Tricyclic carboxamide derivatives as PRMT5 inhibitors

Abstract

The compounds of formula (I) and their pharmaceutically acceptable salts, as well as pharmaceutical compositions thereof, are described herein.The compounds of the present invention are useful for inhibiting PRMT5 activity and may have applications in the treatment of proliferative disorders, such as cancer, metabolic disorders, and blood disorders.The compounds of formula (I) have the following structure: TIFF2023550466000292.tif31170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 117,937, filed on November 24, 2020. [Background technology]

[0002] Epigenetic regulation of gene expression is a crucial biological determinant for protein production and cell differentiation, and plays a vital pathogenic role in many human diseases.

[0003] Epigenetic regulation involves the 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 between the transcriptionally active and inactive states of chromatin. 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 lead to human diseases. PRMT5 is involved in diseases such as proliferative disorders, metabolic disorders, and hematological disorders.

[0004] Homozygous deletions of tumor suppressor genes are major cancer promoters and often result in the associated loss of closely related passenger genes located genomically. These passenger gene deletions can create therapeutically manageable vulnerabilities specific to tumor cells. Homozygous deletions of the chromosome 9p21 locus, which carries the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A), are present in 15% of all tumors and often involve deletions of the passenger gene MTAP (methylthioadenosine phosphorylase), a major enzyme in the methionine and adenine salvage pathway. MTAP deletions lead to the accumulation of its substrate, methylthioadenosine (MTA). MTA shares a close structural similarity with S-adenosylmethionine (SAM), the methyl donor substrate of type II methyltransferase PRMT5. The elevated MTA levels, facilitated by MTAP loss, selectively compete with SAM for binding to PRMT5, leading to a hypophenication of methyltransferase that is more susceptible to further PRMT5 inhibition. Multi-genome scale shRNA dropout screenings conducted in a large tumor cell line panel revealed a strong correlation between MTAP loss and cell line dependence on PRMT5, further highlighting the severity of this metabolic vulnerability. However, PRMT5 is a known cellularly essential gene, and conditional PRMT5 knockout and siRNA knockdown studies have suggested that inhibition of PRMT5 in normal tissues can lead to significant problems (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy). Therefore, novel strategies are needed to leverage this metabolic vulnerability and preferentially target PRMT5 in MTAP-null tumors while preserving PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with MTA-cooperative small molecule inhibitors allows for preferential targeting of the MTA-bound state of PRMT5, which is abundant in MTAP-null tumor cells, while simultaneously improving the therapeutic index for normal cells where MTAP is intact and MTA levels are low. [Overview of the Initiative] [Means for solving the problem]

[0005] In one aspect, the present invention provides a compound of Formula I

Chemical Formula

Chemical Formula

[0006] In another aspect, R may be a tricyclic group independently selected from Formula IB.

Chemical Formula

Chemical Formula

[0007] In one aspect, X 1 , X 2 and X 6 may be N in each case, provided that both X 1 and X 2 cannot be N at the same time. In another aspect, X 1 , X 2 and X 6 may be C. In one embodiment, when X 1 is C, it may be optionally substituted with halo. In a further aspect, halo may be Cl. The present invention further provides that X 3 , X 4 and X 5 may be optionally substituted C in each case. In another aspect, X 3 , X 4 and X 5 may be optionally substituted O in each case. In a further aspect, X 3 , X 4 and X 5In each case, this could be N which may be substituted. In a further embodiment, X 3 , X 4 and X 5 In each case, may be substituted and may be S. In this invention, the substituents are independently C 1~3 Alkyl, C 1~3 The present invention provides that alkyl(OH) groups may be selected, where the alkyl group may be substituted with a halo.

[0008] In one aspect of the present invention, R 3 In each case, this can be H. In another aspect of the present invention, R 3 In each case, C 1~3 It may be alkyl. In a further embodiment, R 3 It can be methyl.

[0009] This invention is Ar 1 However, it is provided that it may be a 6-membered, substituted aryl. In another embodiment, Ar 1 It can be a 6-membered, possibly substituted heteroaryl. In one embodiment, Ar 1 teeth, [ka] It is possible. In another embodiment, Ar 1 teeth, [ka] It is possible. In a further embodiment, Ar 1 teeth, [ka] It is possible. In another embodiment, Ar 1 teeth, [ka] It is possible. In yet another embodiment, Ar 1 teeth, [ka] It is possible. In another embodiment, Ar 1 teeth, [ka] This may be possible. The present invention is Ar 1 The substituents are independently C 1~3 It is provided that the substituent can be selected from alkyl groups. In another embodiment, the substituent is -OC 1~3 The substituent can be selected independently of the alkyl group. In a further embodiment, the substituent can be selected independently of the halo group.

[0010] The present invention is R 1 However, in each case, it is possible that it can be H. In another embodiment, R 1 This can be a halo. In a further embodiment, R 1 C may be substituted. 1~3 It may be alkyl. The substituent can be selected from halo and -CN. In a further embodiment, R 1 may be substituted -OC 1~3 It may be an alkyl group. The substituent may be a halo. In a further embodiment, R 1 -C(O)OC may be substituted. 1~3 Alkyl (C 1~3 The alkyl group may be substituted with a halo and may be morpholinyl.

[0011] The present invention is R 2 However, in each case, C may be substituted. 1~8 It provides that it can be alkyl. 1~8 Alkyl substituents include halo, hydroxy, amino, and -OC. 1~3 It can be selected from alkyl or -CN.

[0012] In further embodiments, R 2 In each case, the substituent may be a substituted 5 or 6-membered ring or heterocycle. The 5 or 6-membered ring or heterocycle substituent may be hydroxyl, amino, or optionally substituted C 1~6 It may be alkyl, and the substituent is selected from halos. In a further embodiment, R2 C may be substituted. 1~6 Alkyl-OC 1~3 It can be alkyl, and the substituent is selected from halos. In another embodiment, R 2 R may be 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, which may be substituted. In another embodiment, R 2 C 1~3 It may be an alkyl heterocyclyl, and the heterocyclyl may be substituted 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl or pyradadinyl or triazolyl or pyrimidinyl or tetrahydrofuranyl or 1H-pyrrolo[2,3-b]pyridinyl or cyclohexyl. The substituent in each case is C 1~3 Alkyl, -CN, or halo, or optionally substituted C 1~6 Alkyl-OC 1~3 It may be alkyl. In the latter case, the substituent can be selected from halo or optionally substituted phenyl, where the phenyl substituent is halo or C 1~3 You can choose from alkyl groups.

[0013] The present invention is R 1 The present invention provides compounds of tautomers thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein R may be a tricyclic compound of formula IA. In another embodiment, R 1 This can be a triring of equation IB. In one embodiment, if the compound is a tricyclic compound of formula IA, then X 1 and X 2 Both can be C. In another embodiment, X 1 and X 2 One of them may be C and the other may be N. In the following embodiments, X 1 If C, then it is either unsubstituted or substituted with a halo. In a further embodiment, X 2 It can be N.

[0014] The present invention further provides compounds, their tautomers, their stereoisomers, or any pharmaceutically acceptable salts thereof, wherein R may be a tricyclic compound of formula IA1. [ka]

[0015] In one embodiment, X 3 This can be an unsubstituted or substituted C with one or more methyl groups.

[0016] The present invention further provides compounds, their tautomers, their stereoisomers, or any pharmaceutically acceptable salts thereof, where R may be a tricyclic compound of formula IA2. [ka]

[0017] In one embodiment of the compound of the present invention, R 3 It can be H, and in another embodiment, R 3 It can be methyl.

[0018] The present invention further includes R 2 However, C may be substituted. 1~8 The present invention provides alkyl compounds, their tautomers, their stereoisomers, or any pharmaceutically acceptable salts thereof. In one embodiment, R 2 This may be substituted with methyl, ethyl, isopropyl, or cyclo-C 1~6 It can be alkyl.

[0019] All possible combinations between the embodiments and aspects disclosed above are included in the present invention.

[0020] The present invention further provides compounds selected from the following, their tautomers, their stereoisomers, or any of the aforementioned pharmaceutically acceptable salts.

[0021] In one embodiment, the compound is selected from the following: 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((2S)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N,3-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(cyclopropylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(2,2-dimethylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2-dimethylpropyl)-3,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-3,3-dimethyl-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2-dimethylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofloflo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-7-fluoro-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-chloro-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-fluoro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-chloro-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-chloro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((6-cyclopropyl-3-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; Methyl 4-(6-((((4-amino-1,3-dihydrofluoro[3,4-c]quinoline-8-yl)carbonyl)(methyl)amino)methyl)-3-pyridinyl)-1-piperazine carboxylate; (3S)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 5-amino-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)benzo[c][2,6]naphthyridine-9-carboxamide; 4-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; Methyl 6-((((4-amino-1,3-dihydrofluoro[3,4-c]quinoline-8-yl)carbonyl)(methyl)amino)methyl)-3',6'-dihydro[3,4'-bipyridine]-1'(2'H)-carboxylate; 5-Oxo-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-5,6-dihydropyrazolo[1,5-c]quinazoline-9-carboxamide; 4-amino-1,3-dimethyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-7-fluoro-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1,3-dimethoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((8S)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((8S)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(4-(3-oxetanyl)benzyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(4-(3-oxetanyl)benzyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1-cyanocyclopropyl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-5-methoxy-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazole-3-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-ylmethyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2S)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-chloro-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(tetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 6-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridine-2-carboxamide; 6-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-(1-methyl-1H-pyrazole-4-yl)-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridine-2-carboxamide; 4-amino-3-methyl-N-(1-methylcyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyrazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-methoxy-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,7-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-1-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,3-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-fluoro-2-pyridinyl)methyl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((6-cyclopropyl-3-pyridazinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3,7-trimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N,1,7-trimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-3-methyl-N-(2-propanyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-(3-fluoro-4-(trifluoromethyl)benzyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((6-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((6-(4-(trifluoromethyl)phenyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(4'-(trifluoromethyl)[biphenyl]-4-yl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(6-(4-(trifluoromethyl)phenyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(4'-(pentafluoro-lambda-6-sulfanyl)[biphenyl]-4-yl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2,3-dihydrofl[3,2-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-(5-chloro-2-pyridinyl)-2,2-difluoroethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2,3-dihydrofl[3,2-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-7-fluoro-1,3-dimethyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoroethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoroethyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-(4-(pentafluoroethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-methyl-7-(trifluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-hydroxy-4-(pentafluoro-lambda-6-sulfanyl)benzyl)-N-methyl-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2S)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-(hydroxymethyl)-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-(hydroxymethyl)-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((1R)-2-cyano-1-cyclopropylethyl)-N-((5-cyano-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((1S)-2-cyano-1-cyclopropylethyl)-N-((5-cyano-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-cyclopropyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N-methyl-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-(fluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 6-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 6-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-2-phenanthidinecarboxamide; 6-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2-phenanthridinecarboxamide; 5-amino-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)benzo[c][2,6]naphthyridine-9-carboxamide; 5-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)benzo[c][2,6]naphthyridine-9-carboxamide; 5-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)benzo[c][2,6]naphthyrizine-9-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-((2S)-1-methoxy-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-((3-fluoro-2-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)thieno[2,3-c]quinoline-8-carboxamide; 5-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)pyrimido[4,5-c]quinoline-9-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-cyclopropyl-2-methoxyethyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1S)-1-cyclopropyl-2-methoxyethyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((1S)-1-cyclopropyl-2-methoxyethyl)-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-(2-methylpropyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(1-methoxy-2-methyl-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(1-methoxy-2-methyl-2-propanyl)-1,3-dihydrofloflo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1S)-1-cyclopropyl-2-methoxyethyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1S)-1-cyclopropyl-2-methoxyethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 6-Amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-7,8,9,10-tetrahydro-2-phenanthidinecarboxamide; 4-amino-7-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(3,3-difluorocyclobutyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(1-methyl-1H-1,2,4-triazole-3-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(2-methylpropyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(1-methyl-1H-1,2,4-triazole-3-yl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(3,3-difluorocyclobutyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofloflo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-(2-methylpropyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-6-methyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-chloro-5-methoxy-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(2-propanyl)-1,3-dihydrofloflo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-chloro-6-methoxy-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-ylmethyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2S)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-cyclopropyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-(1-methyl-1H-pyrazole-4-yl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-methylcyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2,2,2-trifluoroethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(3-oxetanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1-methyl-1H-1,2,4-triazole-3-yl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclobutyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-fluoro-N-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-propanyl)-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1S)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-1-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(cyclopropylmethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((S)-cyclopropyl(5-(trifluoromethyl)-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N-(1-methyl-1H-pyrazole-4-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(1-methyl-1H-pyrazole-4-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)benzo[c][2,6]naphthyridine-9-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrimide[4,5-c]quinoline-9-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrido[4,3-c][1,7]naphthyridine-9-carboxamide; 4-amino-1-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-(2-(4-(trifluoromethyl)phenyl)-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrimide[4,5-c][1,7]naphthyridine-9-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)propyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((R)-cyclopropyl(5-(trifluoromethyl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((S)-cyclopropyl(5-(trifluoromethyl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((R)-cyclopropyl(6-(trifluoromethyl)-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-methyl-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((5-fluoro-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((2,6-difluoro-3-pyridinyl)methyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-(difluoromethyl)-2-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyrazinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R)-1-(5-(difluoromethyl)-2-pyridinyl)ethyl)-N-ethyl-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyrazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyrazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2-fluoro-6-(trifluoromethyl)-3-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((R)-cyclopropyl(6-(trifluoromethyl)-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1R)-1-(4-(pentafluoroethyl)phenyl)ethyl)-3H-pyrazolo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1S)-1-(4-(pentafluoroethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(4-(pentafluoroethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N,1-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-1-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-1-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-1-methyl-N-(1,3-oxazol-4-ylmethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-1-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2-methoxy-6-(trifluoromethyl)-3-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-7-(trifluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-7-(trifluoromethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-7-(trifluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-7-(trifluoromethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-Amino-N-((1R)-1-cyclopropylethyl)-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-Amino-N-((1S)-1-cyclopropylethyl)-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-cyclobutyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclobutyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(4-cyanophenyl)ethyl)-N-ethyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(4-cyanophenyl)ethyl)-N-ethyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)propyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)propyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(3,5-difluoro-2-pyridinyl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,3-dimethyl-3H-pyrazolo[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-methoxy-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-methoxy-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1R)-1-(4-(pentafluoro-lambda-6-sulfanyl)phenyl)ethyl)-3H-pyrazolo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1S)-1-(4-(pentafluoro-lambda-6-sulfanyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(4-(pentafluoro-lambda-6-sulfanyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-1-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-N-((1R)-1-(5-pyrimidinyl)propyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-1-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-N-((1S)-1-(5-pyrimidinyl)propyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((1S)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-7-(trifluoromethyl)-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((1S)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(3-fluorophenyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 5-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-2,3-dihydrofl[3,2-c]quinoline-8-carboxamide; 4-amino-3,3-dimethyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-spiro[2.4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S)-spiro[2,4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-spiro[2.4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S)-spiro[2,4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1-cyanocyclopropyl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1-cyanocyclopropyl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridinid-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridinid-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1-cyanocyclopropyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1-cyanocyclopropyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(2-(cis-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(2-(trans-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-(2-(cis-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-(2-(trans-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1-methyl-1H-1,2,4-triazole-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1-methyl-1H-1,2,4-triazole-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3,3-trimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-3,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-3,3-dimethyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-3,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; and 4-amino-N-((1R)-1-(3-cyano-5-(trifluoromethyl)-2-pyridinyl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.

[0022] In another embodiment, the compound may be selected from the following: (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrido[4,3-c][1,7]naphthyridine-9-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide and 4-amino-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.

[0023] The present invention further provides a method for treating cancer, comprising administering an effective amount of the compound of the present invention, its tautomer, its stereoisomer, or any pharmaceutically acceptable salt thereof to a target. In one embodiment, the cancer is selected from ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0024] The present invention further provides a pharmaceutical composition comprising the compound of the present invention, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

[0025] The present invention also provides a method for treating cancer, comprising administering an effective amount of the compound of the present invention, its tautomer, its stereoisomer, or any pharmaceutically acceptable salt thereof to a target. In one embodiment, the cancer may be ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0026] The present invention also provides compounds of the present invention, their tautomers, their stereoisomers, or any pharmaceutically acceptable salt thereof for use in a method of treating cancer, the method comprising administering an effective amount of such compound to a subject. In one embodiment, the cancer may be ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0027] The present invention also provides the use of the compounds of the present invention, their tautomers, their stereoisomers, or any pharmaceutically acceptable salt thereof in the manufacture of pharmaceuticals for the treatment of cancer. In one embodiment, the cancer is selected from ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0028] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. [Modes for carrying out the invention]

[0029] definition Where used herein, if any variable element is present in two or more instances in a chemical formula, its definition in each instance is independent of its definition in all other instances. Where the chemical structure and chemical name are contradictory, the chemical structure determines the identity of the compound. The compounds of this disclosure may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, any chemical structure shown in relative configuration within the scope of all or part of this specification encompasses all conceivable enantiomers and stereoisomers of the exemplified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomer mixtures and stereoisomer mixtures. Enantiomer mixtures and stereoisomer mixtures can be separated into enantiomer or stereoisomer components using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0030] Certain compounds of the present invention may have an asymmetric carbon atom (optical center) or a double bond; all racemic compounds, enantiomers, diastereomers, geometric isomers, and individual isomers are intended to be included within the scope of the present invention. Furthermore, atropisomers and mixtures thereof resulting from bound rotations around two bonded aromatic rings or aromatic heterocycles are intended to be included within the scope of the present invention. For example, if the substituent is a phenyl group and is substituted with two groups bonded to adjacent carbon atoms at the site bonded to the N atom of the triazole, the rotation of the phenyl group may be bound. In some cases, this rotational barrier is high enough to separate and isolate different atropisomers.

[0031] As used herein and unless otherwise indicated, the terms “stereoisomer” or “stereoisomerically pure” mean one stereoisomer of a compound, i.e., substantially free of other stereoisomers. For example, a stereoisomerically pure compound having one chiral center substantially does not contain enantiomers. A stereoisomerically pure compound having two chiral centers substantially does not contain other diastereomers. Typical stereoisomerically pure compounds include more than about 80% by weight of one stereoisomer and less than about 20% by weight of the other stereoisomer of the compound; more preferably, more than about 90% by weight of one stereoisomer and less than about 10% by weight of the other stereoisomer of the compound; even more preferably, more than about 95% by weight of one stereoisomer and less than about 5% by weight of the other stereoisomer of the compound; and most preferably, more than about 97% by weight of one stereoisomer and less than about 3% by weight of the other stereoisomer of the compound. If the stereochemistry of a structure or a part of a structure is not indicated by, for example, a thick or dashed line, that structure or part of a structure should be interpreted as encompassing all of its stereoisomers. Bonds drawn with a wavy line indicate that both stereoisomers are encompassed. These wavy lines should not be confused with wavy lines drawn perpendicular to the bond (indicating where the group bonds to the rest of the molecule).

[0032] As is known to those skilled in the art, certain compounds of the present invention may exist in one or more tautomerized forms. Since one chemical structure can be used to represent only one tautomerized form, for convenience, a reference to a compound with a given structural formula will be understood to include tautomers of the structure represented by the structural formula. For some compounds, several compounds may exist primarily 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 as one tautomer or the other. Examples of other tautomers related to the compounds of the present invention are those having a pyridone group (pyridinyl) with hydroxypyridine as the tautomer, and compounds having a ketone group with an enol tautomer. These examples are given below. [ka]

[0033] The compounds of this disclosure include, but are not limited to, the 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), chelate compounds, 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” includes not only the compound itself but also its pharmaceutically acceptable salts, solvates, chelate compounds, non-covalent complexes, prodrugs, and any mixtures thereof. In some embodiments, the term “compound” includes the compound itself, its 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” includes the compound itself, its pharmaceutically acceptable salts, tautomers of the compound, and pharmaceutically acceptable salts of the tautomers.

[0034] pharmaceutically acceptable salts of the compounds of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, as well as tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, camphor sulfuric acid, isothionic acid, mucinic acid, gentisic acid, isonicotinic acid, saccharic acid, glucuronic acid, furic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, and embolic acid (pamoic acid). This includes acid addition salts formed from methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid, sulfinilic acid, alginic acid, galacturonic acid, and arylsulfonic acid, such as benzenesulfonic acid and p-toluenesulfonic acid; base addition salts formed from alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, megluamine (N-methylglucamine), lysine, and procaine; and salts formed internally. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. Salts having non-pharmaceutically acceptable anions or cations are within the scope of the present invention as useful intermediates for the preparation of pharmaceutically acceptable salts and / or for non-therapeutic use, such as in vitro situations.

[0035] The term "solvate" refers to a compound formed by the interaction of a solvent with another compound. Solvates of a compound include all forms of the compound. In certain embodiments, the solvent is volatile, non-toxic, and / or tolerable for trace doses to humans. Preferred solvates are pharmaceutically acceptable solvates, such as monohydrates and hemihydrates.

[0036] The compounds of the present invention may also contain isotopes of atoms in one or more of the atoms constituting such compounds, in proportions that are naturally occurring or unnatural. For example, this compound may contain tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 The compounds may be radioactively labeled with radioactive isotopes, such as C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, such as assay reagents and diagnostic agents, such as in vivo contrast agents. All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the invention. For example, where the variable element is stated or indicated as H, it also means that the variable element may be deuterium (D) or tritium (T).

[0037] "Alkyl" refers to a saturated, branched or linear 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, e.g., propan-1-yl and propan-2-yl, butyl, e.g., butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, and tert-butyl. In certain embodiments, the alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms or 1 to 6 carbon atoms, while in other embodiments, the alkyl group contains 1 to 4 carbon atoms. In yet another embodiment, the alkyl group contains 1 or 2 carbon atoms. Branched 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 are sometimes called (C1-C6) alkyl groups, and alkyl groups having 1 to 4 carbon atoms are sometimes called (C1-C4) alkyl groups. This nomenclature can also be used for alkyl groups having different numbers of carbon atoms. The term "alkyl" also includes cycloalkyl groups, where the carbon atoms are arranged in a ring configuration. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobityl, cyclopentyl, and cyclohexyl.

[0038] An "alkenyl" refers to an unsaturated branched or straight hydrocarbon group having at least one carbon-carbon double bond, derived by removing one hydrogen atom from a single carbon atom of a parent alkene. The group can be either Z-type or E-type (cis or trans) with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, e.g., propa-1-en-1-yl, propa-1-en-2-yl, propa-2-en-1-yl(allyl) and propa-2-en-2-yl; butenyl, e.g., buta-1-en-1-yl, buta-1-en-2-yl, 2-methyl-propa-1-en-1-yl, buta-2-en-1-yl, buta-2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1-yl and buta-1,3-dien-2-yl; and others. In certain embodiments, the alkenyl group has 2 to 20 carbon atoms, and in other embodiments, it has 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 cycloalkenyls. Cycloalkenyls refer to alkenyls consisting of three or more carbon atoms bonded together with at least one carbon-carbon double bond to form a structural ring. Examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexanyl.

[0039] An "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, and 3-hexynyl. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms, and in other embodiments, it has 2 to 6 carbon atoms. Alkynyl groups having 2 to 6 carbon atoms are sometimes referred to as -(C2~C6)alkynyl groups.

[0040] "Alkoxy" refers to the group -OR (wherein R represents an alkyl group as defined herein). Typical examples include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy. Typical alkoxy groups contain 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms in 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, the alkoxy group may contain 1 to 4 carbon atoms and may be referred to as -O-(C1-C4)alkyl or -O-(C1-C4 alkyl) groups.

[0041] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom in a carbopic ring system. Aryls include monocyclic carbocyclic aromatic rings, such as benzene. They also include bicyclic carbocyclic aromatic ring systems, such as naphthalene, where each ring is aromatic. Therefore, aryl groups can include fused ring systems where each ring is a carbocyclic aromatic ring. In certain embodiments, aryl groups contain 6 to 10 carbon atoms. Such groups are C6-C 10 These are sometimes referred to as aryl groups. However, aryl groups never include or overlap with heteroaryl groups as defined separately below. Therefore, when one or more carbocyclic aromatic rings condense with an aromatic ring containing at least one heteroatom, the resulting ring system is a heteroaryl group and not an aryl group as defined herein.

[0042] "Carbonyl" refers to the group -C(O), and is sometimes also called the -C(=O) group.

[0043] "Carboxylate" refers to the group -C(O)OH, and is sometimes also called -C(=O)OH.

[0044] "Cyano" refers to the group -CN.

[0045] A "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, and cyclooctane. Cycloalkyl groups are sometimes described by the number of carbon atoms in the ring. For example, a cycloalkyl group with 3 to 8 ring members may be called a (C3-C8) cycloalkyl group, a cycloalkyl group with 3 to 7 ring members may be called a (C3-C7) cycloalkyl group, and a cycloalkyl group with 4 to 7 ring members may be called a (C4-C7) cycloalkyl group. In certain embodiments, a cycloalkyl group may be (C3-C 10 These can be cycloalkyl, (C3-C8)cycloalkyl, (C3-C7)cycloalkyl, (C3-C6)cycloalkyl, or (C4-C7)cycloalkyl, and these can be referred to as C3-C 10 These are sometimes referred to as cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4-C7 cycloalkyl.

[0046] A "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. A bicyclic heterocyclyl group contains at least one non-aromatic ring having at least one heteroatom ring member, which can be condensed to a cycloalkyl ring or to an aromatic ring (which may be carbocyclic or contain one or more heteroatoms). The bonding site of a bicyclic heterocyclyl group can be a non-aromatic ring containing at least one heteroatom, or another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removing a hydrogen atom from one of the nine-membered heterocyclic compounds shown below can be bonded to the remainder of a five-membered or six-membered ring molecule. [ka]

[0047] In some embodiments, the heterocyclyl group comprises 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, the heterocyclyl group comprises 3 to 7 ring members, of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In such 3 to 7-membered heterocyclyl groups, if the ring comprises only 3 ring members, only 1 of the ring atoms is a heteroatom; if the ring comprises 4 ring members, 1 or 2 heteroatoms are included. In some embodiments, the heterocyclyl group comprises 3 or 4 ring members, of which 1 is a heteroatom independently selected from O, S, or N. In other embodiments, the heterocyclyl group comprises 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, aziridines, azetidines, imidazolidines, morpholines, piperazines, piperidines, hexahydropyrimidines, 1,4,5,6-tetrahydropyrimidines, pyrazolidines, pyrrolidines, quinuclidines, tetrahydrofurans, tetrahydropyrans, benzimidazolones, and pyridinones. Heterocyclyl groups can be completely saturated but may 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-azilinyl, and 1,2-dihydroazethenyl. Substituted heterocyclyls contain one or more oxo (=O) or oxide (-O) molecules. -This also includes ring systems substituted with substituents, such as piperidinyl N-oxide, morpholinyl N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazole-2(3H)-onyl, 3,4-dihydroisoquinoline-1(2H)-onyl, indoline-onyl, 1H-imidazo[4,5-c]pyridine-2(3H)-onyl, 7H-purine-8(9H)-onyl, imidazolidine-2-onyl, 1H-imidazole-2(3H)-onyl, and 1,1-dioxo-1-thiomorpholinyl.

[0048] The term “includes” is open-ended, meaning it encompasses everything and is not restrictive. This term may be used synonymously with “have” or “include.” “Includes” is intended to include all indicated or enumerated components or elements, but not exclude any other components or elements.

[0049] "Disease" refers to any disease, disorder, condition, symptom, or sign.

[0050] "Halo" or "halogen" refers to a fluoro, chloro, bromo, or iodine group.

[0051] A "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted with a halogen. Therefore, the term "haloalkyl" includes monohaloalkyls (alkyls substituted with one halogen atom) and polyhaloalkyls (alkyls substituted with two or more halogen atoms). Representative "haloalkyl" groups include difluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trichloroethyl. Unless otherwise specified, the term "perhaloalkyl" refers to an alkyl group in which each hydrogen atom is substituted with a halogen atom. For example, the term "perhaloalkyl" includes, but is not limited to, trifluoromethyl, pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

[0052] A "heteroaryl" refers to a monovalent aromatic heterocyclic group derived by removing one hydrogen atom from a single carbon atom of a polycyclic aromatic system. Heteroaryl groups typically contain 5 to 14 ring members, but more typically include 5 to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more heteroatoms selected from O, S, or N (the remaining ring atoms are carbon). In monocyclic heteroaryl groups, the monocyclic ring is aromatic and contains at least one heteroatom. In some embodiments, monocyclic heteroaryl groups may contain 5 or 6 ring members and may contain 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom, the heteroatoms being independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In a bicyclic heteroaryl group, at least one ring must contain a heteroatom, but both rings do not need to contain heteroatoms, although this is permissible. For example, the term “heteroaryl” includes 5- to 7-membered aromatic heterocycles fused to a carbocyclic aromatic ring or to another aromatic heterocycle. In a tricyclic aromatic ring, all three rings are aromatic, and at least one ring contains at least one heteroatom. In condensations, bicyclic and tricyclic heteroaryl ring systems where only one ring contains one or more heteroatoms, the bonding site can be a ring containing at least one heteroatom or a carbocyclic ring. If the total number of S and O atoms in a heteroaryl group is greater than 1, those heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In certain embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. Heteroaryls do not encompass or overlap with the aryls defined above.Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indidine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazoline, thiadiazole, thiazole, thiophene, triazole, etc. In certain embodiments, the heteroaryl group may be a 5-20 membered heteroaryl, for example, a 5-14 membered or 5-10 membered heteroaryl. In certain embodiments, the heteroaryl group may be derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazolebenzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

[0053] "Pharmacologically acceptable" means that it is generally recognized as being safe for use in animals, and more specifically, in humans.

[0054] A "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound.

[0055] "Pharmacologically acceptable excipients" refers to a wide range of components that can be combined with the compounds or salts of the present invention to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-tacks, flow enhancers, disintegrants, flavorings, coatings, binders, sweeteners, lubricants, adsorbents, and preservatives.

[0056] Stereoisomers are isomers that differ in the arrangement of their constituent atoms in space. Stereoisomers that are mirror images of each other and are optically active are called "enantiomers," while stereoisomers that are not mirror images of each other but are optically active are called "diastereomers."

[0057] "Subjects" include mammals and humans. The terms "human" and "subjects" are used interchangeably herein.

[0058] "Therapeutic dose" means the amount of a compound that, when administered to a subject to treat at least one of the clinical symptoms of a disease or disorder, is sufficient to have an effect on such treatment of the disease, disorder, or symptom. As those skilled in the art will recognize, this amount is not typically limited to a single dose and may include multiple doses over a substantial period of time required to produce a therapeutic or prophylactic response in the subject. Thus, "therapeutic dose" is not limited to the amount in a single capsule or tablet and may include multiple capsules or tablets that are the dose prescribed by a qualified physician or healthcare provider. "Therapeutic dose" may vary depending on the compound, the disease, disorder and / or the symptoms of the disease or disorder, the severity of the symptoms of the disease, disorder and / or the symptoms of the disease or disorder, the age of the subject being treated and / or the weight of the subject being treated. The appropriate amount in any given example may be readily apparent to those skilled in the art or may be determined by conventional experimentation.

[0059] To “treat” any disease or disorder, or “treatment,” means to halt or improve at least one of the disease, disorder, or clinical symptoms of the disease or disorder; to reduce the risk of contracting at least one of the disease, disorder, or clinical symptoms of the disease or disorder; to reduce the onset of at least one of the disease, disorder, or clinical symptoms of the disease or disorder; or to reduce the risk of contracting at least one of the disease, disorder, or clinical symptoms of the disease or disorder. To “treat” or “treatment” means to inhibit the disease or disorder physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both, or to inhibit at least one physical parameter that may not be recognizable to the subject. Furthermore, to “treat” or “treatment” means to delay the onset of the disease or disorder, or at least its symptoms, in a subject who may be exposed to or susceptible to the disease or disorder, even if the subject has not yet experienced or shown any symptoms of the disease or disorder.

[0060] In some embodiments, the compound may be in the form of a salt. Such a salt may be anhydrous or associated with water as a hydrate. In some embodiments, the compound may be in a neutral form as a base or acid.

[0061] Also provided are pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof according to any one of the examples, a tautomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, any of the aforementioned stereoisomers or mixtures thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent. In some such embodiments, the compound or a pharmaceutically acceptable salt thereof according to any one of the embodiments, a tautomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, any of the aforementioned stereoisomers or mixtures thereof are present in an amount effective for the treatment of 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 oral administration, i.e., QD, and some such formulations are tablets in which the effective amount of the active ingredient ranges from 1 mg to 100 mg, 5 mg to 80 mg, 10 mg to 50 mg, or 15 to 30 mg.

[0062] In some embodiments, the subject is a mammal. In some such embodiments, the mammal is a rodent. In other embodiments, the mammal is a dog. In yet another embodiment, the subject is a primate, and in some such embodiments, the subject is a human.

[0063] Pharmaceutical compositions or formulations for the administration of the compounds of the present invention can be conveniently provided in unit dosage forms and can be prepared by any method well known in the art. All methods involve a step of associating the active ingredient with a carrier constituting one or more auxiliary components. Generally, pharmaceutical compositions can be prepared by homogeneously and finely distributing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, forming the product into a desired formulation. In this pharmaceutical composition, the active target compound is present in an amount sufficient to produce a desired effect corresponding to the process or condition of a disease.

[0064] The compounds of the present invention may be administered orally, mucosally (including sublingual, buccal, rectal, nasal, or vaginal), parenterally (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermally, or topically. In some embodiments, the compounds of the present invention are administered mucosally (including sublingual, buccal, rectal, nasal, or vaginal), parenterally (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermally, or topically. In other embodiments, the compounds of the present invention are administered orally. In yet another embodiment, the compounds of the present invention are not administered orally.

[0065] The compounds of the present invention, their pharmaceutically acceptable salts, their tautomers, their pharmaceutically acceptable salts, any of the aforementioned stereoisomers, or mixtures thereof can be used to treat many conditions.

[0066] The compounds and compositions described herein are generally useful for inhibiting PRMT5. In some embodiments, a method is provided 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 the subject in need of treatment. In certain embodiments, the effective amount is a therapeutic effective amount. In certain embodiments, the effective amount is a prophylactic effective amount. In certain embodiments, the subject suffers 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).

[0067] As used herein, the term “PRMT5-mediated disorder” means any disease, disorder, or other medical condition known to be affected by PRMT5. Accordingly, in some aspects, this disclosure relates to treating or mitigating the severity of one or more diseases known to be affected by PRMT5.

[0068] In some embodiments, methods for inhibiting PRMT5 activity in subjects requiring inhibition of PRMT5 activity are provided herein, comprising administering 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 to the subject.

[0069] In further embodiments, the compounds intended by the present invention are useful for treating proliferative disorders such as cancer. In certain embodiments, the 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 embodiments, the oncological compounds described herein are useful for treating pancreatic cancer. In some embodiments, the oncological compounds described herein are useful for treating multiple myeloma (MM). In further embodiments, the oncological compounds described herein are useful for treating breast cancer. Breast cancer may be estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-). In further embodiments, breast cancer may be HER2-negative. In some embodiments, breast cancer is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative, and is also referred to herein as “triple-negative breast cancer”.

[0070] In a further embodiment, breast cancer may be lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, papillary Paget's disease, 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 other breast cancers (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, estrogen and progesterone receptor-positive).

[0071] In one embodiment, the compound of the present invention is useful for treating pancreatic cancer.

[0072] In another embodiment, the compounds of the present invention are useful for the treatment of NSCLC (non-small cell lung cancer). In one embodiment, NSCLC may be squamous cell NSCLC. In another embodiment, NSCLC may be adenocarcinoma.

[0073] In a further embodiment, the cancer may be GBM. In a further embodiment, the cancer may be mesothelioma. In one embodiment, the cancer may be bladder cancer. In another embodiment, the cancer may be esophageal cancer. In a further embodiment, the cancer may be melanoma. In one embodiment, the cancer may be DLBCL, HNSCC, or cholangiomas.

[0074] In some embodiments, one or more compounds described herein are useful for treating any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, such as PRMT5-responsive cancer.

[0075] In one embodiment, cancer lacking p53 (e.g., p53-null cancer) is less sensitive to PRMT5 inhibition than p53-positive cancer. Therefore, PRMT5-responsive cancer can be p53-positive cancer. The term "p53-positive" refers to 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 cancer. In some embodiments, a larger amount of one or more compounds described herein may be required to treat p53-negative cancer (e.g., p53-null cancer) than is required for p53-positive cancer.

[0076] In some embodiments, the present disclosure provides a method for identifying subjects having cancer that is susceptible 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 present in the sample, identifying the subject as having cancer that is susceptible to treatment with a PRMT5 inhibitor. Thus, in some embodiments, subjects having p53-positive cancer are identified as subjects for treatment with a PRMT5 inhibitor. In some embodiments, the method further includes administering a composition comprising a PRMT5 inhibitor to the subject.

[0077] In some embodiments, aspects of the present disclosure relate to a method for identifying subjects having 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 cancer that is insensitive to treatment with a PRMT5 inhibitor (e.g., less sensitive than p53-positive cancer). In some embodiments, p53-negative cancer (e.g., p53-null cancer) is treated with a PRMT5 inhibitor, but a larger dose of PRMT5 inhibitor may be required to treat p53-negative cancer than to p53-positive cancer. However, in some embodiments, subjects having p53-negative cancer (e.g., p53-null cancer) are treated with a therapeutic agent other than a PRMT5 inhibitor.

[0078] "Sample" means any biological sample derived from the 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 tissue. The presence or absence of p53 in the sample can be detected 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, or any combination thereof.

[0079] In some embodiments, one or more of the compounds described herein are used to treat other types of cancer (but not limited to acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, intralymphatic sarcoma, hemangiosarcoma), appendiceal carcinoma, benign monoclonal immunoglobulinemia, biliary tract carcinoma (e.g., cholangiocarcinoma), bladder carcinoma, brain carcinoma (e.g., meningioma; glioma (e.g., astrocytoma, oligodendroglioma); medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical carcinoma (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, and craniopharyngioma. Colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endometrial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma, Ewing's sarcoma), ocular 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)), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer) Cancer, nasopharyngeal cancer, oropharyngeal cancer, hematopoietic cancer (e.g., leukemia such as acute lymphoblastic 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 Parkinson's disease (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 lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, progenitor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;Furthermore, T-cell NHL, e.g., progenitor 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, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemia / lymphomas; and multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, muon chain disease), hemangioblastoma, inflammatory myofibroblastic Cystic tumors, immunocytic amyloidosis, renal 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), also known as myeloid metaplasia of unknown cause (AMM)), Chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis), neuroendocrine carcinoma (e.g., gastrointestinal and pancreatic neuroendocrine neoplasms (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget's disease of the penis and scrotum), pineal gland tumor, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer It should be understood that it may be useful in the treatment of skin cancers (e.g., squamous cell carcinoma (SCC), keratosinous acanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancers (e.g., appendiceal cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancers, sweat gland cancers, synoviomas, testicular cancers (e.g., seminomas, embryonal testicular cancer), thyroid cancers (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancers, vaginal cancers, and vulvar cancers (e.g., vulvar Paget's disease).

[0080] In some embodiments, a method for treating a target cancer comprises administering a composition comprising a PRMT5 inhibitor to the target, wherein treatment with the PRMT5 inhibitor inhibits tumor growth of the cancer by about 25%, about 50%, about 75%, and about 90% (e.g., 25%-50%, 50%-75%, 75%-90%, or 90%-100%). In some embodiments, a method for treating a target cancer comprises administering a composition comprising a PRMT5 inhibitor to the target, wherein methyl marks of the cancer are reduced by about 50%, about 75%, and about 80% (e.g., 50%-75%, 50%-80%, 80%-90%, 80%-100%, or 90%-100%). Methyl marking refers to protein methylation, such as histone methylation (e.g., methylation of one or more lysine and / or arginine sites on histone proteins) or DNA methylation (e.g., epigenetic DNA methylation, e.g., methylated CpG sites). In some embodiments, the methyl marking level of a cell is a measure of the degree to which histones are methylated in the cell (e.g., at one or more specific lysine and / or arginine sites).

[0081] Some methods of the present invention involve the administration of the compound of the present invention and further therapeutic agents (i.e., therapeutic agents other than the compound of the present invention). Thus, the compound of the present invention can be used in combination with at least one other therapeutic agent. Examples of further therapeutic agents include, but are not limited to, antibiotics, antiemetics, antidepressants, antifungals, anti-inflammatory agents, antineoplastic agents, antivirals, cytotoxic agents and other anticancer agents, immunomodulators, alpha-interferons, beta-interferons, alkylating agents, hormones and cytokines. In one embodiment, the present invention encompasses the administration of further therapeutic agents used to treat subjects having chronic heart failure or hypertension.

[0082] As described above, some methods of the present invention involve the administration of the compound of the present invention and further therapeutic agents (i.e., therapeutic agents other than the compound of the present invention). In some embodiments, the present invention includes the administration of further therapeutic agents used to treat a subject, acceptable salts thereof, tautomers thereof, pharmaceutically acceptable salts of tautomers, any of the aforementioned stereoisomers, or mixtures thereof, and further therapeutic agents, for example, further therapeutic agents used to treat a subject with an inhibitor of funny current. In some embodiments, the method of use may include two or more additional therapeutic agents.

[0083] The present invention will be further described with reference to the following examples. These examples are intended to illustrate, but not to limit, the claimed invention. [Examples]

[0084] Unless otherwise specified, all materials were obtained from commercial suppliers and used without further refinement.

[0085] The following abbreviations are used when referring to various reagents and solvents:

[0086] [Table 1]

[0087] [Table 2]

[0088] [Table 3]

[0089] General synthesis scheme [ka] [ka] [ka] Method A: Compound I can be prepared by the reaction of acid IA with secondary amine IB-1 in a solvent such as DMF or DMAc, in the presence of a base such as Et3N or DIPEA, and an activating reagent such as HATU or PyBrOP. When using a racemic amine or acid in Method A, stereoisomers can be separated using chiral SFC, in which case the stereochemistry was arbitrarily assigned to each isomer. Method B: Compound I can be prepared by the reaction of an acid chloride IC with a secondary amine IB in a solvent such as THF, dioxane, DCM, or DCE, in the presence of a base such as Et3N, DIPEA, or pyridine. Alternatively, Compound I can be prepared by the reaction of an acid chloride IC with a secondary amine IB in the presence of DMAP in pyridine. When using a racemic amine or acid in Method B, stereoisomers can be separated using chiral SFCs, in which case the stereochemistry was arbitrarily assigned to each isomer. Method C: Compound I can be prepared by a small-scale one-pot, two-step protocol as illustrated in General Scheme Method C. Primary amine 1D can be combined with aldehyde 1E in the solvent specified in this method, and after imine formation and reduction, secondary amine (Int-1) is obtained as the crude product. Secondary amine (Int-1) is reacted with acid IA and a specific coupling reagent, and product I is obtained after HPLC purification.

[0090] Analytical U / HPLC The following instruments were used for analytical UHPLC: Waters Acquity system with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) using a linear gradient of a two-component solvent system with a flow rate of 0.5 mL / min at ambient temperature and DAD, combined with MS detection SQD I. Linear gradient used (H2O / CH3CN / HCO2H (95 / 5 / 0.1%~0 / 100 / 0.1%)). Agilent Infinity I / II-TOF6230B / CLND Antek 8060 with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) using a linear gradient of a two-component solvent system with a flow rate of 0.75 mL / min, combined with DAD. Linear gradient used (H2O / MeOH / HCO2H (95 / 5 / 0.1%~0 / 100 / 0.1%)).

[0091] Preparative HPLC For preparative HPLC, the following instrument was used: Shimadzu Nexera X2 with a Merck Chromolith SpeedROD RP-18E (5μm, 10x100mm) using a linear gradient of a binary solvent system with a flow rate of 4-7 mL / min and UV detection at 254 nm, combined with MS detection on a Shimadzu LCMS-2020. Linear gradient was used (H2O / MeOH / HCO2H (95 / 5 / 0.1%~0 / 100 / 0.1%)).

[0092] intermediate Intermediate 1: 6-(2,2,2-trifluoroethoxy)pyridazine-3-carbaldehyde [ka]

[0093] Step 1. 3-chloro-6-methylpyridazine (1.00 g, 7.78 mmol), potassium carbonate (2.150 g, 15.56 mmol), and 1,4-dioxane (14.0 mL) were placed in a microwave vial. 2,2,2-trifluoroethanol (2.334 g, 1.704 mL, 23.34 mmol) was added to the resulting suspension, and the mixture was heated in a microwave at 140°C for 14 hours. After cooling to 23°C, the reaction mixture was transferred to a separation funnel containing aqueous solutions of CH2Cl2 (30 mL), H2O (20 mL), and saturated NH4Cl (30 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and dried. The resulting crude residue was purified by flash chromatography (0-100% 3:1 siRNA:EtOH in heptane) to obtain 3-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (662 mg, 3.45 mmol, yield 44.3%) as a pale yellow solid. m / z(ESI):193.2(M+H) + .

[0094] Step 2. A vial was filled with 3-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (662 mg, 3.45 mmol), selenium dioxide (612 mg, 5.51 mmol), and 1,4-dioxane (13.8 mL). Nitrogen was flowed over the resulting mixture for 10 minutes, and then the vial was heated to 110°C. After 1.5 hours, the reaction mixture was cooled to 23°C, filtered through a 1 cm celite pad (30 mL 3:1 Âte:EtOH eluent), and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-50% 3:1 Âte:EtOH in heptane) to obtain 6-(2,2,2-trifluoroethoxy)pyridazine-3-carbaldehyde (1,154.7 mg, 0.751 mmol, yield 21.8%) as a pale yellow solid. m / z(ESI):207.1(M+H) + .

[0095] Intermediate 2: 2-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)propan-1-amine.

Chem.

[0096] 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, then treated with sodium triacetoxyborohydride (5.49 g, 25.9 mmol, Aldrich). The mixture was stirred at room temperature for 1 hour, then neutralized with saturated aqueous Na₂CO₃ solution. 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 2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine (2, 2.81 g, 70% yield) as a brown oil. m / z (ESI): 233.0 (M+H) + . 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 8.81 (s, 1H), 7.88 (dd, J=8.1, 2.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 3.98 (s, 2H), 2.46 (d, J=6.6 Hz, 2H), 1.73-1.84 (m, 1H), 0.94 (d, J=6.6 Hz, 6H). 19 ¹⁹F NMR (376 MHz, chloroform-d) δ ppm -62.26 (s, 3F).

[0097] Secondary amines in Table 1 were prepared in a similar manner as described for Intermediate 2.

[0098]

Table 4

[0099]

Table 5

[0100] [Table 6]

[0101] [Table 7]

[0102] [Table 8]

[0103] [Table 9]

[0104] [Table 10]

[0105] [Table 11]

[0106] Intermediate 97: N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-amine [ka]

[0107] Triethylamine (315 mg, 0.437 mL, 3.11 mmol, Sigma-Aldrich Corporation) was added to a stirred mixture of 5-(trifluoromethyl)picolinealdehyde (534 mg, 3.05 mmol, Chemshuttle) and 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-amine (430 mg, 3.11 mmol, Enamine) in DCM (8 mL). Subsequently, glacial acetic acid (224 mg, 0.216 mL, 3.73 mmol, Sigma-Aldrich Corporation) was added 5 minutes later. The resulting mixture was stirred at room temperature for 15 minutes, after which sodium triacetoxyborohydride (857 mg, 4.05 mmol, Sigma-Aldrich Corporation) was added as a solid all at once. The resulting mixture was stirred at room temperature for 25 minutes. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combiflash column chromatography using a 24 g ISCO gold column eluted with MeOH (containing 0.5% ammonium hydroxide) / DCM (1-20%). After azeotropic dilution with toluene, N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-amine (350 mg, 1.177 mmol, yield 37.8%) was obtained as a colorless oil. m / z(ESI): 298.2(M+H) + . 1 1H NMR (400 MHz, chloroform-d): δ 8.78 (d, J=1.05 Hz, 1 H), 7.81-7.89 (m, 2 H), 7.50 (d, J=8.15 Hz, 1 H), 4.09-4.29 (m, 4 H), 3.97-4.06 (m, 2 H), 2.12-2.33 (m, 2 H), 1.83-2.04 (m, 2 H). 19 F NMR (376 MHz, chloroform-d) δ-62.34 (s, 3F).

[0108] The secondary amines in Table 2 were prepared in the same manner as described for intermediate 97. Compounds 106-109 were derived from commercially available chiral amines.

[0109] [Table 12]

[0110] [Table 13]

[0111] Intermediate 110: (R)-1-(pyrimidine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)ethane-1-amine. [ka]

[0112] Step 1. Potassium acetate (63.7 g, 649 mmol) was added to a stirred solution of (5-(trifluoromethyl)pyridine-2-yl)methaneamine hydrochloride (115 g, 541 mmol) and 1-(pyrimidine-2-yl)ethane-1-one (76 g, 622 mmol) in DCM (3.5 L). The mixture was stirred at room temperature for 30 minutes, 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 1N 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 x 2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude substance was purified by silica gel chromatography (2% MeOH in DCM) to obtain 1-(pyrimidine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)ethane-1-amine (101.97 g, 344 mmol, yield 63%) as a brown oily substance. m / z(ESI): 283.0(M+H) + . 1HNMR (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).

[0113] Step 2. Racemic secondary amine 110 (44 g) was dissolved in 200 mL of MeOH and subjected to chiral SFC using a Chiralpak AD-H column (250 x 30 mm, 5 μm) with a mobile phase of 90% liquid CO2, 10% EtOH, 0.5% DEA, and a flow rate of 100 mL / min. The first elution peak was (S)-1-(pyrimidine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)ethane-1-amine (111, 18 g, >99% ee), and the second elution peak was (R)-1-(pyrimidine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)ethane-1-amine (112, 19 g, >99% ee).

[0114] The racemic amines in Table 3 were prepared in the same manner as described above for amine 110. The racemic amines were subjected to chiral SFC to obtain enantiomerically pure amines (>99% ee).

[0115] [Table 14]

[0116] Intermediate 125: (R)-N-((6-methoxypyridazine-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine. [ka]

[0117] Step 1. A mixture of 6-methoxypyridazine-3-carbaldehyde (0.49 g, 3.54 mmol, Princeton BioMolecular Research, Inc.), 1-(pyrimidine-2-yl)ethane-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 Na2CO3 aqueous solution. The crude product was extracted by DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (30-100% siRNA / EtOH(3 / 1) in heptane) to obtain N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (125, 0.84 g, yield 96%) as an orange oily substance. m / z(ESI):246(M+H) + .

[0118] Step 2. Racemamine 125 was subjected to chiral SFC using a Chiral Technologies IC column (250x30mm, 5μm) at a flow rate of 150 mL / min, with 70% liquid CO2 and 30% MeOH (containing 0.2% TEA) as the mobile phase. The first elution peak was (R)-N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (126, 369 mg, >99% ee). The second elution peak was (S)-N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (127, 374 mg, >99% ee).

[0119] The racemic amines in Table 4 were prepared in the same manner as described above for amine 125. The racemic amines were subjected to chiral SFC to obtain enantiomerically pure amines (>99% ee).

[0120] [Table 15]

[0121] The secondary amines in Table 5 were prepared in the same manner as described for amine 125, and were derived from commercially available enantiomerically pure reagents.

[0122]

Table 16

[0123] Intermediate 153: N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)cyclopropanamine

Chemical Formula

[0124] Step 1. To a mixture of 1-(5-(trifluoromethyl)pyridin-2-yl)ethan-1-one (0.71 g, 3.75 mmol, Enamine), 1,2-dichloroethane (20 mL) and cyclopropanamine (0.257 g, 4.50 mmol, Acros) was added titanium(IV) isopropoxide (1.280 g, 1.334 mL, 4.50 mmol, Aldrich). The mixture was stirred at room temperature overnight, then after addition of MeOH (2 mL), sodium borohydride (0.142 g, 3.75 mmol, Aldrich) was added. The mixture was stirred for 30 minutes until LCMS indicated the formation of the product. The mixture was basified with saturated aqueous Na2CO3 solution and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography with 0 to 100% EtOAc in heptane. The racemic product (153, 631 mg, 73% yield) was obtained as a pale yellow oil. m / z (ESI): 231 (M+H) +

[0125] Step 2. The oil was purified by Prep SFC using a 2x Chiralpak IG column (250x21mm, 5μm) with a mobile phase of 90% liquid CO2 and 10% heptane EtOH (15:85, v:v) at a flow rate of 70 mL / min. The first elution peak was assigned to (S)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)ethyl)cyclopropanamine (154, 198 mg, 97.72% ee). The second elution peak was assigned to (R)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)ethyl)cyclopropanamine (155, 188 mg, 98.9% ee). Absolute stereochemistry was arbitrarily assigned.

[0126] The secondary amines in Table 6 were prepared in the same manner as described for amine 153.

[0127] [Table 17]

[0128] [Table 18]

[0129] Intermediate 171: 1-(2-fluoro-6-(trifluoromethyl)pyridine-3-yl)-N-methylmethaneamine [ka]

[0130] Step 1. In a resealable vial, 3-bromo-2-fluoro-6-(trifluoromethyl)pyridine (0.600 g, 2.385 mmol, Combiblock) and potassium vinyltrifluoroborate (0.639 g, 4.77 mmol, Oakwood Products, Inc.) were placed in 1,4-dioxane (5.96 mL) and water (1.988 mL). Potassium carbonate (1.319 g, 9.54 mmol, Sigma-Aldrich Corporation) was then added to the reaction mixture. Argon (gas) was passed through the reaction mixture for 5 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.044 g, 0.060 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture. The vial was sealed, and then the entire reaction mixture was stirred and heated at 80°C for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered through a celite pad, and concentrated under vacuum. The crude material was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column with an elution gradient of 0–15% ethyl acetate in heptane to obtain 2-fluoro-6-(trifluoromethyl)-3-vinylpyridine (0.206 g, 1.078 mmol, yield 45.2%) as a pale yellow oil. 1 HNMR(400MHz,chloroform-d)δ ppm 8.05(t,J=8.4Hz,1H),7.59(dd,J=7.7,1.3Hz,1H),6.83(dd,J=17.8,11.3Hz ,1H),6.05(d,J=17.8Hz,1H),5.67(d,J=11.3Hz,1H).m / z(ESI):192.3(M+H) + .

[0131] Step 2: 2-Fluoro-6-(trifluoromethyl)-3-vinylpyridine (1.176 g, 6.15 mmol) was added to a 100 mL round-bottom flask in acetone (25.6 mL) / water (5.13 mL) (5:1). To this mixture, potassium(vi) osminate dihydrate (0.227 g, 0.615 mmol, Acros Organics) and 4-methylmorpholine n-oxide (2.52 g, 21.54 mmol, Sigma-Aldrich Corporation) were added. The entire reaction mixture was stirred at room temperature for 45 minutes under an inert (N2) atmosphere. The reaction mixture was quenched by adding solid sodium sulfite (700 mg) and the mixture was stirred for 15 minutes. The reaction mixture was partially concentrated under vacuum (to remove acetone). The mixture was diluted with ethyl acetate and brine. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic compounds were combined, dried with MgSO4, filtered, and concentrated under vacuum. The crude residue was used in the next step of the synthesis without further purification.

[0132] The crude diol was diluted with THF (25 mL), and then sodium periodate (meth) (3.95 g, 18.46 mmol, Sigma-Aldrich Corporation) and water (3 mL) were added to the mixture. The resulting reaction mixture was stirred for 2.5 hours under an inert (N2) atmosphere. The reaction mixture was diluted with a mixture of HCl / heptane (1:1) (36 mL). The mixture was stirred in an ultrasonic device for 1 minute. The mixture was filtered, and the filtrate was collected. The mixture was diluted with a saturated aqueous solution of NaHCO3 (36 mL). The layers were separated, and the aqueous layer was extracted with HCl (3 times). The combined organic extract was washed with aqueous brine (2 times), then dried over MgSO4, filtered, and concentrated under vacuum. This material was used in the next step of the synthesis without further purification to prevent decomposition. 1 1H NMR (400 MHz, chloroform-d) δ ppm 10.29–10.51 (m, 1H), 8.44–8.66 (m, 1H), 7.67–7.88 (m, 1H).

[0133] Step 3. In an oven-dried 100 mL round-bottom flask, 2-fluoro-6-(trifluoromethyl)nicotinaldehyde (0.200 g, 1.036 mmol), titanium(IV) isopropoxide (0.368 g, 0.379 mL, 1.295 mmol, Sigma-Aldrich), and a 2.0 M methylamine solution in tetrahydrofuran (1.036 mL, 2.071 mmol, Sigma-Aldrich Corporation) in dichloromethane (2.59 mL) were added. The reaction mixture was stirred overnight at room temperature. Then, methanol (2.59 mL) was added, the mixture was cooled to 0°C, and sodium borohydride (0.047 g, 1.243 mmol, Sigma-Aldrich) was slowly added to the reaction mixture. The entire reaction mixture was stirred at room temperature for 16 hours, and then the reaction mixture was concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (40 g) with elution in a gradient of 0-25% MeOH in CH2Cl2. This yielded 1-(2-fluoro-6-(trifluoromethyl)pyridine-3-yl)-N-methylmethanamine (0.052 g, 0.250 mmol, yield 24.12%) as a yellowish-brown oil. 1 HNMR(400MHz,DMSO-d6)δ ppm 8.24(t,J=8.3Hz,1H),7.78-7.93(m,1H),3.76(s,2H),3.29(brs,1H),2.21-2.41(m,3H).m / z(ESI):209.2(M+H) +

[0134] Intermediate 172: N-(oxazole-4-ylmethyl)cyclobutanamine [ka]

[0135] Cyclobutylamine (176 mg, 0.21 mL, 2.47 mmol) and 1,3-oxazole-4-carbaldehyde (240 mg, 2.47 mmol) were dissolved in dichloromethane (5 mL), and acetic acid ice (29.7 mg, 0.029 mL, 0.494 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then methanol (5.00 mL) was added, and the solution was cooled to 0°C. Sodium borohydride (112 mg, 3.00 mmol) was added little by little, and the mixture was slowly heated to room temperature. After 16 hours, volatile substances were removed under vacuum, the crude product was absorbed onto silica gel, and the mixture was purified by column chromatography (0-20% MeOH / DCM in 8 minutes) to obtain N-(oxazole-4-ylmethyl)cyclobutanamine (206 mg, 1.35 mmol, yield 54.7%) as a colorless oil. m / z(ESI):153.3(M+H) + .

[0136] The secondary amines in Table 7 were prepared in the same manner as described for amine 172.

[0137] [Table 19]

[0138] Intermediate 176: 2-((methylamino)methyl)-5-(pentafluoro-16-sulfanyl)phenol [ka]

[0139] Step 1. To a solution of 3-(pentafluoro-16-sulfanyl)phenol (2.5 g, 11.36 mmol, Aurum Pharmatech) in trifluoroacetic acid (20 mL), hexamethylenetetramine (HMTA) (2.229 g, 15.90 mmol, Combi-Blocks Inc.) was added and the mixture was stirred at 80°C for 4 hours. Water (40 mL) was added to the reaction mixture and the reaction was stirred at room temperature for a further 30 minutes. The reaction mixture was extracted with toluene (2 x 40 mL). The organic extract was washed with saturated aqueous NaHCO3 solution, water, and brine, and dried over Na2SO4. The solution was filtered and concentrated under vacuum to obtain the crude substance as a colorless oil. The crude product was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (40 g) with an elution gradient of 0-50% siRNA in heptane. This yielded 2-hydroxy-4-(pentafluoro-16-sulfanyl)benzaldehyde (1.176 g, 4.74 mmol, yield 41.7%) as a colorless oil. m / z(ESI): 248.9(M+H) + . 1 H NMR(400MHz,CDCl3)δ 11.06(s,1H),10.00(s,1H),7.71(dd,J=8.2,0.8Hz,1H),7.40-7.45(m,2H). 19 F NMR(376MHz,DMSO-d6)δ ppm 57.10(s),56.70(s)

[0140] Step 2. A solution of 2-hydroxy-4-(pentafluoro-16-sulfanyl)benzaldehyde (300 mg, 1.209 mmol) in dichloromethane (5 mL) was treated with methylamine solution (2.0 M in tetrahydrofuran, 1.813 mL, 3.63 mmol, Sigma Aldrich) and stirred at room temperature for 3 hours. The resulting mixture was concentrated to dryness to obtain (E)-2-((methylimino)methyl)-5-(pentafluoro-16-sulfanyl)phenol as a yellow solid. The above material was dissolved in dichloromethane (5 mL) / methanol (2 mL) and treated with sodium borohydride (45.7 mg, 1.209 mmol, Sigma Aldrich) at room temperature and stirred for 30 minutes. The reaction mixture was diluted with brine and extracted with Â. The organic extract was washed with saturated NaCl aqueous solution and dried over Na2SO4. The solution was filtered and concentrated under vacuum to obtain the crude substance as a yellow oil. The crude product was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (24 g) with elution gradients of 0% to 100% ethyl acetate in heptane, followed by 10% MeOH (containing 2M NH3) in DCM. This yielded 2-((methylamino)methyl)-5-(pentafluoro-16-sulfanyl)phenol (142 mg, 0.539 mmol, 44.6% yield). m / z(ESI): 264.0(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 7.30(d,J=8.4Hz,1H),7.15-7.23(m,1H),7.11(d,J=2.3Hz,1H),6.29(brs,1H),4.14(s,1H),3.84(s,2H),2.30(s,3H).

[0141] Intermediate 177: (R)-1-(5-(difluoromethyl)pyridine-2-yl)-N-ethylethane-1-amine [ka]

[0142] Step 1. (R)-(+)-2-methyl-2-propanesulfinamide (0.310 g, 2.56 mmol, AK Scientific, Inc.) in dichloromethane (5.12 mL) was added to an oven-dried 100 mL round-bottom flask. To this mixture, copper(II) sulfate (0.816 g, 5.12 mmol, Sigma-Aldrich Corporation) was added, followed by 5-(difluoromethyl)-2-pyridinecarboxaldehyde (0.402 g, 2.56 mmol, Enamine). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a celite pad, and the filtrate was washed with DCM. The filtrate was collected and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (80 g) with elution in a gradient of 0-30% siRNA:EtOH (3:1) in heptane, to obtain (R,E)-N-((5-(difluoromethyl)pyridine-2-yl)methylene)-2-methylpropan-2-sulfinamide (0.660 g, 2.54 mmol, 99% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.97(s,1H),8.54(s,1H),8.19-8.25(m,2H),7.25(t,J=55.0Hz,1H),1.23(s,9H).m / z(ESI):261.0(M+H) + .

[0143] Step 2. (R,E)-2-methyl-N-((5-(difluoromethyl)pyridine-2-yl)methylene)propan-2-sulfinamide (0.600 g, 2.31 mmol) in tetrahydrofuran (10.78 mL) was added to an oven-dried 100 mL two-necked round-bottom flask. The reaction mixture was cooled to -78 °C, and then methylmagnesium chloride (3.0 M in THF) (1.294 mL, 3.88 mmol, Oakwood Chemicals) was added dropwise to the reaction mixture. After 10 minutes, the reaction product was quenched by adding saturated NH4Cl (5.8 mL) aqueous solution and extracted with HCl (3 x 25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was absorbed onto a silica gel plug and purified by chromatography using a silica gel column with elution gradient of 0-80% HCl in heptane to obtain both diastereomers. Peak 1 was arbitrarily assigned as N-((R)-1-(5-(difluoromethyl)pyridine-2-yl)ethyl)-2-methylpropan-2-sulfinamide (0.361 g, 1.306 mmol, yield 60.6%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.68-8.74(m,1H),8.02(d,J=8.5Hz,1H),7.70(d,J=8.2Hz,1H),7.14(t,J=55.3Hz,1H),5.83(d,J =7.9Hz,1H),4.51(quin,J=7.1Hz,1H),1.44(d,J=6.9Hz,3H),1.14(s,9H).m / z(ESI):277.1(M+H) + Peak 2 was arbitrarily assigned as a white solid N-((S)-1-(5-(difluoromethyl)pyridine-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.232 g, 0.840 mmol, yield 38.9%). 1H NMR(400MHz,DMSO-d6)δ ppm 8.71(s,1H),8.02(d,J=8.5Hz,1H),7.70(d,J=8.2Hz,1H),7.14(t,J=55.4Hz,1H),5.83(d,J=7 .7Hz,1H),4.51(quin,J=7.1Hz,1H),1.44(d,J=6.9Hz,3H),1.14(s,9H).m / z(ESI):277.1(M+H) + .

[0144] Step 3: In a 100 mL round-bottom flask, (S)-N-((R)-1-(5-(difluoromethyl)pyridine-2-yl)ethyl)-2-methylpropan-2-sulfinamide (0.365 g, 1.321 mmol) and hydrogen chloride solution, along with a 4.0 M dioxane solution (0.413 mL, 1.651 mmol, Sigma-Aldrich Corporation), were added to 1,4-dioxane (8.81 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The crude residue was carried over to the next step of the synthesis without further purification. m / z(ESI): 173.0(M+H) + .

[0145] Step 4: (R)-1-(5-(difluoromethyl)pyridine-2-yl)ethane-1-amine hydrochloride (0.276 g, 1.323 mmol) and acetaldehyde (0.117 g, 0.148 mL, 2.65 mmol, Acros Organics) in methanol (6.61 mL) were added to a 50 mL round-bottom flask. The reaction mixture was cooled to 0°C, and then titanium(IV) isopropoxide (0.470 g, 0.485 mL, 1.654 mmol, Sigma-Aldrich) was added. The resulting mixture was stirred at room temperature for 5 minutes. Then, sodium borohydride (0.300 g, 7.94 mmol, Sigma-Aldrich) was slowly added to the reaction mixture. A fixed additional amount of acetaldehyde (0.117 g, 0.148 mL, 2.65 mmol, Acros Organics) was added to the reaction mixture and stirred for a further 10 minutes. The reaction mixture was quenched with saturated NaHCO3 (0.5 mL) aqueous solution and stirred for 5 minutes, then treated with MgSO4 and filtered through a Celite pad. The filtrate was collected and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography eluting with a gradient of 0-30% MeOH in CH2Cl2 to obtain (R)-1-(5-(difluoromethyl)pyridine-2-yl)-N-ethylethane-1-amine (0.200 g, 0.999 mmol, yield 76%) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.72-8.80(m,1H),8.00-8.07(m,1H),7.60-7.69(m,1H),7.15(t,J=55.3Hz,1H),7.14(brt,J=55.4Hz,1H),4.13 -4.17(m,1H),2.56-2.67(m,1H),2.41-2.49(m,1H),1.04-1.10(m,3H),0.82-0.92(m,3H).m / z(ESI):201.1(M+H) + .

[0146] The secondary amines in Table 8 were prepared in the same manner as described for amine 177. Secondary amines 178 and 179 were synthesized from commercially available chiral primary amines, (R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethaneamine hydrochloride (CAS#1948236-91-6) and (R)-1-(5-(trifluoromethyl)pyridine-2-yl)ethane-1-amine hydrochloride (CAS#1956437-55-0), starting from step 4, respectively.

[0147] [Table 20]

[0148] Intermediate 181: 1-(3,5-difluoropyridine-2-yl)-N-methylethane-1-amine [ka]

[0149] Step 1: 1-(3,5-difluoropyridine-2-yl)ethanamine hydrochloride (0.250 g, 1.285 mmol, Combi-Blocks Inc.) and di-tert-butyl dicarbonate (0.421 g, 0.447 mL, 1.927 mmol, Oakwood Products, Inc.) were added to 1,2-dichloroethane (6.42 mL). Then, triethylamine (0.520 g, 0.722 mL, 5.14 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL) and saturated aqueous solution NaHCO3 (5 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified under a gradient of 0-25% siRNA in heptane to obtain tert-butyl(1-(3,5-difluoropyridine-2-yl)ethyl)carbamate (0.300 g, 1.162 mmol, yield 90%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.46(d,J=1.9Hz,1H),7.87(t,J=9.6Hz,1H),7.21(brd,J=7.5Hz,1H),4.81-4 .98(m,1H),1.34(brd,J=5.9Hz,9H),1.31-1.33(m,3H).m / z(ESI):259.1(M+H) + .

[0150] Step 2: In a 100 mL round-bottom flask, tert-butyl (1-(3,5-difluoropyridine-2-yl)ethyl) carbamate (0.300 g, 1.162 mmol) was added in tetrahydrofuran (5.81 mL). The mixture was cooled to 0°C, and then sodium hydride (60% dispersion in mineral oil) (0.058 g, 1.452 mmol, Oakwood Products, Inc.) was added to the reaction mixture. The resulting mixture was stirred at 0°C for 20 minutes, and then iodomethane (0.198 g, 0.198 mL, 1.394 mmol, Sigma-Aldrich Corporation) was added dropwise to the mixture. The reaction mixture was stirred for a further 20 minutes, maintaining the temperature at 0°C, and then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (40 g) with an elution gradient of 0-30% siRNA in heptane, yielding tert-butyl(1-(3,5-difluoropyridine-2-yl)ethyl)(methyl)carbamate (0.287 g, 1.054 mmol, yield 91%) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ ppm 8.31(d,J=2.3Hz,1H),7.18(ddd,J=9.4,8.3,2.4Hz,1H),5.63(brs,1H),2.75(brs,3H),1.53-1.57(m,3H),1.47(s,9H).m / z(ESI):295.3(M+Na) + .

[0151] The residue was dissolved in dichloromethane (5.81 mL) and treated with trifluoroacetic acid (1.324 g, 0.866 mL, 11.62 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was diluted with DCM and then treated with saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM (three times). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. This yielded 1-(3,5-difluoropyridine-2-yl)-N-methylethane-1-amine (0.109 g, 0.633 mmol, yield 54.5%) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.50(d,J=2.3Hz,1H),7.87(ddd,J=10.0,9.2,2.3Hz,1H),3.98(qd,J=6.7,1.4H z,1H),3.25-3.34(m,1H),2.14(s,3H),1.26-1.30(m,3H).m / z(ESI):173.2(M+H) + .

[0152] The secondary amines in Table 9 were prepared in the same manner as steps 1-2 described for amine 181. The chiral primary amine used in step 1 was synthesized in the same manner as steps 1-3 of Example 177.

[0153] [Table 21]

[0154] Intermediate 185: 1-(3-fluoro-5-(trifluoromethyl)pyridine-2-yl)-N-methylmethaneamine [ka]

[0155] In an oven-dried 100 mL round-bottom flask, a 2.0 M methylamine solution in tetrahydrofuran (1.554 mL, 3.11 mmol, Sigma-Aldrich Corporation) in 3-fluoro-5-(trifluoromethyl)picolinealdehyde (0.300 g, 0.300 mL, 1.554 mmol, Combi-Blocks Inc.) and 2,2,2-trifluoroethanol (4.09 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was then cooled to 0°C, and sodium borohydride (0.071 g, 1.864 mmol, Sigma-Aldrich) was slowly added to the reaction mixture. The entire reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column with a elution gradient of 0-20% MeOH in DCM to obtain 1-(3-fluoro-5-(trifluoromethyl)pyridine-2-yl)-N-methylmethanamine (0.190 g, 0.913 mmol, yield 58.8%) as a yellow oil. m / z(ESI): 209.2(M+H) + .

[0156] The secondary amines in Table 10 were prepared in the same manner as described for amine 185.

[0157] [Table 22]

[0158] Intermediate 188: N-methyl-1-(6-(1-(trifluoromethyl)-1H-pyrazole-4-yl)pyridazine-3-yl)methaneamine [ka]

[0159] Step 1: 1-(6-bromopyridazin-3-yl)-N-methylmethanamine (0.320 g, 1.584 mmol) and di-tert-butyl dicarbonate (0.518 g, 0.552 mL, 2.376 mmol, Oakwood Products, Inc.) were added to 1,2-dichloroethane (7.92 mL). Then, triethylamine (0.641 g, 0.890 mL, 6.33 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture, and the entire mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (5 mL) and saturated NaHCO3 (5 mL) aqueous solution. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified under a gradient of 0-60% SiO in heptane to obtain tert-butyl((6-bromopyridazine-3-yl)methyl)(methyl)carbamate (0.400 g, 1.324 mmol, yield 84%) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.65(brd,J=8.8Hz,1H),7.30-7.51(m,1H),4.71(s,2H),2.94(brs,3H),1.49(brs,9H).m / z(ESI):302.0(M+H) + .

[0160] Step 2. In a resealable vial, tert-butyl((6-bromopyridazin-3-yl)methyl)(methyl)carbamate (0.200 g, 0.662 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1h-pyrazole (0.347 g, 0.347 mL, 1.324 mmol, Enamine), and tribasic potassium phosphate (0.421 g, 1.986 mmol, Sigma-Aldrich Corporation) were added to a mixture of toluene (2.98 mL) / water (0.331 mL). Argon (gas) was passed through the reaction mixture for 5 minutes, then tricyclohexylphosphine (0.074 g, 0.265 mmol, Strem Chemicals, Inc.), followed by palladium(II) acetate (0.030 g, 0.132 mmol, Sigma-Aldrich Corporation), was added to the reaction mixture, and the vial was sealed. The reaction mixture was stirred and heated at 90°C for 16 hours, then cooled to room temperature, and subsequently diluted with ethyl acetate and filtered through a celite pad. The organic filtrate was collected and then concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a packed silica gel column with an elution gradient of 0-45% siRNA in heptane, yielding tert-butylmethyl((6-(1-(trifluoromethyl)-1H-pyrazole-4-yl)pyridazin-3-yl)methyl)carbamate (0.078 g, 0.218 mmol, yield 33.0%) as a yellowish-brown oil.

[0161] Step 3: In a 50 mL round-bottom flask, tert-butylmethyl ((6-(1-(trifluoromethyl)-1H-pyrazole-4-yl)pyridazin-3-yl)methyl)carbamate (0.060 g, 0.168 mmol) and trifluoroacetic acid (0.191 g, 0.191 mL, 1.679 mmol, Apollo Scientific Ltd.) were added to 1,2-dichloroethane (1.6 mL). The entire mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. The crude product was used in the next step of the synthesis without further purification. m / z(ESI): 258.2(M+H) +.

[0162] The secondary amines in Table 11 were prepared in the same manner as described for amine 188.

[0163] [Table 23]

[0164] Intermediate 191: (R)-N-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)ethane-1-amine [ka]

[0165] Step 1. (R)-(+)-2-methyl-2-propanesulfinamide (1.220 g, 10.07 mmol, AK Scientific, Inc.) in dichloromethane (20.13 mL) was added to an oven-dried 100 mL round-bottom flask. Copper(II) sulfate (3.21 g, 20.13 mmol, Sigma-Aldrich Corporation) was added to this mixture, followed by the addition of 6-bromopyridazine-3-carbaldehyde (1.882 g, 10.07 mmol, PharmaBlock Sciences). The resulting reaction mixture was stirred at room temperature for 24 hours, at which point it was filtered through a celite pad, and the filtrate was washed with 1:1 SiO:heptane. The filtrate was collected and concentrated under vacuum. The crude material was triturated with SiO and heptane. The solid was collected and dried for a further 2 hours in a vacuum oven. This yielded (R,E)-N-((6-bromopyridazine-3-yl)methylene)-2-methylpropane-2-sulfinamide (1.667 g, 5.74 mmol, yield 57.1%) as a yellowish-brown solid. 1 ¹H NMR (400MHz, chloroform-d) δ ppm 9.00 (s, 1H), 8.04 (brd, J=8.8Hz, 1H), 7.80 (brd, J=8.8Hz, 1H), 1.32 (s, 9H). m / z (ESI): 314.0 (M+Na) + .

[0166] Step 2. In an oven-dried 150 mL three-necked round-bottom flask equipped with an internal temperature probe, (R,E)-N-((6-bromopyridazin-3-yl)methylene)-2-methylpropane-2-sulfinamide (1.667 g, 5.74 mmol) was added in tetrahydrofuran (28.7 mL). The reaction mixture was cooled to -78 °C, and then methylmagnesium chloride (3.45 mL, 10.34 mmol, Oakwood) was added dropwise to the reaction mixture. (Note: The Grignard reagent was added very slowly, ensuring that the reaction mixture did not warm above -70 °C.) After the addition, the entire reaction mixture was stirred for a further 20 minutes while maintaining the temperature at -78 °C. The reaction was then quenched at -70 °C by adding saturated NH₄Cl (30 mL) aqueous solution. The mixture was warmed to room temperature and extracted with siRNA (3 x 100 mL). The combined organic extracts were washed with brine, then dried with MgSO4, filtered, and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography through an Intertim (15 micron) silica gel column (120 g) using a gradient of elution from 0 to 100% SiO in heptane, followed by a gradient of 0 to 50% SiO:EtOH (3:1) in heptane, to obtain a mixture of both diastereomers: (R)-N-((R)-1-(6-bromopyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.657 g, 2.146 mmol, yield 37.3%) as a yellowish-brown solid, and (R)-N-((S)-1-(6-bromopyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.067 g, 0.219 mmol, yield 3.81%) as a yellowish-brown solid. The stereochemistry of the major isomers was assigned in the same manner as in Kuduk, et al. Tet. Lett. 2004, 45(35), 6641. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.90-8.08(m,1H),7.76-7.85(m,1H),5.96(d,J=8.4Hz,1H),4.61-4.71(m,1H),1.50(d,J=6.9Hz,3H),1.14(s,9H).m / z(ESI):306.1(M+H)+

[0167] In a 50 mL round-bottom flask, (R)-N-((R)-1-(6-bromopyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.650 g, 2.123 mmol) and hydrogen chloride solution, and 4.0 M dioxane solution (0.663 mL, 2.65 mmol, Sigma-Aldrich Corporation) were added to 1,4-dioxane (10.61 mL). The entire reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, the residue was diluted with heptane and DCM (10:1), and then stirred by sonication for 1 minute. The precipitate was collected by filtration, and the solid was washed with heptane (3 times). This yielded (R)-1-(6-bromopyridazin-3-yl)ethane-1-amine hydrochloride as a black crude mixture, which was proceeded to the next step of the synthesis without further purification. m / z(ESI):202.1(M+H) +

[0168] Step 3: In a 100 mL round-bottom flask, (R)-1-(6-bromopyridazin-3-yl)ethane-1-amine hydrochloride (0.500 g, 2.096 mmol) and di-tert-butyl dicarbonate (0.686 g, 0.730 mL, 3.14 mmol, Oakwood Products, Inc.) were added to 1,2-dichloroethane (10.48 mL). Then, triethylamine (1.061 g, 1.473 mL, 10.48 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture, and the entire mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (5 mL) and saturated NaHCO3 (5 mL) aqueous solution. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified under a gradient of 0-80% siRNA in heptane to obtain tert-butyl(R)-(1-(6-bromopyridazine-3-yl)ethyl)carbamate (0.182 g, 0.602 mmol, yield 28.7%) as a yellowish-brown solid. 1H NMR(400MHz,DMSO-d6)δ ppm 7.90(d,J=8.8Hz,1H),7.71(d,J=9.0Hz,1H),7.44-7.66(m,1H),4.78-4.94(m,1H),1.38(brd,J=8.8Hz,12H).m / z(ESI):302.0(M+H) + .

[0169] Step 4. In a 100 mL round-bottom flask, tert-butyl(R)-(1-(6-bromopyridazin-3-yl)ethyl)carbamate (0.170 g, 0.563 mmol) was added in tetrahydrofuran (5.63 mL). The mixture was cooled to 0°C, and then sodium hydride (60% dispersion in mineral oil) (0.028 g, 0.703 mmol, TCI America) was added to the reaction mixture. The resulting mixture was stirred at 0°C for 20 minutes, and then iodomethane (0.096 g, 0.042 mL, 0.675 mmol, Sigma-Aldrich Corporation) was added dropwise to the mixture. The reaction mixture was stirred for a further 20 minutes, the temperature was maintained at 0°C, and then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (40 g) with a heptane gradient of 0-25% ethyl phosphate, yielding tert-butyl(R)-(1-(6-bromopyridazine-3-yl)ethyl)(methyl)carbamate (0.170 g, 0.538 mmol, yield 96%) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ ppm 8.31(d,J=2.3Hz,1H),7.18(ddd,J=9.4,8.3,2.4Hz,1H),5.63(brs,1H),2.75(brs,3H),1.53-1.57(m,3H),1.47(s,9H).m / z(ESI):216.1(M-Boc+H) +

[0170] Step 5. A resealable vial was filled with tert-butyl(R)-(1-(6-bromopyridazin-3-yl)ethyl)(methyl)carbamate (0.160 g, 0.506 mmol), β-[4-(trifluoromethyl)phenyl]-boronic acid (0.288 g, 1.518 mmol, AA block), and potassium carbonate (0.210 g, 1.518 mmol, Oakwood Chemicals) in 1,2-dimethoxyethane (2.300 mL) / water (0.230 mL). Argon was passed through the reaction mixture for 5 minutes. Pd(PPh3)4 (0.117 g, 0.101 mmol, Sigma-Aldrich) was then added to the reaction mixture. The vial was sealed, and the reaction mixture was stirred and heated at 90°C for 16 hours. The reaction mixture was diluted with ELISA and brine solution. The layers were separated, and the aqueous layer was extracted with SiO2 (3 times). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude material was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (40 g) with an elution gradient of 0-100% SiO2 in heptane, yielding tert-butyl(R)-methyl(1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)ethyl)carbamate (0.155 g, 0.406 mmol, yield 80%) as a pale yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 8.16-8.47 (m, 1H), 7.77-7.96 (m, 3H), 7.49-7.72 (m, 2H), 5.07 (s, 1H), 1.51 (s, 3H), 1.28 (s, 12H). m / z (ESI): 382.1 (M+H) +

[0171] Step 6: In a 50 mL round-bottom flask, tert-butyl(R)-methyl(1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)ethyl) carbamate (0.140 g, 0.367 mmol) and trifluoroacetic acid (0.419 g, 0.419 mL, 3.67 mmol, Apollo Scientific Ltd.) were added to 1,2-dichloroethane (3.67 mL). The entire mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. The crude residue was carried over to the next step of the synthesis without further purification. m / z(ESI): 282.2(M+H) +

[0172] The secondary amines (192-193) in Table 12 were prepared using the commercially available chiral amine, (R)-1-(4-bromophenyl)ethylamine (CAS number 45791-36-4), starting from step 3, in the same manner as described for amine 191.

[0173] [Table 24]

[0174] Intermediate 194: 1-(6-cyclopropylpyridazin-3-yl)-N-methylmethaneamine [ka]

[0175] Step 1.1-(6-bromopyridazin-3-yl)-N-methylmethanamine (16 mg, 176.6 mg, 0.874 mmol) and diisopropylethylamine (226 mg, 305 μL, 1.748 mmol, Sigma-Aldrich Corporation) were stirred in dichloromethane (4370 μL), and anhydrous Boc (210 mg, 0.961 mmol, Sigma-Aldrich Corporation) was added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was then partitioned between DCM and water, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude product was then purified by medium-pressure chromatography (silica, 10-100% siRNA:heptane) to obtain tert-butyl((6-bromopyridazin-3-yl)methyl)(methyl)carbamate (204 mg, 0.675 mmol, yield 77%). m / z(ESI):302.0,304.2(M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δ ppm 7.65 (brd, J=7.9Hz, 1H), 7.44 (brd, J=7.1Hz, 1H), 4.71 (s, 2H), 2.93 (brs, 3H), 1.48 (brd, J=5.4Hz, 9H)

[0176] Step 2. A mixture of tert-butyl((6-bromopyridazine-3-yl)methyl)(methyl)carbamate (204.6 mg, 0.677 mmol), cyclopropylboronic acid (291 mg, 3.39 mmol), and toluene (2888 μL) was purged with Ar, and then tribasic potassium phosphate (431 mg, 2.031 mmol, Alfa Aesar) and water (321 μL) were added, and the mixture was stirred at room temperature for 10 minutes. Then, tricyclohexylphosphine (38.0 mg, 0.135 mmol, Strem Chemicals, Inc.) and palladium(II) acetate (15.20 mg, 0.068 mmol, Strem Chemicals, Inc.) were added. The mixture was stirred in a sealed vial at 90°C for 2 hours, then filtered through celite, and concentrated under vacuum. The crude substance was purified by chromatography through a silica gel column eluted with 0-60% 3:1 siRNA:EtOH in heptane to obtain tert-butyl((6-cyclopropylpyridazin-3-yl)methyl)(methyl)carbamate (90.4 mg, 0.343 mmol, yield 50.7%). m / z(ESI):264.2(M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δ ppm 7.39 (brd, J=7.5Hz, 1H), 7.17-7.27 (m, 1H), 4.69 (s, 2H), 2.91 (brs, 3H), 2.11-2.22 (m, 1H), 1.49 (brs, 9H), 1.09-1.24 (m, 4H)

[0177] Step 3. To a solution of tert-butyl((6-cyclopropylpyridazin-3-yl)methyl)(methyl)carbamate (90.4 mg, 0.343 mmol) in dichloromethane (1248 μL), a 4.0 M hydrogen chloride solution in dioxane (687 μL, 2.75 mmol, Sigma-Aldrich Corporation) was added. The solution became a suspension, and MeOH was added to return the suspension to a solution. The mixture was stirred at room temperature for 4 hours until LC-MS showed the product. The mixture was concentrated under vacuum. The product, 1-(6-cyclopropylpyridazin-3-yl)-N-methylmethanamine hydrochloride (74.8 mg, 0.375 mmol, yield 109%), was obtained as a light brown solid and used directly in further experiments. m / z(ESI): 164.2(M+H) + .

[0178] Intermediate 195: 2-(5-chloropyridine-2-yl)-2,2-difluoro-N-methylethane-1-amine [ka]

[0179] Step 1.2-(5-chloropyridine-2-yl)-2,2-difluoroethane-1-amine dihydrochloride (307 mg, 1.16 mmol, 1.0 equivalent, Enamine) and triethylamine (351 mg, 483 μL, 3.47 mmol, 3.0 equivalents, Aldrich) were stirred in a 3.85 mL DCM (Diamond Chamber), and di-tert-butyl dicarbonate (252 mg, 1.16 mmol, 1 equivalent, Aldrich) was added. The resulting mixture was stirred at 0°C for 15 minutes, then over 1.5 hours to room temperature until complete. The crude mixture was directly loaded onto a silica gel column and subjected to medium-pressure column chromatography eluting with Â1 / Heptane (15 min, 0 to 100%) to obtain tert-butyl(2-(5-chloropyridine-2-yl)-2,2-difluoroethyl)carbamate (310 mg, 1.06 mmol, 92% yield). m / z(ESI): 293.1(M+H) + .

[0180] Step 2. To a stirred, ice-cold solution of tert-butyl(2-(5-chloropyridine-2-yl)-2,2-difluoroethyl) carbamate (300 mg, 1.03 mmol, 1.0 equivalent) in THF (5.0 mL), sodium hydride (60% dispersion) (36.9 mg, 1.54 mmol, 1.5 equivalent) was added under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 minutes, and then methyl iodide (145 mg, 64.1 μL, 1.03 mmol, 1.0 equivalent) was added by syringe. The resulting mixture was stirred at 0°C for 15 minutes, and then at ambient temperature for 16 hours. The reaction mixture was cooled in an ice bath and then quenched with MeOH. After removing volatile substances under vacuum and purifying the residue by medium-pressure chromatography (silica, 0-100% Â:heptane), tert-butyl(2-(5-chloropyridine-2-yl)-2,2-difluoroethyl)(methyl)carbamate (210 mg, 0.685 mmol, yield 66.8%). This material was then dissolved in TFA (4.0 mL) and stirred for 25 minutes until complete. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator to obtain the crude TFA salt. This salt was then dissolved in MeOH, loaded onto an SCX column, eluted with 0-2 M ammonia in MeOH, and co-precipitated to obtain 2-(5-chloropyridine-2-yl)-2,2-difluoro-N-methylethane-1-amine (127 mg, 0.615 mmol, yield 60.0%). m / z(ESI):207.1(M+H) + .

[0181] Intermediate 196: (R)-1-(pyrimidine-2-yl)-N-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)ethane-1-amine. [ka]

[0182] Step 1. 1-(pyrimidine-2-yl)ethane-1-amine dihydrochloride (2.79 g, 14.23 mmol, Enamine) in a 1:1 mixture of methanol (21.56 mL) and dichloromethane (21.56 mL) was added to a 150 mL round-bottom flask. The reaction mixture was cooled to 0°C, and then n,n'-diisopropylethylamine (3.51 g, 4.74 mL, 27.2 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture and stirred for 10 minutes. Next, 3-formyl-6-hydroxypyridazine (1.60 g, 12.93 mmol, Aurum Pharmatech LLC) and acetic acid (0.77 g, 0.74 mL, 12.93 mmol, Sigma-Aldrich Corporation) were added to the mixture, followed by the addition of acetic acid (0.77 g, 0.74 mL, 12.93 mmol, Sigma-Aldrich Corporation). The reaction mixture was heated to room temperature over 15 minutes, then sodium triacetoxyborohydride (6.85 g, 32.3 mmol, Sigma-Aldrich Corporation) was added, and the entire mixture was stirred under an inert (N2) atmosphere for 16 hours. 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 a further 16 hours. The reaction mixture was filtered through a celite pad, and the filtered cake was rinsed three times with 1:1 MeOH:DCM. The filtrate was collected and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (120 g) eluting with a gradient of 0-35% MeOH in CH2Cl2. 6-(((1-(pyrimidine-2-yl)ethyl)amino)methyl)pyridazin-3-ol (1.11 g, 4.84 mmol, yield 37.4%) was obtained as a pale yellow solid. m / z(ESI): 232.1(M+H) + . 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).

[0183] Step 2.6-(((1-(pyrimidine-2-yl)ethyl)aminomethyl)pyridazin-3-ol (1.11 g, 4.80 mmol) and triethylamine (1.45 g, 2.02 mL, 14.40 mmol, Sigma-Aldrich Corporation) in 1,2-dichloroethane (24.00 mL) were added to a 150 mL round-bottom flask. Next, di-tert-butyl dicarbonate (1.57 g, 1.67 mL, 7.20 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture. The entire reaction mixture was stirred and heated at 70°C for 2 hours. The reaction mixture was diluted with saturated NaHCO3 and the mixture 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 under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (120 g) with elution in a 0-80% SiO:EtOH (3:1) gradient in heptane, yielding tert-butyl((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (1.043 g, 3.15 mmol, yield 65.6%) as a white solid. m / z(ESI):332.1(M+H) + . 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,1 H),4.88-5.05(m,1H),4.42(brs,2H),1.54(d,J=7.3Hz,3H),1.15-1.34(m,9H).

[0184] Step 3. Racemic tert-butyl((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (1.043 g) was purified by preparative SFC using a Chiral Technologies AD column (250 x 30 mm, 5 mm) with a mobile phase of 0.2% TEA, 80% liquid CO2 and 20% EtOH, flow rate 150 mL / min. The first elution peak was tert-butyl(R)-((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (430 mg, >99% ee). The second elution peak was tert-butyl(S)-((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (455 mg, 98.8% ee). Peak assignment was determined by SFC using an AD column with 10% EtOH containing 0.2% TEA. Peak 1 represents the more active enantiomer.

[0185] Step 4: In a 50 mL round-bottom flask, tert-butyl(R)-((6-hydroxypyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (0.20 g, 0.62 mmol) and cesium carbonate (0.25 g, 0.78 mmol, Sigma-Aldrich Corporation) were added to N,N-dimethylformamide (5.23 mL). Then, 2,2,2-trifluoroethyl triflate (0.18 g, 0.78 mmol, Combi-Blocks Inc.) was added to the reaction mixture over 5 minutes. The resulting reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography through a Redi-Sep packed silica gel column (40 g) eluting under a gradient of 0-60% MeOH in CH2Cl2, yielding tert-butyl(R)-(1-(pyrimidine-2-yl)ethyl)((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)carbamate (0.20 g, 0.48 mmol, yield 77%) as a pale yellow solid. m / z(ESI): 414.1(M+H) + .

[0186] Step 5: In a 50 mL round-bottom flask, tert-butyl(R)-(1-(pyrimidine-2-yl)ethyl)((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)carbamate (0.10 g, 0.25 mmol) and trifluoroacetic acid (1.00 g, 0.65 mL, 8.81 mmol, Sigma-Aldrich Corporation) were added to dichloromethane (1.25 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. Crude (R)-1-(pyrimidine-2-yl)-N-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)ethane-1-amine was concentrated under vacuum and proceeded to the next step of synthesis without further purification. m / z(ESI): 314.0(M+H) + .

[0187] Intermediate 197: (R)-N-((6-cyclopropylpyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka]

[0188] Step 1. (R)-N-((6-bromopyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (133 g, 0.8 g, 2.72 mmol) and DIPEA (0.703 g, 0.950 mL, 5.44 mmol, Aldrich) were stirred in dichloromethane (13.60 mL), and then di-tert-butyl dicarbonate (0.653 g, 0.695 mL, 2.99 mmol, Oakwood Products, Inc.) was added. The reaction mixture was then stirred at room temperature for 4 hours. A further 0.5 equivalents of Boc2O were added, and the mixture was stirred overnight. The mixture was then partitioned between 100 mL of DCM and water. The layers were separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated. Purification of the crude product by flash chromatography (silica, 10-100% ethyl:heptane) yielded tert-butyl(R)-((6-bromopyridazine-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (1.16 g, 2.94 mmol, yield 108%). m / z(ESI): 394,396(M+H) + .

[0189] Step 2. A mixture of tert-butyl(R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl) carbamate (0.2 g, 0.507 mmol), 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 in a sealed vial at 80°C for 4.5 hours. The mixture was then filtered through celite and concentrated under vacuum. The crude substance was purified by chromatography using a silica gel column eluted with 0-100% 3 / 1 ethyl acetate / etOH in heptane. (R)-((6-cyclopropylpyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate tert-butyl (149.2 mg, 0.42 mmol, yield 83%) was obtained as an off-white solid and used in the next step. m / z(ESI): 356.3(M+H) +

[0190] Step 3. To a solution of (R)-((6-cyclopropylpyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate tert-butyl (0.14 g, 0.394 mmol) in dichloromethane (4 mL), 4.0 M HCl (0.788 mL, 3.15 mmol, Aldrich) in dioxane was added. MeOH was added to restore the suspension to a solution. The mixture was stirred overnight at room temperature, then concentrated under vacuum to obtain (R)-N-((6-cyclopropylpyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (155 mg, 0.425 mmol, yield 108%) as an orange solid. m / z(ESI):256(M+H) +

[0191] Intermediate 198: 1-Cyclopropyl-N-((6-Molfolinopyridazine-3-yl)methyl)methaneamine [ka]

[0192] Step 1.1-(6-bromopyridazin-3-yl)-N-(cyclopropylmethyl)methaneamine (18, 0.84 g, 3.47 mmol) and DIPEA (0.897 g, 1.21 mL, 6.94 mmol, Aldrich) were stirred in dichloromethane (17.4 mL), and then di-tert-butyl dicarbonate (1.21 g, 1.29 mL, 5.55 mmol, Oakwood Products, Inc.) was added. The reaction mixture was stirred overnight at room temperature. The mixture was then partitioned between 200 mL of DCM and water. The layers were separated. The organic layer was dried over Na2SO4 and concentrated to obtain crude tert-butyl((6-bromopyridazin-3-yl)methyl)(cyclopropylmethyl)carbamate (1.31 g, 3.83 mmol, yield 110%) contaminated with approximately 30% anhydrous Boc byproduct. We successfully used this material in the following reaction: m / z(ESI):342,344(M+H) +1 H NMR(400MHz,DMSO-d6)δ ppm 7.11(brd,J=8.6Hz,1H),6.76(d,J=9.0Hz,1H),4.02(s,1H),3.96(s,1H),2.40-2.46(m,1H),0 .54-0.73(m,10H),0.25-0.29(m,2H),0.18(brs,1H),-0.36(brd,J=7.3Hz,1H),-0.61(brs,1H)

[0193] Step 2. RuPhos Palladacycle G1 (298 mg, 0.365 mmol, Strem), RuPhos (170 mg, 0.365 mmol, Strem), Morpholine (256 μL, 255 mg, 2.92 mmol, Aldrich), Cesium carbonate (1.55 g, 4.75 mmol, Aldrich), and tert-butyl((6-bromopyridazine-3-yl)methyl)(cyclopropylmethyl)carbamate (500 mg, 1.46 mmol) were combined in THF and heated at 85°C for 2.5 hours. The reaction mixture was then diluted with ethyl acetate and filtered through a diatomaceous earth pad. The residue was purified by medium-pressure chromatography (silica, 0-100% ethyl:heptane) to obtain tert-butyl(cyclopropylmethyl)((6-morpholinopyridazine-3-yl)methyl)carbamate (430 mg, 1.234 mmol, yield 84%). m / z(ESI): 349.1(M+H) +1 H NMR(400MHz,chloroform-d)δ ppm 7.29-7.41(m,1H),6.88(d,J=9.4Hz,1H),4.68(s,2H),3.78-3.86(m,4H),3.55-3.63(m,4H ),3.03-3.20(m,2H),1.46(brs,9H),0.87-1.00(m,1H),0.37-0.43(m,2H),0.17(brs,2H).

[0194] Step 3. Dissolve tert-butyl(cyclopropylmethyl)((6-morpholinopyridazine-3-yl)methyl)carbamate in TFA (12.5 mL) and stir for 15 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH, and eluted through an SCX column with 0-2 M ammonia in MeOH. Upon concentration, 1-cyclopropyl-N-((6-morpholinopyridazine-3-yl)methyl)methanamine (198 mg, 90.0 mg, 0.362 mmol, yield 24.8%) was obtained. m / z(ESI): 249.2(M+H) +

[0195] Intermediate 199: Methyl 4-(6-((methylamino)methyl)pyridine-3-yl)pipe 159 radin-1-carboxylate [ka]

[0196] Intermediate 199 was prepared in the same manner as described above for amine 198. m / z(ESI):265.2(M+H) +

[0197] Intermediate 200: (S)-1-cyclopropyl-2-methoxy-N-((6-morpholinopyridazine-3-yl)methyl)ethane-1-amine [ka]

[0198] Step 1: In a 100 mL round-bottom flask, N-((6-bromopyridazin-3-yl)methyl)-1-cyclopropyl-2-methoxyethane-1-amine (0.075 g, 0.26 mmol) and triethylamine (0.080 g, 0.11 mL, 0.79 mmol, Sigma-Aldrich Corporation) were added to 1,2-dichloroethane (1.30 mL). Then, di-tert-butyl dicarbonate (0.086 g, 0.091 mL, 0.390 mmol, Sigma-Aldrich Corporation) was added to the reaction mixture. The entire reaction mixture was stirred and heated at 70°C for 2 hours. The reaction mixture was diluted with saturated NaHCO3 and the mixture with DCM. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (12 g) with elution in a 0-30% siRNA:EtOH (3:1) gradient in heptane, yielding racemic tert-butyl((6-bromopyridazin-3-yl)methyl)(1-cyclopropyl-2-methoxyethyl) carbamate (0.085 g, 0.220 mmol, yield 84%) as a yellowish-brown solid. m / z(ESI): 386.0(M+H) + .

[0199] Step 2. The racemic sample was purified by preparative SFC using a Chiral Technologies IG column (250x21mm, 5mm) containing 0.2% TEA, 90% liquid CO2, and 10% iPrOH at a flow rate of 80 mL / min, yielding Peak 1 at 390 mg with 98% ee and Peak 2 at 380 mg with 98% ee. Absolute stereochemistry was arbitrarily assigned to these isomers, and the stronger Peak 2 was considered the (S)-isomer below.

[0200] Step 3. Tert-butyl(S)-((6-bromopyridazine-3-yl)methyl)(1-cyclopropyl-2-methoxyethyl) carbamate (Peak 2, 170 mg, 0.440 mmol), RuPhos (51.0 mg, 0.110 mmol, Aldrich), RuPhos PreCat G1 (90.0 mg, 0.110 mmol, Strem), cesium carbonate (470 mg, 1.40 mmol, Aldrich), and morpholine (0.077 mL, 0.88 mmol, Spectrum) were combined in degassed THF (2.9 mL) and heated at 85°C for 2 hours to complete the process. The reaction mixture was then cooled, diluted with ethyl acetate, and filtered through a diatomaceous earth pad. Next, the filtrate was concentrated, and the residue was purified by medium-pressure chromatography (silica, 0-100% ethyl:heptane to 30-100% (3:1 ethyl:ethoh:heptane)) to obtain impure tert-butyl(S)-(1-cyclopropyl-2-methoxyethyl)((6-morpholinopyridazine-3-yl)methyl)carbamate.

[0201] Step 4. This substance was dissolved in TFA (10 mL) and stirred for 10 minutes. The reaction mixture was then concentrated, and the residue was eluted through an SCX column eluted with 0-2 M ammonia in MeOH and concentrated to obtain (S)-1-cyclopropyl-2-methoxy-N-((6-morpholinopyridazine-3-yl)methyl)ethane-1-amine (110 mg, 0.37 mmol, yield 83%). m / z(ESI): 293.1(M+H) + .

[0202] Intermediate 201: N-((6-ethoxypyridazine-3-yl)methyl)-2-methylpropane-1-amine [ka]

[0203] Step 1. N-((6-bromopyridazin-3-yl)methyl)-2-methylpropan-1-amine (17, 0.950 g, 3.89 mmol) and DIPEA (1.01 g, 1.36 mL, 7.78 mmol, Aldrich) were stirred in dichloromethane (19.5 mL), and then di-tert-butyl dicarbonate (1.36 g, 1.45 mL, 6.23 mmol, Oakwood Products, Inc.) was added. The reaction mixture was then stirred overnight at room temperature. The mixture was then partitioned between 200 mL of DCM and water. The layers were separated. The organic layer was dried over MgSO4 and concentrated to obtain crude tert-butyl((6-bromopyridazin-3-yl)methyl)(isobutyl)carbamate (1.89 g, 5.49 mmol, yield 141%), contaminated approximately 30% with anhydrous Boc byproduct. This material was used directly in the following reaction: m / z(ESI):344,346(M+H) +

[0204] Step 2. In a resealable screw-cap test tube (Tube A), tBuBrettPhos (170 mg, 0.350 mmol, 0.150 equivalents), cesium carbonate (1.10 g, 3.30 mmol, 1.40 equivalents), and tert-butyl((6-bromopyridazin-3-yl)methyl)(isobutyl)carbamate (800 mg, 2.3 mmol, 1.0 equivalent) were placed. Tube A was evacuated, filled with argon (3x), and then ethanol (1000 μL, 17.0 mmol, 7.50 equivalents) was added to Tube A via syringe. Simultaneously, tBuBrettPhos Pd G3 (300 mg, 0.350 mmol, 0.150 equivalents) was placed in a resealable screw-cap test tube (Tube B) equipped with a Teflon-coated magnetic stirrer. Next, tube B was evacuated, packed with argon (3x), and 1,4-dioxane (12.0 mL) was added to tube B via syringe. The reaction mixture in tube B was stirred at room temperature for approximately 1 minute to form a homogeneous solution. The preliminary catalyst solution from tube B was transferred to tube A via syringe. The reaction mixture in the resulting tube A was stirred at room temperature for 20 hours. The crude product was diluted with ethyl acetate and concentrated under vacuum using a rotary evaporator. The crude product residue was purified by flash column chromatography using medium-pressure chromatography (silica, 0-100% ethyl:heptane) to obtain ((6-ethoxypyridazine-3-yl)methyl)(isobutyl)carbamate. m / z(ESI): 310.1(M+H) +

[0205] Step 3. Next, this material was dissolved in TFA (10 mL) and stirred for 15 minutes until complete. Then, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH, and eluted through an SCX column eluted with 0-2 M ammonia in MeOH. By concentration, N-((6-ethoxypyridazin-3-yl)methyl)-2-methylpropan-1-amine was obtained as a free base with a purity of approximately 80%, which was successfully used in the next reaction. 100 mg was obtained in the first pass through an SCX column with trace amounts of TFA present. m / z (ESI): 210.1 (M+H) +1H NMR(400MHz,chloroform-d)δ ppm 7.41-7.52(m,1H),6.92(d,J=9.0Hz,1H),4.57(q,J=7.1Hz,2H),4.00(s,2H),2. 43-2.51(m,2H),1.74-1.89(m,2H),1.45(t,J=7.1Hz,3H),0.93(d,J=6.5Hz,6H)

[0206] Intermediate 202: 1-(5-(3,6-dihydro-2H-pyran-4-yl)pyridine-2-yl)-N-methylmethaneamine [ka]

[0207] Step 1.1-(5-bromopyridine-2-yl)-N-methylmethanamine (0.950 g, 4.72 mmol, 34) and DIPEA (1.22 g, 1.65 mL, 9.45 mmol, Aldrich) were stirred in dichloromethane (23.6 mL), and di-tert-butyl dicarbonate (1.65 g, 1.76 mL, 7.56 mmol, Oakwood Products, Inc.) was added. The reaction was then stirred overnight at room temperature until complete. The mixture was then partitioned between 200 mL of DCM and 50 mL of water. The layers were separated. The organic layer was dried over MgSO4 and concentrated to obtain crude tert-butyl((5-bromopyridine-2-yl)methyl)(methyl)carbamate (1.42 g, 4.71 mmol, yield 100%). m / z (ESI): 301.2, 303.1 (M+H) + .

[0208] Step 2.2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (837 mg, 3.98 mmol, Combi-Blocks), tricyclohexylphosphine (112 mg, 0.398 mmol, Strem), tert-butyl((5-bromopyridine-2-yl)methyl)(methyl)carbamate (0.600 g, 1.99 mmol, from Step 1) and Pd2(dba)3 (182 mg, 0.199 mmol, Acros) were slurryed in dioxane (7.00 mL), and then argon was spurged. Next, potassium carbonate (1.30 M solution) (4.14 mL, 5.38 mmol, Aldrich) was added, and the reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled and then concentrated until the volume decreased. Next, the residue was dissolved in water (30 mL) and extracted with dichloromethane (2 x 80 mL). The combined organic layers were dried on magnesium sulfate and concentrated. The crude product was purified by medium-pressure chromatography (silica, 0-100% Â:heptane) to obtain tert-butyl((5-(3,6-dihydro-2H-pyran-4-yl)pyridine-2-yl)methyl)(methyl)carbamate (372 mg, 1.22 mmol, yield 61.3%).

[0209] Step 3. Next, this material was dissolved in 7 mL of TFA and stirred for 10 minutes to obtain complete deprotection. The reaction mixture was then concentrated, and the resulting TFA salt was dissolved in MeOH. Elution was performed through an SCX column using 0-2 M ammonia in MeOH, and the mixture was concentrated to obtain 1-(5-(3,6-dihydro-2H-pyran-4-yl)pyridine-2-yl)-N-methylmethaneamine (90.0 mg, 440 mmol, yield 22.1%) as the free base. m / z(ESI): 205.2(M+H) + .

[0210] Intermediate 203: 6-((methylamino)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate [ka]

[0211] Step 1. Diisopropylamine (185 mg, 0.261 mL, 1.83 mmol, Aldrich) was dissolved in THF (7.00 mL) and cooled to -78°C. Then, n-butyllithium (2.50 M in hexane) (0.732 mL, 1.83 mmol, Aldrich) was added dropwise at -78°C and stirred for 25 minutes. The mixture was lifted from the dry ice bath for 15 minutes and then re-immersed. Then, methyl 4-oxopiperidine-1-carboxylate (250 mg, 1.59 mmol, Combi-Blocks) was dissolved in THF (4.00 mL) and slowly added to the LDA solution at -78°C and stirred for 45 minutes. N-phenyl-bis(trifluoromethanesulfonimide) (625 mg, 1.75 mmol, Combi-Blocks) dissolved in THF (5.00 mL) was slowly added, and the reaction mixture was stirred overnight while being heated to room temperature. The reaction mixture was quenched with water (20 mL), and the mixture was extracted with hexane (3 x 50 mL). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by medium-pressure chromatography (silica, 0-40% ethyl acetate:hexane) to obtain methyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (249 mg, 0.861 mmol, yield 54.1%). m / z(ESI): 290.1(M+H) + .

[0212] Step 2. Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (230 mg, 0.795 mmol), bis(pinacolato)diborone (242 mg, 0.954 mmol, Aldrich), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (64.9 mg, 0.080 mmol, Strem Chemicals, Inc.), and potassium acetate (312 mg, 3.18 mmol, Aldrich) were added to a flask containing dioxane (2.65 mL). This mixture was heated overnight at 80°C. The reaction mixture was cooled, filtered, and washed with ethyl acetate. The filtrate was concentrated and purified by medium-pressure chromatography (silica, 0-60% ethyl acetate:heptane) to obtain methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (130 mg, 0.487 mmol, yield 61.2%). m / z(ESI):268.2(M+H) + .

[0213] Step 3. Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (133 mg, 0.498 mmol, from Step 2), tricyclohexylphosphine (27.9 mg, 0.100 mmol, Strem), tert-butyl((5-bromopyridine-2-yl)methyl)(methyl)carbamate (0.150 g, 0.498 mmol, Boc-34, see Step 1 for intermediate 202), and Pd2(dba)3 (45.6 mg, 0.050 mmol, Acros) were slurryed in dioxane (1.74 mL), and argon was flowed over it. Potassium carbonate (1.30 M solution) (1.03 mL, 1.35 mmol, Aldrich) was added, and the reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled and concentrated until its volume decreased. The residue was dissolved in water (15 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic layers were dried on magnesium sulfate and concentrated. The crude product was purified by medium-pressure chromatography (silica, 0-100% ethyl acetate:heptane) to obtain methyl 6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (93.0 mg, 0.257 mmol, yield 51.7%). The material was dissolved in TFA and stirred for 10 minutes to deprotect Boc. The mixture was concentrated to obtain the TFA salt of the desired product. Next, the free base was obtained by eluting through an SCX column eluting with 0-2 M ammonia in methanol, and upon concentration, methyl 6-((methylamino)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (63.0 mg, 0.241 mmol, yield 48.4%). m / z(ESI):262.2(M+H) + .

[0214] Intermediate 204: (R)-N-ethyl-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethane-1-amine [ka]

[0215] Step 1: (R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethane-1-amine (0.50 g, 2.41 mmol, AP Bioscience) and pyridine (0.27 g, 0.27 mL, 3.38 mmol, Sigma-Aldrich Corporation) were added to a 100 mL two-necked round-bottom flask in 12 mL of dichloromethane. The reaction mixture was cooled to -78°C, and then, under an inert (N2) atmosphere, acetic anhydride (0.30 g, 0.27 mL, 2.90 mmol, Sigma-Aldrich Corporation) was added dropwise to the reaction mixture over 2 minutes. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and then the reaction mixture was quenched with 1N HCl (2.4 mL). This mixture was diluted with heptane (20 mL), washed with 1N HCl (6 mL x 2), and then washed with saturated NaHCO3 (12 mL) aqueous solution and brine (12 mL). The organic matter was recovered, then dried over MgSO4, filtered, and concentrated under vacuum to obtain (R)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)acetamide (0.43 g, 1.73 mmol, yield 72%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.48(brd,J=7.3Hz,1H),7.53-7.66(m,3H),5.13(quin,J=7.2Hz,1H),1.86(s,3H),1.35(d,J=7.1Hz,3H).m / z(ESI):250.0(M+H) + .

[0216] Step 2: (R)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)acetamide (0.42 g, 1.69 mmol) was added to tetrahydrofuran (9 mL) in a 150 mL round-bottom flask. Then, 2.0 M lithium aluminum hydride solution (2.1 mL, 4.21 mmol, Sigma-Aldrich Corporation) in tetrahydrofuran was slowly added to the reaction mixture over 2 minutes. The resulting reaction mixture was stirred at room temperature for 1 hour, then stirred and heated at 55°C for 5 hours. The reaction mixture was diluted with heptane (15 mL) and cooled to 0°C. Then, water (0.4 mL) was added to the mixture and stirred for 1 minute. Then, 15% NaOH (0.4 mL) aqueous solution was added to the mixture and stirred for 1 minute. Then, water (3 x 1.2 mL) was added to the mixture and the resulting mixture was heated to room temperature over 15 minutes. MgSO4 was added to the mixture and stirred for a further 15 minutes. The entire reaction mixture was filtered through a Celite pad, and the filtrate was collected and concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a Redi-Sep packed silica gel column (40 g) with elution in a gradient of 0-60% HCl:EtOH (3:1) in heptane to obtain (R)-N-ethyl-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethane-1-amine (0.081 g, 0.344 mmol, yield 20.43%) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.76(t,J=7.7Hz,1H),7.53-7.61(m,2H),4.07(q,J=6.6Hz,1H),2.26-2.40(m,2H),2 .08-2.17(m,1H),1.26(d,J=6.7Hz,3H),0.98(t,J=7.1Hz,3H).m / z(ESI):236.1(M+H) + .

[0217] Intermediate 205: (R)-N-ethyl-1-(4-(trifluoromethyl)phenyl)ethane-1-amine [ka]

[0218] Intermediate 205 was prepared in the same manner as described for intermediate 204. m / z(ESI): 218.1(M+H) +

[0219] Preparation of intermediate 206: (S)-N-(cyclopropyl(5-(trifluoromethyl)pyridine-2-yl)methyl)ethaneamine [ka]

[0220] Step 1. (R)-(+)-2-methyl-2-propanesulfinamide (0.50 g, 4.13 mmol, AK Scientific, Inc.) in dichloromethane (8.25 mL) was added to an oven-dried 100 mL round-bottom flask. To this mixture, copper(II) sulfate (1.32 g, 8.25 mmol, Sigma-Aldrich Corporation) was added, followed by 5-(trifluoromethyl)picoline aldehyde (0.75 g, 4.13 mmol, J&W Pharmlab). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a celite pad, and the filtration cake was thoroughly washed with DCM. The filtrate was collected and concentrated under vacuum. The crude product was purified by flash chromatography (0-20% siRNA:EtOH (3:1) in silica and heptane) to obtain (R,E)-2-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methylene)propan-2-sulfinamide (1.105 g, 3.97 mmol, yield 96%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.15-9.19(m,1H),8.56(s,1H),8.42(dd,J=8.2,2.3Hz,1H),8.28(d,J=8.2Hz,1H),1.23(s,9H).m / z(ESI):279.0(M+H) + .

[0221] Step 2. (R,E)-2-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methylene)propan-2-sulfinamide (0.40 g, 1.44 mmol) in tetrahydrofuran (7.19 mL) was added to an oven-dried 100 mL two-necked round-bottom flask. The reaction mixture was cooled to -78 °C, and then 0.5 M cyclopropyl magnesium bromide solution in THF (5.17 mL, 2.59 mmol, Sigma-Aldrich Corporation) was added dropwise to the reaction mixture. After 10 minutes, saturated NH4Cl (5.8 mL) was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification of the crude product by flash chromatography (silica, 0-60% Â:DCM) yielded both diastereomers, with peak 1 assigned as the pale yellow oil (R)-sulfinamine (0.176 g, 0.55 mmol, 38% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.91(s,1H),8.24(dd,J=8.4,2.3Hz,1H),7.79(d,J=8.4Hz,1H),5.82(d,J=7.5Hz,1H) ,3.81(t,J=8.0Hz,1H),1.12-1.24(m,10H),0.36-0.62(m,4H).m / z(ESI):321.1(M+H) + Peak 2 was identified as (S)-sulfinamine (0.099 g, 0.309 mmol, 22% yield), a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.89(s,1H),8.24(dd,J=8.4,2.3Hz,1H),7.75(d,J=8.4Hz,1H),5.64(d,J=6.3Hz,1H),3.74(dd,J=9.0, 6.5Hz,1H),1.25-1.32(m,1H),1.10(s,9H),0.59-0.64(m,1H),0.42-0.51(m,3H).m / z(ESI):321.1(M+H) +The absolute stereochemistry was assigned to the sulfinimine intermediate and the purchased enantiopuramine based on its similarity to the example in the literature (Tetrahedron Letters, SDKuduk et al, 45(2004) 6641-6643).

[0222] Step 3: In a 50 mL round-bottom flask, (S)-sulfinamide (0.16 g, 0.48 mmol, peak 2) and 4.0 M dioxane solution (0.15 mL, 0.61 mmol, Sigma-Aldrich Corporation) were added to 1,4-dioxane (2.42 mL). The resulting reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under vacuum, and the crude product was carried over to the next step of the synthesis without further purification. m / z(ESI): 217.0(M+H) + .

[0223] Step 4: In a 50 mL round-bottom flask, (S)-cyclopropyl(5-(trifluoromethyl)pyridine-2-yl)methaneamine hydrochloride (0.12 g, 0.48 mmol) and acetaldehyde (0.03 g, 0.03 mL, 0.61 mmol, Sigma-Aldrich Corporation) were added to dichloromethane (2.4 mL). Then, titanium(IV) isopropoxide (0.17 g, 0.18 mL, 0.60 mmol, Aldrich) was added to the reaction mixture and stirred at room temperature for 16 hours. The mixture was cooled to 0°C, and then methanol (0.16 g, 0.2 mL, 4.83 mmol, Sigma-Aldrich Corporation) was added to the mixture, followed by sodium borohydride (0.02 g, 0.48 mmol, Aldrich), and the resulting reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum. Purification of the crude product by flash chromatography (silica, 0-35% MeOH:DCM) yielded (S)-N-(cyclopropyl(5-(trifluoromethyl)pyridine-2-yl)methyl)ethaneamine (0.040 g, 0.164 mmol, yield 33.9%) as a yellowish-brown solid. m / z(ESI): 245.1(M+H) + .

[0224] The primary and secondary amines in Table 13 were prepared in the same manner as described for intermediate 206.

[0225] [Table 25]

[0226] Intermediate 211: N-methyl-1-(5-(trifluoromethyl)pyridine-2-yl)propan-1-amine [ka]

[0227] Step 1. In a 100 mL two-necked round-bottom flask that had been oven-dried, N-methoxy-N-methyl-5-(trifluoromethyl)picolinamide (0.29 g, 1.21 mmol, J&W Pharmlab) was added in tetrahydrofuran (6.1 mL). The reaction mixture was cooled to -78 °C, and then 2.0 M ethylmagnesium chloride solution in THF (1.83 mL, 3.65 mmol, Sigma-Aldrich Corporation) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at -78 °C for 15 minutes, and then the mixture was quenched with saturated NH₄Cl (6 mL) aqueous solution. The mixture was warmed to room temperature. The reaction mixture was then diluted with RINKAN (30 mL), and the aqueous layer was extracted with RINKAN (3x). The combined organic extract was dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was used without further purification. m / z (ESI): 204.0 (M+H) + .

[0228] Step 2: 1-(5-(trifluoromethyl)pyridine-2-yl)propan-1-one (0.10 g, 0.49 mmol) and a 2.0 M methylamine solution in tetrahydrofuran (0.37 mL, 0.74 mmol, Sigma-Aldrich Corporation) in methanol (2.5 mL) were added to a 50 mL round-bottom flask. Then, titanium(IV) isopropoxide (0.18 g, 0.18 mL, 0.62 mmol, Sigma-Aldrich) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 30 minutes under an inert atmosphere. The mixture was then cooled to 0°C, and sodium borohydride (0.09 g, 2.46 mmol, Sigma-Aldrich) was slowly added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with saturated NaHCO3 (0.5 mL) aqueous solution, and the resulting mixture was stirred for 10 minutes. Next, the mixture was diluted with MeOH (2 mL) and filtered through a celite pad. The filtrate was concentrated under vacuum. This yielded N-methyl-1-(5-(trifluoromethyl)pyridine-2-yl)propan-1-amine as a pale yellow solid. The mixture was proceeded to the next step of the synthesis without further purification. m / z(ESI): 219.1(M+H) + .

[0229] The secondary amines in Table 14 were prepared in the same manner as described for intermediate 211.

[0230] [Table 26]

[0231] Intermediate 214: (R)-N-((6-ethoxypyridazine-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka]

[0232] Step 1. (R)-N-((6-bromopyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (133, 0.840 g, 3.47 mmol) and DIPEA (0.897 g, 1.21 mL, 6.94 mmol, Aldrich) were stirred in dichloromethane (17.4 mL), and di-tert-butyl dicarbonate (1.21 g, 1.29 mL, 5.55 mmol, Oakwood Products, Inc.) was added. The reaction mixture was then stirred overnight at room temperature until complete. The mixture was partitioned between 200 mL of DCM and water. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. Purification of the crude product by medium-pressure chromatography (silica, 0-100% SiO:heptene) yielded tert-butyl(R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (1.61 g, 4.70 mmol, yield 136%). m / z(ESI): 394.1,396.1(M+H) + .

[0233] Step 2. t-butylBrettPhos (55.0 mg, 0.110 mmol, Aldrich) was mixed in dioxane (1.0 mL). In a separate flask, t-butylBrettPhosPd G3 (98.0 mg, 0.110 mmol, Aldrich), ethanol (0.300 mL, 5.70 mmol, Aldrich), (R)-((6-bromopyridazin-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (300 mg, 0.76 mmol), and cesium carbonate (350 mg, 1.10 mmol, Aldrich) were slurryed in dioxane (2.50 mL). The t-butylBrettPhos mixture was added to the second flask. This slurry was then stirred overnight to complete the process. The mixture was concentrated under reduced pressure, and the residue was purified by medium-pressure chromatography (silica, 0-100% ethyl:heptane) to obtain tert-butyl(R)-((6-ethoxypyridazine-3-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamate (231 mg, 0.643 mmol, yield 84.0%). m / z(ESI): 360.0(M+H)+ This substance was dissolved in TFA (10 mL) and stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH, and eluted through an SCX column eluted with 0-2 M ammonia in MeOH. The mixture was then concentrated to obtain (R)-N-((6-ethoxypyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (214, 166 mg, 0.640 mmol, yield 84%) as a free base. m / z(ESI): 260.0(M+H) + .

[0234] Intermediate 215: 4-amino-1,3-dihydrofloflo[3,4-c]quinoline-8-carboxylic acid. [ka]

[0235] Step 1. To a stirred solution of 4-oxotetrahydrofuran-3-carbonitrile (0.500 g, 4.50 mmol) in dichloromethane (5.00 mL), DIPEA (0.943 mL, 5.40 mmol) was added, and the reaction mixture was cooled to -78°C. Then, anhydrous trifluoromethanesulfonic acid (0.760 mL, 4.50 mmol) was added dropwise at -78°C for 1 minute, and the reaction mixture was stirred at the same temperature for 15 minutes. After the reaction was complete, the reaction mixture was diluted with water, the organic layer was separated, washed with brine (2 x 10 mL), dried on sodium sulfate, and concentrated to obtain crude 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (1.05 g, 4.32 mmol, yield 96%), which was used in the next step without further purification.

[0236] Step 2: In a 150 mL round-bottom flask, methyl 4-amino-3-bromobenzoate (4 g, 17.39 mmol, Combi-Blocks Inc.) and bis(pinacolato)diborone (8.83 g, 34.8 mmol, Frontier Scientific, Inc.) were added to 1,4-dioxane (58.0 mL). Potassium acetate (5.12 g, 52.2 mmol, Sigma-Aldrich Corporation) was then added to the solution, and the mixture was degassed by bubbling with argon for 5 minutes. Next, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) complex with dichloromethane (1.420 g, 1.739 mmol, Strem Chemicals, Inc.) was added. The reaction mixture was stirred at 100 °C. After 18 hours, the reaction mixture was cooled, the solid was filtered under vacuum, and washed with DCM. The mother liquor was then concentrated to obtain a semi-solid residue. DCM was added, and the resulting solid was recovered by vacuum filtration. The mother liquor was concentrated again, and this process was repeated. The desired methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.6 g, 9.38 mmol, yield 54.0%) was isolated as a gray solid. m / z(ESI): 196.1(M+H) + (Boronic acid). 1 H NMR(400MHz,chloroform-d)δ ppm 8.33(d,J=2.1Hz,1H),7.90(dd,J=8.6,2.2Hz,1H),6.57(d,J=8.5Hz,1H),5.20(brs,2H),3.87(s,3H),1.37(s,12H).

[0237] Step 3.4-Cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (10 g, 41.1 mmol) was stirred in 1,4-dioxane (200 mL) and water (20.00 mL). Methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.12 g, 32.9 mmol), K2CO3 (17.05 g, 123 mmol), and Pd(PPh3)4 (4.75 g, 4.11 mmol) were added under nitrogen purging. The reaction mixture was then heated at 80°C for 16 hours. The reaction mixture was concentrated and then diluted with ethyl acetate (50 mL) and water (50 mL), and stirred at room temperature for 30 minutes. Next, the formed solid was filtered, washed with ethyl acetate (50 mL) and 2% MeOH in DCM (50 mL), and then dried under vacuum to obtain methyl 4-amino-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (6.6 g, 27.0 mmol, yield 65.7%) as a gray solid. m / z(ESI): 245.3(M+H) + . 1 ¹H NMR (400MHz, TFA-d) δ ppm 8.59–8.67 (2H,m), 7.97 (1H,d,J=9.3Hz), 5.94 (2H,t,J=3.5Hz), 5.65 (2H,t,J=3.4Hz), 4.24 (3H,s). Note: For some heterocycles, Pd(dppf)Cl2 was used instead of Pd(PPh3)4.

[0238] Step 4. 30 g, 123 mmol of methyl 4-amino-1,3-dihydroflour[3,4-c]quinoline-8-carboxylate was stirred in 300 mL of water, 300 mL of tetrahydrofuran, and 300 mL of methanol. LiOH (11.77 g, 491 mmol) was added, and the reaction mixture was heated at 75°C for 3 hours. The reaction mixture was concentrated and acidified to pH 6.0 with 1.5 N HCl. The resulting solid was filtered, washed with 300 mL of methanol, and dried to obtain 4-amino-1,3-dihydroflour[3,4-c]quinoline-8-carboxylic acid (28 g, 122 mmol, 99% yield) as an off-white solid. m / z (ESI): 231.2 (M+H) + .1 H NMR(400MHz,DMSO-d)δ ppm 12.83(1H,s),7.88-8.30(2H,m),7.59(1H,d,J=8.8Hz),7.02(2H,s),5.40(2H,t,J=3.5Hz),5.03(2H,t,J=3.6Hz).

[0239] The acids in Table 15 were prepared in the same manner as described for intermediate 215.

[0240] [Table 27]

[0241] [Table 28]

[0242] [Table 29]

[0243] [Table 30]

[0244] Intermediate 245: 6-amino-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylic acid. [ka]

[0245] Step 1. A mixture of methyl 2-oxocyclopentane carboxylate (1.0 g, 0.877 mL, 7.03 mmol, Matrix Scientific) and 1,1'-dimethyltriethylamine (1.000 g, 1.352 mL, 7.74 mmol, Sigma-Aldrich Corporation) in DCM (15 mL) was cooled to -78°C, and trifluoromethanesulfonic anhydride (7.03 mL, 7.03 mmol, Sigma-Aldrich Corporation) was added. After the addition was complete, the mixture was stirred at -78°C for 5 minutes, then the dry ice bath was removed and the mixture was stirred at room temperature. After 15 minutes, the mixture was concentrated to obtain quantitative methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopenta-1-ene-1-carboxylate. It was obtained as a pale yellow solid and can be used as is. m / z(ESI):275(M+H) + .

[0246] Step 2. The mixture of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopenta-1-ene-1-carboxylate (1.982 g, 7.23 mmol), (2-amino-5-(methoxycarbonyl)pyridine-3-yl)boronic acid (1.70 g, 8.67 mmol), potassium phosphate, tribasic (3.78 g, 21.69 mmol, Acros), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), dichloromethane (0.177 g, 0.217 mmol, Strem Chemicals, Inc.) in 1,4-dioxane / water (10 / 0.60 mL) was heated at 80°C for 1 hour, then allowed to cool to room temperature and diluted with ethyl acetate. A precipitate corresponding to the desired product was formed. The precipitate was filtered and washed with ethyl acetate to obtain a pale gray solid quantitatively containing methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,8]naphthyridine-2-carboxylate. Yield: m / z(ESI): 245(M+H) + . 1H NMR(400MHz,DMSO-d6)δ ppm 11.93-12.58(m,1H),8.96(d,J=2.1Hz,1H),8.33(d,J=2.1Hz,1H),3.89(s ,3H),3.13(brt,J=7.6Hz,2H),2.78(brt,J=7.3Hz,2H),2.08-2.18(m,2H).

[0247] Step 3. The mixture of methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,8]naphthirizine-2-carboxylate (1.76 g, 7.21 mmol) in POCl3 (24.68 g, 15 mL, 161 mmol, Aldrich) was heated under reflux for 30 minutes. After the reaction was complete, the reaction was carefully added to cold saturated NaHCO3 to basicize the product. After stirring for 15 minutes, the mixture was extracted with phenylethylamine, and the combined organic matter was concentrated to quantitatively obtain methyl 6-chloro-8,9-dihydro-7H-cyclopenta[c][1,8]naphthirizine-2-carboxylate as a yellow solid. Yield: m / z(ESI): 263(M+H) + .

[0248] Step 4. To a suspension of methyl 6-chloro-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyrizine-2-carboxylate (1.89 g, 7.19 mmol) in DMSO (15 mL), DIPEA (2.79 g, 3.77 mL, 21.58 mmol, Aldrich) was added, followed by (2,4-dimethoxyphenyl)methaneamine (1.564 g, 1.405 mL, 9.35 mmol, Aldrich). The resulting mixture was heated overnight at 90°C. The reaction product was then cooled to room temperature, diluted with water, washed with saturated NH4Cl, and extracted with ethyl acetate. The combined organic matter was dried over Na2SO4, filtered, and concentrated to obtain methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyrizine-2-carboxylate (2.18 g, 5.54 mmol, yield 77%) as a yellow solid, which was used directly. m / z(ESI):394(M+H) + .

[0249] Step 5: To a solution of methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthirizine-2-carboxylate (2.18 g, 5.54 mmol) in THF / MeOH (10 / 10 mL), NaOH (10 mL, 10.00 mmol) was added. The resulting solution was heated at 70°C for 2 hours, then cooled to room temperature and acidified with 10 mL of 1 M HCl. A pale yellow precipitate formed, which was filtered off and azeotropically dried with toluene to obtain 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthirizine-2-carboxylate hydrochloride (1.44 g, 3.46 mmol, yield 62.5%) as a yellow solid. m / z(ESI): 380.2(M+H) + .

[0250] The acids in Table 16 were prepared in the same manner as described for intermediate 245.

[0251] [Table 31]

[0252] [Table 32]

[0253] [Table 33]

[0254] Intermediate 259: 4-amino-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxylic acid [ka]

[0255] Step 1. To a suspension of sodium hydride (11.10 g, 278 mmol, 0.5 equivalents, 60% in mineral oil) in anhydrous tetrahydrofuran (250 mL), methyl glycolate (42.4 mL, 555 mmol, 1.0 equivalent) was added at room temperature under an N2 atmosphere. (E)-buta-2-ennitrile (54.5 mL, 666 mmol, 1.2 equivalents) was slowly added to the reaction mixture at 65°C and stirred at the same temperature for 2 hours. The reaction mixture was cooled, quenched with 2N NaOH solution (250 mL), and extracted with diethyl ether (500 mL). The aqueous layer was acidified with concentrated HCl to adjust the pH to approximately 1 and extracted with dichloromethane (2 x 500 mL). The combined organic layers were washed with brine (200 mL), dried on sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel (230-400 mesh) with 10% ethyl acetate as the eluent to obtain 2-methyl-4-oxotetrahydrofuran-3-carbonitrile (22 g, 176 mmol, 32% yield) as a brown solid. m / z (ESI, negative): 124.3[M-1]. 1H NMR (400 MHz, chloroform-d): δ ppm 4.40-4.27 (m, 2H), 4.26-4.19 (m, 1H), 3.24-2.99 (m, 1H), 1.61 (dd, J=18.6, 6.2 Hz, 3H).

[0256] Step 2.2-Methyl-4-oxotetrahydrofuran-3-carbonitrile (25.0 g, 200 mmol, 1.0 equivalent) was stirred in dichloromethane (500 mL) to which DIPEA (69.8 mL, 400 mmol, 2.0 equivalents) and anhydrous trifluoromethanesulfonic acid (47.1 mL, 280 mmol, 1.4 equivalents) were added at -78°C and stirred at the same temperature for 15 minutes. The reaction mixture was quenched by slowly adding water (250 mL) and, after reaching room temperature, extracted with dichloromethane (2 x 500 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was stirred in diethyl ether and filtered. The mother liquor was concentrated under reduced pressure to obtain 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (35.0 g, crude) as a light brown adduct. The crude substance was used in the next process without further purification. m / z: 257.1 [not ionized]

[0257] Step 3.4-Cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (35 g, 136 mmol, 1.0 equivalent) was stirred in 1,4-dioxane (1400 mL) and water (70.0 mL). Methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (37.7 g, 136 mmol, 1.0 equivalent) and potassium phosphate (87 g, 408 mmol, 3.0 equivalents) were added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 15 minutes, and then PdCl2(dppf)-DCM adduct (9.96 g, 13.61 mmol, 0.1 equivalent) was added. The reaction mixture was heated at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude residue was purified by column chromatography using silica gel (60-120 mesh) with 50% ethyl acetate and hexane as the eluent to obtain methyl 4-amino-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (25 g, 97 mmol, yield 71%) as a brown solid. m / z: 259.2(M+H) +1H NMR(400MHz,DMSO-d6):δ 8.11(d,J=2.0Hz,1H),8.00(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.8Hz,1H),6.87(s,2 H),4.11(q,J=5.3Hz,1H),3.87(s,2H),3.17(d,J=5.3Hz,3H),1.41(d,J=5.9Hz,3H).

[0258] Step 4. To a stirred solution of methyl 4-amino-3-methyl-1,3-dihydroflou[3,4-c]quinoline-8-carboxylate (26.0 g, 101 mmol, 1.0 equivalent) in tetrahydrofuran (130 mL), methanol (78 mL), and water (52 mL), lithium hydroxide (9.64 g, 403 mmol, 4.0 equivalent) was added and the mixture was stirred at 75°C for 4 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in water (100 mL) and filtered to remove insoluble particles. The aqueous layer was acidified with concentrated HCl (pH 6-6.5). The precipitated solid was filtered, washed with water, and dried under vacuum to obtain 4-amino-3-methyl-1,3-dihydroflou[3,4-c]quinoline-8-carboxylic acid (17.5 g, 71.6 mmol, yield 71%) as an off-white solid. m / z:245.1(M+H) +1 H NMR(TFA,400MHz):δ(ppm) 8.68(t,J=6.2Hz,2H),8.01(dd,J=9.1,4.2Hz,1H),6.15(s,1H),5.94(m,2H),1.86(t,J=5.4Hz,3H)

[0259] Step 5. Chiral SFC Separation: 44.5 g of racemic 4-amino-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxylic acid was separated by chiral SFC to obtain 14 g of each isomer. Stereochemistry was assigned arbitrarily.

[0260] Separation information:

[0261] [Table 34]

[0262] The racemic acid shown in Table 17 was prepared using the same method as described for intermediate 259.

[0263] [Table 35]

[0264] Intermediate 268: 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylic acid [ka]

[0265] Step 1. To a stirred solution of diethyl(cyanomethyl)phosphonate (130 g, 732 mmol, 1.1 equivalents) in tetrahydrofuran (2000 mL), potassium tert-butoxide (1 M solution in THF; 732 mL, 732 mmol, 1.1 equivalents) was added at -78°C and stirred for 30 minutes. 2-(benzyloxy)acetaldehyde (100 g, 666 mmol, 1.0 equivalent) was added to the reaction mixture at -78°C and left at room temperature for 1 hour. After completion, the reaction mixture was quenched with saturated NH4Cl solution (1500 mL) and extracted with ethyl acetate (2 x 3000 mL). The combined organic layers were washed with aqueous brine (1000 mL), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography using 15% ethyl acetate with petroleum ether as the eluent on silica gel (60-120 mesh) to obtain 4-(benzyloxy)buta-2-ennitrile (100.6 g, yield 87%) as a colorless oil. m / z: 174.1 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz): δ (ppm) proton NMR showed a mixture of isomers. 7.47–7.32 (m, 5H), 6.80–6.62 (m, 1H), 5.77–5.72 (m, 1H), 4.59 (d, J=2.8 Hz, 2H), 4.18–4.16 (m, 2H).

[0266] Step 2. To a stirred solution of potassium tert-butoxide (1M solution in THF; 289.0 mL, 289 mmol, 1.0 equivalent) in tetrahydrofuran (260 mL), methyl 2-hydroxyacetate (22.03 mL, 289 mmol, 1.0 equivalent) was added at room temperature and heated to 50°C under a nitrogen atmosphere. 4-(benzyloxy)buta-2-ennitrile (50.0 g, 289 mmol, 1.0 equivalent) was added and stirred at the same temperature for 4 hours. The reaction temperature was raised to 70°C and stirred for 16 hours. After completion, the reaction mixture was cooled to 0°C and quenched with ice water (500 mL). The resulting solution was washed with diethyl ether (2 x 200 mL), then acidified with concentrated HCl (to approximately pH 1-2), and then extracted with DCM (2 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography using silica gel (60-120 mesh) with 26% ethyl acetate containing petroleum ether as the eluent to obtain 2-((benzyloxy)methyl)-4-oxotetrahydrofuran-3-carbonitrile (9.2 g, yield 14%) as a colorless oil. LC-MS (ESI, positive) m / z: 232.0 (M+H) + . 1 H NMR(400MHz,chloroform-d)δ 7.41-7.28(m,5H),4.83-4.60(m,2H),4.52(dd,J=11.8,6.6Hz,1H),4.33(dd,J=17.0,9.0Hz,1H),4.11-3.89(m,2H),3.82-3.68(m,2H).

[0267] Step 3.2-((benzyloxy)methyl)-4-oxotetrahydrofuran-3-carbonitrile (5.8 g, 25.08 mmol, 1.0 equivalent) was stirred in dichloromethane (116 mL). Under an N2 atmosphere, trifluic anhydride (6.75 mL, 40.1 mmol, 1.6 equivalents) and DIPEA (8.76 mL, 50.2 mmol, 2.0 equivalents) were added at -78°C and the mixture was stirred for 10 minutes. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2 x 200 mL). The combined organic layer was washed with aqueous brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was washed with diethyl ether (200 mL) and filtered. The organic layer was concentrated under reduced pressure to obtain 5-((benzyloxy)methyl)-4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (7.65 g) as a light brown liquid, which was then used directly in the next step.

[0268] Step 4.5-((benzyloxy)methyl)-4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (7.65 g, 20.93 mmol, 1.0 equivalent) was stirred in 1,4-dioxane (232 mL) and water (11.60 mL). Methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5.8 g, 20.93 mmol, 1.0 equivalent) and potassium carbonate (8.68 g, 62.8 mmol, 3.0 equivalent) were added at room temperature. The reaction mixture was purged with N2 gas for 15 minutes, and then Pd(PPh3)4 (1.209 g, 1.046 mmol, 0.05 equivalent) was added. The reaction mixture was heated at 80°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by column chromatography using silica gel (60-120 mesh) with petroleum ether and 80% ethyl acetate as the eluent to obtain 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (4.4 g, yield 58%) as an off-white solid. m / z: 365.2 (M+H) + . 1¹H NMR (400MHz, DMSO-d6) δ 8.12 (d, J=2.0Hz, 1H), 8.01 (dd, J=8.9, 2.0Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.34-7.20 (m, 5H), 6.91 (brs, 2H), 5.49 (dq, J=5.6, 3.6, 2.7Hz, 1H), 5.44-5.32 (m, 2H), 4.56-4.44 (m, 2H), 3.90-3.73 (m, 5H). Ester 268 was treated with LiOH in THF, and the lithium salt of 268 was used crudely in the amide coupling reaction.

[0269] Intermediate 269: Lithium 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate hydroxide [ka]

[0270] Step 1. K3PO4·H2O (1.08g, 4.70mmol, Sigma-Aldrich Corporation), X-Phos (0.08g, 0.16mmol, Sigma-Aldrich Corporation), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii)methanesulfonate (0.14mg, 0.16mmol, Sigma-Aldrich Corporation), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole-4-carbonitrile (1.10g, 4.70mmol, Enamine) and methyl 4-amino-5-bromo-2-(trifluoromethyl)benzoate (0.700g, 2.349mmol, Combi The blocks were suspended in a degassed mixture of water (1.0 mL) and 1,4-dioxane (5.0 mL) and stirred at 60°C overnight, followed by 18 hours at 90°C. After removing volatiles under vacuum, the crude product was purified by silica column chromatography (0-5% MeOH / DCM + 0.5% NH3 / MeOH) to obtain methyl 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (0.63 g, 1.94 mmol, yield 83%) as a slightly brownish solid. m / z(ESI): 324.8(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.71-8.76(m,1H),8.33-8.37(m,1H),7.87-7.92(m,1H),7.54-7.61(m,2H),4.41-4.46(m,3H),3.92(s,3H). 19 F NMR(376MHz,DMSO-d6)δ ppm -58.06.

[0271] Step 2. Methyl 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (0.62 g, 1.90 mmol) and lithium hydroxide (0.91 g, 3.79 mmol, Sigma-Aldrich Corporation) were suspended in methanol (3.0 mL), H2O (3.0 mL), and THF (3.0 mL), and stirred at 50°C for 2 hours. Volatile residues of the crude mixture were removed under vacuum, and the light brown solid was co-evaporated twice with DCM, followed by co-evaporation with toluene to obtain lithium 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate hydroxide (585 mg, 1.720 mmol, yield 91%), which was used in subsequent steps without further purification. m / z(ESI): 310.9(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.33(s,1H),8.27(s,1H),7.68(s,1H),7.03(brs,2H),4.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ ppm -57.47.

[0272] Intermediate 270: Lithium 4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylate hydroxide [ka]

[0273] Step 1.1H-pyrazole-5-carbonitrile, 4-bromo-1-methyl (273 mg, 1.47 mmol), methyl 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (457 mg, 1.47 mmol), phosphoric acid, tripotassium salt, monohydrate (1.35 g, 5.87 mmol, Sigma-Aldrich Corporation), and Pd(amphos)Cl2 (72.7 mg, 0.10 mmol) were suspended in degassed water (1.0 mL) and 1,4-dioxane (4.00 mL), and stirred overnight at 90°C to form a yellow solid. The mixture was cooled to room temperature, the precipitate was filtered, washed with DCM, MeOH, and acetone, and then water (10 mL) was added. 92 mg of the solid was dried, and the organic washing solution was absorbed onto silica gel. Purification by column chromatography using 0-20% MeOH + 0.5% NH3 in MeOH / DCM yielded methyl 4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylate (164 mg, 0.564 mmol, yield 38.5%) as an orange solid. m / z(ESI):291.000(M+H) + .1H NMR(400MHz,DMSO-d6)δ ppm 8.52-8.63(m,2H),7.60(s,1H),7.25(s,2H),4.35(s,3H),3.89(s,3H).

[0274] Step 2. Methyl 4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylate (164 mg, 0.56 mmol) was suspended in water (0.5 mL), methanol (0.5 mL), and tetrahydrofuran (0.5 mL). Then, lithium hydroxide hydrate (47.3 mg, 1.13 mmol, Sigma-Aldrich Corporation) was added, and the reaction mixture was stirred at 50°C for 90 minutes. Volatile substances were removed under vacuum to obtain lithium 4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylate hydroxide (170 mg, 0.56 mmol, yield 98%) as a yellow solid. m / z(ESI): 277.0(M+H) + .

[0275] Intermediate 271: Lithium 4-amino-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate [ka]

[0276] Step 1: In a 100 mL round-bottom flask, 17.10 mL of 1,4-dioxane was mixed with 5-bromo-1H-pyrazole-4-carbonitrile (1 g, 5.81 mmol, Enamine), cesium carbonate (3.79 g, 11.63 mmol, Sigma-Aldrich Corporation), and 2,2,2-trifluoroethyl triflate (1.687 g, 1.054 mL, 7.27 mmol, Combi-Blocks Inc.). The reaction mixture was stirred at 35°C for 20 hours. After determination by LC-MS, the reaction was filtered and concentrated under vacuum to obtain the crude product. This was used directly in the next step without further purification. m / z (ESI): 253.9 (M+H) +

[0277] Step 2: In a 25 mL pressure vial, methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (534 mg, 1.810 mmol), 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbonitrile (418 mg, 1.646 mmol), anhydrous potassium carbonate (1137 mg, 8.23 ​​mmol, Acros Organics), and tetrakis(triphenylphosphine)palladium (190 mg, 0.165 mmol, Strem) were added to 1,4-dioxane (4388 μL) and water (1097 μL). The solution was degassed with N2 for 10 minutes and heated at 90°C for 18 hours. After determination by LC-MS, the reaction mixture was cooled to room temperature and 5 ml of water was added. The product was filtered, and the precipitate was washed twice with 5 ml of water and three times with 5 ml of DCM. The crude product was isolated as a solid and used directly in the next step without further purification. m / z(ESI):343.0(M+H) +

[0278] Step 3: Methyl 4-amino-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (544 mg, 1.589 mmol) and lithium hydroxide were added to a 20 ml pressure vial. The monohydrate (133 mg, 3.18 mmol, Sigma-Aldrich Corporation) was then mixed in tetrahydrofuran (1766 μL), methanol (1766 μL), and water (1766 μL) and stirred at 50°C for 12 hours. After completion by LC-MS, the reaction mixture was cooled to room temperature, evaporated to dryness, and used directly in the next step. m / z(ESI): 329.1(M+H) +

[0279] Intermediate 272: 4-amino-3-(fluoromethyl)-1,3-dihydrofloo[3,4-c]quinoline-8-carboxylate hydrochloride [ka]

[0280] Step 1. Methyl 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (3.40 g, 9.33 mmol, 1.0 equivalent, intermediate 206-methyl ester) was dissolved in tetrahydrofuran (46.7 mL), and triethylamine (4.16 mL, 29.9 mmol, 3.2 equivalents, Aldrich) and phthalic anhydride (2.76 g, 18.7 mmol, 2.0 equivalents, Aldrich) were added. The reaction mixture was heated under reflux for 4 days. The reaction product was then concentrated to dryness and dissolved in water (100 mL) and DCM (150 mL). The layers were separated, and the aqueous layer was extracted with DCM (1 x 200 mL). The combined organic layers were dried over MgSO4 and filtered. The crude product was purified by medium-pressure chromatography (silica, 0-100% toluene:heptane) to obtain methyl 3-((benzyloxy)methyl)-4-(1,3-dioxoisoindorin-2-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (3.22 g, 6.51 mmol, yield 69.8%). m / z(ESI):495.1(M+H) + .

[0281] Step 2. Methyl 3-((benzyloxy)methyl)-4-(1,3-dioxoisoindolin-2-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (4.22 g, 8.53 mmol, 1.0 equivalent) was dissolved in dichloromethane (114 mL), cooled to -78°C, and then boron trichloride (1.0 M in DCM) (21.3 mL, 21.3 mmol, 2.5 equivalents, Aldrich) was added. The resulting mixture was stirred in a dry ice bath for 1.5 hours to complete the process. The slurry was cooled again to -78°C, and methanol (3.5 mL) was slowly added to quench the reaction mixture. The slurry was removed from the dry ice bath and slowly warmed. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over MgSO4. The filtrate was concentrated and then triturated with toluene / hexane to obtain the desired methyl 4-(1,3-dioxoisoindolin-2-yl)-3-(hydroxymethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (2.83 g, 7.00 mmol, yield 82%). m / z(ESI): 405.1(M+H) + .

[0282] Step 3. Methyl 4-(1,3-dioxoisoindolin-2-yl)-3-(hydroxymethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxylate (998 mg, 2.47 mmol, 1.0 equivalent) was dissolved in DCE (24.7 mL), and DAST (1.31 mL, 9.87 mmol, 4.0 equivalents, Aldrich) was slowly added. The resulting mixture was stirred for 1.5 hours to complete the reaction. The reaction mixture was quenched by slowly adding it to 40 mL of saturated NaHCO3. This mixture was extracted with ELISA (2 x 100 mL). The combined organic layers were washed with brine (1 x 45 mL) and dried over MgSO4. The crude product was triturated with phenylethylamine, the precipitate was filtered, and washed to obtain methyl 4-(1,3-dioxoisoindolin-2-yl)-3-(fluoromethyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxylate (690 mg, 1.70 mmol, yield 68.8%). m / z(ESI): 406.9(M+H) + .

[0283] Step 4. Lithium hydroxide monohydrate (273 mg, 6.50 mmol, 4.0 equivalents, Sigma-Aldrich Corporation) was added to a suspension of methyl 4-(1,3-dioxoisoindolin-2-yl)-3-(fluoromethyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxylate (660 mg, 1.62 mmol, 1.0 equivalent) in MeOH (8.5 mL), THF (8.5 mL), and water (8.5 mL). The mixture was heated at 70 °C for 19 hours and then cooled to room temperature. The organic solvent was removed under vacuum, and the resulting aqueous solution was adjusted to pH 6 with 5N HCl solution. The resulting suspension was filtered and air-dried to obtain 4-amino-3-(fluoromethyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxylate hydrochloride (490 mg, 1.64 mmol, yield 101%). m / z(ESI):263.1(M+H) + .

[0284] Examples Example 300: 4-amino-N-(cyclopropylmethyl)-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide [ka]

[0285] A mixture of 1-cyclopropyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)methaneamine (2, 0.050 g, 0.217 mmol), 4-amino-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxylic acid (165, 0.057 g, 0.250 mmol), N,N-dimethylacetamide (2 mL), HATU (0.099 g, 0.261 mmol, Combi-Blocks), and diisopropylethylamine (0.112 g, 0.151 mL, 0.869 mmol, Aldrich) was stirred overnight at room temperature. The mixture was filtered, and the crude substance was purified by reverse-phase preparative HPLC (10-70% MeCN in water containing 0.1% TFA) to obtain 4-amino-N-(cyclopropylmethyl)-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate (105 mg, 0.189 mmol, yield 87%) as a white solid. m / z(ESI):443(M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.88(brs,1H),8.04-8.16(m,1H),7.89-7.99(m,2H),7.46-7.88(m,2H),5.34-5.60(m,2H),4 .86-5.25(m,4H),3.33-3.60(m,2H),0.93-1.18(m,1H),0.37-0.57(m,2H),0.00-0.31(m,2H). 19 F NMR (377 MHz, methanol-d4) δ ppm -63.87 (s, 3F), -77.15 (s, 3F).

[0286] The compounds in Table 18 were prepared using the amide coupling reagents shown in the table, in the same manner as in Example 300 above.

[0287] [Table 36]

[0288] [Table 37]

[0289] [Table 38]

[0290] [Table 39]

[0291] [Table 40]

[0292] [Table 41]

[0293] [Table 42]

[0294] [Table 43]

[0295] [Table 44]

[0296] [Table 45]

[0297] Table 46

[0298] Table 47

[0299] Table 48

[0300] Table 49

[0301] Table 50

[0302] Table 51

[0303] Table 52

[0304] Table 53

[0305] Table 54

[0306] Table 55

[0307] Table 56

[0308] Table 57

[0309] Table 58

[0310] Table 59

[0311] Table 60

[0312] Table 61

[0313] Table 62

[0314] Table 63

[0315] Table 64

[0316] Table 65

[0317] Table 66

[0318] Table 67

[0319] Table 68

[0320] Table 69

[0321] Table 70

[0322] Table 71

[0323] Table 72

[0324] Table 73

[0325] Table 74

[0326] Table 75

[0327] Table 76

[0328] Table 77

[0329] Table 78

[0330] Table 79

[0331] Table 80

[0332] Table 81

[0333] Table 82

[0334] Table 83

[0335] Table 84

[0336] Table 85

[0337] Table 86

[0338] Table 87

[0339] Table 88

[0340] Table 89

[0341] Table 90

[0342] Table 91

[0343] Table 92

[0344] Table 93

[0345] Table 94

[0346] Table 95

[0347] Table 96

[0348] Table 97

[0349] [Table 98]

[0350] [Table 99]

[0351] [Table 100]

[0352] [Table 101]

[0353] [Table 102]

[0354] Examples 577 and 578: 4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide [ka]

[0355] Step 1. A mixture of 4-amino-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxylic acid (215 mg, 131 mg, 0.569 mmol), 6-(((1-fluoropropan-2-yl)amino)methyl)nicotinonitrile (102 mg, 100 mg, 0.518 mmol), and bromotri(pyrrolidine-1-yl)phosphonium hexafluorophosphate (V) (483 mg, 1.035 mmol, Aldrich) was stirred in DMAC (1.5 mL) at room temperature. N-ethyl-N-isopropylpropan-2-amine (201 mg, 0.271 mL, 1.553 mmol, Aldrich) was added to the mixture. The resulting mixture was briefly sonicated and stirred at room temperature for 1 hour. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combiflash column chromatography on a 12 g ISCO gold column, eluting with MeOH / DCM (0% to 18% in 15 mins) (2x) to obtain two portions of the desired product. The less pure portion was dissolved in DMSO / methanol / TFA and subjected to preparative reverse-phase HPLC (Gemini® Prep C18 10 μm column; Phenomenex; both solvents containing 0.1% TFA in 15 mins on a 24-minute gradient, eluting with 10-75% MeCN in water) to obtain 140 mg of 4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate as a white solid. m / z(ESI):406.2(M+H) + . 1 H NMR (methanol-d4,400MHz)δ 8.89(s,1H),8.0-8.3(m,1H),7.4-7.9(m,4H),6.1-6.1(m,1H),5.4-5.6 (m,2H),5.1-5.3(m,2H),4.97(s,2H),4.2-4.6(m,3H),1.1-1.5(m,3H). 19 F NMR (methanol - d4, 376 MHz) δ-221.55 (brs, 1F).

[0356] Step 2. The racemic mixture was purified by preparative SFC using a Chiral Technologies OJ column (250x21mm, 5mm) containing 75% liquid CO2 and 25% MeOH and 0.2% TEA as the mobile phase, at a flow rate of 80 mL / min. IC was obtained using the more potent (HCT116 MTAP null cell viability assay). 50 (Measured by) Assign the enantiomer to (R)- and the less potent one (HCT116 MTAP null cell viability assay IC 50 The enantiomer was assigned to (S)- (measured by [method]). The first elution peak was (R)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide (577, 54.0 mg, 0.133 mmol, yield 25.7%). The second elution peak was (S)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide (578, 56.1 mg, 0.138 mmol, yield 26.7%). m / z(ESI):406.2(M+H) + . 1 H NMR(DMSO-d6,500MHz)δ 8.99(d,1H,J=1.8Hz),8.26(brs,1H),7.56(brs,4H),6.67(brs,2H),5.34(brs,2H ),5.01(brs,2H),4.7-4.9(m,2H),4.2-4.7(m,3H),3.1-3.3(m,1H),1.15(brs,3H).

[0357] The compounds in Table 19 were prepared using the indicated coupling agents in the same manner as described for 577 and 578.

[0358] [Table 103]

[0359] [Table 104]

[0360] [Table 105]

[0361] [Table 106]

[0362] [Table 107]

[0363] [Table 108]

[0364] [Table 109]

[0365] Example 606: (R)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide. [ka]

[0366] Step 1. A solution of (R)-6-((((1-(pyrimidine-2-yl)ethyl)amino)methyl)nicotinonitrile (121, 0.118 g, 0.495 mmol), 4-((4-methoxybenzyl)amino)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxylate hydrochloride (251, 0.160 g, 0.413 mmol), and 1,1'-dimethyltriethylamine (0.533 g, 0.721 mL, 4.13 mmol, Sigma-Aldrich Corporation) in DMF (5 mL) is mixed with bromotripyrrolidinophosphonium hexafluorophosphate (0.192 g, 0.413 mmol, Sigma-Aldrich (Corporation) was added, and the resulting mixture was heated at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, diluted with water and saturated NaHCO3, and extracted with ELISA (3x). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was diluted in toluene (3 mL) and concentrated (3x). The residue was then subjected to silica gel chromatography using 0-50% 3:1 ELISA / EtOH in heptane to obtain (R)-N-((5-cyanopyridine-2-yl)methyl)-4-((4-methoxybenzyl)amino)-N-(1-(pyrimidine-2-yl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide (0.112 g, 0.196 mmol, yield 47.4%) as a pale yellow solid. m / z(ESI): 573.2(M+H) + .

[0367] Step 2. To a solution of (R)-N-((5-cyanopyridine-2-yl)methyl)-4-((4-methoxybenzyl)amino)-N-(1-(pyrimidine-2-yl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide (0.112 g, 0.196 mmol, yield 47.4%) in DCM (2 mL), TFA (22.20 g, 15 mL, 195 mmol, Aldrich) was added, and the resulting mixture was stirred at 70°C for 24 hours. The reaction product was washed with 10% Na2CO3 and extracted with DCM. The combined organic layers were concentrated and subjected to chromatography on silica gel using 0-50% 3:1 ELISA / EtOH in heptane, followed by re-purification by HPLC to obtain (R)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide as a grayish-white solid (606, 0.070 g, 0.155 mmol, yield 78.9%). m / z(ESI):453.2(M+H) + .1H NMR(400MHz,DMSO-d6)δ ppm 8.58-8.93(m,4H),8.24(dd,J=8.3,2.1Hz,1H),7.80(s,1H),7.31-7.54(m,2H),6.97-7.12(m,2H), 5.78-5.88(m,1H),5.18-5.44(m,2H),4.96-5.09(m,3H),4.55(d,J=17.2Hz,1H),1.54-1.72(m,3H).

[0368] Example 607: 6-amino-N-isobutyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide. [ka]

[0369] Step 1. Bromotripyrrolidinophosphonium hexafluorophosphate (0.203 g, 0.435 mmol, Sigma-Aldrich Corporation) was added to a solution of 2-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)propan-1-amine (2, 0.101 g, 0.435 mmol), 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyrizine-2-carboxylate hydrochloride (245, 0.217 g, 0.522 mmol), and 1,1'-dimethyltriethylamine (0.562 g, 0.760 mL, 4.35 mmol, Sigma-Aldrich Corporation) in DMA (4 mL), and the resulting mixture was heated at 60°C for 1 hour. The reaction product was allowed to cool to room temperature, diluted with water and saturated NaHCO3, and extracted with siRNA (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was then subjected to chromatography on silica gel using 0-40% 3:1 siRNA / EtOH in heptane to obtain 6-((2,4-dimethoxybenzyl)amino)-N-isobutyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide as a pale yellow oil. m / z(ESI): 594.2(M+H) + .

[0370] Step 2.6-((2,4-dimethoxybenzyl)amino)-N-isobutyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyrizine-2-carboxamide was dissolved in DCM (2 mL) and TFA (14.80 g, 10 mL, 130 mmol, Aldrich) was added. The resulting mixture was heated at 50°C for 1 hour. The reaction product was concentrated, washed with 10% Na2CO3, and extracted with DCM. The combined organic compounds were concentrated and subjected to chromatography in silica gel using 0-60% 3:1 siRNA / EtOH in heptane to obtain 6-amino-N-isobutyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyrizine-2-carboxamide (607, 0.035 g, 0.079 mmol, yield 18.15%) as a white solid. m / z(ESI):444.2(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.98(s,1H),8.62-8.74(m,1H),8.13-8.27(m,1H),7.86-8.11(m,1H),7.48(brs,1H),6.58-7.06(m,2H),4.62-5 .04(m,3H),2.90-3.23(m,2H),2.82(brd,J=5.2Hz,2H),2.10-2.28(m,2H),1.83-2.12(m,1H),0.65-1.01(m,7H).

[0371] The compounds in Table 20 were prepared in the same manner as described above for Examples 606 and 607.

[0372] [Table 110]

[0373] [Table 111]

[0374] [Table 112]

[0375] Table 113

[0376] Table 114

[0377] Table 115

[0378] Table 116

[0379] Table 117

[0380] Table 118

[0381] Table 119

[0382] Table 120

[0383] Table 121

[0384] Examples 646 and 647: (R) or (S)-4-amino-N-((6-methoxypyridazin-3-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide. [ka]

[0385] Step 1. Bromotripyrrolidinophosphonium hexafluorophosphate (0.285 g, 0.612 mmol, Sigma-Aldrich Corporation) was added to a solution of N-((6-methoxypyridazin-3-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (125, 0.150 g, 0.612 mmol), 4-((2,4-dimethoxybenzyl)amino)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxylate hydrochloride (249, 0.330 g, 0.795 mmol), and 1,1'-dimethyltriethylamine (0.790 g, 1.068 mL, 6.12 mmol, Sigma-Aldrich Corporation) in DMF (5 mL), and the resulting mixture was heated at 50°C for 45 minutes. The reaction mixture was brought to room temperature, diluted with water and saturated NaHCO3, and extracted with ELISA (3x). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was then subjected to chromatography on silica gel using 0-50% 3:1 ELISA / EtOH in heptane, yielding 4-((2,4-dimethoxybenzyl)amino)-N-((6-methoxypyridazin-3-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide as a pale yellow solid. m / z(ESI): 606.2(M+H) + .

[0386] Step 2. To a solution of 4-((2,4-dimethoxybenzyl)amino)-N-((6-methoxypyridazin-3-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide in DCM (2 mL), TFA (1.5 mL, 19.5 mmol, Aldrich) was added, and the resulting mixture was heated at 50°C for 1 hour. The reaction product was concentrated, washed with 10% Na2CO3, and extracted with DCM. The combined organic matter was concentrated and subjected to chromatography on silica gel using 0-50% 3:1 ELISA / EtOH in heptane to obtain 4-amino-N-((6-methoxypyridazine-3-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide (0.067 g, 0.147 mmol, yield 24.05%) as a pale yellow solid.

[0387] Step 3. The racemic sample was purified by preparative SFC using a Chiral Technologies AD column (250x21mm, 5mm) containing 50% liquid CO2, 50% MeOH, and 0.2% TEA, at a flow rate of 50 mL / min. IC was obtained using the more potent (HCT116 MTAP null cell viability assay). 50 (Measured by) Assign the enantiomer to (R)- and the less potent one (HCT116 MTAP null cell viability assay IC 50 The enantiomers were assigned to (S)- (measured by [method]). The first elution peak was (R)-4-amino-N-((6-methoxypyridazin-3-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide (646, 0.016 g, 0.035 mmol), which was isolated as a pale brown solid. The second elution peak was (S)-4-amino-N-((6-methoxypyridazin-3-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide (647, 0.015 g, 0.033 mmol), which was isolated as a pale yellow solid. m / z(ESI):456(M+H) + .1 H NMR(400MHz,DMSO-d6)δ ppm 8.80(d,J=5.0Hz,2H),7.71(brd,J=1.9Hz,1H),7.47-7.62(m,3H),7.42( t,J=4.9Hz,1H),7.14(d,J=9.1Hz,1H),6.44(brs,2H),5.33-5.51(m,1H) ,4.94(brd,J=16.0Hz,1H),4.52-4.72(m,1H),4.00(s,3H),2.89-3.16(m ,2H),2.75-2.86(m,2H),2.16(brt,J=7.6Hz,2H),1.60(d,J=7.0Hz,3H).

[0388] The compounds in Table 21 were prepared in the same manner as described above for Examples 646 and 647.

[0389] [Table 122]

[0390] [Table 123]

[0391] Example 652: 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide. [ka]

[0392] Step 1.4-Amino-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxylic acid (217, 0.500 g, 2.163 mmol) was stirred in dichloromethane (5.00 mL) and HCl (4 M in dioxane, 1.622 mL, 6.49 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated, co-distilled with toluene (3 x 50 mL), and dried. This crude substance was dissolved in dichloromethane (5.00 mL) and cooled to 0°C. Oxalyl chloride (1.136 mL, 12.98 mmol) and DMF (0.033 mL, 0.433 mmol) were added dropwise at the same temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure in a nitrogen atmosphere, and the resulting crude product was polished with heptane (3 x 5 mL). When dried in a nitrogen atmosphere, 4-amino-1,3-dihydroflou[3,4-c][1,7]naphthirizine-8-carbonyl chloride hydrochloride (0.500 g, 1.748 mmol, yield 81%) was obtained as a yellow solid.

[0393] Step 2. To a mixture of 1-cyclopropyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)methaneamine (3, 0.050 g, 0.217 mmol), tetrahydrofuran (2 mL), and diisopropylethylamine (0.112 g, 0.151 mL, 0.869 mmol, Aldrich), 4-amino-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carbonyl chloride hydrochloride (0.065 g, 0.228 mmol) was added. The mixture was stirred at room temperature until complete, and then concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% siRNA / EtOH(3 / 1) in heptane). 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-1,3-dihydrofluoro[3,4-c][1,7]naphthirizine-8-carboxamide (652 mg, 49.5 mg, 0.112 mmol, yield 51.4%) was isolated as an off-white solid. m / z(ESI):444(M+H) + . 1H NMR(400MHz, methanol-d4)δ ppm 8.75-8.97(m,2H),8.02-8.16(m,1H),7.82(brs,1H),7.59-7.78(m,1H),5.31-5.49(m,2H),5 .04-5.19(m,4H),3.44-3.54(m,2H),1.06-1.31(m,1H),0.37-0.55(m,2H),0.04-0.31(m,2H). 19 1F NMR (377MHz, methanol-d4) δ ppm -63.86 (m, 3F).

[0394] The compounds in Table 22 were prepared in the same manner as described above for Example 652.

[0395] [Table 124]

[0396] [Table 125]

[0397] [Table 126]

[0398] [Table 127]

[0399] [Table 128]

[0400] [Table 129]

[0401] [Table 130]

[0402] Table 131

[0403] Table 132

[0404] Table 133

[0405] Table 134

[0406] Table 135

[0407] Table 136

[0408] Table 137

[0409] Table 138

[0410] Table 139

[0411] Table 140

[0412] Table 141

[0413] Table 142

[0414] Table 143

[0415] Table 144

[0416] Table 145

[0417] Table 146

[0418] Table 147

[0419] Table 148

[0420] Table 149

[0421] Table 150

[0422] Table 151

[0423] Table 152

[0424] Table 153

[0425] Table 154

[0426] Table 155

[0427] Table 156

[0428] Table 157

[0429] Table 158

[0430] Table 159

[0431] Table 160

[0432] Table 161

[0433] Table 162

[0434] Table 163

[0435] Table 164

[0436] Table 165

[0437] Table 166

[0438] Table 167

[0439] Table 168

[0440] Table 169

[0441] Table 170

[0442] Table 171

[0443] [Table 172]

[0444] [Table 173]

[0445] [Table 174]

[0446] [Table 175]

[0447] Example 819: (S)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide. [ka]

[0448] 6-(((1-fluoropropan-2-yl)amino)methyl)nicotinonitrile (102 mg, 80 mg, 0.41 mmol) and N-ethyl-N-isopropylpropan-2-amine (107 mg, 0.145 mL, 0.828 mmol, Aldrich) were stirred in DCM (1 mL) and tetrahydrofuran (1 mL) and then 4-amino-1,3-dihydrofluoro[3,4-c][1,7]naphthyrizine-8-carbonyl chloride (derived from Acid 217, 119 mg, 0.476 mmol) was added as a solid in one step. The resulting mixture was stirred at 0°C for 1 hour. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combiflash column chromatography on a 12-g ISCO gold column eluted with MeOH (containing 0.5% ammonium hydroxide) / DCM (0-18%, 15 min) to obtain 4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofluoro[3,4-c][1,7]naphthirizine-8-carboxamide (100 mg, 0.246 mmol, yield 59.4%) as a white solid.

[0449] The racemic product was purified by preparative SFC at a flow rate of 80 mL / min using a Chiral Technologies OJ column (250 x 21 mm, 5 mm) containing 80% liquid CO2, 20% MeOH, and 0.2% TEA. Stereochemistry was arbitrarily assigned. The first elution peak was assigned to (S)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofluoro[3,4-c][1,7]naphthirizine-8-carboxamide (48.6 mg, 0.120 mmol, yield 28.9%), which was obtained as an off-white solid. The first elution peak was arbitrarily assigned to (S)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofl[3,4-c][1,7]naphthirizine-8-carboxamide, and the second elution peak was arbitrarily assigned to (R)-4-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(1-fluoropropan-2-yl)-1,3-dihydrofl[3,4-c][1,7]naphthirizine-8-carboxamide (43.881 mg, 0.108 mmol, yield 26.1%), and the solution was obtained as an off-white solid. m / z(ESI):407.2(M+H) + . 1 H NMR(DMSO-d6,500MHz)δ8.6-9.1(m,2H),8.1-8.3(m,1H),7.5-7.8(m,2H),6.9-7.2 (m,2H),5.2-5.4(m,2H),4.3-5.1(m,7H),3.2-3.3(m,1H),1.20(brd,3H,J=6.4Hz). 1 ¹H NMR (methanol-d4 with some CDCl3, 400MHz): δ 8.7-9.0 (m,2H), 7.9-8.1 (m,1H), 7.6-7.8 (m,2H), 5.3-5.5 (m,2H), 5.15 (brs,2H), 4.8-5.1 (m,2H), 4.7-4.8 (m,1H), 4.3-4.6 (m,2H), 1.2-1.4 (m,3H). 19 F NMR (methanol -d4, 376MHz) δ-227.9--221.0 (m, 1F).

[0450] The compounds in Table 23 were prepared in the same manner as described above for Examples 819 and 820.

[0451] [Table 176]

[0452] [Table 177]

[0453] [Table 178]

[0454] [Table 179]

[0455] [Table 180]

[0456] [Table 181]

[0457] [Table 182]

[0458] [Table 183]

[0459] [Table 184]

[0460] [Table 185]

[0461] [Table 186]

[0462] [Table 187]

[0463] [Table 188]

[0464] [Table 189]

[0465] [Table 190]

[0466] [Table 191]

[0467] Example 882: 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide 2,2,2-trifluoroacetate. [ka]

[0468] 4-amino-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carbonyl chloride hydrochloride (168 mg, 0.588 mmol) prepared as described above was added to a stirred suspension of 1-methyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-amine (21 mg, 100 mg, 0.392 mmol) and N,N-dimethylpyridine-4-amine (14.36 mg, 0.118 mmol, Aldrich) in pyridine (930 mg, 1000 μL, 11.75 mmol, Sigma-Aldrich Corporation). The mixture was heated in an oil bath at 60°C for 6 hours. The resulting residue was partitioned into 50 mL of ethyl acetate and 5 mL of 1N NaOH. The organic layer was concentrated, and the residue was purified by reverse-phase HPLC (10%-80% CH3CN in water containing 0.1% TFA) to obtain 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofluoro[3,4-c][1,7]naphthirizine-8-carboxamide 2,2,2-trifluoroacetate (882 mg, 100 mg, 0.172 mmol, yield 43.8%) as a brown solid. m / z(ESI):469.0(M+H) + . 1 ¹H NMR (methanol-d4, 400MHz): δ 8.88 (s, 1H), 7.88 (s, 1H), 7.68 (m, 2H), 7.60 (m, 2H), 7.40 (s, 1H), 7.12 (s, 1H), 5.47 (m, 2H), 5.1-5.2 (m, 4H), 3.65 (s, 3H). 19 F NMR (methanol -d4, 376MHz): δ -64.04 (s, 3F), -77.30 (s, 3F).

[0469] The compounds in Table 24 were prepared in the same manner as described above for Example 882.

[0470] [Table 192]

[0471] Example 887: 5-amino-N-[(1R)-1-pyrimidine-2-ylethyl]-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,4-dihydro-1H-pyrano[3,4-c]quinoline-9-carboxamide. [ka]

[0472] Step 1. (R)-1-(pyrimidine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)ethane-1-amine (112, 0.123 g, 0.436 mmol) and triethylamine (0.240 g, 0.334 mL, 2.376 mmol, Sigma-Aldrich Corporation) were added to a stirred mixture of crude 5-((4-methoxybenzyl)amino)-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-carbonyl chloride (0.152 g, 0.396 mmol, from acid 258) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with saturated aqueous NH4Cl solution (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain crude (R)-5-((4-methoxybenzyl)amino)-N-(1-(pyrimidine-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-carboxamide as a brown oil, which was used directly in the next step assuming a 100% yield. m / z(ESI):629.1(M+H) + .

[0473] Step 2. Crude (R)-5-((4-methoxybenzyl)amino)-N-(1-(pyrimidine-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-carboxamide (249 mg, 0.396 mmol) was mixed in trifluoroacetic acid (1530 mg, 1 mL, 13.42 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at 60°C for 24 hours, then concentrated and purified using an XBridge column (19 x 100 mm, 5 μm) with 0.1% NH4OH (A) and ACN (B) in H2O as the mobile phase. (R)-5-amino-N-(1-(pyrimidine-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-carboxamide 2,2,2-trifluoroacetate (80 mg, 0.129 mmol, yield 32.5%) was isolated as a brown solid. m / z(ESI): 509.2[M+H] + .

[0474] Example 888: 4-amino-N-[(1R)-1-pyrimidine-2-ylethyl]-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,3-dihydrofl[3,2-c]quinoline-8-carboxamide [ka]

[0475] Example 888 was prepared in the same manner as described above for Example 887. m / z(ESI): 495.0(M+H) +

[0476] Example 889: 2-amino-N-(cyclobutylmethyl)-3-methyl-N-[[5-(trifluoromethyl)-2-pyridyl]methyl]quinoline-6-carboxamide [ka]

[0477] Step 1. A solution of isobutylamine (1 equivalent, 100 mM in dry DMSO) and a solution of 5-(trifluoromethyl)picoline aldehyde (1 equivalent, 100 mM in dry DMSO) were mixed with equal volumes of dry THF and dry MeOH (final concentration 25 mM) and MS 3 Å. The mixture was shaken at room temperature. Then, SiliaBond® boron cyanohydride (2.5 equivalents) was added, and the reaction mixture was shaken at room temperature. The reaction mixture was filtered, and the filtered cake was rinsed with CH3CN. The combined washings and filtrate were concentrated under reduced pressure to obtain 2-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)propan-1-amine.

[0478] Step 2. 4-amino-3,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxylic acid (170, 1 equivalent, 100 mM in dry DMSO), HOAt (1 equivalent, 100 mM in dry DMSO), and solutions of EDC and DIPEA (100 mM and 200 mM in dry DMF, respectively) were sequentially added to the crude amine mixture. The reaction mixture was then shaken overnight at room temperature, and then concentrated under reduced pressure to obtain the crude product. This crude product was purified by HPLC to obtain the final product, 4-amino-N-isobutyl-3,3-dimethyl-N-[[5-(trifluoromethyl)-2-pyridine]methyl]-1H-fl[3,4-c]quinoline-8-carboxamide, with 99% purity obtained by UV. m / z(ESI):473.2(M+H) + .

[0479] The compounds in Table 25 were prepared in the same manner as described above for Example 889.

[0480] [Table 193]

[0481] [Table 194]

[0482] Table 195

[0483] Table 196

[0484] Table 197

[0485] Table 198

[0486] Table 199

[0487] Table 200

[0488] Table 201

[0489] Table 202

[0490] Table 203

[0491] Table 204

[0492] Table 205

[0493] Example 936: 4-amino-N-(1-(3-cyano-5-(trifluoromethyl)pyridine-2-yl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide [ka]

[0494] Step 1: In a 1.50 mL round-bottom flask, 1-(3-bromo-5-(trifluoromethyl)pyridine-2-yl)-N-methylethane-1-amine (0.090 g, 0.318 mmol) and n,n-diisopropylethylamine (0.123 g, 0.167 mL, 0.954 mmol, Sigma-Aldrich Corporation) were added to tetrahydrofuran (1.590 mL) and dichloromethane (1.590 mL). The reaction mixture was cooled to 0°C, and then 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl chloride hydrochloride (0.110 g, 0.350 mmol) was slowly added to the reaction mixture. The entire reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a silica gel column that eluted with a gradient of 0-8% MeOH in CH2Cl2, followed by elution with 8% MeOH in CH2Cl2, yielding 4-amino-N-(1-(3-bromo-5-(trifluoromethyl)pyridine-2-yl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (0.040 g, 0.076 mmol, yield 23.95%) as a grayish-white solid. m / z(ESI): 525.0(M+H) + .

[0495] Step 2. A resealable reaction vessel was charged with 1,4-dioxane (0.190 mL) and water (0.190 mL) containing 4-amino-N-(1-(3-bromo-5-(trifluoromethyl)pyridine-2-yl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (0.040 g, 0.076 mmol), potassium ferrocyanide trihydrate (0.257 g, 0.609 mmol, Toronto Research Chemicals), and potassium acetate (0.022 g, 0.228 mmol, Sigma-Aldrich Corporation). Argon (gas) was passed through the reaction mixture for 5 minutes, then methanesulfonate (2-dicyclohexylphosphinol-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(ii)(XPhos Pd G3) (0.012 g, 0.015 mmol, Strem Chemicals, Inc.) was added to the mixture, and the vial was sealed. The mixture was stirred and heated at 100°C for 2 hours. The reaction mixture was concentrated under vacuum. The crude substance was absorbed onto a silica gel plug and purified by chromatography using a silica gel column with elution under a gradient of 0-8% MeOH in CH2Cl2. This yielded 4-amino-N-(1-(3-cyano-5-(trifluoromethyl)pyridine-2-yl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (0.020 g, 0.042 mmol, yield 55.7%) as a grayish-white solid. m / z(ESI): 472.1(M+H) + .

[0496] HCT116 proliferation activity HCT116 MTAP null cells and WT cells were seeded in RPMI1640 medium + 10% fetal bovine serum in 96-well tissue culture plates. The plates were incubated overnight at 37°C and 5% CO2. The cells were then treated with 8 or 9 serial dilutions of the compound, using the highest concentration of 1 μM or 10 μM, a 1:3 serial dilution step, and a control of DMSO only. The cells were incubated in the presence of the drug for 6 days. The effect on cell viability was measured using CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer's recommendations. Assay plates were read using an EnVision® Multilabel Reader with an ultra-sensitive luminescence module. IC 50 The values ​​were calculated using GraphPad Prism v5.01, which employs the least squares method for symmetric sigmoid dose-response, fitting the values ​​to a hill slope set to -1 (top constraint set to 100%), or using Gene Data Screener, which fits the dose-response curve using a four-parameter logistic model.

[0497] Alternatively, the compound could be assayed in a 384-well plate format:

[0498] The compound was pre-spotted into 384-well plates using 22 serial dilutions of the compound at the highest concentrations of 10 or 50 μM, 1:2 serial dilution steps, and a control of DMSO only. HCT116MTAP null cells and WT cells were then seeded as described above, and after 6 days, the effect on cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). Assay plates were read as described above, and IC was performed using GeneData Screener with a 4-parameter logistic model. 50 The values ​​were calculated and the dose-response curve was fitted. The reported IC 50 This represents the value at which the curve passes through 50% of the symmetrical range.

[0499] Table 206

[0500] Table 207

[0501] Table 208

[0502] Table 209

[0503] Table 210

[0504] Table 211

[0505] Table 212

[0506] Table 213

[0507] Table 214

[0508] Table 215

[0509] Table 216

[0510] All publications and patent applications cited herein are incorporated herein by reference in whole for all purposes, as if each individual publication or patent application were specifically and individually incorporated by reference, and as if each reference were fully contained within the whole. Although the above invention has been described in some detail by illustration and examples for the purpose of clarifying the understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of the invention, certain modifications and alterations can be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. Compound of formula I 【Chemistry 1】 The tautomer thereof, the stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein in the formula, R is a tricyclic formula independently selected from formulas IA and IB. 【Chemistry 2】 During the ceremony, 【Transformation 3】 These are single or double bonds, X １ , X ２ , X ６ and X ７ In each case, N or C, and X １ and X ２ Both cannot be N at the same time, X １ If it is C, it may be substituted with a halo. X ３ , X ４ and X ５ are each independently selected from optionally substituted C, O, N and S in each case, wherein said substituents are independently selected from C １～３ alkyl, C １～３ alkyl(OH), wherein alkyl may be substituted with halo, R ３ In each case, H or C １～３ Selected independently of alkyl, Ar １ is a six-membered, optionally substituted aryl or heteroaryl, independently selected from the following: 【Chemistry 4】 The substituents are, independently, C １～３ Alkyl, -OC １～３ Selected from alkyl or halo, R １ In each case, independently, H, halo, and C may be substituted. １～３ Alkyl (the substituent is selected from halo and -CN), possibly substituted -O-C １～３ Alkyl (the substituent is selected from halos); -C(O)OC １～３ Alkyl (C １～３ Alkyl may be substituted with a halo, and morpholinyl, R ２ In each case, C may be substituted independently. １～８ Alkyl (the substituents are halo, hydroxy, amino, -O-C) １～３ (Selected from alkyl or -CN); hydroxy, amino, or optionally substituted C １～６ A 5- or 6-membered ring or heterocycle which may be substituted with alkyl (the substituent is selected from halos); a substituted C １～６ Alkyl-O-C １～３ Alkyl (the substituent is selected from halos); 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl; C １～３ Alkyl-heterocyclyl (the heterocyclyl is selected from 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, pyradadinyl, triazolyl, pyrimidinyl, tetrahydrofuranyl, 1H-pyrrolo[2,3-b]pyridinyl, and cyclohexyl, which may be substituted, C １～３ C (selected from alkyl, -CN, and halo), or optionally substituted C １～６ Alkyl-O-C １～３ Alkyl (the substituent is selected from halo), optionally substituted phenyl (the substituent is halo or C) １～３ A compound of formula I, its tautomer, its stereoisomer, or any pharmaceutically acceptable salt thereof, selected from alkyl groups.

2. The compound according to Claim 1, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein R is a tricyclic compound of formula IA.

3. The compound according to Claim 1, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein R is a tricyclic compound of formula IB.

4. X １ and X ２ The compound according to claim 2, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein both are C.

5. X １ The compound according to claim 4, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein the compound is unsubstituted or substituted with a halo.

6. X ２ The compound according to claim 3, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts, wherein C is C.

7. X ２ The compound according to claim 3, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts, wherein is N.

8. The compound according to claim 4, wherein R is a tricyclic compound of formula IA1, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts. 【Transformation 5】

9. The compound according to claim 4, wherein R is a tricyclic compound of formula IA2, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts. 【Transformation 6】

10. X ３ The compound according to claim 8, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein is C and is either unsubstituted or substituted with methyl.

11. R ３ The compound according to claim 1, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts, wherein H is present.

12. R ３ The compound according to claim 1, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein the compound is methyl.

13. R ２ However, C may be substituted. １～８ The compound according to claim 8, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein the compound is alkyl.

14. R ２ However, it may be substituted with methyl, ethyl, isopropyl, or cyclo-C １～６ The compound according to claim 8, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, wherein the compound is alkyl.

15. Ar １ but, 【Transformation 7】 The compound according to claim 14, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts.

16. Ar １ but, 【Transformation 8】 The compound according to claim 14, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts.

17. R １ The compound according to claim 15, its tautomer, its stereoisomer, or any of the aforementioned pharmaceutically acceptable salts, which is a halo.

18. R １ However, C may be substituted. １～３ The compound according to claim 15, which is alkyl or -CN, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts.

19. R １ However, C may be substituted. １～３ The compound according to claim 3, wherein the compound is alkyl or -CN, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts.

20. A compound selected from the following, its tautomer, its stereoisomer, or any of the pharmaceutically acceptable salts mentioned above: 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-((2S)-1-methoxy-2-propanyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N,3-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(cyclopropylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(2,2-dimethylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2-dimethylpropyl)-3,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-3,3-dimethyl-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2-dimethylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-7-fluoro-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofloflo[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-chloro-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-fluoro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-chloro-N-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-chloro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((1-methylcyclopropyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((6-cyclopropyl-3-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N-((6-cyclopropyl-3-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; Methyl 4-(6-((((4-amino-1,3-dihydrofluoro[3,4-c]quinoline-8-yl)carbonyl)(methyl)amino)methyl)-3-pyridinyl)-1-piperazine carboxylate; (3S)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-chloro-2-pyridinyl)methyl)-3-methyl-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 5-amino-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)benzo[c][2,6]naphthyrizine-9-carboxamide; 4-amino-N-((5-(3,6-dihydro-2H-pyran-4-yl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; Methyl 6-((((4-amino-1,3-dihydrofluoro[3,4-c]quinoline-8-yl)carbonyl)(methyl)amino)methyl)-3',6'-dihydro[3,4'-bipyridine]-1'(2'H)-carboxylate; 5-oxo-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-5,6-dihydropyrazolo[1,5-c]quinazoline-9-carboxamide; 4-amino-1,3-dimethyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3S)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-7-fluoro-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1,3-dimethoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((8S)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((8R)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((8S)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(4-(3-oxetanyl)benzyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(4-(3-oxetanyl)benzyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1-cyanocyclopropyl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-5-methoxy-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(1-methyl-1H-1,2,4-triazole-3-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-ylmethyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2S)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-cyclopropyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-7-fluoro-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-N-((5-cyclopropyl-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-chloro-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2R)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2S)-1-methoxy-2-propanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(tetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 6-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridine-2-carboxamide; 6-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-(1-methyl-1H-pyrazole-4-yl)-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridine-2-carboxamide; 4-amino-3-methyl-N-(1-methylcyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyradinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-methoxy-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,7-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-1-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,3-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-fluoro-2-pyridinyl)methyl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-cyclopropyl-3-pyridazinyl)methyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((6-cyclopropyl-3-pyridazinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3,7-trimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N,1,7-trimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-7-fluoro-3-methyl-N-(2-propanyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-(3-fluoro-4-(trifluoromethyl)benzyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((6-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((6-(4-(trifluoromethyl)phenyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(4'-(trifluoromethyl)[biphenyl]-4-yl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(6-(4-(trifluoromethyl)phenyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(4'-(pentafluorolambda-6-sulfanyl)[biphenyl]-4-yl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2,3-dihydrofl[3,2-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(2-(5-chloro-2-pyridinyl)-2,2-difluoroethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2,3-dihydrofl[3,2-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-7-fluoro-1,3-dimethyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyclopropyl-2-pyridinyl)methyl)-N-ethyl-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N,1-dimethyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoroethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluoroethyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-(4-(pentafluoroethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-1-methyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-methyl-7-(trifluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-(4-(pentafluoro-lambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-hydroxy-4-(pentafluoro-lambda-6-sulfanyl)benzyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2S)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-(hydroxymethyl)-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-(hydroxymethyl)-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-2-cyano-1-cyclopropylethyl)-N-((5-cyano-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-2-cyano-1-cyclopropylethyl)-N-((5-cyano-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-6-methyl-2-pyridinyl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-N-cyclopropyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-(fluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-bromo-2-pyridinyl)methyl)-N,3-dimethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 6-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-3-methyl-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 6-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((5-chloro-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((1R)-1-(3-fluoro-2-pyridinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxamide; 6-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-2-phenanthidinecarboxamide; 6-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2-phenanthridinecarboxamide; 5-amino-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)benzo[c][2,6]naphthyrizine-9-carboxamide; 5-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)benzo[c][2,6]naphthyrizine-9-carboxamide; 5-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)benzo[c][2,6]naphthyrizine-9-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-((2S)-1-methoxy-2-propanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide; 4-amino-N-((3-fluoro-2-pyridinyl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-(2-pyrimidinylmethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)thieno[2,3-c]quinoline-8-carboxamide; 5-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)pyrimide[4,5-c]quinoline-9-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-cyclopropyl-2-methoxyethyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1S)-1-cyclopropyl-2-methoxyethyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-cyclopropyl-2-methoxyethyl)-N-((6-(4-morpholinyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-(2-methylpropyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(1-methoxy-2-methyl-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(1-methoxy-2-methyl-2-propanyl)-1,3-dihydrofloflo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((6-methoxy-3-pyridazinyl)methyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1S)-1-cyclopropyl-2-methoxyethyl)thieno[2,3-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1S)-1-cyclopropyl-2-methoxyethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 6-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-7,8,9,10-tetrahydro-2-phenanthidinecarboxamide; 4-amino-7-chloro-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(3,3-difluorocyclobutyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(1-methyl-1H-1,2,4-triazole-3-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(2-methylpropyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((1S)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-((1R)-1-(1-methyl-1H-1,2,4-triazole-3-yl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(3,3-difluorocyclobutyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-methylpropyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-(2-methylpropyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-chloro-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-bromo-6-methyl-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((5-(trifluoromethoxy)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-chloro-5-cyano-2-pyridinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydroflof[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-((2R)-1-methoxy-2-propanyl)-1,3-dihydroflof[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(cyclopropylmethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-chloro-5-methoxy-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-(2-propanyl)-1,3-dihydroflof[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((5-chloro-6-methoxy-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydroflof[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-ylmethyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2R)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((2S)-1-fluoro-2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-cyclopropyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((5-(difluoromethyl)-2-pyridinyl)methyl)-N-(1-methyl-1H-pyrazole-4-yl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-methylcyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-ethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 4-amino-N-ethyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((6-bromo-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2,2,2-trifluoroethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(3-oxetanyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((5-chloro-2-pyridinyl)methyl)-N-(2-propanyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1-methyl-1H-1,2,4-triazole-3-yl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclobutyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((6-(difluoromethoxy)-3-pyridazinyl)methyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((2R)-1-methoxy-2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-fluoro-N-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(2-propanyl)-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-cyclopropyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1S)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(6-chloro-3-pyridinyl)ethyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-1-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(cyclopropylmethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-cyclopropyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-ethyl-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((S)-cyclopropyl(5-(trifluoromethyl)-2-pyridinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-N-((1R)-1-(2-pyrimidinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-fluoro-N-(1-methyl-1H-pyrazole-4-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(1-methyl-1H-pyrazole-4-yl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-7-fluoro-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)benzo[c][2,6]naphthyridine-9-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrimide[4,5-c]quinoline-9-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrido[4,3-c][1,7]naphthyridine-9-carboxamide; 4-amino-1-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-(2-(4-(trifluoromethyl)phenyl)-2-propanyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrimide[4,5-c][1,7]naphthyridine-9-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)propyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((R)-cyclopropyl(5-(trifluoromethyl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-((S)-cyclopropyl(5-(trifluoromethyl)-2-pyridinyl)methyl)-N-methyl-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-N-((6-ethoxy-3-pyridazinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((R)-cyclopropyl(6-(trifluoromethyl)-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-methyl-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((5-fluoro-2-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((2,6-difluoro-3-pyridinyl)methyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-(difluoromethyl)-2-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyradinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R)-1-(5-(difluoromethyl)-2-pyridinyl)ethyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyradinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyradinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2-fluoro-6-(trifluoromethyl)-3-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((R)-cyclopropyl(6-(trifluoromethyl)-3-pyridazinyl)methyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1R)-1-(4-(pentafluoroethyl)phenyl)ethyl)-3H-pyrazolo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1S)-1-(4-(pentafluoroethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(4-(pentafluoroethyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N,1-dimethyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-ethyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-1-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclobutyl-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-1-methyl-N-(2,2,2-trifluoroethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-1-methyl-N-(1,3-oxazole-4-ylmethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-1-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((2-methoxy-6-(trifluoromethyl)-3-pyridinyl)methyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-7-(trifluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-7-(trifluoromethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-7-(trifluoromethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-7-(trifluoromethyl)-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-cyclopropylethyl)-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-cyclopropylethyl)-7-fluoro-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-ethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-3-methyl-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3S)-4-amino-N-cyclobutyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-N-cyclobutyl-3-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N-(2-(trifluoromethoxy)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(4-cyanophenyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(4-cyanophenyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1S)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R)-1-(5-cyano-2-pyridinyl)ethyl)-N-ethyl-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(2-propanyl)-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)propyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-methyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)propyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((1S)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(3,5-difluoro-2-pyridinyl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N,1-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,3-dimethyl-3H-pyrazolo[3,4-c][1,7]naphthyridine-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-methoxy-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-methoxy-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,3-dimethyl-N-((1R)-1-(4-(pentafluorolambda-6-sulfanyl)phenyl)ethyl)-3H-pyrazolo[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1S)-1-(4-(pentafluoro-lambda-6-sulfanyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(4-(pentafluoro-lambda-6-sulfanyl)phenyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-1-methyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-N-((1R)-1-(5-pyrimidinyl)propyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-1-methyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-N-((1S)-1-(5-pyrimidinyl)propyl)-1H-pyrazolo[4,3-c][1,7]naphthyrizine-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-N-((1S)-1-(5-fluoro-2-pyridinyl)ethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((1S)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-7-(trifluoromethyl)-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((1S)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-cyclopropyl-1-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrofl[3,4-c][1,7]naphthyridine-8-carboxamide; 4-amino-N-(3-fluorophenyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,7]naphthyrizine-8-carboxamide; 4-amino-N-(1-methyl-1H-pyrazole-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c][1,8]naphthyrizine-8-carboxamide; 5-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-carboxamide; 4-amino-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-2,3-dihydrofl[3,2-c]quinoline-8-carboxamide; 4-amino-3,3-dimethyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((3-fluoro-2-pyridinyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-((1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-((trans-4-hydroxycyclohexyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-cyanocyclopentyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofluoro[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-[1,1'-bi(cyclopropyl)]-2-yl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S)-spiro[2.5]octan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-aminocyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2R)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,2S)-2-ethoxycyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S)-2,2-dimethylcyclopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-spiro[2.4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S)-spiro[2.4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-spiro[2.4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S)-spiro[2.4]heptan-1-yl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1R)-1-(2-pyrimidinyl)ethyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((5-cyano-2-pyridinyl)methyl)-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1-cyanocyclopropyl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1-cyanocyclopropyl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-N-((5-cyano-2-pyridinyl)methyl)-3-methyl-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-(5,6-dihydro-2H-pyran-3-ylmethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1-cyanocyclopropyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1-cyanocyclopropyl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2-amino-1,3-thiazole-5-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(2-methylpropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S,3R)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S,3S)-3-hydroxy-2-butanyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1R,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((1S,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1R,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,3R)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((1S,3S)-3-hydroxycyclohexyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(2-(cis-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-(2-(trans-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-(2-(cis-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-(2-(trans-3-hydroxycyclobutyl)ethyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S)-2-hydroxypropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S)-3-hydroxy-2-methylpropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((2R)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((2S)-3,3,3-trifluoro-2-hydroxypropyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((1-methyl-1H-1,2,4-triazole-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((1-methyl-1H-1,2,4-triazole-3-yl)methyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3R)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-((3S)-tetrahydro-3-furanylmethyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2R)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-((2S)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2R)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-((2S)-2-cyanopropyl)-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-N-ethyl-3-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3R)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; (3S)-4-amino-3-methyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,3,3-trimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-ethyl-3,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-3,3-dimethyl-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-3,3-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; and 4-amino-N-((1R)-1-(3-cyano-5-(trifluoromethyl)-2-pyridinyl)ethyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.

21. A compound selected from the following, its tautomer, its stereoisomer, or any of the pharmaceutically acceptable salts mentioned above: (3R)-4-amino-N-ethyl-7-fluoro-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-((1R)-1-(3-fluoro-5-(trifluoromethyl)-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N,1-dimethyl-N-(4-(pentafluorolambda-6-sulfanyl)benzyl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 5-amino-N-(2-propanyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)pyrido[4,3-c][1,7]naphthyridine-9-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-chloro-N-((1R)-1-(5-fluoro-2-pyridinyl)ethyl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclobutyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-ethyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((6-(trifluoromethyl)-3-pyridazinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((1R)-1-(5-(trifluoromethyl)-2-pyridinyl)ethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; (3R)-4-amino-N-ethyl-3-methyl-N-((1R)-1-(6-(trifluoromethyl)-3-pyridazinyl)ethyl)-1,3-dihydrofl[3,4-c]quinoline-8-carboxamide; 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide; 4-amino-7-fluoro-N,1-dimethyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide and 4-amino-N-ethyl-1-methyl-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.

22. A pharmaceutical composition for treating cancer comprising an effective amount of any one of the compounds described in claim 1, 20, or 21, its tautomers, its stereoisomers, or any of the aforementioned pharmaceutically acceptable salts.

23. The pharmaceutical composition according to claim 22, wherein the cancer is selected from ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

24. A pharmaceutical composition comprising a compound according to any one of claims 1, 20, or 21, a tautomer thereof, a stereoisomer thereof, or any of the aforementioned pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

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