Prmt5 inhibitor

Abstract

To provide a compound for curing a cancer, such as ovarian cancer, lung cancer, HNSCC, lymphocytic cancer, glioblastoma, colon cancer, melanoma, stomach cancer, bile duct cancer, pancreas cancer, or bladder cancer.SOLUTION: Specifically, for example, the following compound is disclosed.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 126,416, filed December 16, 2020, which is incorporated by reference in its entirety herein. [Background technology]

[0002] Epigenetic regulation of gene expression is a critical biological determinant of protein production and cell differentiation, and plays an important pathogenetic role in many human diseases.

[0003] Epigenetic regulation involves the genetic modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones), which control the conformational transition of chromatin between transcriptionally active and inactive states. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that can cause human disease. PRMT5 influences diseases such as proliferative, metabolic, and hematological disorders.

[0004] Homozygous deletion of tumor suppressor genes is a major driver of cancer and often results in the concomitant loss of passenger genes located in close genomic proximity to the tumor suppressor. Deletion of these passenger genes can result in tumor cell-specific therapeutically tractable vulnerabilities. Homozygous deletion of the chromosome 9p21 locus harboring the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A) is present in 15% of all tumors and often involves deletion of the passenger gene MTAP (methylthioadenosine phosphorylase), a key enzyme in the methionine and adenine salvage pathway. Deletion of MTAP leads to the accumulation of its substrate, methylthioadenosine (MTA). MTA shares close structural similarity with S-adenosylmethionine (SAM), the methyl donor substrate for the type II methyltransferase PRMT5. The increased levels of MTA promoted by the loss of MTAP selectively compete with SAM for binding to PRMT5, rendering the methyltransferase in a hypomorphic state susceptible to further PRMT5 inhibition. Multiple genome-scale shRNA dropout screens performed in a large panel of tumor cell lines revealed a strong correlation between MTAP loss and cell line dependency on PRMT5, further highlighting the strength of this metabolic vulnerability. However, PRMT5 is a known cellular essential gene, and conditional PRMT5 knockout and siRNA knockdown studies suggest that inhibition of PRMT5 in normal tissues may be associated with significant problems (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy). Thus, novel strategies are needed to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-null tumors while sparing PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with MTA-cooperative small molecule inhibitors allows us to preferentially target the MTA-bound state of PRMT5, which is abundant in MTAP-null tumor cells, while improving the therapeutic index versus normal cells in which MTAP is intact and MTA levels are low. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the present invention provides a compound of formula I [ka] (In the formula, R 1 , R 2 and the nitrogen atom to which they are attached form a 5-, 6- or 7-membered ring which may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms, the same or different, selected from O, N or S, the S atoms being optionally substituted with 1 or 2 oxo groups; R 1 , R 2 and the ring formed by the nitrogen atom to which they are attached may be 0, 1, 2 or 3 R 3 may be replaced by; R 3 In each case, C 1~6 Alkyl, halo, C 1~6 Haloalkyl, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, -C(O)OC 1~6 Alkyl, -C(O)OC 1~6 haloalkyl and 5- or 6-membered rings which may be saturated, partially saturated or aromatic and contain 0, 1 or 2 heteroatoms, which may be the same or different, selected from O, N and S, and the ring may be selected from one or more R a and optionally substituted with R a In each case, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, pentafluorosulfanyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl; R is a group of formulas IA and IB: [ka] is a tricyclic ring selected from [ka] is a single bond or a double bond, X 1 , X 2 , X 6 , X 7 and X 8 is selected from optionally substituted N and C, in each occurrence, and the substituents are 1~3 alkyl; X 1 and X 2 Both of them cannot be N at the same time, and X 6 and X 7 And X 7 and X 8 cannot simultaneously be N; Furthermore, X 1 When is C, it may be optionally substituted with halo; X 3 , X 4 and X 5 is selected from optionally substituted C, O, N and S, in each occurrence, and the substituents are C 1~3 Alkyl and C 1~3 alkyl(OH), which may be optionally substituted with halo. or a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0006] In one embodiment, the present invention provides a method for the preparation of a compound according to the present invention, wherein R is of formula IA [ka] or a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0007] In one embodiment, R is [ka] It could be.

[0008] In another embodiment, R is [ka] It could be.

[0009] The present invention is 1 Further provided is a compound, wherein X is C, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing. 1 may be substituted with halo.

[0010] In one embodiment, X 1 can be N.

[0011] The present invention relates to a compound in which R is of formula IB [ka] or a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0012] In one embodiment, X 1 can be N. In another embodiment, X 7 can be N.

[0013] The present invention relates to 1 , R 2 and the nitrogen atom to which they are attached forms a 6-membered ring which may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms selected from O, N or S, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0014] In one embodiment, the six-membered ring is [ka] It could be.

[0015] In another embodiment, the six-membered ring is [ka] It is.

[0016] In one embodiment, R 3 is one or more R a The group may be phenyl, pyridinyl, pyridazinyl or pyrimidinyl, optionally substituted with

[0017] In one embodiment, R 3 is R a In a further embodiment, R a is C 1~6 In another embodiment, R a can be pentafluorosulfanyl.

[0018] In another embodiment, R 3 is one or more R a In a further embodiment, R a is C 1~6 In another embodiment, R a can be pentafluorosulfanyl.

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

[0020] In one aspect, the present invention provides a compound selected from the following, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing: (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2R,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2S,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2S,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((1R,3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((1S,3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4,5-dichloro-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazepan-4-yl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazepan-4-yl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanethione, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R,5S)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S,5R)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[rac-(3S)-3-(6-cyclopropyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[rac-(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanethione, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(3-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(4-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(2-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(3-bromophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(3-fluorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(4-bromophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(4-fluorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(4-methoxyphenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(6-bromopyridazin-3-yl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(o-tolyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(p-tolyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-phenylmorpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-pyrimidin-2-ylmorpholin-4-yl]methanone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-2,3-dihydrofuro[3,2-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3,3-dimethyl-1H-furo[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-3,3-dimethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((1S,5R)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-fluorophenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((4S)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-2,3-dihydrofuro[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl) ((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-aminoimidazo[1,2-a]quinoxalin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (5-amino-1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (5-aminobenzo[c][2,6]naphthyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (5-aminopyrido[4,3-c][1,7]naphthyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (5-aminopyrimido[4,5-c][1,7]naphthyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (5-aminopyrimido[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (6-amino-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridin-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (6-amino-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridin-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (R)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)morpholino)methanone, (R)-(4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)morpholino)methanone, (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)morpholino)methanone, [(3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, [(3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, 1-((3S)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl)-1-piperazinyl)ethanone, 4-((3R)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-3-morpholinyl)benzonitrile, 4-((3R,5S)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-5-methyl-3-morpholinyl)benzonitrile, 4-((3S)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-3-morpholinyl)benzonitrile, 4-((3S,5R)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-5-methyl-3-morpholinyl)benzonitrile, 4-chloro-6-[rac-(3S)-4-(4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)morpholin-3-yl]pyridine-3-carbonitrile, 6-[(3R)-4-(4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)morpholin-3-yl]pyridine-3-carbonitrile, 6-[(3S)-4-(4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)morpholin-3-yl]pyridine-3-carbonitrile, Methyl (3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, Methyl (3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, tert-Butyl (3R)-4-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, and tert-Butyl (3S)-4-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate.

[0021] In one aspect, the present invention provides the following compound: (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl)methanone; ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-lambda 6 -sulfanyl)phenyl)-4-morpholinyl)methanone; (4-Amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone; (4-Amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone; (4-Amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methanone; (4-Amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone; ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone; [(3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone; (4-Amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone; (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone; and (4-Amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone.

[0022] The present invention further provides a method for treating cancer, comprising administering to a subject an effective amount of a compound of the present invention, its tautomer, its stereoisomer, or a pharma- ceutically acceptable salt of any of the foregoing.In one embodiment, the cancer is selected from lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphatic cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer.In one embodiment, the lung cancer can be non-small cell lung cancer (NSCLC).

[0023] The present invention further provides a pharmaceutical composition comprising a compound of the present invention, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least one pharma- ceutically acceptable excipient.

[0024] The present invention also provides a method for preparing a medicament for treating cancer, comprising administering to a subject an effective amount of a compound of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing. In one embodiment, the cancer can be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphatic cancer, glioblastoma, colon cancer, bile duct cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer. In one embodiment, the lung cancer can be non-small cell lung cancer (NSCLC). The present invention also provides a compound of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, for use in a method for treating cancer, comprising administering to a subject an effective amount of such a compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer can be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphatic cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer. In one aspect, the lung cancer can be non-small cell lung cancer (NSCLC).

[0025] The present invention also provides the use of the compound of the present invention, its tautomer, its stereoisomer, or any of the pharma- ceutically acceptable salts thereof in the manufacture of a medicament for treating cancer.In one aspect, the cancer can be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphatic cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer.In one aspect, the lung cancer can be non-small cell lung cancer (NSCLC).

[0026] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] definition As used herein, when any variable occurs more than once in a chemical formula, its definition at each occurrence is independent of its definition at all other occurrences. In the event of a conflict between chemical structures and chemical names, the chemical structure determines the identity of the compound. The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, any chemical structure depicted in its relative configuration within all or part of this specification encompasses all possible enantiomers and stereoisomers of the exemplified compound, including stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be separated into their enantiomeric or stereoisomeric constituents using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0028] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds; racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be included within the scope of the present invention. In addition, atropisomers and mixtures thereof resulting from restricted rotation around two aromatic or heteroaromatic rings bonded to each other are also 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 the C atom adjacent to the point of bonding to the N atom of the triazole, the rotation of the phenyl may be restricted. In some cases, this rotation barrier is high enough to allow different atropisomers to be separated and isolated.

[0029] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound, i.e., the compound is substantially free of other stereoisomers. For example, a stereoisomerically pure compound having one chiral center means that the compound is substantially free of mirror image enantiomers. A stereoisomerically pure compound having two chiral centers means that the compound is substantially free of other diastereomers. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound 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 of the compound 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 of the compound 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 of the compound and less than about 3% by weight of the other stereoisomer of the compound. If the stereochemistry of a structure or portion of a structure is not shown, for example, with bold or dashed lines, then the structure or portion of a structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates where a group is attached to the remainder of the molecule.

[0030] As known to those skilled in the art, certain compounds of the present invention may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, for convenience, reference to a compound of a given structural formula will be understood to include the tautomers of the structure represented by the structural formula. Some compounds may exist predominantly in one form rather than another. Also, depending on the compound and the energy required to convert one tautomer to the other, some compounds may exist as a mixture at room temperature, while others may be isolated in one tautomer or the other tautomer. Other examples of tautomers related to the compounds of the present invention are those with a pyridone group (pyridinyl), of which hydroxypyridine is a tautomer, and those with a ketone group that have an enol tautomer. Examples of these are shown below. [ka]

[0031] The compounds of the present disclosure include, but are not limited to, compounds of formula I and all pharma- ceutically acceptable forms thereof. The present invention includes compounds in pharma- ceutically acceptable form, pharma- ceutically acceptable salts, solvates, crystalline forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. The present invention discloses compounds and pharma- ceutically acceptable salts thereof, solvates thereof, chelates thereof, non-covalent complexes thereof, prodrugs thereof, and ester prodrugs, such as (C1-C4) alkyl esters, and mixtures of any of the foregoing.

[0032] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric, and sulfuric acids, as well as the acid addition salts formed with tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isethionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embolic, and acetic acids. Acid addition salts formed with organic acids such as (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid, sulfanilic acid, alginic acid, galacturonic acid, and arylsulfonic acids, e.g., benzenesulfonic acid and p-toluenesulfonic acid; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine; and internally formed salts. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. Salts with pharmaceutically unacceptable anions or cations are within the scope of the present invention as useful intermediates for the preparation of pharmaceutically acceptable salts and / or for use in non-therapeutic, e.g., in vitro, situations.

[0033] The term "solvate" refers to a compound formed by the interaction of a solvent and a compound. A solvate of a compound includes all forms of the solvate of the compound. In certain embodiments, the solvent is volatile, non-toxic, and / or acceptable for administration to humans in trace amounts. Suitable solvates are pharma- ceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0034] The present invention discloses compounds that may also contain natural or unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 Radiolabeled compounds may be radiolabeled with radioisotopes such as 1,2-dihydro-1,3-tritium (C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For example, the present invention also includes deuterium (D) or tritium (T)-containing compounds.

[0035] "Alkyl" refers to a saturated, branched or straight chain, monovalent hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, such as propan-1-yl and propan-2-yl, butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, the alkyl group comprises 1-20 carbon atoms. In some embodiments, the alkyl group comprises 1-10 carbon atoms or 1-6 carbon atoms, while in other embodiments, the alkyl group comprises 1-4 carbon atoms. In still other embodiments, the alkyl group comprises 1 or 2 carbon atoms. Branched chain alkyl groups comprise at least 3 carbon atoms, and typically comprise 3-7, or in some embodiments 3-6 carbon atoms. Alkyl groups having 1-6 carbon atoms may be referred to as (C1-C6) alkyl groups, and alkyl groups having 1-4 carbon atoms may be referred to as (C1-C4) alkyl groups. This nomenclature can also be used for alkyl groups having different numbers of carbon atoms.

[0036] "Alkenyl" refers to an unsaturated branched or straight chain hydrocarbon group with at least one carbon-carbon double bond derived by removing one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z or E configuration (cis or trans) about the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl) and prop-2-en-2-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl and buta-1,3-dien-2-yl. In certain embodiments, alkenyl groups have from 2 to 20 carbon atoms, and in other embodiments, from 2 to 6 carbon atoms. Alkenyl groups having from 2 to 6 carbon atoms are sometimes referred to as (C2-C6) alkenyl groups.

[0037] "Alkynyl" refers to an unsaturated branched or straight chain hydrocarbon having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, and the like. In certain embodiments, alkynyl groups have 2-20 carbon atoms, and in other embodiments, 2-6 carbon atoms. Alkynyl groups having 2-6 carbon atoms may be referred to as -(C2-C6)alkynyl groups.

[0038] "Alkoxy" refers to the group -OR, where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groups contain 1-10 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms in the R group. An alkoxy group containing 1-6 carbon atoms may be referred to as an -O-(C1-C6)alkyl or -O-(C1-C6alkyl) group. In some embodiments, an alkoxy group may contain 1-4 carbon atoms and may be referred to as an -O-(C1-C4)alkyl or -O-(C1-C4alkyl) group.

[0039] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes monocyclic carbocyclic aromatic rings, such as benzene. Aryl also includes bicyclic carbocyclic aromatic ring systems in which each ring is aromatic, such as naphthalene. Thus, aryl groups can include fused ring systems in which each ring is a carbocyclic aromatic ring. In certain embodiments, aryl groups contain from 6 to 10 carbon atoms. Such groups include C6 to C8 10 They are sometimes referred to as aryl groups. However, aryl does not in any way encompass or overlap with heteroaryl, as defined separately below. Thus, when one or more carbocyclic aromatic rings are fused with an aromatic ring that contains at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group as defined herein.

[0040] "Carbonyl" refers to the group -C(O), which may also be referred to as the -C(=O) group.

[0041] "Carboxy" refers to the group -C(O)OH, which may also be referred to as -C(=O)OH.

[0042] "Cyano" refers to the group --CN.

[0043] "Cycloalkyl" refers to a saturated cyclic alkyl group derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 3 to 8 ring members may be referred to as a (C3-C8)cycloalkyl, a cycloalkyl group having 3 to 7 ring members may be referred to as a (C3-C7)cycloalkyl, and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C4-C7)cycloalkyl. In certain embodiments, a cycloalkyl group may be a (C3-C8)cycloalkyl, a (C3-C7)cycloalkyl, or a (C4-C7)cycloalkyl. 10 )cycloalkyl, (C3-C8)cycloalkyl, (C3-C7)cycloalkyl, (C3-C6)cycloalkyl or (C4-C7)cycloalkyl groups, which may be represented by C3-C 10 It may be referred to as cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl or C4-C7 cycloalkyl group.

[0044] "Heterocyclyl" refers to a cyclic group containing at least one saturated (partially unsaturated) cyclic ring. Heterocyclyl groups contain at least one heteroatom as a ring member. Exemplary heteroatoms include O, S, and N, which are independently selected. Heterocyclyl groups include monocyclic and bicyclic ring systems. Bicyclic heterocyclyl groups contain at least one non-aromatic ring with at least one heteroatom ring member, which may be fused to a cycloalkyl ring or fused to an aromatic ring (which may be carbocyclic or may contain one or more heteroatoms). The point of attachment of a bicyclic heterocyclyl group may be to a non-aromatic ring containing at least one heteroatom, or to another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removing a hydrogen atom from one of the 9-membered heterocyclic compounds shown below may be attached to the remainder of a 5- or 6-membered molecule. [ka]

[0045] In some embodiments, the heterocyclyl group contains 5 to 10 ring members, of which 1, 2, 3, or 4 are heteroatoms independently selected from O, S, or N. In other embodiments, the heterocyclyl group contains 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, when the ring contains only 3 ring members, only one of the ring atoms is a heteroatom, and when the ring contains 4 ring members, 1 or 2 heteroatoms are included. In some embodiments, the heterocyclyl group contains 3 or 4 ring members, of which one is a heteroatom selected from O, S, or N. In other embodiments, the heterocyclyl group contains 5 to 7 ring members, of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Heterocyclyl groups can be fully saturated, but can contain one or more double bonds. Examples of such heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like. Substituted heterocyclyl includes one or more oxo (=O) or oxide (-O -) substituents, such as, for example, piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-onyl, 3,4-dihydroisoquinolin-1(2H)-onyl, indolin-onyl, 1H-imidazo[4,5-c]pyridin-2(3H)-onyl, 7H-purin-8(9H)-onyl, imidazolidin-2-onyl, 1H-imidazol-2(3H)-onyl, 1,1-dioxo-1-thiomorpholinyl, and the like.

[0046] The term "comprising" is meant to be open ended, i.e., all-inclusive and non-limiting. This term may be used interchangeably herein with "having" or "including." Comprising is intended to include any components or elements shown or listed, but not to exclude other components or elements.

[0047] "Disease" refers to any disease, disorder, condition, symptom, or symptom.

[0048] "Halo" or "halogen" refers to a fluoro, chloro, bromo or iodo group.

[0049] "Haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). Representative "haloalkyl" groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. The term "perhaloalkyl" refers to an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom, unless otherwise specified. For example, the term "perhaloalkyl" includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

[0050] "Heteroaryl" refers to a monovalent aromatic heterocyclic group derived by removing one hydrogen atom from a single carbon atom of a parent heteroaromatic ring system. Heteroaryl groups typically contain 5-14 ring members, but more typically include 5-10 membered aromatic monocyclic, bicyclic and tricyclic rings containing one or more, e.g., 1, 2, 3 or 4 (or in certain embodiments 1, 2 or 3) heteroatoms selected from O, S or N (the remaining ring atoms are carbon). In monocyclic heteroaryl groups, the monocyclic ring is aromatic and contains at least one heteroatom. In some embodiments, monocyclic heteroaryl groups can contain 5 or 6 ring members and can contain 1, 2, 3 or 4 heteroatoms, 1, 2 or 3 heteroatoms, 1 or 2 heteroatoms or 1 heteroatom, 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 of the rings must contain a heteroatom, but both rings need not contain heteroatoms, although it is permissible for them to do so. For example, the term "heteroaryl" includes a 5-7 membered aromatic heterocycle fused to a carbocyclic aromatic ring or fused to another aromatic heterocycle. In a tricyclic aromatic ring, all three of the rings are aromatic and at least one of the rings contains at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems in which only one of the rings contains one or more heteroatoms, the point of attachment may be the ring containing at least one heteroatom or may be a carbocyclic ring. If the total number of S and O atoms in a heteroaryl group exceeds one, the heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in a heteroaryl group is two or less. In certain embodiments, the total number of S and O atoms in an aromatic heterocycle is one or less. Heteroaryl does not encompass or overlap with aryl as defined above.Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, etc. In certain embodiments, the heteroaryl group can be a 5-20 membered heteroaryl, such as a 5-14 membered or 5-10 membered heteroaryl. In certain embodiments, heteroaryl groups can be derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole, benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

[0051] "MTAP" refers to the mammalian methylthioadenosine phosphorylase enzyme.

[0052] "Pharmaceutically acceptable" refers to something generally recognized for use in animals, and more specifically, humans.

[0053] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharma-ceutically acceptable and that possesses the desired pharmacological activity of the parent compound.

[0054] "Pharmaceutically acceptable excipient" refers to a wide variety of ingredients that can be combined with the compounds or salts of the present invention to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adhesive agents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0055] "PRMT5" refers to the mammalian protein arginine N-methyltransferase 5 (PRMT5) enzyme.

[0056] "PRMT5 inhibitor" refers to a compound that inhibits or negatively regulates all or part of the PRMT5 enzyme activity.

[0057] "MTA-cooperative PRMT5 inhibitor" refers to a compound that, in the presence of bound MTA, inhibits or negatively regulates all or part of PRMT5 enzyme activity in vitro or in vivo in cells that have elevated levels of MTA.

[0058] "Stereoisomers" refer to isomers that differ in the arrangement of their atoms in space. Stereoisomers that are mirror images of each other and are optically active are termed "enantiomers" and those that are not mirror images of each other and are optically active are termed "diastereomers".

[0059] A "subject" includes mammals and humans. The terms "human" and "subject" are used interchangeably herein.

[0060] A "therapeutically effective amount" refers to an 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 affect such treatment of the disease, disorder, or condition. As one of ordinary skill in the art will recognize, this amount is typically not limited to a single dose, but may include multiple doses over a significant period of time required to produce a therapeutic or prophylactic response in a subject. Thus, a "therapeutically effective amount" is not limited to the amount in a single capsule or tablet, but may include multiple capsules or tablets, the dosage of which is prescribed by a qualified physician or health care provider. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age 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 one of ordinary skill in the art, or may be determined by routine experimentation.

[0061] "Treating" or "treatment" of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one clinical symptom of a disease or disorder, reducing the risk of contracting a disease, disorder, or at least one clinical symptom of a disease or disorder, reducing the onset of a disease, disorder, or at least one clinical symptom of a disease or disorder, or reducing the risk of contracting a disease, disorder, or at least one clinical symptom of a disease or disorder. "Treating" or "treatment" refers to inhibiting a disease or disorder physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both, or inhibiting at least one physical parameter that may not be discernible to the subject. Additionally, "treating" or "treatment" refers to delaying the onset of a disease or disorder, or at least a symptom thereof, in a subject who may be exposed to or susceptible to a disease or disorder, even if the subject does not yet experience or show symptoms of the disease or disorder.

[0062] Also provided is a pharmaceutical composition comprising a compound according to any one of the embodiments, or a pharma- ceutically acceptable salt thereof, a tautomer thereof, a pharma- ceutically acceptable salt of a tautomer thereof, a stereoisomer of any of the foregoing, or a mixture thereof, and at least one pharma- ceutically acceptable excipient, carrier, or diluent. In some embodiments, the compound according to any one of the embodiments, or a pharma- ceutically acceptable salt thereof, a tautomer thereof, a pharma- ceutically acceptable salt of a tautomer thereof, a stereoisomer of any of the foregoing, or a mixture thereof, is present in an amount effective for treating 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 oral administration once a day, i.e., QD, some such formulations are tablets in which the effective amount of active ingredient ranges from 1 mg to 1000 mg.

[0063] In some aspects, the subject is a mammal. In some such aspects, the mammal is a rodent. In other aspects, the mammal is a dog. In yet other embodiments, the subject is a primate, and in some embodiments, the subject is a human.

[0064] The pharmaceutical composition or preparation for administration of the compound of the present invention can be conveniently provided in unit dosage form and can be prepared by any method well known in the art.All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.In general, the pharmaceutical composition is prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.In the pharmaceutical composition, the desired active compound is present in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0065] The compounds of the invention may be administered orally, mucosally (including sublingually, buccally, rectally, nasally, or vaginally), parenterally (including subcutaneously, intramuscularly, bolus injection, intraarterially, or intravenously), transdermally, or topically. In some embodiments, the compounds of the invention are administered mucosally (including sublingually, buccally, rectally, nasally, or vaginally), parenterally (including subcutaneously, intramuscularly, bolus injection, intraarterially, or intravenously), transdermally, or topically. In other embodiments, the compounds of the invention are administered orally.

[0066] The compounds of the present invention, their pharma- ceutically acceptable salts, their tautomers, their pharma- ceutically acceptable salts of their tautomers, stereoisomers of any of the foregoing or mixtures thereof can be used in the treatment of a number of conditions.

[0067] 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 pharma- ceutically acceptable salt thereof) to a subject in need of treatment. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the subject 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).

[0068] As used herein, the term "PRMT5-mediated disorder" refers to any disease, disorder, or other condition that PRMT5 is known to affect. Thus, in some aspects, the present disclosure relates to treating or reducing the severity of one or more diseases that PRMT5 is known to affect.

[0069] In some aspects, provided herein is a method of inhibiting PRMT5 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula I or a pharma- ceutical acceptable salt thereof) or a pharmaceutical composition thereof.

[0070] The present invention provides methods of treating cancers and other disorders resulting from homozygous deletions of the chromosome 9p21 locus harboring the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A). In one aspect, the invention encompasses methods of treating cancers and tumors that are MTAP (methylthioadenosine phosphorylase)-null. In some embodiments, these types of cancers exhibit accumulation of the MTAP substrate, methylthioadenosine (MTA).

[0071] The methods of treating PRMT5 disorders encompassed by the present invention preferentially target PRMT5 in MTAP-null tumors while sparing PRMT5 in normal tissues (MTAP WT). Thus, the compounds of the present invention include MTA-cooperative small molecule inhibitors that can preferentially target the MTA-bound state of PRMT5 that is abundant in MTAP-null tumor cells while improving the therapeutic index versus normal cells where MTAP is intact and MTA levels are low.

[0072] In further aspects, the PRMT5 inhibitor MTA cooperative compounds contemplated by the present invention are useful in the treatment of proliferative diseases such as cancer. In some embodiments, the cancer compounds described herein are useful for treating pancreatic cancer. In some aspects, the cancer compounds described herein are useful for treating multiple myeloma (MM). In further embodiments, the cancer compounds described herein are useful for treating breast cancer. The breast cancer can be estrogen receptor negative (ER-) or the breast cancer can be progesterone receptor negative (PR-). In further embodiments, the breast cancer can be HER2 negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative and HER2 negative, also referred to herein as "triple negative breast cancer".

[0073] In further aspects, the breast cancer can be lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer (including, but not limited to, triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive).

[0074] In one embodiment, the compounds of the invention are useful for the treatment of pancreatic cancer.

[0075] In another embodiment, the compounds of the present invention are useful for treating NSCLC (non-small cell lung cancer). In one embodiment, the NSCLC can be squamous NSCLC. In another embodiment, the NSCLC can be adenocarcinoma.

[0076] In a further aspect, the cancer may be glioblastoma (GBM). In a further aspect, the cancer may be mesothelioma. In one aspect, the cancer may be bladder cancer. In another aspect, the cancer may be esophageal cancer. In a further aspect, the cancer may be melanoma. In one aspect, the cancer may be DLBCL, HNSCC, or cholangiocarcinoma.

[0077] In some aspects, one or more compounds described herein are useful for treating any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, for example, a cancer that is PRMT5-responsive.

[0078] In one aspect, cancers that lack p53 (e.g., p53 null cancers) are less sensitive to PRMT5 inhibition than p53 positive cancers. Thus, a PRMT5-responsive cancer can be a p53 positive cancer. The term "p53 positive" refers to a cancer that does not lack p53 expression and / or activity. In some embodiments, one or more compounds described herein are useful for treating p53 positive cancers. In some aspects, a larger amount of one or more compounds described herein may be required to treat a p53 negative cancer (e.g., p53 null cancer) than a p53 positive cancer.

[0079] In some aspects, the present disclosure provides a method for identifying a subject having a cancer that is 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 identifying the subject as having a cancer that is sensitive to treatment with a PRMT5 inhibitor if p53 is present in the sample. Thus, in some embodiments, a subject having a p53-positive cancer is identified as a subject for treatment with a PRMT5 inhibitor. In some embodiments, the method further includes administering a composition comprising a PRMT5 inhibitor to the subject.

[0080] In some embodiments, aspects of the disclosure relate to a method for identifying a subject having a cancer that is insensitive (or less sensitive) to treatment with a PRMT5 inhibitor. In some embodiments, the method includes obtaining a sample from a subject; detecting the presence or absence of p53; and if p53 is not present in the sample (e.g., the cancer is a p53 null cancer), identifying the subject as having a cancer that is not sensitive to treatment with a PRMT5 inhibitor (e.g., a cancer that is less sensitive than a p53 positive cancer). In some embodiments, a p53 negative cancer (e.g., a p53 null cancer) is treated with a PRMT5 inhibitor, but a larger amount of a PRMT5 inhibitor may be required to treat a p53 negative cancer than a p53 positive cancer. However, in some embodiments, a subject having a p53 negative cancer (e.g., a p53 null cancer) is treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0081] "Sample" refers to any biological sample derived from a subject, including, but not limited to, cells, tissue samples, bodily fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cells, and cancer tissues. Detection of the presence or absence of p53 in a sample can be performed by any suitable method for detecting p53 nucleic acid or protein, such as nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, etc., or any combination thereof.

[0082] In some embodiments, one or more of the compounds described herein may be used to treat other types of cancers, including but not limited to acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangiosarcoma, intravascular sarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, brain cancer (e.g., meningioma; glioma (e.g., astrocytoma, oligodendroglioma); medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, and the like. , colorectal cancer (e.g., colon cancer, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine carcinoma, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma, Ewing's sarcoma), eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), throat cancer (e.g., laryngeal cancer, pharyngeal cancer), cancer), nasopharyngeal cancer, oropharyngeal cancer), hematopoietic cancer (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenström's macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixed one or more of the above leukemia / lymphomas; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic lymphoma, Alveolar tumors, immunocytic amyloidosis, renal cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), 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 syndromes (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), myelofibrosis of unknown etiology myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannoma), neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer It will be appreciated that the present invention may be useful in the treatment of cancers including skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovium, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva);

[0083] In some aspects, a method of treating cancer in a subject includes administering a composition comprising a PRMT5 inhibitor to the subject, where treatment with the PRMT5 inhibitor inhibits tumor growth of the cancer by more than about 25%, more than about 50%, more than about 75%, or more than about 90% (e.g., 25%-50%, 50%-75%, 75%-90%, or 90%-100%). In some embodiments, a method of treating cancer in a subject includes administering a composition comprising a PRMT5 inhibitor to the subject, where methyl marks in the cancer are reduced by more than about 50%, more than about 75%, or more than about 80% (e.g., 50%-75%, 50%-80%, 80%-90%, 80%-100%, or 90%-100%). Methyl mark refers to protein methylation, e.g., histone methylation (e.g., methylation of one or more lysines and / or arginines of a histone protein) or DNA methylation (e.g., epigenetic DNA methylation, e.g., methylated CpG sites). In some embodiments, the methyl mark level of a cell is a measure of the extent to which histones are methylated in the cell (e.g., at one or more specific lysine and / or arginine positions).

[0084] The invention will be further described with reference to the following examples, which are intended to illustrate, but not in any way limit, the invention as claimed. EXAMPLES

[0085] Unless otherwise noted in the Intermediates section, all materials were obtained from commercial suppliers and used without further purification.

[0086] The following abbreviations are used to refer to various reagents, solvents or equipment:

[0087] [Table 1]

[0088] [Table 2]

[0089] [ka] [ka] [ka] [ka] Method A: Compound I can be prepared from the reaction of acid IA with secondary amine IB-1 in the presence of a base such as Et3N or DIPEA, an activating agent such as HATU or PyBrOP, in a solvent such as DMF or DMAc. When racemic amines or acids are utilized in Method A, the stereoisomers can be separated using chiral SFC, where stereochemistry was arbitrarily assigned to each isomer.

[0090] Method B: Compound I can be prepared from the reaction of acid chloride IC with secondary amine IB in the presence of a base such as Et3N or DIPEA or pyridine in a solvent such as THF or dioxane or DCM or DCE. Alternatively, compound I can be prepared from the reaction of acid chloride IC with secondary amine IB in the presence of DMAP in pyridine. When racemic amines or acids are utilized in Method B, the stereoisomers can be separated using chiral SFC, where stereochemistry was arbitrarily assigned to each isomer.

[0091] Analytical U / HPLC The following equipment was used for analytical UHPLC: Waters Acquity system equipped with Acquity BEH C18 (1.7 μm, 2.1×50 mm) with a linear gradient of the binary solvent system using a flow rate of 0.5 mL / min at ambient temperature and DAD coupled with MS detection SQD I. A linear gradient was used (H2O / CH3CN / HCO2H (95 / 5 / 0.1% to 0 / 100 / 0.1%)). Agilent Infinity I / II - TOF6230B / CLND Antek 8060 equipped with Acquity BEH C18 (1.7 μm, 2.1×50 mm) with a linear gradient of the binary solvent system using a flow rate of 0.75 mL / min coupled with DAD. A linear gradient was used (H2O / MeOH / HCO2H (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0092] Preparative HPLC The following equipment was used for preparative HPLC: Shimadzu Nexera X2 equipped with a Merck Chromolith SpeedROD RP-18E (5 μm, 10 × 100 mm) with a linear gradient of a binary solvent system using a flow rate of 4-7 mL / min and UV detection at 254 nm, coupled with MS detection on a Shimadzu LCMS-2020. A linear gradient was used (HO / MeOH / HCOH (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0093] Intermediates Intermediate 1: 6-(difluoromethoxy)pyridazine-3-carbaldehyde [ka] Step 1. A vial was charged with 3-chloro-6-(difluoromethoxy)pyridazine (675 mg, 3.74 mmol), sodium carbonate (1190 mg, 11.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (274 mg, 0.374 mmol). 1,4-dioxane (16.8 mL) and water (1.87 mL) were then added, followed by vinylboronic acid pinacol ester (1.73 g, 1.90 mL, 11.2 mmol). The resulting mixture was sparged with nitrogen for 15 min and then heated to 80° C. After 15 h, the mixture was cooled to 23° C. and transferred to a separatory funnel with EtOAc (20 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL) and the combined organic extracts were dried over Na2SO4 and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-50% 3:1 EtOAc:EtOH in heptane) to give 3-(difluoromethoxy)-6-vinylpyridazine (573 mg, 3.33 mmol, 89% yield) as a light brown solid. m / z (ESI): 173.2 [M+H] + .

[0094] Step 2. A vial was charged with 3-(difluoromethoxy)-6-vinylpyridazine (573 mg, 3.33 mmol), acetone (7.93 mL) and water (1.59 mL). To the resulting solution was added potassium osmate(VI) dihydrate (123 mg, 0.333 mmol) followed by 4-methylmorpholine 4-oxide (1.37 g, 11.7 mmol) and the resulting mixture was allowed to stir at 23° C. After 1.5 h, the reaction mixture was concentrated in vacuo and then co-evaporated with toluene (5 mL) and the resulting crude residue was purified by flash column chromatography (0-100% 3:1 EtOAc:EtOH in heptane) to give 1-(6-(difluoromethoxy)pyridazin-3-yl)ethane-1,2-diol (300 mg, 1.45 mmol, 43.7% yield) as a black oil. m / z(ESI):207.1[M+H] + .

[0095] Step 3. A vial was charged with 1-(6-(difluoromethoxy)pyridazin-3-yl)ethane-1,2-diol (300 mg, 1.45 mmol) and tetrahydrofuran (13.4 mL). To the resulting solution was added sodium (meta)periodate (933 mg, 4.36 mmol) and water (1.12 mL) and the resulting mixture was allowed to stir at 23° C. After 1 h, the reaction mixture was diluted with H2O (10 mL), transferred to a separatory funnel with CHCl2 (20 mL) and brine (20 mL) and extracted with CHCl2 (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The resulting crude residue was purified by flash column chromatography (0-100% 3:1 EtOAc:EtOH in heptane) to give 6-(difluoromethoxy)pyridazine-3-carbaldehyde (1, 217 mg, 1.25 mmol, 86% yield) as a clear oil. m / z (ESI): 175.2 [M+H] + .

[0096] Intermediate 2: 6-Cyclopropoxypyridazine-3-carbaldehyde [ka] Step 1. A round-bottom flask was charged with sodium hydride (60% dispersion in mineral oil, 1.556 g, 38.9 mmol) and tetrahydrofuran (31.1 mL). The headspace was flushed with nitrogen and the mixture was cooled to 0° C. Cyclopropanol (2.281 g, 1.901 mL, 39.3 mmol) was then added and the resulting mixture was allowed to warm to 23° C. under nitrogen for 1 h. 3-Chloro-6-methylpyridazine (1.00 g, 7.78 mmol) was then added dropwise as a solution in tetrahydrofuran (8.0 mL) and the reaction mixture was allowed to stir at 23° C. After 16 h, the reaction mixture was transferred to a separatory funnel with CHCl (30 mL), HO (20 mL) and saturated aqueous NHCl (30 mL), the layers were separated and the aqueous layer was extracted with CHCl (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-100% EtOAc in heptane) to give 3-cyclopropoxy-6-methylpyridazine (308.5 mg, 2.054 mmol, 26.4% yield) as a pale yellow oil. m / z (ESI): 151.2 [M+H] + .

[0097] Step 2. A vial was charged with 3-cyclopropoxy-6-methylpyridazine (308.5 mg, 2.054 mmol), selenium dioxide (365 mg, 3.29 mmol) and 1,4-dioxane (8.22 mL). The resulting mixture was sparged with nitrogen for 10 min, after which the vial was heated to 110° C. After 30 min, the reaction mixture was allowed to cool to 23° C., filtered through a pad of Celite (30 mL 3:1 EtOAc:EtOH eluent) and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-50% 3:1 EtOAc:EtOH in heptane) to give 6-cyclopropoxypyridazine-3-carbaldehyde (2, 111.7 mg, 0.680 mmol, 33.1% yield) as an orange oil. m / z (ESI): 165.1 [M+H] + .

[0098] Intermediate 3: 6-ethoxypyridazine-3-carbaldehyde [ka] A microwave vial was charged with 3-chloro-6-methylpyridazine (1.00 g, 7.78 mmol, Combi Blocks) and ethanol (15.6 mL). To the resulting solution was added potassium carbonate (2.69 g, 19.45 mmol) and the mixture was heated in a microwave to 140 °C for 14 h. The reaction mixture was then transferred to a separatory funnel with CHCl (30 mL), HO (20 mL) and saturated aqueous NHCl (30 mL), the layers were separated and the aqueous layer was extracted with CHCl (2 x 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-100% 3:1 EtOAc:EtOH in heptane) to give 3-ethoxy-6-methylpyridazine (1.07 g, 7.72 mmol, 99% yield) as a pale yellow oil. m / z(ESI): 139.15[M+H] + .

[0099] A vial was charged with 3-ethoxy-6-methylpyridazine (1.07 g, 7.72 mmol), selenium dioxide (1.37 g, 12.3 mmol), and 1,4-dioxane (30.9 mL). The resulting mixture was sparged with nitrogen for 10 min, after which the vial was heated to 110 °C. After 30 min, the reaction mixture was allowed to cool to 23 °C, filtered through a 1 cm pad of Celite (30 mL 3:1 EtOAc:EtOH eluent), and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-50% 3:1 EtOAc:EtOH in heptane) to give 6-ethoxypyridazine-3-carbaldehyde (3, 332.7 mg, 2.187 mmol, 28% yield) as a pale yellow solid. 1 H NMR(400MHz,chloroform-d)δ ppm 10.26(d,J=0.8Hz,1H),7.96(d,J=9.1Hz,1H),7.08(dd,J=9.0,0.9Hz,1H),4.75(q,J=7.0Hz,2H),1.52(t,J=7.2Hz,3H);m / z(ESI):153.1[M+H] +This route can also be applied to other non-commercially available aldehyde intermediates in Table 1.

[0100] Intermediates 4-6: 3-(6-methoxypyridazin-3-yl)-5-methylmorpholine: [ka] Step 1. An oven-dried vial was charged with 4 Å molecular sieves (2.00 g, 2.64 mmol), dichloromethane (10.6 mL), and 6-methoxypyridazine-3-carbaldehyde (365 mg, 2.64 mmol, Enamine). To the resulting suspension was added 1-((tributylstannyl)methoxy)propan-2-amine (SnAP 3Me-M reagent, 0.907 mL, 2.64 mmol) via syringe, and the resulting mixture was allowed to stir at 23° C. After 17 h, the reaction mixture was filtered (20 mL dichloromethane eluent) and the filtrate was concentrated in vacuo to give (E)-1-(6-methoxypyridazin-3-yl)-N-(1-((tributylstannyl)methoxy)propan-2-yl)methanimine as a brown oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.55 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.00 (dd, J=9.2, 0.6 Hz, 1H), 4.20 (s, 3H), 3.62-3.81 (m, 3H), 3.38-3.49 (m, 2H), 1.18-1.69 (m, 20H), 0.76-1.01 (m, 18H). The material was used in the subsequent step without further purification.

[0101] Step 2. A vial was charged with oven-dried copper(II) trifluoromethanesulfonate (191 mg, 0.528 mmol), (4S,4'S)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (88 mg, 0.264 mmol), (4R,4'R)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (88 mg, 0.264 mmol) and hexafluoroisopropanol (4 mL). The resulting mixture was stirred at 23° C. for 7 h. The mixture was then added via syringe to a solution of (E)-1-(6-methoxypyridazin-3-yl)-N-(1-((tributylstannyl)methoxy)propan-2-yl)methanimine (1316 mg, 2.64 mmol) in hexafluoroisopropanol (19.1 mL). The resulting mixture was sparged with nitrogen for 10 min and then allowed to stir at 23 °C. After 16 h, the reaction mixture was treated with 30% aqueous NH4OH and brine (1:1, 10 mL) and stirred vigorously for 1 h at 23 °C. The mixture was transferred to a separatory funnel with CHCl (20 mL) and brine (20 mL), the layers were separated, and the aqueous layer was extracted with CHCl (2 x 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to afford 3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (4, 337 mg, 1.611 mmol, 61% yield) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ ppm 7.50(d,J=9.1Hz,1H),6.97(d,J=9.1Hz,1H),4.27-4.38(m,1H),4.14(s,3H),4.07(dd,J =11.0,3.3Hz,1H),3.81-3.92(m,1H),3.41(t,J=10.7Hz,1H),3.07-3.25(m,2H),1.92(br s,1H),1.07(d,J=6.0Hz,3H);m / z(ESI):210.1[M+H] + .

[0102] Step 3. Racemic secondary amine 4 (337 mg) was purified by preparative SFC using a Chiral Technologies IG column (250×21 mm, 5 mm) with a mobile phase of 50% liquid CO2 and 50% MeOH containing 0.2% TEA using a flow rate of 80 mL / min. Peak assignments were determined by SFC on the IG column using 50% MeOH with 0.2% TEA. The first eluting peak was arbitrarily assigned as (3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (5, 150.7 mg, >99% ee) and the second eluting peak was arbitrarily assigned as (3R,5S)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (6, 152.7 mg, >99% ee).

[0103] The racemic amines summarized in Table 1 were prepared in a manner similar to that described above for amine 4.

[0104] [Table 3]

[0105] [Table 4]

[0106] [Table 5]

[0107] [Table 6]

[0108] The chiral amines in Table 2 were prepared in a manner similar to that described above for amines 5 and 6. The racemic amines were subjected to chiral SFC to afford the enantiomerically pure amines (>99% ee).

[0109] [Table 7]

[0110] [Table 8]

[0111] [Table 9]

[0112] [Table 10]

[0113] [Table 11]

[0114] Intermediate 57: 2-(4-bromophenyl)-4,4-difluoropiperidine [ka] Step 1. Carried out as in Angew.Chem.Int.Ed.2016,55,9676-9, to a vigorously stirred mixture of Boc-l-homoPro(4,4-difluoro) (1.050 g, 3.96 mmol, RSP Amino Acids, LLC), 4,5,6,7-tetrachloro-2-hydroxyisoindoline-1,3-dione (1.191 g, 3.96 mmol, Aldrich) and 4-(dimethylamino)pyridine (0.048 g, 0.396 mmol, Sigma-Aldrich Corporation) in DCM (25 mL) in a 25 mL reaction vial, N,N'-diisopropylcarbodiimide (0.550 g, 0.674 mL, 4.35 mmol, Sigma-Aldrich Corporation) was added dropwise via syringe at room temperature. The resulting mixture was stirred at room temperature for 17 hours. The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography using a 40 g ISCO Gold column eluted with EtOAc / heptane (17 min 10-70%) to give 1-(tert-butyl) 2-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl) 4,4-difluoropiperidine-1,2-dicarboxylate (1.45 g, 2.65 mmol, 66.8% yield) as a white solid. 1 H NMR (chloroform-d, 400 MHz) δ 5.2-5.7 (m, 1H), 4.1-4.4 (m, 1H), 3.2-3.5 (m, 1H), 2.85 (br d, 1H, J=1.3 Hz), 2.1-2.5 (m, 2H), 1.8-2.0 (m, 1H), 1.51 (s, 9H). m / z (ESI): 569.0, 570.8 and 572.8 (M+Na). + .

[0115] Step 2. A 25 mL reaction vessel containing nickel(ii) chloride hexahydrate (50.3 mg, 0.212 mmol, Sigma-Aldrich Corporation) and 1,10-bathophenanthroline (70.3 mg, 0.212 mmol, Combi-Blocks Inc.) was evacuated and then backfilled with argon (three times) before introducing N,N-dimethylformamide (4.10 mL). The resulting mixture was stirred under argon at room temperature for 2.5 hours as a green solution. Separately, a 250 mL single-necked reaction vessel containing 1-(tert-butyl) 2-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl) 4,4-difluoropiperidine-1,2-dicarboxylate (580 mg, 1.058 mmol, from step 1) and (4-bromophenyl)boranediol (1062 mg, 5.29 mmol, Oakwood Products, Inc.) was evacuated and then backfilled with nitrogen (three times) before introducing 1,4-dioxane (41 mL). The resulting mixture was stirred under nitrogen at room temperature for 2 minutes before adding triethylamine (1071 mg, 1.487 mL, 10.58 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 5 minutes before introducing the previously prepared catalyst solution via syringe under nitrogen. The resulting mixture was immediately placed in a preheated oil bath at 90° C. and stirred for 17 h. The volume was reduced and the crude residue was loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography using a 24 g ISCO Gold column eluted with MeOH / DCM (20 min 0-5%) and monitored in the 215 nm UV channel to give 290 mg of impure tert-butyl 2-(4-bromophenyl)-4,4-difluoropiperidine-1-carboxylate as a colorless film, which was taken on to the next step without further purification. m / z (ESI): 398.0 and 400.0 (M+Na). + .

[0116] Step 3. To a stirred solution of tert-butyl 2-(4-bromophenyl)-4,4-difluoropiperidine-1-carboxylate (290 mg, 0.771 mmol, impure, from step 2) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (88 mg, 4.0 mL, 0.771 mmol, Aldrich) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The volatiles were removed in vacuo and the residue was loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography using a 12 g ISCO Gold column eluting with 20% MeOH (containing 0.5% ammonium hydroxide) / DCM (1%-20% in 12 min) to give the impure desired product 57, which was dissolved in DCM / MeOH and loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography using a 12 g ISCO Gold column eluting with (EtOH / EtOAc, 1 / 3, v / v) / heptane (0-80% in 15 min) monitored by a 215 nm UV channel to give 2-(4-bromophenyl)-4,4-difluoropiperidine (142 mg, 0.514 mmol, 49% yield for two steps) (57) as a colorless film. 1 H NMR (chloroform-d, 400 MHz) δ 7.48 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4 Hz), 3.82 (br d, 1H, J = 11.7 Hz), 3.23 (tdd, 1H, J = 2.6, 5.3, 12.1 Hz), 2.9-3.0 (m, 1H), 2.1-2.3 (m, 2H), 1.7-2.0 (m, 3H). 19 F NMR (chloroform-d, 376 MHz) δ -88.35 (d, 1F, J = 237.6 Hz), -101.82 (d, 1F, J = 237.6 Hz). m / z (ESI): 276.0 and 278.0 [M+H] + .

[0117] The racemic amines in Table 3 were prepared in a manner similar to that described above for amine 57.

[0118] [Table 12]

[0119] Intermediate 100: 4-Amino-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid. [ka] Step 1. To a 150 mL round bottom flask was added methyl 4-amino-3-bromobenzoate (4 g, 17.39 mmol, Combi-Blocks Inc.) and bis(pinacolato)diboron (8.83 g, 34.8 mmol, Frontier Scientific, Inc.) in 1,4-dioxane (58.0 mL). To the solution was then added potassium acetate (5.12 g, 52.2 mmol, Sigma-Aldrich Corporation) and the mixture was degassed by bubbling argon through for 5 minutes. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complex with dichloromethane (1.420 g, 1.739 mmol, Strem Chemicals, Inc.) was added. The reaction was then left stirring at 100°C. After 18 hours, the reaction was cooled and the solid was filtered under vacuum and washed with DCM. The mother liquor was then concentrated to give a semi-solid residue. DCM was added and the solid that formed was collected by vacuum filtration. The mother liquor was concentrated again and the 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, 54.0% yield) was isolated as a grey 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(br s,2H),3.87(s,3H),1.37(s,12H).

[0120] Step 2. To a stirred solution of 4-oxotetrahydrofuran-3-carbonitrile (0.500 g, 4.50 mmol) in dichloromethane (5.00 mL) was added DIPEA (0.943 mL, 5.40 mmol) and the reaction mixture was cooled to −78° C. Then trifluoromethanesulfonic anhydride (0.760 mL, 4.50 mmol) was added dropwise at −78° C. for 1 min and the reaction mixture was stirred at the same temperature for 15 min. After completion of the reaction, the reaction mixture was diluted with water and the organic layer was separated, washed with brine (2×10 mL), dried over sodium sulfate and concentrated to give crude 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (1.05 g, 4.32 mmol, 96% yield) which was used in the next step without further purification.

[0121] Step 3. To a stirred solution of 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (10 g, 41.1 mmol) in 1,4-dioxane (200 mL) and water (20.00 mL) was added 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) with 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. The solid that formed was then filtered, washed with ethyl acetate (50 mL) and 2% MeOH in DCM (50 mL), then dried under vacuum to give methyl 4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate (6.6 g, 27.0 mmol, 65.7% yield) as a grey solid. m / z (ESI): 245.3 [M+H] + . 1H NMR (400 MHz, TFA-d) δ ppm 8.59-8.67 (2H, m), 7.97 (1H, d, J = 9.3 Hz), 5.94 (2H, t, J = 3.5 Hz), 5.65 (2H, t, J = 3.4 Hz), 4.24 (3H, s). Note: For some heterocyclyls, Pd(dppf)Cl2 was used instead of Pd(PPh3)4.

[0122] Step 4. To a stirred solution of methyl 4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate (30 g, 123 mmol) in water (300 mL):tetrahydrofuran (300 mL):methanol (300 mL) was added LiOH (11.77 g, 491 mmol) and the reaction mixture was heated at 75° C. for 3 h. The reaction mixture was concentrated and then the aqueous layer was acidified to pH 6.0 with 1.5 N HCl. The resulting solid was filtered, washed with methanol (300 mL) and dried to give 4-amino-1,3-dihydrofuro[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).

[0123] The acids in Table 4 were prepared in a manner similar to that described for Intermediate 100.

[0124] [Table 13]

[0125] [Table 14]

[0126] [Table 15]

[0127] [Table 16]

[0128] Intermediate 132: 6-Amino-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylic acid. [ka] Step 1. A mixture of methyl 2-oxocyclopentanecarboxylate (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 min, then the dry ice bath was removed and stirred at room temperature. After 15 min, the mixture was concentrated to give methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate as a light yellow solid in quantitative yield, which was used as is. m / z(ESI): 275 [M+H] + .

[0129] Step 2. A mixture of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (1.982 g, 7.23 mmol), (2-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (1.70 g, 8.67 mmol), tribasic potassium phosphate (3.78 g, 21.69 mmol, Acros) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complex with 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 h. When the reaction reached completion, it was brought to room temperature and diluted with EtOAc. A precipitate corresponding to the desired product formed. It was filtered and washed with EtOAc to give methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,8]naphthyridine-2-carboxylate as a light grey solid in quantitative yield. m / z(ESI): 245[M+H] + . 1 H 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(br t,J=7.6Hz,2H),2.78(br t,J=7.3Hz,2H),2.08-2.18(m,2H).

[0130] Step 3. A mixture of methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,8]naphthyridine-2-carboxylate (1.76 g, 7.21 mmol) in POCl3 (24.68 g, 15 mL, 161 mmol, Aldrich) was heated at reflux for 30 min. The reaction was complete and was carefully added to cold saturated aqueous NaHCO3 to basify the reaction. After stirring for 15 min, the mixture was extracted with EtOAc and the combined organics were concentrated to give methyl 6-chloro-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylate as a yellow solid in quantitative yield. m / z (ESI): 263 [M+H] + .

[0131] Step 4. To a suspension of methyl 6-chloro-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylate (1.89 g, 7.19 mmol) in DMSO (15 mL) was added DIPEA (2.79 g, 3.77 mL, 21.58 mmol, Aldrich) followed by (2,4-dimethoxyphenyl)methanamine (1.564 g, 1.405 mL, 9.35 mmol, Aldrich). The resulting mixture was heated at 90° C. overnight. The reaction was cooled to room temperature, diluted with water, washed with saturated NH4Cl, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylate (2.18 g, 5.54 mmol, 77% yield) as a yellow solid that was used as is. m / z (ESI): 394 [M+H] + .

[0132] Step 5. To a solution of methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylate (2.18 g, 5.54 mmol) in THF / MeOH (10 / 10 mL) was added NaOH (10 mL, 10.00 mmol) and the resulting solution was heated at 70° C. for 2 h. When the reaction reached completion, it was brought to room temperature and acidified with 10 mL 1M HCl. A light yellow precipitate formed, which was filtered off and azeotropically dried with toluene to give 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopenta[c][1,8]naphthyridine-2-carboxylate hydrochloride (1.44 g, 3.46 mmol, 62.5% yield) as a yellow solid. m / z (ESI): 380.2 [M+H] + .

[0133] Intermediate 138: 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid. [ka] Step 1. A mixture of 3-furancarboxylic acid, tetrahydro-4-oxomethyl ester (3.0 g, 3.00 mL, 20.82 mmol, Ambeed, Inc.) and DIPEA (2.96 g, 4.00 mL, 22.90 mmol, Aldrich) in DCM (20 mL) was cooled to -78 °C and trifluoromethanesulfonic anhydride (20.82 mL, 20.82 mmol, Sigma-Aldrich Corporation) was added. After the addition was complete, the mixture was stirred at -78 °C for 5 min, then the dry ice bath was removed and stirred at room temperature. After 15 min, LCMS showed the desired mass. The mixture was concentrated to give methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate, which was used as is. m / z (ESI): 277 (M+H) + .

[0134] Step 2. A mixture of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (2.349 g, 8.50 mmol), (5-amino-2-(methoxycarbonyl)pyridin-4-yl)boronic acid (2.0 g, 10.21 mmol), tribasic potassium phosphate (4.44 g, 25.5 mmol, Acros) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complex with dichloromethane (0.347 g, 0.425 mmol, Strem Chemicals, Inc.) in 1,4-dioxane / water (20 / 1.20 mL) was heated at 90° C. for 1 h. It was then brought to room temperature and diluted with EtOAc. A precipitate corresponding to the desired product formed. It was filtered and washed with EtOAc. Methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate was obtained as a grey solid. m / z(ESI): 247(M+H). + Theoretical yields were considered.

[0135] Step 3. A mixture of methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate (2.0 g, 8.12 mmol) and POCl3 (32.9 g, 20 mL, 215 mmol, Aldrich) was heated at reflux for 3 h. The reaction was brought to room temperature and carefully added to cold saturated NaHCO3 to basify the reaction. After stirring for 15 min, the mixture was extracted with EtOAc and the combined organics were concentrated to give methyl 4-chloro-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate. m / z (ESI): 265 (M+H). + Theoretical yields were considered.

[0136] Step 4. To a mixture of methyl 4-chloro-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate (2.15 g, 8.12 mmol) in DMSO (20 mL) was added DIPEA (3.15 g, 4.26 mL, 24.37 mmol, Aldrich), followed by (2,4-dimethoxyphenyl)methanamine (1.630 g, 1.464 mL, 9.75 mmol, Aldrich). The resulting mixture was heated at 90° C. overnight. The reaction was brought to room temperature, diluted with water and extracted with EtOAc. The combined organics were chromatographed on silica gel using 0-30% 3:1 EtOAc:EtOH in heptane to give methyl 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate (0.500 g, 1.264 mmol, 15.57% yield) as a brown solid. m / z (ESI): 396 (M+H). + .

[0137] Step 5. To a solution of methyl 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate (0.500 g, 1.264 mmol) in THF / MeOH (10 / 10 mL) was added NaOH (5.0 mL, 5.00 mmol, EDM) and the resulting solution was heated at 70° C. for 2 h. The reaction was then brought to room temperature and acidified with 1M HCl (5 mL). The resulting mixture was concentrated and azeotropically dried with toluene to give 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate hydrochloride as a brown solid. m / z (ESI): 382 (M+H) + Theoretical yields were considered.

[0138] The acids in Table 5 were prepared in a manner similar to that described for Intermediates 132 and 138.

[0139] [Table 17]

[0140] [Table 18]

[0141] [Table 19]

[0142] Intermediate 146: 4-Amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid [ka] Step 1: To a suspension of sodium hydride (11.10 g, 278 mmol, 0.5 eq, 60% in mineral oil) in anhydrous tetrahydrofuran (250 mL) was added methyl 2-hydroxyacetate (42.4 mL, 555 mmol, 1.0 eq) at room temperature under N2 atmosphere. To the reaction mixture was added (E)-but-2-enenitrile (54.5 mL, 666 mmol, 1.0 eq) slowly at 65° C. and stirred at the same temperature for 2 h. 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 about 1 and extracted with dichloromethane (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate and hexane as eluent to give 2-methyl-4-oxotetrahydrofuran-3-carbonitrile (22 g, 176 mmol, 32% yield) as a brown solid. f :0.3 (50% ethyl acetate in hexane) m / z (ESI, negative): 124.3 [M-1]. 1 H 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).

[0143] Step 2: To a stirred solution of 2-methyl-4-oxotetrahydrofuran-3-carbonitrile (25.0 g, 200 mmol, 1.0 equiv.) in dichloromethane (500 mL), DIPEA (69.8 mL, 400 mmol, 2.0 equiv.) and trifluoromethanesulfonic anhydride (47.1 mL, 280 mmol, 1.4 equiv.) were added at −78° C. and stirred at the same temperature for 15 min. The reaction mixture was quenched by slow addition of water (250 mL) and extracted with dichloromethane (2×500 mL) after reaching room temperature. The combined organic layers were 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 give 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (35.0 g, crude) as a light brown adduct. The crude material was used in the next step without further purification. f : 0.5 (40% ethyl acetate in hexane). m / z: 257.1 [not ionized].

[0144] Step 3: To a stirred solution of 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (35 g, 136 mmol, 1.0 equiv) in 1,4-dioxane (1400 mL) and water (70.0 mL) was added methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (37.7 g, 136 mmol, 1.0 equiv) and potassium phosphate tribasic (87 g, 408 mmol, 3.0 equiv) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 15 min, then PdCl2(dppf)-DCM adduct (9.96 g, 13.61 mmol, 0.1 equiv) was added and the reaction mixture was heated at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mass was concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 50% ethyl acetate and hexane as eluent to give methyl 4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate (25 g, 97 mmol, 71% yield) as a brown solid. Product R f: 0.3 (100% ethyl acetate). m / z: 259.2 [M+H] + 1 H 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).

[0145] Step 4: To a stirred solution of methyl 4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate (26.0 g, 101 mmol, 1.0 equiv.) in tetrahydrofuran (130 mL), methanol (78 mL) and water (52 mL), lithium hydroxide (9.64 g, 403 mmol, 4.0 equiv.) was added and stirred at 75° C. for 4 h. LCMS showed the reaction was complete. 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 (pH 6-6.5) with concentrated HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give compound 146 (17.5 g, 71.6 mmol, 71% yield) as an off-white solid. Product R f : 0.1 (100% ethyl acetate). 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).

[0146] Step 5: Chiral SFC separation: 44.5 g of racemic 4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid was separated by chiral SFC to give 14 g of each isomer. Stereochemistry is arbitrarily assigned.

[0147] Separation information:

[0148] [Table 20]

[0149] The acids in Table 6 were prepared in a manner similar to that described for Intermediate 146.

[0150] [Table 21]

[0151] Intermediate 151: 4-Amino-3-((benzyloxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid [ka] Step 1: To a stirred solution of diethyl(cyanomethyl)phosphonate (130 g, 732 mmol, 1.1 equiv) in tetrahydrofuran (2000 mL) was added potassium tert-butoxide (1M in THF; 732 mL, 732 mmol, 1.1 equiv) at -78°C and stirred for 30 min. To the reaction mixture was added 2-(benzyloxy)acetaldehyde (100 g, 666 mmol, 1.0 equiv) at -78°C and the mixture was allowed to warm to room temperature over 1 h. 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 brine solution (1000 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 15% ethyl acetate and petroleum ether as eluent to give 4-(benzyloxy)but-2-enenitrile (100.6 g, 87% yield) as a colorless oil. f :0.5 (30% ethyl acetate in hexane). m / z:174.1[M+H] + . 1H NMR (chloroform-d, 400 MHz): δ (ppm) 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). Proton NMR indicated a mixture of isomers.

[0152] Step 2: To a stirred solution of potassium tert-butoxide (1M in THF; 289.0 mL, 289 mmol, 1.0 equiv) in tetrahydrofuran (260 mL) was added methyl 2-hydroxyacetate (22.03 mL, 289 mmol, 1.0 equiv) at room temperature and heated to 50° C. under nitrogen atmosphere. To this, 4-(benzyloxy)but-2-enenitrile (50.0 g, 289 mmol, 1.0 equiv) was added and stirred at the same temperature for 4 h. The reaction was monitored by TLC. The reaction temperature was increased to 70° C. and stirred for 16 h. 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 (2×200 mL) and then acidified with concentrated HCl (to a pH of about 1-2) and then extracted with DCM (2×500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 26% ethyl acetate and petroleum ether as eluent to give 2-((benzyloxy)methyl)-4-oxotetrahydrofuran-3-carbonitrile (9.2 g, 14% yield) as a colorless oil. f : 0.2 (80% ethyl acetate in hexane). LCMS (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).

[0153] Step 3: To a stirred solution of 2-((benzyloxy)methyl)-4-oxotetrahydrofuran-3-carbonitrile (5.8 g, 25.08 mmol, 1.0 equiv) in dichloromethane (116 mL) was added trifluoromethanesulfonic anhydride (6.75 mL, 40.1 mmol, 1.6 equiv) and DIPEA (8.76 mL, 50.2 mmol, 2.0 equiv) at −78° C. under N2 atmosphere and stirred for 10 min. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with brine solution (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 give 5-((benzyloxy)methyl)-4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (7.65 g) as a light brown liquid, which was carried on directly to the next step. f :0.4 (40% ethyl acetate in hexane).

[0154] Step 4: To a stirred solution of 5-((benzyloxy)methyl)-4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (7.65 g, 20.93 mmol, 1.0 equiv.) 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 equiv.), potassium carbonate (8.68 g, 62.8 mmol, 3.0 equiv.) 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 equiv.) 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 on silica gel (60-120 mesh) using 80% ethyl acetate and petroleum ether as eluent to give 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate (4.4 g, 58% yield) as an off-white solid. f: 0.2 (100% ethyl acetate in hexane). LCMS (ESI, positive / negative ion) m / z: 365.2 [M+H] + . 1 H 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(br s,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).

[0155] Ester 151 was treated with LiOH in THF (analogous to step 4 of intermediate 146) and the lithium salt of 151 was used crude in the amide coupling reaction.

[0156] Intermediate 152: 4-Aminoimidazo[1,2-a]quinoxaline-8-carboxylic acid [ka] Step 1: To a stirred suspension of methyl 3-fluoro-4-nitrobenzoate (1.07 g, 5.37 mmol, 1.00 equiv.) and 1H-imidazole-2-carbonitrile (0.500 g, 5.37 mmol, 1.0 equiv.) in dimethylsulfoxide (5.00 mL), DIPEA (2.35 mL, 13.43 mmol, 2.5 equiv.) was added at room temperature and the reaction mixture was stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to give the crude material, diluted with EtOAc and washed with water. The layers were separated and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by medium pressure chromatography (silica, 35% EtOAc in heptane) to give methyl 3-(2-cyano-1H-imidazol-1-yl)-4-nitrobenzoate (1.20 g, 4.41 mmol, 82% yield) as a light brown solid. m / z: 273.1 [M+H] + .

[0157] Step 2: To a stirred solution of methyl 3-(2-cyano-1H-imidazol-1-yl)-4-nitrobenzoate (0.900 g, 3.31 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) and water (2.00 mL), acetic acid (0.946 mL, 16.53 mmol, 5.0 equiv.) and iron powder (1.85 g, 33.1 mmol, 10.0 equiv.) were added at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was then diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was then concentrated and the residue was then recrystallized using EtOAc to give methyl 4-aminoimidazo[1,2-a]quinoxaline-8-carboxylate (350 mg, 1.45 mmol, 44% yield) as a light yellow solid. m / z: 243.1 [M+H] + .

[0158] Step 3: To a suspension of methyl 4-aminoimidazo[1,2-a]quinoxaline-8-carboxylate (0.650 g, 2.68 mmol, 1.0 equiv) in a mixture of tetrahydrofuran (12.0 mL), methanol (4.00 mL) and water (4.00 mL) was added lithium hydroxide monohydride (0.450 g, 10.7 mmol, 4.0 equiv) at 0° C. The reaction mixture was then heated to 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to the crude product, which was diluted with water and acidified to pH=6 with 1.50 N HCl solution. An off-white solid formed as a precipitate and was filtered and washed with diethyl ether to give 4-aminoimidazo[1,2-a]quinoxaline-8-carboxylic acid (480 mg, 2.10 mmol, 78% yield) as an off-white solid. m / z: 228.9 [M+H] + .

[0159] Intermediate 153: 4-Amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid [ka] Step 1: To a solution of ethyl 5-methyl-1H-pyrazole-4-carboxylate (5.00 g, 32.4 mmol, 1.0 equiv., Combi-Blocks) in acetic acid (100 mL), bromine (5.01 mL, 97.0 mmol, 3.0 equiv.) and sodium acetate (10.6 g, 130 mmol, 4.0 equiv.) were added at room temperature. The reaction mixture was then stirred and heated for 16 h. The reaction was slowly quenched with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give pure crude ethyl 3-bromo-5-methyl-1H-pyrazole-4-carboxylate (4.80 g, 20.6 mmol, 63.5% yield). m / z: 230.8, 232.9 [M+H] + .

[0160] Step 2: To a stirred solution of ethyl 3-bromo-5-methyl-1H-pyrazole-4-carboxylate (4.80 g, 20.6 mmol, 1.0 equiv) in dichloromethane (15 mL) was added DHP (2.26 mL, 24.7 mmol, 1.2 equiv) and tosylic acid (0.78 g, 4.12 mmol, 0.2 equiv) at 0° C. The resulting reaction mixture was stirred for 16 h until completion. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated to give the crude material. The crude material was purified by chromatography (silica, 40% ethyl acetate in hexanes) to give ethyl 3-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (4.80 g, 15.1 mmol, 73.5% yield) as a colorless viscous liquid. m / z: 314.9, 317.0 [M+H] + .

[0161] Step 3: To a stirred solution of methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7.34 g, 26.5 mmol, 1.2 equiv, LabNetwork) in 1,4-dioxane (112 mL) and water (28.0 mL), ethyl 3-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (7.00 g, 22.1 mmol, 1.0 equiv), potassium phosphate tribasic (9.36 g, 44.1 mmol, 2.0 equiv) was added at room temperature with nitrogen purging for 10 min. Pd(amphos)Cl2 adduct (0.781 g, 1.10 mmol, 0.05 equiv) was then added and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 7.00 grams of crude ethyl 5-(2-amino-5-(methoxycarbonyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate.

[0162] To a stirred solution of ethyl 5-(2-amino-5-(methoxycarbonyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (600 mg, 1.55 mmol, 1.0 equiv) in 1,4-dioxane (9.60 mL) and water (2.40 mL) was added DBU (2.00 mL, 13.3 mmol, 12 equiv) at room temperature under nitrogen and the reaction mixture was heated to 90° C. for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (silica, 5% MeOH in DCM) to give pure methyl 4-hydroxy-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (220 mg, 0.644 mmol, 41.6% yield). m / z: 258.0 [M-THP+H] + .

[0163] Step 4: To a stirred solution of methyl 4-hydroxy-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (600 mg, 1.76 mmol, 1.0 equiv) in dichloromethane (3.00 mL), trifluoromethanesulfonic anhydride (992 mg, 3.52 mmol, 2.0 equiv) and DIPEA (921 μL, 5.27 mmol, 3.0 equiv) were added and the reaction mixture was maintained at 30-32° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give 300 mg (31% crude yield) of crude methyl 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate.

[0164] To a stirred solution of the crude methyl 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (300 mg, 0.634 mmol, 1.0 equiv.) in N,N-dimethylacetamide (2.00 mL) was added DIPEA (332 μL, 1.90 mmol, 3.0 equiv.). (4-Methoxyphenyl)methanamine (130 mg, 0.950 mmol, 1.5 equiv.) was then added and the reaction mixture was heated at 90° C. for 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (silica, 50% EtOAc:Hexanes) to give pure methyl 4-((4-methoxybenzyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (250 mg, 0.543 mmol, 86.0% yield). m / z: 377.1 [M-THP+H] + .

[0165] Step 5: A solution of methyl 4-((4-methoxybenzyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (2.80 g, 6.08 mmol, 1.0 equiv) in trifluoroacetic acid (28.0 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude methyl 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (3.50 g, 13.7 mmol, 225% crude yield). m / z: 257.3 [M+H] + .

[0166] Step 6: To a stirred solution of methyl 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (3.50 g, 13.7 mmol, 1.0 equiv.) in tetrahydrofuran (35.0 mL), methanol (35.0 mL), water (35.0 mL) at room temperature, lithium hydroxide monohydrate (4.02 g, 96.0 mmol, 7.0 equiv.) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and precipitation of a solid was observed. The solid was filtered and dried under vacuum. The solid was washed with diethyl ether and dried to give 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (1.40 g, 5.78 mmol, 42.3% yield). m / z: 243.1 [M+H] + .

[0167] Intermediate 154: Lithium 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate hydroxide [ka] Step 1. K3PO4·H2O (1.08 g, 4.70 mmol, Sigma-Aldrich Corporation), X-Phos (0.08 g, 0.16 mmol, Sigma-Aldrich Corporation), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) methanesulfonate (0.14 mg, 0.16 mmol, Sigma-Aldrich Corporation), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole-4-carbonitrile (1.10 g, 4.70 mmol, Enamine) and methyl 4-amino-5-bromo-2-(trifluoromethyl)benzoate (0.700 g, 2.349 mmol, Combi Blocks) was suspended in a degassed mixture of water (1.0 mL) and 1,4-dioxane (5.0 mL) and stirred at 60 °C overnight and then at 90 °C for 18 h. Volatiles were removed in vacuo and the crude product was purified by silica column chromatography (0-5% MeOH / DCM + 0.5% NH3 / MeOH) to give methyl 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (0.63 g, 1.94 mmol, 83% yield) 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.

[0168] 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), HO (3.0 mL) and THF (3.0 mL) and stirred at 50° C. for 2 h. The crude mixture was removed of volatiles in vacuo and the slightly brownish solid was coevaporated twice with DCM followed by coevaporation with toluene to give lithium 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate hydroxide (585 mg, 1.720 mmol, 91% yield), which was used in the subsequent step 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(br s,2H),4.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ ppm -57.47.

[0169] Example 300: Preparation of (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(pyrimidin-2-yl)morpholino)methanone [ka] To a 50 mL round bottom flask was added 3-(pyrimidin-2-yl)morpholine (35, 0.20 g, 1.21 mmol) and 4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid (100, 0.33 g, 1.45 mmol) in N,N-dimethylacetamide (6.0 mL). Bromotripyrrolidinophosphonium hexafluorophosphate (0.56 g, 1.21 mmol, Sigma-Aldrich Corporation) and triethylamine (0.61 g, 0.9 mL, 6.05 mmol, Sigma-Aldrich Corporation) were then added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an Interchim (15 micron) silica gel column (40 grams) eluting with a gradient of 0-35% MeOH in DCM. The product was collected and then purified by reverse phase HPLC: purification was performed on an XBridge column (19 × 100 mm, 5 μm) with 0.1% NH4OH (A) and ACN (B) in HO as the mobile phase, which gave (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(pyrimidin-2-yl)morpholino)methanone (0.120 g, 0.318 mmol, 26% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.88(br d,J=4.6Hz,2H),7.61(br s,2H),7.46(t,J=4.8Hz,2H),6.68(br s,2H),5.51-5.69(m,1H),5.37(br s,2H),5.00(br s,3H),4.63(br s,1H),4.18-4.37(m,1H),3.87-3.97(m,1H),3.66-3.79(m,1H),3.54-3.62(m,1H).m / z(ESI):378.1[M+H] + .

[0170] The examples in Table 7 were prepared in a manner similar to that described above for Example 300 above, using the amide coupling reagents indicated in the table.

[0171]

Table 22

[0172]

Table 23

[0173]

Table 24

[0174]

Table 25

[0175]

Table 26

[0176]

Table 27

[0177]

Table 28

[0178]

Table 29

[0179]

Table 30

[0180]

Table 31

[0181]

Table 32

[0182]

Table 33

[0183]

Table 34

[0184]

Table 35

[0185]

Table 36

[0186]

Table 37

[0187]

Table 38

[0188]

Table 39

[0189]

Table 40

[0190]

Table 41

[0191]

Table 42

[0192]

Table 43

[0193]

Table 44

[0194]

Table 45

[0195]

Table 46

[0196]

Table 47

[0197]

Table 48

[0198]

Table 49

[0199]

Table 50

[0200]

Table 51

[0201]

Table 52

[0202]

Table 53

[0203]

Table 54

[0204]

Table 55

[0205]

Table 56

[0206]

Table 57

[0207]

Table 58

[0208]

Table 59

[0209]

Table 60

[0210]

Table 61

[0211]

Table 62

[0212]

Table 63

[0213]

Table 64

[0214]

Table 65

[0215]

Table 66

[0216]

Table 67

[0217]

Table 68

[0218]

Table 69

[0219]

Table 70

[0220]

Table 71

[0221] Examples 452 and 453: ((R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((S)-3-(4-(trifluoromethyl)phenyl)morpholino)methanone and ((S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((S)-3-(4-(trifluoromethyl)phenyl)morpholino)methanone [ka] A mixture of (S)-3-(4-(trifluoromethyl)phenyl)morpholine (0.079 g, 0.342 mmol, PharmaBlock Science), 4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrochloride (0.125 g, 0.444 mmol, acid 149), HATU (0.169 g, 0.444 mmol, Combi-Blocks), DMF (2 mL) and DIPEA (0.221 g, 0.298 mL, 1.708 mmol, Aldrich) was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and aqueous Na2CO3. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-100% EtOAc / EtOH (3 / 1) in heptane. The racemic product was obtained as an off-white solid (0.108 g, 69%). m / z (ESI): 459 [M+H] + .

[0222] 100 mg of the racemic product was purified by preparative SFC using a Chiral Technologies OJ column (250 x 21 mm, 5 mm) with a mobile phase of 75% liquid CO2 and 25% MeOH with 0.2% TEA using a flow rate of 80 mL / min to produce 39.7 mg of peak 1 with >99% ee and 40.5 mg of peak 2 with 99.8% ee. Peak assignments were determined by SFC on the OJ column with 25% MeOH with 0.2% TEA. Stereochemistry is arbitrarily assigned.

[0223] Peak 1:1 H NMR(500MHz,DMSO-d6)δ ppm 8.73-8.92(m,1H),7.84(s,1H),7.59-7.81(m,4H),6.98(br s,2H),5.57-5.79(m,1H),5.42-5.50(m,1H),5.35-5.40(m,1H),5.22-5.34(m,1H),4.38-4.58(m,1H),3.69-3.94(m,3H),3.57(br s,1H),3.17(d,J=5.0Hz,1H),1.33-1.48(m,3H).

[0224] Peak 2: 1 H NMR(500MHz,DMSO-d6)δ ppm 8.71-8.97(m,1H),7.82-7.86(m,1H),7.59-7.82(m,4H),6.98(br s,2H),5.63-5.80(m,1H),5.46(br s,1H),5.25-5.41(m,2H),4.23-4.59(m,1H),3.71-3.99(m,3H),3.56(br s,1H),3.17(d,J=5.0Hz,1H),1.41(br d,J=6.2Hz,3H).

[0225] The examples in Table 8 were prepared in a manner similar to that described above for Examples 452 and 453, using the amide coupling reagents and purification conditions indicated in the table.

[0226] [Table 72]

[0227] [Table 73]

[0228] [Table 74]

[0229] [Table 75]

[0230] [Table 76]

[0231] [Table 77]

[0232] [Table 78]

[0233] [Table 79]

[0234] [Table 80]

[0235] [Table 81]

[0236] Examples 481 and 482: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone [ka] Step 1: To a solution of 3-(4-(trifluoromethyl)phenyl)morpholine (0.100 g, 0.432 mmol, Enamine), 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrochloride (138) (0.271 g, 0.649 mmol) and 1,1′-dimethyltriethylamine (0.559 g, 0.755 mL, 4.32 mmol, Sigma-Aldrich Corporation) in DMF (4 mL) was added bromotripyrrolidinophosphonium hexafluorophosphate (0.202 g, 0.432 mmol, Sigma-Aldrich Corporation) and the resulting mixture was heated at 50° C. for 30 min. The reaction was brought to room temperature, diluted with water, saturated NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was then chromatographed on silica gel using 0-50% 3:1 EtOAc:EtOH in heptane to give (4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2% yield) as a light yellow solid. m / z (ESI): 595 (M+H). + .

[0237] To a solution of (4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2% yield) in DCM (2 mL) was added TFA (14.80 g, 10 mL, 130 mmol, Aldrich) and the resulting mixture was heated at 50° C. for 1 h. The reaction was concentrated, washed with 10% Na2CO3, and extracted with DCM. The combined organics were concentrated and chromatographed on silica gel using 0-50% 3:1 EtOAc:EtOH in heptane to give (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone as the TFA salt (0.078 g, 0.140 mmol, 32.3% yield) as an off-white solid. m / z (ESI): 445 (M+H). + .

[0238] Step 2: (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone and (R)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (4-Amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 2,2,2-trifluoroacetate was obtained from Chiral Technologies Separation was performed by preparative SFC using an AD column (150×21 mm, 5 mm) with a mobile phase of 60% liquid CO 2 and 40% MeOH containing 0.2% TEA using a flow rate of 80 mL / min to produce peak 1, (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of >99% and peak 2, (R)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of 99.28%. Peak assignments were determined by SFC using an AD column with 60% liquid CO 2 and 40% MeOH containing 0.2% TEA and the absolute stereochemistry was arbitrarily assigned.

[0239] Peak 1: (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (481) as a white solid. m / z (ESI): 445 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.67-9.03(m,1H),7.85(s,1H),7.77(br s,4H),7.07(br s,2H),5.75(s,1H),5.37(br s,2H),5.04(br s,2H),4.46-4.61(m,1H),3.89(br dd,J=12.2,3.3Hz,4H),3.58(br d,J=5.8Hz,1H). 19 F NMR(377MHz,DMSO-d6)δ ppm -60.90(br s,3 F).

[0240] Peak 2: (R)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (482) as a white solid. m / z (ESI): 445 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.88(br s,1H),7.85(s,1H),7.77(br d,J=1.7Hz,4H),7.07(br s,2H),5.69-5.78(m,1H),5.37(br s,2H),5.04(br s,2H),4.45-4.61(m,1H),3.89(br dd,J=12.4,3.3Hz,4H),3.51-3.64(m,1H). 19 F NMR(DMSO-d6,377MHz)δ -60.90(s,3 F).

[0241] Example 483: rac-(4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone [ka] Example 483 was prepared in a similar manner to compound 481-rac above. m / z(ESI): 445.1[M+H] + .

[0242] Example 484: (5-amino-2,4-dihydro-1H-pyrano[3,4-c]quinolin-9-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone [ka] Example 484 was prepared in a manner similar to compound 481-rac above using commercially available enantiopure (3S)-3-[4-(trifluoromethoxy)phenyl]morpholine hydrochloride (NetChem, CAS number 1391448-60-4). m / z (ESI): 474.0 [M+H] + .

[0243] The following examples were prepared in a manner similar to that described for Examples 481 and 482.

[0244] [Table 82]

[0245] [Table 83]

[0246] Example 491: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholino)methanone [ka] Step 1. To a stirred suspension of 4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid (500 mg, 2.163 mmol) in CHCl (10.0 mL) was added 4M HCl in 1,4-dioxane (1.62 mL, 6.49 mmol) and the resulting suspension was left stirring at room temperature for 30 min. The mixture was concentrated under reduced pressure and then coevaporated with toluene (2×5 mL). The resulting crude material was resuspended in dichloromethane (20.0 mL), cooled to 0° C. and treated with oxalyl chloride (2.0 M in CHCl, 4.33 mL, 8.65 mmol) followed by DMF (5 drops). The reaction vessel was flushed with nitrogen and the reaction mixture was left stirring at room temperature under nitrogen overnight. After 16 h, the reaction mixture was concentrated under reduced pressure and the crude residue was rinsed with heptane (30 mL) and dried in vacuo to give 4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl chloride hydrochloride (463 mg, 1.62 mmol, 75% yield) as a tan solid; after quenching an aliquot with MeOH, m / z (ESI): 246.1 [M+H] + was observed for the corresponding methyl ester.

[0247] Step 2. A vial was charged with (3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (35.9 mg, 0.172 mmol), 4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl chloride hydrochloride (63.8 mg, 0.223 mmol) and dichloromethane (3.43 mL). To the resulting suspension was added N,N-diisopropylethylamine (111 mg, 150 μL, 0.858 mmol) and the resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and transferred to a separatory funnel with brine (10 mL) and CHCl2 (20 mL) and extracted with CHCl2 (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The resulting crude residue was purified by flash chromatography (0-100% 3:1 EtOAc:EtOH in heptane) to afford (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholino)methanone (59.8 mg, 0.142 mmol, 83% yield) as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 9.03(br s,1H),7.94(br s,1H),7.72(br d,J=7.1Hz,1H),6.99(d,J=9.2Hz,1H),5.97(d,J=3.8Hz,1H),5.50(t,J=3.7Hz,2H),5.29-5.44(m,1H),5.15-5.23(m ,2H),4.97(s,2H),4.37-4.65(m,1H),4.17(s,3H),3.68-3.99(m,3H),1.05(d,J=7.1Hz,3H);m / z(ESI):423.25[M+H] + .

[0248] The following examples were prepared in a manner similar to that described for Example 491.

[0249] [Table 84]

[0250]

Table 85

[0251]

Table 86

[0252]

Table 87

[0253]

Table 88

[0254]

Table 89

[0255]

Table 90

[0256]

Table 91

[0257]

Table 92

[0258]

Table 93

[0259]

Table 94

[0260] [Table 95]

[0261] [Table 96]

[0262] [Table 97]

[0263] [Table 98]

[0264] [Table 99]

[0265] [Table 100]

[0266] Examples 566 and 567: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methanone and (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methanone. [ka] A mixture of 4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl chloride hydrochloride (71 mg, 0.25 mmol, from Example 491, Step 1), triethylamine (97 mg, 130 μL, 0.96 mmol, Aldrich) and racemic cis-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholine (55 mg, 0.19 mmol, prepared by following the procedure described in Bode, JW; et. al.; Org. Lett.; 2014, pp. 1236-1239) in THF (1.9 mL) was stirred for 4.5 h. The reaction was then concentrated and the residue was dissolved in DMSO and purified by reverse phase preparative HPLC (C18, 10-100% MeCN:water (+0.1% TFA) to give racemic (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methanone (2,2,2-trifluoroacetate salt (80 mg, 0.055 mmol, 49% yield). This racemic mixture was then submitted for chiral separation. The sample was purified by SFC using a column Chiralpak IC (250 x 21 mm, 5 μm) with a modifier of 25% MeOH+TEA using a flow rate of 100 mL / min. The submitted sample was 70 mg and diluted with 10 mL MeOH:DCM From the dissolved sample, 16.7 mg of peak 1 with >99% ee (>99% chemical purity) and 20.6 mg of peak 2 with >99% ee (>99% chemical purity) were isolated and then optionally purified as cis-enantiomer (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl) ((3S,5R)-3-isobutyl-5-(4-(trifluoromethyl) ... The results were assigned to (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methanone 2 (peak 1, chiral column) (17 mg, 0.033 mmol, 17% yield) and (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methanone 3 (peak 2, chiral column) (21 mg, 0.041 mmol, 22% yield). 1H NMR (400MHz, methanol-d4) δ ppm 9.14(s,1H),8.10(br s,1H),7.88-8.00(m,2H),7.62-7.76(m,2H),5.76-5.99(m,1H),5.47-5.63(m,2H),5.24(t,J=3 .9Hz,2H),4.62-4.88(m,1H),3.82-4.08(m,4H),1.13-1.35(m,2H),1.00-1.08(m,1H),0.25(br d,J=1.5Hz,6H).m / z(ESI):501.0[M+H] + .

[0267] The examples in Table 11 were prepared in a manner similar to that described for Examples 566 and 567.

[0268] [Table 101]

[0269] [Table 102]

[0270] [Table 103]

[0271] [Table 104]

[0272] [Table 105]

[0273] [Table 106]

[0274] [Table 107]

[0275] [Table 108]

[0276] [Table 109]

[0277] [Table 110]

[0278] [Table 111]

[0279] [Table 112]

[0280] Example 623: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)thiomorpholino)methanone. [ka] To a solution of (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)thiomorpholino)methanone (30 mg, 0.065 mmol) in 1.5 mL of DCM at room temperature was added 3-chloroperbenzoic acid (36.5 mg, 0.163 mmol, Sigma-Aldrich Corporation). The mixture was stirred at room temperature for 2 h (LCMS showed a mixture of sulfone and sulfoxide formed) and then partitioned between 2.5 mL of 0.5 N NaOH and 25 mL of DCM. The organic phase was separated and concentrated. The residue was purified by RP-HPLC (10-90% CH3CN with 0.1% TFA in water) to give (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)thiomorpholino)methanone 2,2,2-trifluoroacetate (2 mg, 3.39 μmol, 5.2% yield) as an off-white solid. m / z(ESI): 476.9[M+H] + . 19 F NMR (methanol-d4, 376 MHz) δ -64.16 (s, 3F), -77.26 (s, 3F). 1 H NMR (methanol-d4,400MHz)δ 9.04(s,1H),8.11(s,1H),7.78(m,4H),6.34(m,1H),5.56(m,2H),5.23( t,J=3.9Hz,2H),4.05(dd,J=5.4,13.2Hz,1H),3.45(m,3H),3.13(m,2H).

[0281] Example 624: (S)-1-(4-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-3-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one. [ka] To a solution of (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(2-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methanone (50 mg, 0.113 mmol) in 1.5 mL of DCM at 0° C. was added acetic anhydride (13.81 mg, 0.135 mmol, Sigma-Aldrich Corporation), followed by triethylamine (31.7 μL, 0.226 mmol, Sigma-Aldrich Corporation). The mixture was stirred at 0° C. for 20 min, followed by stirring at room temperature for 10 min, then partitioned between 1 mL of 0.5 N NaOH and 10 mL of DCM. The organic phase was washed with 1 mL of brine, concentrated and the residue was purified by RP-HPLC (10-90% CH3CN in water with 0.1% TFA) to give (S)-1-(4-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-3-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one bis(2,2,2-trifluoroacetate) (55 mg, 0.077 mmol, 68.4% yield) as a brown solid. m / z (ESI): 486.1 [M+H] + . 19 F NMR(DMSO-d6,376MHz)δ -60.88(s,3F),-74.63(s,6F). 1 H-NMR showed a mixture of rotamers (1 / 3 ratio). 1 H NMR(DMSO-d6,400MHz)δ 9.00(br s,0.75H),8.86(br s,0.25H),7.97(m,2H),7.78(m,3H),7.63(m,2H),5.86(br s,0.75H),5.64(br s,0.25H),5.42(br s,1.5H),5.37(br s,0.5H),5.09(br s,2H),3.8-4.0(m,6H),2.8-3.0(m,2H),1.96(br s,3H).

[0282] Example 625: (S)-(4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanethione [ka] A mixture of Lawesson's reagent (63.8 mg, 0.158 mmol, Aldrich) and (S)-(4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (70 mg, 0.158 mmol) in 1 mL of THF in a sealed glass tube was heated in a microwave at 95 °C for 6 h. RP-HPLC purification of the crude mixture (10-90% CH3CN in water with 0.1% TFA) afforded (S)-(4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanethione 2,2,2-trifluoroacetate (69.7 mg, 0.122 mmol, 77% yield) as a yellow solid. m / z(ESI):460.3[M+H] + . 19 F NMR (methanol-d4, 376 MHz) δ -64.14 (s, 3F), -77.05 (s, 3F). 1 H NMR (400MHz, methanol-d4) δ ppm 7.91(m,1H),7.69-7.83(m,3H),7.64(m,1H),7.51(br s,1H),7.05(br s,1H),5.52(br s,2H),5.20(br s,2H),4.90-5.06(m,2H),4.73(m,1H),4.11(m,1H),3.89(m,1H),3.81(m,1H),3.71(m,1H).

[0283] Example 626: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanethione [ka] Example 626 was prepared in the same manner as Example 625. m / z(ESI): 461.10 [M+H] + .

[0284] HCT116 proliferation activity To evaluate the selective anti-proliferative activity of the compounds of the present invention in cells with loss of expression of MTAP, we utilized a pair of HCT-116 isogenic cell lines, one of which was engineered to genetically knock out both MTAP alleles. Cell viability was then evaluated in both the parental HCT-116 cell line and the MTAP null cell line after 6 days of treatment with the compounds of the present invention. The selective anti-proliferative activity in the MTAP null cell line indicates the MTA cooperative inhibition of PRMT5 and the ability to inhibit the growth of cancer cells with loss of MTAP.

[0285] HCT116 MTAP null and WT cells were seeded in 96-well tissue culture plates in RPMI 1640 medium + 10% fetal bovine serum. Plates were incubated overnight at 37°C and 5% CO2. Cells were then treated with 8- or 9-point serial dilutions of compounds using a top concentration of 1 or 10 μM, 1:3 serial dilution steps, and DMSO-only control. Cells were incubated in the presence of drugs for 6 days. Effects on cell viability were measured by CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer's recommendations. Assay plates were read on an EnVision™ Multilabel Reader using the Ultra-Sensitive luminescence module. IC 50 Values ​​were calculated by GraphPad Prism v 5.01 using a symmetric sigmoidal dose-response least squares fit with the Hill slope fixed at -1 and the top constrain fixed at 100%, or by GeneData Screener using a four-parameter logistic model to fit the dose-response curves.

[0286] Alternatively, compounds could be assayed in a 384-well plate format. Compounds were pre-spotted into 384-well plates with a top concentration of 10 or 50 μM, 22-point serial dilutions of compound using 1:2 serial dilution steps, and a DMSO-only control. HCT116 MTAP null and WT cells were then seeded as above, and after 6 days the effect on cell viability was measured by CellTiter-Glo® Luminescent Cell Viability Assay (Promega). Assay plates were read as above, and IC 50 Values ​​were calculated by GeneData Screener using a four-parameter logistic model to fit dose-response curves. Reported IC 50 represents the value at which the curve passes through 50% of the control.

[0287] [Table 113]

[0288] [Table 114]

[0289] [Table 115]

[0290] [Table 116]

[0291] [Table 117]

[0292] [Table 118]

[0293] All publications and patent applications cited in this specification are incorporated herein by reference in their entirety for all purposes as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference and as if each reference was set forth in its entirety. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of the invention, certain changes and modifications thereto can be made without departing from the spirit or scope of the appended claims.

Claims

1. Formula I 【Chemistry 1】 (In the formula, R １ , R ２ and the nitrogen atom to which they are attached form a 5-, 6- or 7-membered ring which may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms, the same or different, selected from O, N or S, said S atoms being optionally substituted with 1 or 2 oxo groups; R １ , R ２ and the ring formed by the nitrogen atom to which they are attached may be 0, 1, 2 or 3 R ３ may be replaced with; R ３ In each case, C １～６ Alkyl, halo, C １～６ Haloalkyl, -OC １～６ Alkyl, -OC １～６ Haloalkyl, —C(O)C １～６ Alkyl, -C(O)C １～６ Haloalkyl, -C(O)OC １～６ Alkyl, -C(O)OC １～６ haloalkyl and 5- or 6-membered rings which may be saturated, partially saturated or aromatic and contain 0, 1 or 2 heteroatoms, which may be the same or different, selected from O, N and S, said rings being selected from one or more R ａ may be optionally substituted with R ａ In each case, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, pentafluorosulfanyl, -OC １～３ Alkyl and -OC １～３ haloalkyl; R is represented by formulas IA and IB: 【Chemistry 2】 is a tricyclic ring selected from 【Chemistry 3】 is a single bond or a double bond, X 1 and X 2 are each selected from N and C, and X 1 and X 2 cannot both be N at the same time, and further, when X 1 is C, it may be optionally substituted with C 1-3 alkyl or halo; X 6 , X 7 and X 8 , at each occurrence, are independently selected from optionally substituted N and optionally substituted C; the substituents on N and C are independently selected from １～３ alkyl; X ６ and X ７ , and X ７ and X ８ cannot both be N at the same time; X 3 , X 4 and X 5 , at each occurrence, are selected from O, S, optionally substituted C and optionally substituted N, said substituents on N and C being independently selected from C １～３ Alkyl and C １～３ alkyl(OH), wherein alkyl may be optionally substituted with halo. or a tautomer, a stereoisomer, or a pharma- ceutically acceptable salt of any of the foregoing.

2. R is a group of formula IA 【Chemistry 4】 or a tautomer, a stereoisomer, or a pharma- ceutically acceptable salt of any of the foregoing.

3. R is 【Chemistry 5】 3. The compound of claim 1 or 2, wherein:

4. The compound of claim 1, wherein X1 is C, C substituted with halo, or N, or a tautomer, a stereoisomer, or a pharma- ceutically acceptable salt of any of the foregoing.

5. The compound according to claim 1, wherein X 1 is N.

6. R is 【Chemistry 6】 The compound according to any one of claims 1 to 5,

7. R is of formula IB 【Chemistry 7】 or a tautomer, a stereoisomer, or a pharma- ceutically acceptable salt of any of the foregoing.

8. 8. The compound of claim 7, wherein X1 is N, X7 is N, or both X1 and X7 are N, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

9. R １ , R ２ and the nitrogen atom to which they are attached form a 6-membered ring which may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms selected from O, N or S, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

10. The six-membered ring is 【Chemistry 8】 10. The compound of claim 9, wherein:

11. R ３ In each case, C １～６ 11. The compound according to any one of claims 1 to 10, wherein each of the rings is independently selected from alkyl, halo and a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms which may be saturated, partially saturated or aromatic and selected from O, N and S, a tautomer thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt of any of the foregoing.

12. R ３ is one or more R ａ 12. The compound of claim 11, wherein R is phenyl, pyridinyl, pyridazinyl or pyrimidinyl, optionally substituted with R, ...

13. The six-membered ring is 【Chemistry 9】 13. The compound of claim 12, wherein

14. R ａ In each case, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, -OC １～３ Alkyl and -OC １～３ 14. The compound of any one of claims 1 to 13, wherein the compound is selected from haloalkyl, a tautomer, a stereoisomer, or a pharma- ceutically acceptable salt of any of the foregoing.

15. The compound of claim 14, wherein R a , at each occurrence, is C 1-6 haloalkyl or —OC 1-3 haloalkyl.

16. The six-membered ring is 【Chemistry 10】 16. The compound of claim 15,

17. The group consisting of: (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2R,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2S,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((2S,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,6aR)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,6aS)-3-phenylhexahydrocyclopenta[b]pyrrol-1(2H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrol-1(4H)-yl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl)methanone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, ((3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((1R,3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((1S,3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4,5-dichloro-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazepan-4-yl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazepan-4-yl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanethione, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(6-(2-propanyloxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3R,5S)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S,5R)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[rac-(3S)-3-(6-cyclopropyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[rac-(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c][1,8]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanethione, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(3-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(4-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidyl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(2-chlorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(3-bromophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(3-fluorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(4-bromophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(4-fluorophenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(4-methoxyphenyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(6-bromopyridazin-3-yl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(o-tolyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-(p-tolyl)morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-phenylmorpholin-4-yl]methanone, (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[rac-(3S)-3-pyrimidin-2-ylmorpholin-4-yl]methanone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-2,3-dihydrofuro[3,2-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3,3-dimethyl-1H-furo[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, (4-amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-3,3-dimethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((1S,5R)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-fluorophenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((4S)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azetidinyl)methanone, (4-amino-7-fluoro-2,3-dihydrofuro[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone, (4-aminoimidazo[1,2-a]quinoxalin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidyl]methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (4-aminothieno[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone, (5-amino-1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (5-aminobenzo[c][2,6]naphthyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (5-aminopyrido[4,3-c][1,7]naphthyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (5-aminopyrimido[4,5-c][1,7]naphthyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (5-aminopyrimido[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone, (6-amino-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridin-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone, (6-amino-8,9-dihydro-7H-cyclopenta[c][1,7]naphthyridin-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl)methanone, (R)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)morpholino)methanone, (R)-(4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)morpholino)methanone, (S)-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(3-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)morpholi)methanone, [(3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, [(3S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone, 1-((3S)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl)-1-piperazinyl)ethanone, 4-((3R)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-3-morpholinyl)benzonitrile, 4-((3R,5S)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-5-methyl-3-morpholinyl)benzonitrile, 4-((3S)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-3-morpholinyl)benzonitrile, 4-((3S,5R)-4-((4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)carbonyl)-5-methyl-3-morpholinyl)benzonitrile, 4-chloro-6-[rac-(3S)-4-(4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)morpholin-3-yl]pyridine-3-carbonitrile, 6-[(3R)-4-(4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)morpholin-3-yl]pyridine-3-carbonitrile, 6-[(3S)-4-(4-amino-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)morpholin-3-yl]pyridine-3-carbonitrile, methyl (3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, methyl (3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, tert-butyl (3R)-4-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, and tert-Butyl (3S)-4-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate A compound selected from: a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

18. (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl)methanone; ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl)methanone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl) ((3S)-3-(4-(pentafluoro-lambda ６ -sulfanyl)phenyl)-4-morpholinyl)methanone; (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone; (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone; (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methanone; (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methanone; ((3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone; [(3R)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone; (4-amino-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methanone; (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl)methanone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methanone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl)methanone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methanone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methanone; and (4-Amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone 18. The compound of claim 17 selected from: a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

19. The compound according to claim 1, wherein the compound is (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone: 【Chemistry 11】 20. The compound of claim 18, wherein: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone. 【Chemistry 12】 The free base. (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone. 【Chemistry 13】 A pharma- ceutically acceptable salt of 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, a tautomer thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least one pharma- ceutically acceptable excipient.

23. 23. A pharmaceutical composition according to claim 22 for use as a medicament.

24. A pharmaceutical composition as described in claim 22 or 23 for use in a method for treating cancer in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition.

25. 24. Use of a compound according to any one of claims 1 to 21, a tautomer thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 22 or 23, in the manufacture of a medicament.

26. 25. The pharmaceutical composition of claim 24, wherein the cancer is selected from ovarian cancer, lung cancer, HNSCC, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, pancreatic cancer or bladder cancer.

27. ​​The pharmaceutical composition described in claim 25, wherein the cancer is lung cancer.

28. The pharmaceutical composition described in claim 25, wherein the cancer is pancreatic cancer.

29. The group consisting of: 【Chemistry 14】 an intermediate selected from: (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone. 【Chemistry 15】 30. A process for the synthesis of an intermediate of claim 29, its tautomer, or a pharma- ceutically acceptable salt thereof, comprising reacting an intermediate of claim 29, its tautomer, or a pharma- ceutically acceptable salt thereof, 【Chemistry 16】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

31. The method of claim 30, comprising: 【Chemistry 17】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 18】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

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