90 mL / min with 80% liquid CO₂ and 20% iPrOH (with 0.2% TEA) as the mobile phase. The first peak was (R)-2-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (557, 70 mg, ee >99%) as a white solid. m / z (ESI): 481.3 (M+H). + . 1H NMR(400MHz, methanol-d4)δ ppm 8.75(brs,2H),8.49(d,J=1.9Hz,1H),7.52-8.00(m,5H),7.41(brd,J=8.1Hz,1H),7.33(brt,J=4.7Hz,1H),6.29 (dt,J=3.0,1.4Hz,1H),5.38-5.86(m,1H),4.91-5.13(m,1H),4.45-4.72(m,1H),4.32(q,J=2.8Hz,2H),3.95(t, J = 5.5 Hz, 2H), 2.49-2.57 (m, 2H), 2.32 (brs, 3H), 1.69 (brd, J = 6.2 Hz, 3H). The second peak was (S)-2-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (65 mg, ee > 98%) as a white solid. m / z (ESI): 481.3 (M+H). + .

[0320] Example 558: 2-amino-N-((5-(5,6-dihydro-2H-pyran-3-yl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl))ethyl)-6-quinolinecarboxamide. [ka] This molecule was prepared in a similar manner as described in Example 557. SFC conditions: Chiral Technologies AD column (250 x 21 mm, 5 μm) and AD (150 x 21 mm, 5 μm) with a mobile phase of 65% liquid CO2 and 35% iPrOH (with 0.2% TEA) using a flow rate of 50 mL / min. The first eluting peak was 558 (ee > 96%). m / z (ESI): 481.3 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 8.75(br s,2H),8.39(d,J=1.9Hz,1H),7.51-7.97(m,5H),7.40(br d,J=7.9Hz,1H),7.33(br t,J=4.6Hz,1H),6.30-6.40(m,1H),5.36-5.91(m,1H),4.94-5.13(m,1H),4.48(br d,J=1.7Hz,3H),3.85(t,J=5.5Hz,2H),2.27-2.39(m,5H),1.68(br d,J=6.1Hz,3H).

[0321] Example 559: 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-6-quinolinecarboxamide. [ka] A mixture of 2-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (557a, 155 mg, 0.32 mmol), EtOH (5.0 mL), and palladium on carbon (34.3 mg, 0.323 mmol) was hydrogenated under 45 psi of hydrogen at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% in heptane (EtOAc:EtOH 3:1)) to afford 2-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methyl)quinoline-6-carboxamide (26.5 mg, 0.055 mmol, 17% yield) as a white solid. m / z (ESI): 483.0 (M+H). +The racemic material was subjected to two steps of chiral SFC under the conditions shown below, yielding two eluents. Chiral SFC: 1) Chiralcel OD-H (2 × 50 cm, 5 μm) with a mobile phase of 60% liquid CO and 40% MeOH (with 0.2% DEA) using a flow rate of 80 mL / min. 2) Chromega CCC (2 × 25 cm, 5 μm) with a mobile phase of 40% liquid CO and 60% MeOH (with 0.2% DEA) using a flow rate of 60 mL / min. The first peak was 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-6-quinolinecarboxamide (559, 14 mg, ee >99%) as a white solid. m / z(ESI):483.0(M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.74(brs,2H),8.31(d,J=1.9Hz,1H),7.53-7.99(m,5H),7.29-7.45(m,2H),5.34-5.93(m,1H),4.9 2-5.11(m,1H),4.00-4.13(m,2H),3.54-3.65(m,2H),2.79-2.95(m,1H),2.64-2.70(m,1H),2.32(br s, 3H), 1.61-1.83 (m, 7H). The second peak was 2-amino-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-6-quinolinecarboxamide (559, 12 mg, ee >99%) as a white solid. m / z (ESI): 483.0 (M+H). + .

[0322] Example 560: 2-amino-N-((5-(dimethylcarbamoyl)-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide. [ka] A mixture of methyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((3-fluoro-2-pyridinyl)methyl)amino)methyl)-3-pyridinecarboxylate (331, 0.103 g, 0.224 mmol), lithium hydroxide hydrate (0.020 g, 0.471 mmol), MeOH (2 mL), and water (1 mL) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. 0.5 mL of 1N HCl was added to form a suspension. The mixture was concentrated in vacuo to give 6-((2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methylquinoline-6-carboxamido)methyl)nicotinic acid (560a) as a white solid, which was used crude. MS: m / z (ESI): 446 (M+H). + .

[0323] A mixture of 560a (0.025 g, 0.056 mmol), dimethylamine (0.14 mL of 2.0 M in THF, 0.28 mmol, Aldrich), triethylamine (0.039 mL, 0.281 mmol), and HATU (0.028 g, 0.073 mmol, ChemPep) in DMF (1 mL) was stirred at room temperature for 18 h. The mixture was purified by reverse-phase HPLC (10-70% water in CHCN containing 0.1% TFA) to afford the title compound as the TFA salt (560, 25 mg, 63% yield) as a white solid. MS: m / z (ESI): 473 (M+H). + . 1 H NMR (400 MHz, methanol-d4) δ ppm 8.52 (s, 10H), 4.86-5.04 (m, 4H), 3.13 (s, 3H), 3.03 (s, 3H), 2.38 (s, 3H).

[0324] Example 561: 2-amino-N-((5-(dimethylcarbamoyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide. This molecule was prepared from Example 403 in a similar manner as described for Example 560. m / z (ESI): 487 (M+H) + . [ka]

[0325] Example 562: 2-amino-N-(cyclobutylmethyl)-3-methyl-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide (Method C-1) [ka] Step 1: A solution of cyclobutylmethanamine (1 eq., 100 mM in dry DMSO) and a solution of 5-(trifluoromethyl)pyridine-2-carbaldehyde (1 eq., 100 mM in dry DMSO) were dissolved in equal volumes of dry THF and dry MeOH (final concentration 25 mM) and MS The mixture was mixed with 562a and 562b at room temperature for 3 min. The mixture was shaken overnight at room temperature. SiliaBond® cyanoborohydride (2.5 equiv.) was then added and the reaction mixture was shaken at room temperature. The reaction mixture was filtered and the filter cake was rinsed with CH3CN. The combined washings and filtrate were concentrated under reduced pressure to give 562a.

[0326] Step 2: 2-Amino-3-methyl-quinoline-6-carboxylic acid (Int-1, 1 eq., 100 mM in dry DMSO), HOAt (1 eq., 100 mM in dry DMSO), and a solution of EDC and DIPEA (100 mM and 200 mM, respectively, in dry DMF) were added sequentially to 562a. The reaction was then shaken overnight at room temperature and then concentrated under reduced pressure to give the crude product, which was subsequently purified by HPLC to give the final product, 2-amino-N-(cyclobutylmethyl)-3-methyl-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide (99% pure by UV). m / z (ESI): 429.2 (M+H). + . RT: 2.32 minutes.

[0327] [Table 103]

[0328] [Table 104]

[0329] [Table 105]

[0330] [Table 106]

[0331] Example 579: 2-amino-3-methyl-N-[(5-methyloxazol-4-yl)methyl]-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide (Method C-2) [ka] Step 1: Reductive amination was carried out similarly to step 1 of Example 562 by using [5-(trifluoromethyl)-2-pyridyl]methanamine and 5-methyloxazole-4-carbaldehyde to form 579a. Step 2: 2-Amino-3-methyl-quinoline-6-carboxylic acid (1 eq, 100 mM in dry DMSO), HATU (1.1 eq, 100 mM in dry DMSO), and DIPEA (10 eq, 1 M in dry DMF) were added sequentially to 579a. The reaction was then shaken overnight at room temperature, concentrated under reduced pressure, and then purified by HPLC to give 2-amino-3-methyl-N-[(5-methyloxazol-4-yl)methyl]-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide (99% pure by UV). m / z (ESI): 456.2 (M+H). + . RT: 2.32 minutes.

[0332] [Table 107]

[0333] [Table 108]

[0334] [Table 109]

[0335] [Table 110]

[0336] [Table 111]

[0337] Example 597: 2-amino-N-((5-fluoropyridin-3-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (Method C-3) [ka] Step 1: To a solution of (5-fluoro-3-pyridyl)methanamine (1 eq., 100 mM in dry DMSO) and 5-(trifluoromethyl)pyridine-2-carbaldehyde (1 eq., 100 mM in dry DMSO) was added TEOS (10 eq., neat) and the mixture was shaken overnight at room temperature. SiliaBond® cyanoborohydride (2.5 eq.) was then added and the reaction was again shaken overnight at room temperature. The reaction mixture was then filtered and the filter cake was rinsed with CH3CN and THF. The combined washings and filtrate were concentrated under reduced pressure to give 597a.

[0338] Step 2: Followed step 2 of 579 using 597a to give 2-amino-N-((5-fluoropyridin-3-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (99% pure by UV). m / z (ESI): 470.2 (M+H) + . RT: 1.99 minutes.

[0339] [Table 112]

[0340] [Table 113]

[0341] [Table 114]

[0342] [Table 115]

[0343] [Table 116]

[0344] [Table 117]

[0345] [Table 118]

[0346] [Table 119]

[0347] Example 629: 2-amino-N-(2-cyclobutylethyl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (Method C-4) [ka] Step 1: Analogously to step 1 of example 597, 629a was formed by using 5-(trifluoromethyl)pyridine-2-carbaldehyde and 2-cyclobutylethanamine.

[0348] Step 2: 2-Amino-3-methyl-quinoline-6-carboxylic acid (1 eq, 100 mM in dry DMSO) and DIPEA (5 eq, 0.5 M in dry DMA) were added to 629a, and the mixture was mixed vigorously. PyBroP (1.1 eq, 110 mM in dry DMA) was then added, and the reaction was then shaken overnight at room temperature. The reaction was then concentrated under reduced pressure and subsequently purified by HPLC to give 2-amino-N-(2-cyclobutylethyl)-3-methyl-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide as the final product with a purity of 99% by UV. m / z (ESI): 443.2 (M+H). + . RT: 2.71 minutes.

[0349] [Table 120]

[0350] [Table 121]

[0351] [Table 122]

[0352] [Table 123]

[0353] [Table 124]

[0354] [Table 125]

[0355] Table 126

[0356] Table 127

[0357] Table 128

[0358] Table 129

[0359] Table 130

[0360] Table 131

[0361] Table 132

[0362] Table 133

[0363] Table 134

[0364] Table 135

[0365] [Table 136]

[0366] [Table 137]

[0367] [Table 138]

[0368] Example 708: 2-Amino-3-methyl-N-[(4-methylthiazol-2-yl)methyl]-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide (Method D) [ka] N-[(4-methylthiazol-2-yl)methyl]-1-[5-(trifluoromethyl)-2-pyridyl]methanamine (100 mM in dry DMSO) and 2-amino-3-methyl-quinoline-6-carboxylic acid (100 mM in dry DMSO) were used to obtain 2-amino-3-methyl-N-[(4-methylthiazol-2-yl)methyl]-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide (99% purity by UV). m / z (ESI): 472.1 (M+H). + . RT: 2.12 minutes.

[0369] [Table 139]

[0370] Example 833: 2-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide and 2-amino-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide [ka] Step 1. 2-(bis(4-methoxybenzyl)amino)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (racemic compound) (833a) was prepared from acid 20 and amine 151 by Method A-PyBroP in a manner similar to that described in Example 345. The resulting impure product was used in the next step without further purification. m / z (ESI): 701.2 (M+H). + .

[0371] Step 2. To an ice-cooled, stirred solution of impure 2-(bis(4-methoxybenzyl)amino)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (racemic compound) (833a) (110 mg, 0.157 mmol) in THF (3.0 mL) was added 1.0 m lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.165 mL, 0.165 mmol, Acros Organics) under nitrogen. The resulting mixture was stirred at 0° C. for 20 minutes, and then iodomethane (22.28 mg, 9.77 μL, 0.157 mmol, Sigma-Aldrich Corporation) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction was cooled again in an ice bath before being quenched with methanol (1.5 mL). The volatiles were removed, and the residue was dissolved in DCM, loaded onto a silica gel precolumn (25 g), and subjected to Combi-Flash column chromatography on a 12-g ISCO Gold column eluting with EtOAc / heptane to afford 20 mg of impure 2-(bis(4-methoxybenzyl)amino)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (racemic compound) (833b) as an off-white solid, which was used in the next step. m / z (ESI): 715.2 (M+H). + .

[0372] Step 3. A mixture of 2-(bis(4-methoxybenzyl)amino)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (racemate) (833b) (30 mg, 0.042 mmol) and 2,2,2-trifluoroacetic acid (4.79 mg, 4.0 mL, 0.042 mmol, Aldrich) in a microwave reaction vessel was irradiated at 60° C. for 20 hours. The volatiles were removed and the residue was dissolved in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep C18 10 μm column; Phenomenex, Torrance, CA; gradient elution of 5 to 85% MeCN in water, both solvents containing 0.1% TFA for 15 min in a 24 min method) to give 6 mg of 2-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (racemic) (833) as the TFA salt as a white solid after lyophilization. 1 H NMR (methanol-d4,400MHz)δ 8.87(s,1H),8.28(s,1H),8.12(brd,1H,J=7.3Hz),8.02(s,1H),7.89(brd,1H,J=9.0Hz),7.4-7.8(m,2H),4.9-5.0(m, 2H),3.7-4.1(m,3H),3.5-3.7(m,2H),3.3-3.4(m,1H),3.28(s,3H),2.3-2.5(m,3H),2.1-2.3(m,1H),1.0-1.3(m,1H). 19 F NMR (methanol-d4, 376 MHz) δ-63.84 (s, 3F). m / z (ESI): 475.2 (M+H) + .

[0373] Example 834: 2-amino-N-(2-methylpropyl)-3-phenyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide [ka] To a stirred mixture of methyl 4-amino-3-formylbenzoate (55 mg, 0.307 mmol) and phenylacetonitrile (36.0 mg, 0.036 mL, 0.307 mmol, Aldlab Chemicals, LLC) in dimethyl sulfoxide (2 mL) in a 10 mL microwave reaction vessel, 2-methyl-2-propanol potassium salt (78 mg, 0.691 mmol, Sigma-Aldrich Corporation) was added at room temperature. The vessel was sealed, briefly sonicated, and subjected to microwave reaction conditions (15 min, 55 °C). To this crude reaction mixture was added 2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine (26) (78 mg, 0.338 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V) (329 mg, 0.706 mmol, Aldrich), and N-ethyl-N-isopropylpropan-2-amine (119 mg, 0.161 mL, 0.921 mmol, Aldrich) at room temperature. When LC-MS showed near completion, the resulting mixture was sonicated briefly and stirred at room temperature for 15 min. The crude mixture was directly subjected to mass-directed purification using an XBridge column (19 × 100 mm, 5 μm), MS mode: ESI+, with 0.1% NHOH in HO (A) and ACN (B) as the mobile phase to give 2-amino-N-isobutyl-3-phenyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (50 mg, 0.104 mmol, 34.0% yield) as a colorless film. 1 H NMR(DMSO-d6,600MHz)δ 8.94(brs,1H),8.19(brs,1H),7.8-8.0(m,2H),7.3-7.7(m,8H),6.16(brs,2H),4.7-5.0(m, 2H),3.1-3.3(m,2H),1.8-2.2(m,1H),0.92(brs,3H),0.69(brs,3H).m / z(ESI):479.2(M+H) + .

[0374] Example 835: 2-amino-7-hydroxy-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide [ka] A mixture of 2-amino-7-fluoro-3-methylquinoline-6-carboxylic acid (5) (200 mg, 0.908 mmol) and 25 wt% sodium methanolate in MeOH (2835 mg, 3.0 mL, 52.5 mmol, Aldrich) was irradiated in a microwave at 120 °C for 2 h. The crude was diluted with water and lyophilized to give 400 mg of crude 2-amino-7-methoxy-3-methylquinoline-6-carboxylic acid as a gray solid, which was used directly in the next step. m / z (ESI): 233.2 (M+H). + .

[0375] To a stirred mixture of 2-amino-7-methoxy-3-methylquinoline-6-carboxylic acid (100 mg, 0.431 mmol), 2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine (26) (150 mg, 0.646 mmol), and bromotripyrrolidinophosphonium hexafluorophosphate (401 mg, 0.861 mmol, Sigma-Aldrich Corporation) in DMA (2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (111 mg, 0.150 mL, 0.861 mmol, Sigma-Aldrich). The resulting mixture was stirred at room temperature for 1 h. The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to Combi-Flash column chromatography on a 24-g ISCO Gold column eluting with MeOH (containing 0.5% ammonium hydroxide) / DCM to give 2-amino-N-isobutyl-7-methoxy-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (77 mg, 0.172 mmol, 40.1% yield) (1) as a white solid. m / z (ESI): 447.20 (M+1). + .

[0376] To a stirred ice-cold solution of 2-amino-N-isobutyl-7-methoxy-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (77 mg, 0.172 mmol) in DMA (2.0 mL) was added 1.0 M tribromoborane in DCM (0.517 mL, 0.517 mmol, Sigma-Aldrich Corporation) under nitrogen. The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 30 minutes, after which the solvent was removed. To the residue cooled in an ice-water bath was added water (0.2 mL) followed by DMSO (2.5 mL). The resulting clear solution was subjected to preparative reverse-phase HPLC (Gemini™ Prep C18 10 μm column; Phenomenex, Torrance, CA; gradient elution of 10–95% MeCN in water, both solvents containing 0.1% TFA for 15 min in a 24-minute method) to afford, after lyophilization, 2-amino-7-hydroxy-N-isobutyl-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (835, 20 mg, 0.046 mmol, 26.8% yield) as the TFA salt as a white solid. 1 H NMR (methanol-d4,400MHz)δ 8.6-9.0(m,1H),8.15(brs,1H),7.9-8.1(m,1H),7.4-7.9(m,2H),7.0-7.2(m,1H),5.01(s,1H),4.69 (s,1H),3.44(brd,1H,J=7.5Hz),3.18(brd,1H,J=7.3Hz),2.2-2.4(m,3H),1.9-2.2(m,1H),1.04(br d,3H,J=6.5Hz),0.78(brd,3H,J=6.5Hz). 19 F NMR (methanol-d4,376MHz)δ-63.90(d,3F,J=13.9Hz).m / z(ESI):433.15(M+1) + .

[0377] Example 836: (R)-2-amino-N-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl)-3-iodo-N-(1-(pyrimidin-2)-yl)ethyl)quinoline-6-carboxamide. [ka] 2-Amino-3-bromo-N-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl)-N-(1-(pyrimidin)-2-yl)ethyl)quinoline-6-carboxamide (racemic-777, 0.300 g, 0.578 mmol) and sodium iodide (0.26 g, 1.73 mmol, Sigma-Aldrich Corporation) in 1,4-dioxane (6 mL) were placed in a resealable vial. Copper(i) iodide (0.02 g, 0.12 mmol, Alfa Aesar) and (1r,2r)-(-)-n,n"-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.23 mmol, Sigma-Aldrich Corporation) were then added to the reaction mixture. The vial was sealed, and the reaction mixture was stirred and heated at 120° C. for 48 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep-packed silica gel column (80 g) eluting with a gradient of 0% to 100% EtOAc:EtOH (3:1) in heptane to afford 2-amino-N-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl)-3-iodo-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (0.165 g, 0.291 mmol, 50% yield) as a tan solid.

[0378] The racemic mixture was purified by preparative SFC using a Chiral Technologies AS column (250 × 21 mm, 5 μm) with a mobile phase of 60% liquid CO and 40% MeOH (with 0.2% TEA) using a flow rate of 70 mL / min to yield 75.9 mg of peak 1, (R)-2-amino-N-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl)-3-iodo-N-(1-(pyrimidin-2)-yl)ethyl)quinoline-6-carboxamide (0.075 g, 0.13 mmol; ee >99%). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.54-8.81(m,3H),7.89(br s,2H),7.67(br s,1H),7.52(br s,1H),7.38(t,J=4.8Hz,1H),6.95(br s,1H),6.65(br s,2H),5.32(br s,1H),4.75(br d,J=15.0Hz,1H),4.58(br s,1H),4.10-4.18(m,2H),2.61-2.80(m,2H),1.90(br s,2H),1.58(br d,J=6.1Hz,3H).m / z(ESI):567.2(M+H) + Next, peak 2, (S)-2-amino-N-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl)-3-iodo-N-(1-(pyrimidin-2-yl)ethyl)quinoline-6-carboxamide (0.072 g, 0.13 mmol; ee >99%), was produced. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.77(br d,J=4.8Hz,2H),8.69(br s,1H),7.89(br s,2H),7.67(br s,1H),7.51(br s,1H),7.38(t,J=4.9Hz,1H),6.95(br s,1H),6.65(br s,2H),5.32(br s,1H),4.75(br d,J=15.5Hz,1H),4.58(br s,1H),4.15(br m / z(ESI):567.2(M+H) + .

[0379] [Table 140]

[0380] [Table 141]

[0381] Biological assays MTase-Glo methyltransferase assay Method A: The PRMT5 inhibitory activity of test compounds was determined using the MTase-Glo™ assay (Promega), which monitors the product of the methyltransferase reaction (S-adenosylhomocysteine, or SAH). The PRMT5 MTase-Glo assay was performed in a total volume of 12 μL in a 384-well white ProxiPlate (PerkinElmer). The PRMT5 enzyme reaction (in 4 μL) contained 10 nM PRMT5 / MEP50 (manufactured by Amgen), 5 μM S-adenosylmethionine (SAM, Promega), 1 μM histone H4(1-21)-Lys(biotin) (Anaspec), 1 μM 5′-methylthioadenosine (MTA, Sigma), and two-fold serial dilutions of compounds in a reaction buffer of 50 mM Tris (pH 8.0), 50 mM NaCl, 0.01% Tween® 20, 0.01% BSA, and 1 mM DTT. Test compounds were preincubated with PRMT5 / MEP50, SAM, and MTA for 24 hours before the addition of histone H4 peptide to initiate the PRMT5 reaction. The reaction was allowed to proceed for 2 hours at room temperature and then terminated by adding 2 μL of 3X MTase-Glo™ Reagent (Promega) and 150 μM EPZ015666 (Sigma). After 30 minutes of incubation at room temperature, 6 μL of MTase-Glo™ Detection Solution (Promega) was added, and the plate was incubated for an additional 30 minutes at room temperature. The light signal, corresponding to the amount of SAH generated by the PRMT5 reaction, was then measured using an Envision multimode reader (PerkinElmer). The IC was determined by analyzing the dose-response curve using Genedata Screener (Genedata). 50 and K. I got the value.

[0382] Method B: The PRMT5 inhibitory activity of test compounds was determined using the MTase-Glo™ assay (Promega), which monitors the product of the methyltransferase reaction (S-adenosylhomocysteine, or SAH). The PRMT5 MTase-Glo assay was performed in a total volume of 16 μL in a 384-well white ProxiPlate (PerkinElmer). The PRMT5 enzyme reaction (in 8 μL) contained 4 nM PRMT5 / MEP50 (Reaction Biology Corp, catalog no. RD-11-292), 5 μM S-adenosylmethionine (SAM, Promega), 2.5 μM FL-histone H2A (BPS Bioscience, catalog no. 52021), 1 μM 5′-methylthioadenosine (MTA, Sigma), and half-log serial dilutions of compounds in a reaction buffer of 50 mM Tris (pH 8.0), 50 mM NaCl, 0.01% Tween® 20, 0.01% BSA, and 1 mM TCEP. Test compounds were preincubated with PRMT5 / MEP50, SAM, and MTA for 1 hour before the addition of FL-histone H2A to initiate the PRMT5 reaction. The reaction was allowed to proceed for 20 hours at room temperature and then terminated by adding 1 μL of 9X MTase-Glo™ Reagent (Promega). After 30 minutes of incubation at room temperature, 8 μL of MTase-Glo™ Detection Solution (Promega) was added, and the plate was incubated for an additional 30 minutes at room temperature. The light signal, corresponding to the amount of SAH generated by the PRMT5 reaction, was then measured using an Envision multimode reader (PerkinElmer). The IC was determined by analyzing the dose-response curve using GraphPad Prism®. 50 and K. I got the value.

[0383] HCT116 proliferation assay: HCT116 MTAP-null and WT cells were seeded in 96-well tissue culture plates in RPMI1640 medium + 10% fetal bovine serum. Plates were incubated overnight at 37°C and 5% CO2. Cells were then treated with 8 or 9 serial dilutions of compounds, using a top concentration of 1 μM or 10 μM, 1:3 serial dilution steps, and a DMSO-only control. Cells were incubated in the presence of drugs for 6 days. The effect on cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer's recommendations. Assay plates were read on an EnVision™ Multilabel Reader using the ultra-sensitive luminescence module. IC 50 Values ​​were calculated using GraphPad Prism v5.01 using least squares fitting of a symmetric sigmoidal dose-response with the Hill slope set to -1 (top constraint set to 100%), or using Gene Data Screener to fit the dose-response curve using a four-parameter logistic model.

[0384] [Table 142]

[0385] [Table 143]

[0386] [Table 144]

[0387] [Table 145]

[0388] [Table 146]

[0389] Table 147

[0390] Table 148

[0391] Table 149

[0392] Table 150

[0393] Table 151

[0394] Table 152

[0395] Table 153

[0396] Table 154

[0397] Table 155

[0398] Table 156

[0399] [Table 157]

[0400] All publications and patent applications cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference and to the same extent as if each reference were set forth in full in its entirety. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of the invention, certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims. The present invention provides, for example, the following items. (Item 1) Formula I [ka] (In the formula, [ka] represents a single or double bond; X 1 and X 2 are, in each occurrence, both independently N or C; X 1 is C, C is halo or C 1~6 may be optionally substituted with alkyl; Ar is a 6-membered aromatic ring having 0-2 N atoms, and each Ar is a groups; R a In each case, cyano, halo, optionally substituted C 1~6 Alkyl, C 1~6 Haloalkyl, OR b , N.R. c R d , -C(O)NR c Rd , =S, -SO2, -SO2C 1~6 Alkyl, -C(O)H, -C(O)C 1~6 Alkyl, C(O)OC 1~6 alkyl, difluoro-pyrrolidinyl, and a 4-6 membered heterocycle having 0-2 heteroatoms independently selected from O and N, and the heterocycle is independently selected from 0-2 halogen, C 1~6 Alkyl, -C(O)H, -C(O)C 1~6 may be further independently substituted with alkyl or optionally substituted cycloalkoxyl; Each R b is, in each case, H, optionally substituted C 1~6 alkyl (wherein the substituents may be selected from halo) or oxetanyl; each R c and R d is H, C 1~3 Alkyl, C 1~3 independently selected from haloalkyl or -CO; R e is in each case H or C 1~6 alkyl; R f and R g In each case, H and C 1~6 independently selected from alkyl; R is H or methyl; R 1 and R 2 is, in each case, H, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkynyl, -C(OR e ), optionally substituted single and double cyclyl having 0-3 N, S or O atoms, where the substituents are halo, optionally substituted C 1~6 Alkyl, -C(O)NR f R g , OH, and an optionally substituted 5-membered ring having 0-3 N atoms; or R 1and R 2 and the carbon atoms to which they are attached can form an optionally substituted single or double carbocyclic or heterocyclic ring, which can be saturated, partially saturated, or aromatic, and further, said heterocyclic ring contains 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the substituent is an optionally substituted C 1~6 Alkyl, Halo, CN, OR e and -C(OR e ) selected from the group However, R 1 and R 2 provided that both are not simultaneously H; R 3 and R 4 is, in each case, H, halogen, alkynyl, cyano, and C optionally substituted with halo or deuterium; 1~6 alkyl) a compound of the formula: embedded image or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 2) X 1 is C, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 3) X 2 is C, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 4) Formula IA [ka] 4. The compound according to item 3, wherein: (Item 5) Formula IB [ka] 2. The compound according to item 1, wherein: (Item 6) X 2 is N, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 7) X 1 is N, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 8) 2. The compound according to item 1, wherein Ar is pyridinyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 9) 2. The compound according to item 1, wherein Ar is pyradazinyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 10) 2. The compound according to item 1, wherein Ar is pyrazinyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 11) 2. The compound according to item 1, wherein Ar is phenyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 12) R 1 and R 2 are each independently selected from methyl and pyrimidinyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 13) R 1 and R 2 are each independently selected from methyl and pyridinyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 14) R 1 and R 2 is H, methyl, C1~6 2. The compound according to item 1, wherein each independently is selected from alkyl and optionally substituted mono- or bicyclyl having 0-3 N, S, or O atoms, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 15) 15. The compound according to item 14, wherein said cyclyl is optionally substituted thiophenyl, optionally substituted thiazolyl or optionally substituted oxazolyl, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt of any of the foregoing. (Item 16) R 1 and R 2 and the carbon atoms to which they are attached can form an optionally substituted single or double carbocyclic or heterocyclic ring which can be saturated, partially saturated or aromatic, and further, said heterocyclic ring contains 1, 2 or 3 heteroatoms independently selected from N, O and S, a compound according to item 1, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt of any of the foregoing. (Item 17) R 4 is methyl or halogen, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 18) R a is cyano, halo or optionally substituted C 1~6 2. The compound according to item 1, wherein R is alkyl, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. (Item 19) 2-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-methoxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((7R)-4,5,6,7-tetrahydro-1H-indazol-7-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(6-cyano-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-methoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(1,3-thiazol-4-yl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(1,2,4-oxadiazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-pyrazinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5-methyl-2-pyrazinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-(2-pyrazinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-((5-methyl-1,2-oxazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrazinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyrimidinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-bromo-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-pyrimidinylmethyl)-6-quinolinecarboxamide, 2-amino-N-((5-fluoro-2-pyrimidinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((3-fluoro-2-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((3-fluoro-2-pyridinyl)methyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((4R)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-methyl-N-((1R)-1-(2-pyrazinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-(cyclopropylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((3,5-difluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3,5-difluoro-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 7-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-6-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((8R)-5,6,7,8-tetrahydro-8-quinolinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((8R)-5,6,7,8-tetrahydro-8-isoquinolinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(5-methyl-1,2-oxazol-3-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-cyclopropylethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(2-methylpropyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((4R)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-N-((5-(methylsulfonyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-(4-(trifluoromethyl)benzyl)-6-quinolinecarboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-(2-methyl-4-(trifluoromethyl)benzyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-(cyclopropylsulfonyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-N-((1R)-1-(3-chloro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(5-chloro-2-pyridinyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-methylpropyl)-6-quinolinecarboxamide, 2-amino-N-((1R)-1-(4-fluorophenyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-ethynyl-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((7R)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-7-fluoro-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-3-methyl-N-(2-pyridinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, methyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((3-fluoro-2-pyridinyl)methyl)amino)methyl)-3-pyridinecarboxylate, 2-amino-N-((5-(difluoromethoxy)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, methyl 6-((((2-amino-3-methyl-6-quinolinyl)carbonyl)((1R)-1-(3-fluoro-2-pyridinyl)ethyl)amino)methyl)-3-pyridinecarboxylate, 2-amino-N-((5-(dimethylcarbamoyl)-2-pyridinyl)methyl)-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1-(2-pyrimidinyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-1,3-thiazol-2-yl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(3-pyridinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((2-amino-1,3-thiazol-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(3,5-difluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5-((2H_3_)methyloxy)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(4-carbamoylbenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-bromo-2-pyridinyl)methyl)-3-methyl-N-((3R)-1-methyl-2-oxo-3-piperidinyl)-6-quinolinecarboxamide, 2-amino-N-((5-(dimethylcarbamoyl)-2-pyridinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyridinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,7-naphthyridine-6-carboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((4R)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-pyridinylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3-methyl-2-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4-methyl-1,3-thiazol-2-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(4-(1-piperidinyl)benzyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-6-quinolinecarboxamide, 2-amino-N-(cyclobutylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1,2,3-thiadiazol-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(1H-indol-3-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((5-methyl-1,3-oxazol-4-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-3-methyl-N-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((4-methyl-1,3-thiazol-5-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(3-fluoro-4-(hydroxymethyl)benzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((6-amino-3-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2-fluorobenzyl)-3-methyl-N-((3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-(1,3-oxazol-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3R)-1-methyl-2-oxo-3-piperidinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((3R)-2-oxo-3-piperidinyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-6-quinolinecarboxamide, 2-amino-4-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((3R)-1-cyclopropyl-2-oxo-3-piperidinyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((2-methyl-6-(trifluoromethyl)-3-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-bromo-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((3-chloro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-3-methyl-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-(4-cyanobenzyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-6-quinolinecarboxamide, 2-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-fluorophenyl)ethyl)-3-methyl-6-quinolinecarboxamide, 2-amino-N-((5-chloro-3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)propyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-6-quinolinecarboxamide, 2-amino-3-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 2-amino-N-cyclopropyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-6-quinolinecarboxamide, 7-amino-6-bromo-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,8-naphthyridine-3-carboxamide, 7-amino-6-bromo-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,8-naphthyridine-3-carboxamide, 2-amino-7-chloro-3-methyl-N-(2-meth...

Claims

[Claim 1] The invention described in this specification.

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