Prmt5 inhibitors

Abstract

Described herein are novel PRMT5 inhibitors of Formula I and pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof. The compounds of the invention are useful for inhibiting PRMT5 activity and can be used in the treatment of proliferative disorders, metabolic disorders, and blood disorders. The compounds of Formula I have the following structure:

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 126,416, filed December 16, 2020, which is incorporated herein by reference in its entirety. Background Technology

[0003] Epigenetic regulation of gene expression is an important biological determinant of protein production and cell differentiation, and plays a significant pathogenic role in many human diseases.

[0004] Epigenetic regulation involves heritable modifications of genetic material without altering its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones), which control conformational transitions between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that can lead to human diseases. PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.

[0005] Homozygous loss of tumor suppressor genes is a key driver in cancer, often leading to the incidental loss of passenger genes located in the genome adjacent to the tumor suppressor. The loss of these passenger genes can create therapeutically vulnerable vulnerabilities specific to tumor cells. Homozygous loss of the chromosome 9p21 locus (carrying the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A)) occurs in 15% of all tumors and typically includes the passenger gene MTAP (methylthioadenosine phosphorylase, a key enzyme in the methionine and adenine rescue pathway). MTAP loss leads to the accumulation of its substrate, methylthioadenosine (MTA). MTA shares close structural similarity with S-adenosylmethionine (SAM) (the methyl donor substrate of the type II methyltransferase PRMT5). Elevated MTA levels driven by MTAP loss selectively compete with SAM for binding to PRMT5, leaving the methyltransferase in a suballelic state, vulnerable to further PRMT5 inhibition. Multiple genome-wide drop-outscreening in large tumor cell lines has identified a strong correlation between MTAP loss and cell line dependence on PRMT5, further highlighting the intensity of this metabolic deficit. However, PRMT5 is a known cellular essential gene, and conditional PRMT5 knockout and siRNA knockdown studies have shown that significant burdens (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy) may be associated with PRMT5 inhibition in normal tissues. Therefore, novel strategies are needed to exploit this metabolic deficit and preferentially target PRMT5 in MTAP-nullifying tumors without impairing PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with MTA-cooperative small molecule inhibitors can preferentially target the MTA-binding state of PRMT5 enriched in MTAP-nullifying tumor cells, while providing an improved therapeutic index beyond that of normal cells (where MTAP is intact and MTA levels are low). Summary of the Invention

[0006] In one aspect, the present invention provides compounds having formula I.

[0007]

[0008] Its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing:

[0009] Where R 1 R 2They form five-, six-, or seven-membered rings with the nitrogen atoms to which they are attached. These five-, six-, or seven-membered rings may be saturated or partially saturated and contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, either the same or different, wherein the S atom is optionally substituted with one or two oxo groups.

[0010] Among them, R 1 R 2 The rings formed by the nitrogen atoms to which they are attached can have 0, 1, 2, or 3 R atoms. 3 replace;

[0011] Where R 3 In each case, select C. 1-6 Alkyl, Halogenated, C 1-6 Halogenated alkyl groups, -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 The alkyl halide and a five- or six-membered ring, which may be saturated, partially saturated, or aromatic, and contains 0, 1, or 2 identical or different heteroatoms selected from O, N, and S, wherein the ring may optionally be separated by one or more R atoms. a replace,

[0012] Where R a In each case, it is selected from halogen, CN, C. 1-6 Alkyl, C 1-6 Halogenated alkyl, pentafluorosulfonyl, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups;

[0013] Where R is a three-ring selected from formulas IA and IB:

[0014]

[0015] in Is it a single or double bond?

[0016] X 1 X 2 X 6 X 7 and X 8 In each case, the N and C are selected from optionally substituted N and C, wherein the substituent is selected from C. 1-3 alkyl;

[0017] Where X 1 and X 2 Both cannot be N at the same time, and X6 and X 7 and X 7 and X 8 Cannot be N at the same time;

[0018] Furthermore, where X 1 It is C, which can be optionally halogenated;

[0019] X 3 X 4 and X 5 In each case, the substituents are selected from optionally substituted C, O, N, and S, wherein these substituents are selected from C. 1-3 Alkyl and C 1-3 Alkyl (OH), wherein the alkyl group may optionally be halogenated.

[0020] In one embodiment, the invention provides a compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is a tricyclic compound having formula IA.

[0021]

[0022] In one embodiment, R can be

[0023]

[0024] In another embodiment, R can be

[0025]

[0026] The present invention further provides a pharmaceutically acceptable salt of a compound, its tautomer, its stereoisomer, or any of the foregoing, wherein X 1 It is C. In one embodiment, X 1 It can be replaced by halogenation.

[0027] On the one hand, X 1 It can be N.

[0028] This invention discloses a compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is a tricyclic compound having the formula IB.

[0029]

[0030] In one embodiment, X 1 It can be N. In another embodiment, X 7 It can be N.

[0031] This invention provides a pharmaceutically acceptable salt of a compound, its tautomer, its stereoisomer, or any of the foregoing, wherein R 1 R 2 They form a six-membered ring with the nitrogen atoms to which they are attached. The six-membered ring may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms selected from O, N or S.

[0032] In one embodiment, the six-membered ring can be

[0033]

[0034] In another embodiment, the six-membered ring is

[0035]

[0036] On the one hand, R 3 It can be phenyl, pyridyl, pyridazinyl, or pyrimidinyl, optionally with one or more R a replace.

[0037] In one embodiment, R 3 It can be a phenyl group, which is optionally R a Replacement. In yet another embodiment, R a It can be C 1-6 Halogenated alkyl group. In another embodiment, R a It can be pentafluorosulfonyl.

[0038] In another embodiment, R3 may be pyridyl, optionally substituted with one or more Ra groups. In yet another embodiment, R... a It can be C 1-6 Halogenated alkyl group. In another embodiment, R a It can be pentafluorosulfonyl.

[0039] This invention includes all possible combinations of the aspects and embodiments disclosed above.

[0040] In one aspect, the present invention provides a compound, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from:

[0041] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone,

[0042] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0043] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0044] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0045] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0046] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-morpholino) methyl ketone,

[0047] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0048] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0049] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0050] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0051] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0052] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0053] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0054] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl)methyl ketone,

[0055] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0056] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0057] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0058] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0059] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0060] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0061] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-morpholino) methyl ketone,

[0062] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0063] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0064] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0065] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0066] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0067] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0068] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone,

[0069] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2R,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone,

[0070] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2S,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone,

[0071] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2S,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone,

[0072] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone,

[0073] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0074] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0075] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0076] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0077] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aR,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) methyl ketone,

[0078] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aR,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone,

[0079] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0080] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0081] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) methyl ketone,

[0082] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone,

[0083] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0084] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0085] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone,

[0086] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolyl) methyl ketone,

[0087] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone,

[0088] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl) methyl ketone,

[0089] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl) methyl ketone,

[0090] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone,

[0091] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone,

[0092] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0093] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0094] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0095] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0096] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0097] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0098] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0099] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone,

[0100] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0101] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0102] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0103] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0104] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0105] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0106] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0107] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0108] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone,

[0109] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) methyl ketone,

[0110] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0111] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0112] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) methyl ketone,

[0113] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone,

[0114] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0115] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl) methyl ketone,

[0116] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone,

[0117] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl) methyl ketone,

[0118] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl) methyl ketone,

[0119] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone,

[0120] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone,

[0121] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolyl) methyl ketone,

[0122] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone,

[0123] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone,

[0124] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0125] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0126] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0127] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0128] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0129] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0130] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolyl) methyl ketone,

[0131] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone,

[0132] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-azacyclobutane) methyl ketone,

[0133] ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0134] ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0135] ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0136] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0137] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0138] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0139] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0140] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0141] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0142] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0143] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0144] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0145] ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0146] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((1R,3S)-1-oxo-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone,

[0147] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((1S,3S)-1-oxo-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone,

[0148] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methyl ketone

[0149] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methyl ketone,

[0150] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholino)methyl ketone

[0151] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone

[0152] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholino)methyl ketone

[0153] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholino)methyl ketone,

[0154] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(4-(trifluoromethyl)-2-thienyl)-4-morpholino)methyl ketone,

[0155] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(4,5-dichloro-2-thienyl)-4-morpholino) methyl ketone,

[0156] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-morpholino)methyl ketone,

[0157] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholino)methyl ketone

[0158] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0159] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-thienyl)-4-morpholino) methyl ketone,

[0160] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl) methyl ketone,

[0161] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0162] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0163] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0164] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholino) methyl ketone,

[0165] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0166] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridyl)-5-methyl-4-morpholino) methyl ketone,

[0167] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0168] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0169] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholino) methyl ketone,

[0170] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholino) methyl ketone,

[0171] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0172] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0173] (4-Amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0174] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl) methyl ketone,

[0175] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0176] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0177] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0178] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholino)methyl ketone,

[0179] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0180] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholino)methyl ketone

[0181] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholino)methyl ketone,

[0182] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholino)methyl ketone,

[0183] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane-4-yl)methyl ketone

[0184] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane-4-yl)methyl ketone

[0185] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholino)methionine,

[0186] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone,

[0187] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone,

[0188] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-morpholino)methyl ketone,

[0189] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholino)methyl ketone

[0190] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0191] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0192] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-thienyl)-4-morpholino) methyl ketone,

[0193] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-morpholinyl) methyl ketone,

[0194] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(6-(2-propyloxy)-3-pyridyl)-4-morpholino)methyl ketone,

[0195] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0196] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0197] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0198] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholino) methyl ketone,

[0199] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholino) methyl ketone,

[0200] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0201] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0202] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridyl)-5-methyl-4-morpholino) methyl ketone,

[0203] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0204] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0205] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0206] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0207] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0208] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl) methyl ketone,

[0209] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0210] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone

[0211] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]methyl ketone

[0212] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone

[0213] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone

[0214] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]methyl ketone

[0215] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone

[0216] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone

[0217] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methyl ketone

[0218] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0219] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methyl ketone

[0220] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R,5S)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0221] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone

[0222] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methyl ketone

[0223] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0224] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholino-4-yl]methyl ketone

[0225] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methyl ketone

[0226] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S,5R)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0227] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[racemic-(3S)-3-(6-cyclopropyl-3-pyridyl)morpholin-4-yl] methyl ketone

[0228] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[racemic-(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone

[0229] (4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0230] (4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0231] (4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0232] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methyl ketone

[0233] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-morpholino)methyl ketone,

[0234] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone

[0235] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0236] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0237] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0238] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone

[0239] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone

[0240] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0241] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl) methyl ketone

[0242] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0243] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0244] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methionine

[0245] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone

[0246] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0247] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-morpholinyl) methyl ketone

[0248] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone

[0249] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone,

[0250] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0251] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0252] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0253] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0254] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0255] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone

[0256] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0257] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone

[0258] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0259] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(3-chlorophenyl)morpholin-4-yl]methyl ketone

[0260] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(4-chlorophenyl)morpholin-4-yl]methyl ketone

[0261] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)morpholin-4-yl]methyl ketone

[0262] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone

[0263] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0264] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methyl ketone

[0265] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methyl ketone

[0266] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0267] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl)morpholin-4-yl]methyl ketone

[0268] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl)morpholin-4-yl]methyl ketone

[0269] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)morpholin-4-yl] methyl ketone

[0270] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl]methyl ketone

[0271] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0272] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0273] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methyl ketone

[0274] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methyl ketone

[0275] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methyl ketone

[0276] (4-Amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0277] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone

[0278] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone

[0279] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidinyl] methyl ketone

[0280] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone

[0281] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(2-chlorophenyl)morpholin-4-yl] methyl ketone

[0282] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(3-bromophenyl)morpholin-4-yl] methyl ketone

[0283] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(3-fluorophenyl)morpholin-4-yl] methyl ketone

[0284] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-bromophenyl)morpholin-4-yl] methyl ketone

[0285] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-fluorophenyl)morpholin-4-yl] methyl ketone

[0286] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-methoxyphenyl)morpholin-4-yl] methyl ketone

[0287] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(6-bromopyridazin-3-yl)morpholin-4-yl] methyl ketone

[0288] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(o-tolyl)morpholin-4-yl] methyl ketone

[0289] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)morpholin-4-yl] methyl ketone

[0290] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl] methyl ketone

[0291] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-phenylmorpholin-4-yl] methyl ketone

[0292] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-pyrimidin-2-ylmorpholin-4-yl]methyl ketone

[0293] (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0294] (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0295] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone,

[0296] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone,

[0297] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0298] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0299] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0300] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0301] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone,

[0302] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone,

[0303] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0304] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0305] (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0306] (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0307] (4-Amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0308] (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0309] (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0310] (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0311] (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0312] (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0313] (4-amino-2,3-dihydrofurano[3,2-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0314] (4-Amino-3,3-dimethyl-1H-furano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone

[0315] (4-Amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0316] (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0317] (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0318] (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0319] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0320] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0321] (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0322] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0323] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0324] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0325] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0326] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-morpholinyl) methyl ketone,

[0327] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0328] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0329] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone

[0330] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone

[0331] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0332] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0333] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0334] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone

[0335] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0336] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0337] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl) methyl ketone,

[0338] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone,

[0339] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0340] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0341] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0342] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0343] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0344] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone

[0345] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0346] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0347] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone

[0348] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone

[0349] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0350] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0351] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone

[0352] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0353] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone,

[0354] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0355] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0356] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0357] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0358] (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0359] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0360] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0361] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidinyl) methyl ketone,

[0362] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0363] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0364] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0365] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azacyclobutane) methyl ketone,

[0366] (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0367] (4-Amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0368] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone

[0369] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0370] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone

[0371] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0372] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0373] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0374] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone

[0375] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0376] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0377] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0378] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0379] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0380] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0381] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0382] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0383] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone

[0384] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone

[0385] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0386] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone

[0387] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone

[0388] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0389] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0390] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-morpholinyl) methyl ketone

[0391] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0392] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0393] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0394] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0395] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone,

[0396] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0397] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone,

[0398] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0399] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone

[0400] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone,

[0401] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0402] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-3,3-dimethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone,

[0403] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone,

[0404] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone,

[0405] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0406] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-azacyclobutane) methyl ketone,

[0407] (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0408] (4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-yl) methyl ketone,

[0409] (4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((1S,5R)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-yl) methyl ketone,

[0410] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl) methyl ketone,

[0411] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone,

[0412] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone,

[0413] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0414] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0415] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl) methyl ketone,

[0416] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidinyl) methyl ketone,

[0417] (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) methyl ketone,

[0418] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl) methyl ketone,

[0419] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone,

[0420] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0421] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone,

[0422] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone,

[0423] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0424] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-fluorophenyl)-4-morpholinyl) methyl ketone,

[0425] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone,

[0426] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl) methyl ketone

[0427] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0428] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0429] (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) methyl ketone,

[0430] (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) methyl ketone,

[0431] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0432] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4S)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0433] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0434] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azacyclobutane) methyl ketone,

[0435] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone,

[0436] (4-amino-7-fluoro-2,3-dihydrofurano[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0437] (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone,

[0438] (4-Amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0439] (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0440] (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0441] (4-Amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone,

[0442] (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0443] (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone,

[0444] (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) methyl ketone,

[0445] (4-Aminoimidazo[1,2-a]quinoxalin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0446] (4-Aminothio[2,3-c]quinolin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone

[0447] (4-Aminothiopheno[2,3-c]quinolin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone

[0448] (4-Aminothio[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0449] (4-Aminothio[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone

[0450] (5-amino-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholino)methyl ketone,

[0451] (5-Aminobenzo[c][2,6]naphthid-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methyl ketone,

[0452] (5-Aminopyrido[4,3-c][1,7]naphthid-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone,

[0453] (5-aminopyrimidino[4,5-c][1,7]naphthid-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholino) methyl ketone,

[0454] (5-aminopyrimidino[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone,

[0455] (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7]naphthid-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone,

[0456] (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7]naphthid-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone,

[0457] (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(pentafluoro-16-thioalkyl)phenyl)morpholino)methyl ketone

[0458] (R)-(4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)morpholino)methyl ketone

[0459] (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(pentafluoro-16-thioalkyl)phenyl)morpholino)methyl ketone,

[0460] [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone,

[0461] [(3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone,

[0462] 1-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl)-1-piperazinyl)acetone,

[0463] 4-((3R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-3-morpholino)benzonitrile,

[0464] 4-((3R,5S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-5-methyl-3-morpholino)benzonitrile,

[0465] 4-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-3-morpholino)benzonitrile,

[0466] 4-((3S,5R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-5-methyl-3-morpholino)benzonitrile,

[0467] 4-Chloro-6-[racemic-(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)morpholino-3-yl]pyridine-3-carboxynitrile,

[0468] 6-[(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)morpholino-3-yl]pyridine-3-carboxynitrile,

[0469] 6-[(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)morpholino-3-yl]pyridine-3-carboxynitrile,

[0470] Methyl(3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate

[0471] Methyl(3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate

[0472] tert-butyl(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, and

[0473] tert-Butyl(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate.

[0474] In one aspect, the present invention provides the following composition:

[0475] (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone;

[0476] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone;

[0477] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone;

[0478] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone;

[0479] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone;

[0480] (4-Amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ-6-sulfonyl)phenyl)-4-morpholinyl) methyl ketone;

[0481] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone;

[0482] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone;

[0483] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl] methyl ketone;

[0484] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone;

[0485] ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone;

[0486] [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone;

[0487] (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone;

[0488] (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl) methyl ketone;

[0489] (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone;

[0490] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone;

[0491] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone;

[0492] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone; and

[0493] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone.

[0494] The present invention further provides a method for treating cancer, the method comprising administering to a subject an effective amount of the compound of the present invention, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer is selected from lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer. In another aspect, the lung cancer may be non-small cell lung cancer (NSCLC).

[0495] The present invention further provides a pharmaceutical composition comprising the compound of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0496] The present invention also provides a method for preparing a medicament for treating cancer, the method comprising administering to a subject an effective amount of the compound of the present invention, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer may be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, cholangiocarcinoma, melanoma, gastric cancer, pancreatic cancer, or bladder cancer. In one aspect, the lung cancer may be non-small cell lung cancer (NSCLC). The present invention also provides the compound of the present invention, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing for use in a method of treating cancer, the method comprising administering to a subject an effective amount of such compound. In one aspect, the cancer may be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, cholangiocarcinoma, or bladder cancer. In one aspect, the lung cancer may be non-small cell lung cancer (NSCLC).

[0497] The present invention also provides the use of the compounds of the present invention, their tautomers, their stereoisomers, or pharmaceutically acceptable salts of any of the foregoing in the preparation of a medicament for treating cancer. In one aspect, the cancer may be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer. In another aspect, the lung cancer may be non-small cell lung cancer (NSCLC).

[0498] Other objectives, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. Detailed Implementation

[0499] definition

[0500] As used herein, if any variable appears more than once in a chemical formula, its definition for each occurrence is independent of its definition for each subsequent occurrence. If a chemical structure and chemical name conflict, the chemical structure will determine the identity of the compound. These compounds disclosed herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double-bonded isomers (i.e., geometric isomers), enantiomers, or diastereomers. Therefore, any chemical structure having a relative configuration within (all or part of) the scope of this specification as described covers all possible enantiomers and stereoisomers of the compounds shown, including pure stereoisomeric forms (e.g., geometrically pure forms, enantiomerically pure forms, or diastereomerically pure forms) as well as mixtures of enantiomers and mixtures of stereoisomers. Mixtures of enantiomers and mixtures of stereoisomers can be separated into component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0501] Some compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds; racemic, enantiomers, diastereomers, geometric isomers, and individual isomers are all intended to be covered within the scope of the present invention. Furthermore, rotation-resistant isomers and mixtures thereof (e.g., those resulting from restricted rotation of about two aromatic or heteroaromatic rings bonded to each other) are intended to be covered within the scope of the present invention. For example, rotation of the phenyl group may be restricted when the substituent is a phenyl group and is replaced by two groups bonded to a C atom adjacent to the N atom attachment site of the triazole. In some cases, the rotation barrier is high enough to separate and isolate different rotation-resistant isomers.

[0502] As used herein and unless otherwise stated, the terms "stereoisomer" or "stereoisomerically pure" mean a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of its mirror-image enantiomers. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises, by weight, more than about 80% of one stereoisomer of the compound and less than about 20% of other stereoisomers of the compound, more preferably more than about 90% of one stereoisomer of the compound and less than about 10% of other stereoisomers of the compound, even more preferably more than about 95% of one stereoisomer of the compound and less than about 5% of other stereoisomers of the compound, and most preferably more than about 97% of one stereoisomer of the compound and less than about 3% of other stereoisomers of the compound. If the stereochemistry of a structure or part thereof is not indicated by, for example, thick or dashed lines, then the structure or part thereof should be interpreted as encompassing all its stereoisomers. Bonds drawn with wavy lines indicate that both stereoisomers are covered. Do not confuse this with wavy lines drawn perpendicular to the bonds, indicating the attachment points of groups to the rest of the molecule.

[0503] As is known to those skilled in the art, certain compounds of the present invention can exist in one or more tautomer forms. Because a chemical structure can only be used to represent one tautomer form, it should be understood for convenience that references to compounds having a given structural formula include tautomers of the structure represented by that formula. Depending on the compound, some compounds may exist primarily in one form rather than another. Furthermore, depending on the compound and the energy required to convert one tautomer to another, some compounds may exist as mixtures at room temperature, while others may be isolated in tautomer or other forms. Examples of other tautomers associated with the compounds of the present invention are those having a pyridone group (pyridyl group) (where hydroxypyridine is a tautomer) and compounds having a ketone group (having an enol tautomer). Examples of these are shown below.

[0504]

[0505] The compounds disclosed herein include, but are not limited to, compounds having Formula I and all of their pharmaceutically acceptable forms. This invention includes pharmaceutically acceptable forms of compounds, pharmaceutically acceptable salts, solvates, crystalline forms (including polymorphs and inclusion compounds), chelates, non-covalent complexes, prodrugs, and mixtures thereof. This invention discloses compounds, and their pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs and ester prodrugs (e.g., (C1-C4) alkyl esters), and mixtures of any of the foregoing substances.

[0506] Pharmaceutically acceptable salts of the compounds of the present invention include those with inorganic acids (e.g., hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and with organic acids (e.g., tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, camphorsulfonic acid, isothiosulfonic acid, mucoic acid, gentianic acid, isonicotinic acid, gluconic acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylethylamine, etc.). Acid addition salts formed with acids, mandelic acid, methylene dihydroxynaphthyl acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid, sulfurous 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 (e.g., N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), lysine, and procaine); and salts formed internally. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. Salts having non-pharmaceuticalally acceptable anions or cations as intermediates for the preparation of pharmaceutically acceptable salts and / or for use in non-therapeutic (e.g., in vitro) situations are within the scope of this invention.

[0507] The term "solvent" refers to a compound formed by the interaction of a solvent and a compound. Solvents of a compound include all forms of solvates of that compound. In some embodiments, the solvent is volatile, non-toxic, and / or acceptable for administration to humans in trace amounts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0508] This invention discloses compounds that may also contain naturally occurring or non-natural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, the compound may use a radioactive isotope, such as tritium (3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling. Radiolabeled compounds can be used as therapeutic or prophylactic agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All radioactive or non-radioactive isotope variants of the compounds of this invention are intended to be covered within the scope of this invention. For example, this invention also includes compounds containing deuterium (D) or tritium (T).

[0509] "Alkyl" refers to a saturated branched or straight-chain monovalent hydrocarbon group obtained by removing a hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., propyl-1-yl and propyl-2-yl), butyl (e.g., butyl-1-yl, butyl-2-yl, 2-methyl-propyl-1-yl, 2-methyl-propyl-2-yl, tert-butyl), etc. In some embodiments, the alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms or 1 to 6 carbon atoms; however, in other embodiments, the alkyl group contains 1 to 4 carbon atoms. In still other embodiments, the alkyl group contains 1 or 2 carbon atoms. Branched alkyl groups contain at least 3 carbon atoms and typically 3 to 7, or in some embodiments, 3 to 6 carbon atoms. Alkyl groups having 1 to 6 carbon atoms may be referred to as (C1-C6) alkyl groups, and alkyl groups having 1 to 4 carbon atoms may be referred to as (C1-C4) alkyl groups. This nomenclature can also be used for alkyl groups with different numbers of carbon atoms.

[0510] "Alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond, obtained by removing a hydrogen atom from a single carbon atom of a parent alkene. This group can be in a Z- or E-form (cis or trans) surrounding one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl; propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl); butenyl (e.g., buten-1-en-1-yl, buten-1-en-2-yl, 2-methyl-propen-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, and buten-1,3-dien-2-yl); and so on. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, and in other embodiments, it has 2 to 6 carbon atoms. Alkenyl groups having 2 to 6 carbon atoms can be called (C2-C6) alkenyl groups.

[0511] "Alynyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon triple bond obtained by removing a hydrogen atom from a single carbon atom of the parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, etc. In some embodiments, the alkynyl group has 2 to 20 carbon atoms, and in other embodiments, it has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a -(C2-C6) alkynyl group.

[0512] "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, etc. A typical alkoxy group contains 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms in the R group. Alkoxy groups containing 1 to 6 carbon atoms may be designated as -O-(C1-C6)alkyl or -O-(C1-C6 alkyl) groups. In some embodiments, the alkoxy group may contain 1 to 4 carbon atoms and may be designated as -O-(C1-C4)alkyl or -O-(C1-C4 alkyl) groups.

[0513] "Aryl" refers to a monovalent aromatic hydrocarbon group obtained by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. Aryl groups encompass monocyclic carbocyclic aromatic rings, such as benzene. Aryl groups also encompass bicyclic carbocyclic aromatic ring systems, where each ring is aromatic, such as naphthalene. Therefore, aryl groups can comprise fused ring systems, where each ring is a carbocyclic aromatic ring. In some embodiments, aryl groups contain 6 to 10 carbon atoms. Such groups may be referred to as C6-C. 10 Aryl groups. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined separately below. Thus, if one or more carbocyclic aromatic rings are fused with an aromatic ring containing at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group as defined herein.

[0514] "Carbonyl" refers to the group -C(O), and can also be called the -C(=O) group.

[0515] "Carboxyl group" refers to the group -C(O)OH, which can also be called -C(=O)OH.

[0516] "Cyano" refers to the group -CN.

[0517] "Cycloalkyl" refers to a saturated cyclic alkyl group obtained by removing a hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc. Cycloalkyl groups can be described by the number of carbon atoms in the ring. For example, cycloalkyl groups with 3 to 8 ring members can be referred to as (C3-C8)cycloalkyl, cycloalkyl groups with 3 to 7 ring members can be referred to as (C3-C7)cycloalkyl, and cycloalkyl groups with 4 to 7 ring members can be referred to as (C4-C7)cycloalkyl. In some embodiments, the cycloalkyl group can be (C3-C8)cycloalkyl. 10 Cycloalkyl groups, (C3-C8)cycloalkyl groups, (C3-C7)cycloalkyl groups, (C3-C6)cycloalkyl groups, or (C4-C7)cycloalkyl groups, and these can be referred to as C3-C using alternative terminology. 10 Cycloalkyl groups, C3-C8 cycloalkyl groups, C3-C7 cycloalkyl groups, C3-C6 cycloalkyl groups, or C4-C7 cycloalkyl groups.

[0518] A "heterocyclic group" is a cyclic group comprising at least one saturated, partially unsaturated, cyclic ring. A heterocyclic group contains at least one heteroatom as a ring member. Typical heteroatoms include O, S, and N, and can be chosen independently. Heterocyclic groups include monocyclic and bicyclic ring systems. A bicyclic heterocyclic group comprises at least one non-aromatic ring having at least one heteroatom ring member, which may be fused to a cycloalkyl ring or to an aromatic ring, wherein the aromatic ring may be a carbocyclic ring or may contain one or more heteroatoms. The attachment point of a bicyclic heterocyclic group can be on a non-aromatic cyclic ring containing at least one heteroatom or on another ring of the heterocyclic group. For example, a heterocyclic group obtained by removing a hydrogen atom from one of the following 9-membered heterocyclic compounds can be attached to the remainder of the molecule on a 5-membered ring or a 6-membered ring.

[0519]

[0520] In some embodiments, the heterocyclic group comprises 5 to 10 ring members, wherein 1, 2, 3, or 4 are heteroatoms independently selected from O, S, or N. In other embodiments, the heterocyclic group comprises 3 to 7 ring members, wherein 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In such 3- to 7-membered heterocyclic groups, only 1 ring atom is a heteroatom when the ring comprises only 3 members, and 1 or 2 heteroatoms are contained when the ring comprises 4 members. In some embodiments, the heterocyclic group comprises 3 or 4 ring members, wherein 1 is a heteroatom selected from O, S, or N. In other embodiments, the heterocyclic group comprises 5 to 7 ring members, wherein 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclic groups include, but are not limited to, groups derived from epoxides, aziridines, aziridines, imidazolides, morpholines, piperazines, piperidines, hydrogenated pyrimidines, 1,4,5,6-tetrahydropyrimidines, pyrazolidines, pyrrolidines, quinine rings, tetrahydrofurans, tetrahydropyrans, benzimidazolones, pyridones, etc. Heterocyclic groups can be fully saturated, but may also contain one or more double bonds. Examples of such heterocyclic 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-pyrroleyl, 2,3-dihydro-1H-pyrroleyl, 1H-azirinyl, 1,2-dihydroaziridine, etc. Substituted heterocyclic groups also include those oxidized (=O) or oxidized (-O) by one or more oxo groups. - ) ring systems substituted with substituents, such as piperidinyl N-oxide, morpholino-N-oxide, 1-oxo-1-thiomorpholino, pyridinone, benzimidazolone, benzo[d]oxazol-2(3H)-keto, 3,4-dihydroisoquinoline-1(2H)-keto, indoline-keto, 1H-imidazo[4,5-c]pyridin-2(3H)-keto, 7H-purine-8(9H)-keto, imidazoline-2-keto, 1H-imidazo-2(3H)-keto, 1,1-dioxo-1-thiomorpholino, etc.

[0521] The term "comprising" is open-ended, meaning it covers all and is not restrictive. It may be used synonymously with "having" or "including" herein. "Comprising" is intended to include each and every specified or described component or element without excluding any other component or element.

[0522] "Disease" means any disease, disorder, symptom, or indication.

[0523] "Halogen" or "halogen" refers to a fluorine, chlorine, bromine, or iodine group.

[0524] "Haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen. Therefore, the term "haloalkyl" includes monohaloalkyl (an alkyl group substituted with one halogen atom) and polyhaloalkyl (an alkyl group substituted with two or more halogen atoms). Representative "haloalkyl" groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Unless otherwise stated, the term "perhaloalkyl" means an alkyl group in which every hydrogen atom is replaced by a halogen atom. For example, the term "perhaloalkyl" includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, etc.

[0525] "Heteroaryl" refers to a monovalent heteroaryl group obtained by removing a hydrogen atom from a single atom of a parent heteroaryl ring system. Heteroaryl groups typically comprise 5 to 14 members, but more typically 5 to 10 members, and are monocyclic, bicyclic, or tricyclic aromatic, containing one or more (e.g., 1, 2, 3, or 4) heteroatoms, or in some embodiments, 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the remaining ring atom is carbon. In a monocyclic heteroaryl group, the monocycle is aromatic and contains at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may comprise 5 or 6 ring members and may contain 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom, wherein one or more heteroatoms are independently selected from O, S, or N. In a bicyclic aromatic ring, both rings are aromatic. In a bicyclic heteroaryl group, at least one ring must contain a heteroatom, but both rings do not necessarily need to contain heteroatoms, although this is permissible. For example, the term "heteroaryl" includes 5- to 7-membered heteroaryl rings fused to a carbocyclic aromatic ring or fused to another heteroaryl ring. In a tricyclic aromatic ring, all three rings are aromatic, and at least one ring contains at least one heteroatom. For fused, bicyclic, and tricyclic heteroaryl ring systems (where only one ring contains one or more heteroatoms), the attachment point can be on the ring containing at least one heteroatom or on the carbocyclic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. A heteroaryl does not cover or overlap with an aryl group as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, zoline, furan, imidazole, indazole, indole, indoleazine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthidine, oxadiazole, oxazole, pteridine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrrole, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, etc. In some embodiments, the heteroaryl group may be a 5- to 20-membered heteroaryl group, for example, a 5- to 14-membered or a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group may be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazolium, and pyrazine.

[0526] “MTAP” refers to mammalian methylthioadenosine phosphorylase.

[0527] "Pharmaceutical acceptable" means that it is generally accepted for use in animals (and more particularly in humans).

[0528] "Pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the pharmacological activity of the desired parent compound.

[0529] "Pharmaceutically acceptable excipients" refers to a broad range of ingredients that can be combined with the compounds or salts of this invention to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, mediators, anti-adhesives, flow aids, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0530] “PRMT5” refers to mammalian protein arginine N-methyltransferase 5 (PRMT5).

[0531] "PRMT5 inhibitors" are compounds that inhibit or negatively regulate all or part of the activity of the PRMT5 enzyme.

[0532] "MTA-cooperative PRMT5 inhibitors" are compounds that inhibit or negatively regulate all or part of the PRMT5 enzyme activity in cells with elevated MTA levels, either in vitro or in vivo, in the presence of bound MTA.

[0533] "Stereoisomers" refer to isomers whose constituent atoms are arranged differently in space. Stereoisomers that are mirror images of each other and are optically active are called "enantiomers", while stereoisomers that are not mirror images of each other and are optically active are called "diastereomers".

[0534] The term “subject” includes mammals and humans. The terms “human” and “subject” are used interchangeably in this document.

[0535] "Therapeutic effective amount" means the amount of a compound that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect that disease, disorder, or symptom. As those skilled in the art will recognize, this amount is generally not limited to a single dose but may include multiple doses over a significant period of time, such as when a therapeutic or preventative response is required in the subject. Therefore, "therapeutic effective amount" is not limited to the amount in a single capsule or tablet but may include more than one capsule or tablet, as prescribed by a qualified physician or healthcare provider. "Therapeutic effective amount" can vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given case, the appropriate amount will be obvious to those skilled in the art or can be determined by routine experiments.

[0536] "Treating" or "treatment" for any disease or disorder means preventing or improving the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the risk of acquiring the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the development of the disease, disorder, or at least one clinical symptom of the disease or disorder, or reducing the risk of developing the disease or disorder or at least one clinical symptom of the disease or disorder. "Treating" or "treatment" also means suppressing the disease or disorder physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of bodily parameters), or both, or suppressing at least one bodily parameter that is not identifiable by the subject. Furthermore, "treating" or "treatment" means delaying the onset of the disease or disorder, or at least its symptoms, in a subject who may be exposed to or predisposed to having the disease or disorder (even if the subject has not yet experienced or displayed symptoms of the disease or disorder).

[0537] Pharmaceutical compositions are also provided comprising a compound as described in any one of the examples, or a pharmaceutically acceptable salt thereof, its tautomers, pharmaceutically acceptable salts of tautomers, stereoisomers of any of the foregoing, or mixtures thereof, and at least one pharmaceutically acceptable excipient, carrier, or diluent. In some examples, the compound as described in any of these aspects, or a pharmaceutically acceptable salt thereof, its tautomers, pharmaceutically acceptable salts of tautomers, stereoisomers of any of the foregoing, or mixtures thereof, are present in an amount effective for treating PRMT5-dependent cancers. In some aspects, 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 daily or QD, and in some such formulations is a tablet, wherein the effective amount of the active ingredient is in the range of 1 mg to 1000 mg.

[0538] In some aspects, the subject is a mammal. In some such aspects, the mammal is a rodent. In other aspects, the mammal is a dog. In still other embodiments, the subject is a primate, and in some embodiments, the subject is a human.

[0539] Pharmaceutical compositions or formulations for administering the compounds of the present invention can conventionally be present in unit dose form and can be prepared by any method well known in the art. All methods involve the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, the pharmaceutical composition is prepared by the following steps: homogenizing and tightly binding the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if desired, shaping the product into a desired formulation. The active target compound is included in such a pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0540] The compounds of the present invention can be administered orally, via mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), percutaneously, or topically. In some aspects, the compounds of the present invention are administered via mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), percutaneously, or topically. In other aspects, the compounds of the present invention are administered orally.

[0541] The compounds of the present invention, their pharmaceutically acceptable salts, their tautomers, pharmaceutically acceptable salts of the tautomers, stereoisomers of any of the foregoing, or mixtures thereof, can be used to treat a variety of ailments.

[0542] The compounds and compositions described herein are generally used to inhibit PRMT5. In some aspects, a method of treating a PRMT5-mediated disorder in a subject is provided, the method comprising administering to a subject requiring treatment an effective amount of a compound described herein (e.g., a compound having formula I or a pharmaceutically acceptable salt thereof). In some aspects, this effective amount is a therapeutically effective amount. In some aspects, this effective amount is a prophylacticly effective amount. In some aspects, the subject has a PRMT5-mediated disorder (e.g., cancer, such as lymphoma, breast cancer, or pancreatic cancer). In other aspects, the subject is susceptible to a PRMT5-mediated disorder (e.g., cancer, such as lymphoma, breast cancer, or pancreatic cancer).

[0543] As used herein, the term "PRMT5-mediated disorder" means any disease, disorder, or other pathological condition in which PRMT5 is known to play a role. Therefore, in some respects, this disclosure relates to treating or alleviating the severity of diseases in which one or more PRMT5s are known to play a role.

[0544] In some respects, this article provides a method for inhibiting PRMT5 activity in subjects in need, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound having Formula I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0545] This invention provides methods for treating cancers and other disorders caused by homozygous loss of the chromosome 9p21 gene locus (carrying the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A)). In one aspect, the invention covers methods for treating MTAP (methylthioadenosine phosphorylase)-ineffective cancers and tumors. In some embodiments, these types of cancer exhibit accumulation of the MTAP substrate methylthioadenosine (MTA).

[0546] The methods for treating PRMT5 impairment covered by this invention preferentially target PRMT5 in MTAP-ineffective tumors without impairing PRMT5 in normal tissue (MTAP WT). The compounds of this invention therefore contain MTA-cooperative small molecule inhibitors that preferentially target the MTA-binding state of PRMT5 enriched in MTAP-ineffective tumor cells, while providing an improved therapeutic index exceeding that of normal cells (where MTAP is intact and MTA levels are low).

[0547] In another aspect, compounds cooperating with the PRMT5 inhibitor MTA of this invention can be used to treat proliferative disorders, such as cancer. In some embodiments, the cancer compounds described herein can be used to treat pancreatic cancer. In some aspects, the cancer compounds described herein can be used to treat multiple myeloma (MM). In another embodiment, the cancer compounds described herein can be used to treat breast cancer. Breast cancer may be estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-). In another embodiment, the breast cancer may be HER2-negative. In some embodiments, the breast cancer is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative, and is also referred to herein as "triple-negative breast cancer".

[0548] In other aspects, 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, renal tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or other breast cancers, including but not limited to triple-negative, HER-positive, estrogen receptor-positive, progesterone receptor-positive, HER and estrogen receptor-positive, HER and progesterone receptor-positive, estrogen and progesterone receptor-positive, and HER and estrogen and progesterone receptor-positive breast cancers.

[0549] In one embodiment, the compounds of the present invention can be used to treat pancreatic cancer.

[0550] In another embodiment, the compounds of the present invention can be used to treat NSCLC (non-small cell lung cancer). In one embodiment, the NSCLC may be squamous NSCLC. In another embodiment, it may be adenocarcinoma.

[0551] On the other hand, cancer can be glioblastoma (GBM). On another hand, cancer can be mesothelioma. On one hand, cancer can be bladder cancer. On the other hand, cancer can be esophageal cancer. On another hand, cancer can be melanoma. On yet another hand, cancer can be DLBCL, HNSCC, or bile duct cancer.

[0552] In some respects, one or more of the compounds described herein can be used to treat any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, such as PRMT5-responsive cancer.

[0553] On the one hand, cancers lacking p53 (e.g., p53-ineffective cancers) are less sensitive to PRMT5 inhibition than p53-positive cancers. Therefore, PRMT5-responsive cancers can be p53-positive cancers. The term "p53-positive" refers to cancers that do not lack p53 expression and / or activity. In some embodiments, one or more compounds described herein may be used to treat p53-positive cancers. In some aspects, larger quantities of one or more compounds described herein may be needed to treat p53-negative cancers (e.g., p53-ineffective cancers) than those needed to treat p53-positive cancers.

[0554] In some aspects, this disclosure provides methods for identifying subjects with cancers that are sensitive to treatment with PRMT5 inhibitors. In some embodiments, the method includes obtaining a sample from the subject; detecting the presence of p53; and if p53 is present in the sample, identifying the subject as having cancers sensitive to treatment with PRMT5 inhibitors. Thus, in some embodiments, subjects with p53-positive cancers are identified as subjects treated with PRMT5 inhibitors. In some embodiments, the method further includes administering a composition comprising a PRMT5 inhibitor to the subject.

[0555] In some embodiments, aspects of this disclosure relate to methods for identifying subjects with cancers that are insensitive to or have low sensitivity to PRMT5 inhibitors. In some embodiments, the method includes obtaining a sample from the subject; detecting the presence of p53; and identifying the subject as having a cancer insensitive to PRMT5 inhibitors (e.g., a cancer less sensitive than p53-positive cancers) if p53 is not present in the sample (e.g., if the cancer is p53-ineffective). In some embodiments, p53-negative cancers (e.g., p53-ineffective cancers) are treated with PRMT5 inhibitors, but a larger dose of PRMT5 inhibitor may be required to treat p53-negative cancers than for p53-positive cancers. However, in some embodiments, subjects with p53-negative cancers (e.g., p53-ineffective cancers) are treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0556] "Sample" means 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 cancerous tissue. The presence of p53 in a sample can be detected by any suitable method for detecting p53 nucleic acid or protein, such as nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, or any combination thereof.

[0557] It should be understood that, in some respects, one or more of the compounds described herein can be used to treat other types of cancer, including but not limited to acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, and angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma). Sarcoma), appendiceal cancer, benign monoclonal gammopathy, biliary tract tumors (e.g., bile duct cancer), bladder cancer, brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumors, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's sarcoma). Cancers include adenocarcinoma, Ewing's sarcoma, eye cancers (e.g., intraocular melanoma, retinoblastoma), common eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancers (e.g., squamous cell carcinoma of the head and neck), oral cancers (e.g., oral squamous cell carcinoma (OSCC)), pharyngeal cancers (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic system cancers (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML)). L), 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 (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenström macroglobulinemia"), hairy cell Leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Cezari syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); and a mixture of one or more leukemias / lymphomas as described above;And multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immune-mediated amyloidosis, renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS), mast cell hyperplasia (e.g., generalized mast cell hyperplasia) Myelodysplastic syndromes (MDS), mesothelioma, myelodysplastic disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myelopathic myelogenesis of unknown cause (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)), neuroblastoma, neurofibromatosis (e.g., neurofibromatosis (NF) type 1) Type 2 or schwannoma); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic 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), pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma), Basal cell carcinoma (BCC), small bowel cancer (e.g., appendix cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovial tumor, testicular cancer (e.g., seminoma, embryonal testis 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).

[0558] In some aspects, a method of treating a subject's cancer includes administering to the subject a composition comprising a PRMT5 inhibitor, wherein treatment with the PRMT5 inhibitor inhibits tumor growth of the cancer by more than about 25%, more than about 50%, more than about 75%, or more than about 90% (e.g., 25%-50%, 50%-75%, 75%-90%, or 90%-100%). In some embodiments, a method of treating a subject's cancer includes administering to the subject a composition comprising a PRMT5 inhibitor, wherein methylation of the cancer is 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%). Methylation refers to protein methylation, such as histone methylation (e.g., methylation of one or more lysine and / or arginine residues in a histone protein) or DNA methylation (e.g., epigenetic DNA methylation, such as methylated CpG sites). In some embodiments, the methyl labeling level of a cell is a measure of the degree of histone methylation in that cell (e.g., at one or more specific lysine and / or arginine sites).

[0559] The invention is further described with reference to the following examples, which are intended to illustrate the claimed invention but do not limit the invention in any way.

[0560] Example

[0561] Unless otherwise stated in the intermediate section, all materials are obtained from market suppliers and are ready for use without further purification.

[0562] The following abbreviations are used to refer to various reagents, solvents, or instruments:

[0563]

[0564]

[0565]

[0566]

[0567] General synthesis scheme:

[0568]

[0569]

[0570] Method A:Compound I can be prepared by reacting acid IA and secondary amine IB-1 in a solvent (e.g., DMF or DMAc) in the presence of a base (e.g., Et3N or DIPEA) and an activating agent (e.g., HATU or PyBrOP). If a racemic amine or acid is used in method A, chiral SFC can be used to separate stereoisomers, in which case stereochemistry is arbitrarily assigned to each isomer.

[0571] Method B: Compound I can be prepared by reacting an acyl chloride IC with a secondary amine IB in a solvent (e.g., THF, dioxane, DCM, or DCE) in the presence of a base (e.g., Et3N, DIPEA, or pyridine). Alternatively, compound I can be prepared by reacting an acyl chloride IC with a secondary amine IB in pyridine in the presence of DMAP. If a racemic amine or acid is used in method B, a chiral SFC can be used to separate stereoisomers, in which case the stereochemistry is arbitrarily assigned to each isomer.

[0572] Analytical U / HPLC

[0573] The following equipment is used for analytical UHPLC:

[0574] The Waters Acquity system, equipped with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm), features a linear gradient in a binary solvent system, operating at a flow rate of 0.5 mL / min with DAD, and is used for MS detection of SQDI at ambient temperature. The linear gradient used is (H₂O / CH₃CN / HCO₂H (95 / 5 / 0.1% to 0 / 100 / 0.1%)). The Agilent Infinity I / II-TOF6230B / CLND Antek 8060 system, equipped with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm), features a linear gradient in a binary solvent system, operating at a flow rate of 0.75 mL / min with DAD. The linear gradient used is (H₂O / MeOH / HCO₂H (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0575] Preparative HPLC

[0576] The following equipment was used for preparative HPLC: a Shimadzu Nexera X2 equipped with a Merck ChromolithSpeedROD RP-18E (5 μm, 10 x 100 mm) with a linear gradient in a binary solvent system, using flow rates between 4 mL / min and 7 mL / min and UV detection at 254 nm, combined with MS detection on a Shimadzu LCMS-2020. The linear gradient used was (H₂O / MeOH / HCO₂H (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0577] intermediate

[0578] Intermediate 1: 6-(difluoromethoxy)pyridazine-3-carboxaldehyde

[0579]

[0580] Step 1. In a vial, 3-chloro-6-(difluoromethoxy)pyridazine (675 mg, 3.74 mmol), sodium carbonate (1190 mg, 11.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (274 mg, 0.374 mmol) were added. Then, 1,4-dioxane (16.8 mL) and water (1.87 mL) were added, followed by pinacol ester of vinylborate (1.73 g, 1.90 mL, 11.2 mmol). The resulting mixture was bubbled under 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 containing 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 rapid chromatography (0 to 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] + .

[0581] Step 2. In a vial, 3-(difluoromethoxy)-6-vinylpyridazine (573 mg, 3.33 mmol), acetone (7.93 mL), and water (1.59 mL) were added. Potassium (VI) osmium tetroxide dihydrate (123 mg, 0.333 mmol) was added to the resulting solution, followed by 4-methylmorpholine 4-oxide (1.37 g, 11.7 mmol), and the mixture was stirred at 23 °C. After 1.5 h, the reaction mixture was concentrated under vacuum, then co-evaporated with toluene (5 mL), and the resulting crude residue was purified by rapid column chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to give 1-(6-(difluoromethoxy)pyridazine-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] + .

[0582] Step 3. In a vial, add 300 mg (1.45 mmol) of 1-(6-(difluoromethoxy)pyridazin-3-yl)ethane-1,2-diol and 13.4 mL of tetrahydrofuran. Add sodium meta-periodate (933 mg, 4.36 mmol) and water (1.12 mL) to the resulting solution and stir the mixture at 23 °C. After 1 h, dilute the reaction mixture with 10 mL of H₂O, transfer it to a separatory funnel containing 20 mL of CH₂Cl₂ and 20 mL of brine, and extract with 2 x 20 mL of CH₂Cl₂. Dry the combined organic layers over anhydrous Na₂SO₄, filter, and concentrate to dryness. The crude residue was purified by rapid column chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to give 6-(difluoromethoxy)pyridazine-3-carboxaldehyde (1,217 mg, 1.25 mmol, 86% yield) as a clear oil. m / z (ESI): 175.2 [M+H] + .

[0583] Intermediate 2: 6-Cyclopropoxypyridazine-3-carboxaldehyde

[0584]

[0585] Step 1. In a round-bottom flask, sodium hydride (60% dispersion in mineral oil, 1.556 g, 38.9 mmol) and tetrahydrofuran (31.1 mL) were added. 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 heated to 23 °C under nitrogen for 1 h. 3-Chloro-6-methylpyridazine (1.00 g, 7.78 mmol) was then added dropwise to the tetrahydrofuran solution (8.0 mL), and the reaction mixture was stirred at 23 °C. After 16 h, the reaction mixture was transferred to a separatory funnel containing CH2Cl2 (30 mL), H2O (20 mL), and a saturated aqueous solution of NH4Cl (30 mL), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The resulting crude residue was purified by rapid chromatography (0 to 100% EtOAc in heptane) to give 3-cyclopropoxy-6-methylpyridazine (308.5 mg, 2.054 mmol, 26.4% yield), a pale yellow oil. m / z (ESI): 151.2 [M+H] + .

[0586] Step 2. In a vial, 3-cyclopropoxy-6-methylpyridazine (308.5 mg, 2.054 mmol), selenium dioxide (365 mg, 3.29 mmol), and 1,4-dioxane (8.22 mL) were added. The resulting mixture was bubbled under nitrogen for 10 min, and then the vial was heated to 110 °C. After 30 min, the reaction mixture was cooled to 23 °C, filtered through a diatomaceous earth pad (30 mL 3:1 EtOAc:EtOH eluent), and concentrated to dryness. The resulting crude residue was purified by rapid chromatography (0 to 50% 3:1 EtOAc:EtOH in heptane) to give 6-cyclopropoxypyridazine-3-carboxaldehyde (2,111.7 mg, 0.680 mmol, 33.1% yield) as an orange oil. m / z (ESI): 165.1 [M+H] + .

[0587] Intermediate 3: 6-ethoxypyridazine-3-carboxaldehyde

[0588]

[0589] 3-Chloro-6-methylpyridazine (1.00 g, 7.78 mmol, CombiBlocks) and ethanol (15.6 mL) were placed in a microwave-safe vial. Potassium carbonate (2.69 g, 19.45 mmol) was added to the resulting solution, and the mixture was heated in a microwave oven to 140 °C for 14 h. The reaction mixture was then transferred to a separatory funnel containing CH2Cl2 (30 mL), H2O (20 mL), and a saturated aqueous solution of NH4Cl (30 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The resulting crude residue was purified by rapid chromatography (0 to 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] + .

[0590] 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) were charged into a vial. The resulting mixture was bubbled under nitrogen for 10 min, and then the vial was heated to 110 °C. After 30 min, the reaction mixture was cooled to 23 °C, filtered through a 1 cm diatomaceous earth pad (30 mL of 3:1 EtOAc:EtOH eluent), and concentrated to dryness. The resulting crude residue was purified by rapid chromatography (0 to 50% 3:1 EtOAc:EtOH in heptane) to give 6-ethoxypyridazine-3-carboxaldehyde (3,332.7 mg, 2.187 mmol, 28% yield) as a pale yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δppm 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 approach can be applied to other non-commercial aldehyde intermediates listed in Table 1.

[0591] Intermediate 4-6: 3-(6-methoxypyridazine-3-yl)-5-methylmorpholine:

[0592]

[0593] Step 1. Fill the small bottle with the contents of the oven-dried product. Molecular sieve (2.00 g, 2.64 mmol), dichloromethane (10.6 mL), and 6-methoxypyridazin-3-carboxaldehyde (365 mg, 2.64 mmol, Enamine) were used. 1-((tributyltinyl)methoxy)propyl-2-amine (SnAP 3Me-M reagent, 0.907 mL, 2.64 mmol) was added to the resulting suspension via syringe, and the mixture was stirred at 23 °C. After 17 h, the reaction mixture was filtered (eluent with 20 mL of dichloromethane), and the filtrate was concentrated under vacuum to give (E)-1-(6-methoxypyridazin-3-yl)-N-(1-((tributyltinyl)methoxy)propyl-2-yl)methylimine as a brown oil. 1 ¹H NMR (400MHz, chloroform-d) δppm 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). This substance was used in subsequent steps without further purification.

[0594] Step 2. In a vial, oven-dried copper trifluoromethanesulfonate (II) (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) were added. The resulting mixture was stirred at 23 °C for 7 h. Then, the mixture was added via syringe to a solution of (E)-1-(6-methoxypyridazin-3-yl)-N-(1-((tributylmethanesulfonyl)methoxy)propyl-2-yl)methylimine (1316 mg, 2.64 mmol) in hexafluoroisopropanol (19.1 mL). The resulting mixture was bubbled with nitrogen for 10 min and then stirred at 23 °C. After 16 h, the reaction mixture was treated with 30% NH4OH aqueous solution and brine (1:1, 10 mL) and stirred vigorously at 23 °C for 1 h. The mixture was transferred to a separatory funnel containing CH2Cl2 (20 mL) and brine (20 mL), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude residue was purified by rapid chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to give 3-(6-methoxypyridazine-3-yl)-5-methylmorpholine (4,337 mg, 1.611 mmol, 61% yield) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δppm: 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] + .

[0595] Step 3. Racemic secondary amine 4 (337 mg) was purified by preparative SFC using a Chiral Technologies IG column (250 x 21 mm, 5 mm) (mobile phase: 50% liquid CO2 and 50% MeOH with 0.2% TEA, flow rate: 80 mL / min). Peak partitioning was determined by SFC using an IG column (with 50% MeOH containing 0.2% TEA). The first elution peak was arbitrarily designated as (3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (5, 150.7 mg, >99% ee), and the second elution peak was arbitrarily designated as (3R,5S)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (6, 152.7 mg, >99% ee).

[0596] The racemic amines summarized in Table 1 are prepared in a manner similar to that described above for amine 4.

[0597] Table 1

[0598]

[0599]

[0600]

[0601]

[0602] The chiral amines summarized in Table 2 were prepared in a manner similar to that described above for amines 5 and 6. Chiral SFC was performed on racemic amines to provide enantiomeric pure amines (>99% ee).

[0603] Table 2

[0604]

[0605]

[0606]

[0607]

[0608]

[0609] Intermediate 57: 2-(4-bromophenyl)-4,4-difluoropiperidine

[0610]

[0611] Step 1. As described in Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2016, 55, 9676-9: At room temperature, via syringe, N,N'-diisopropylcarbodiimide (0.550 g, 0.674 mL, 4.35 mmol, Sigma-Aldrich Corporation) was added dropwise to a mixture of vigorously stirred Boc-l-homoPro (4,4-difluoro) (1.050 g, 3.96 mmol, RSP amino acid, LLC), 4,5,6,7-tetrachloro-2-hydroxyisoindoline-1,3-dione (1.191 g, 3.96 mmol, Aldrich Corporation) and 4-(dimethylamino)pyridine (0.048 g, 0.396 mmol, Sigma-Aldrich Corporation) in a 25-mL reaction vial in a DCM (25 mL) mixture. The resulting mixture was stirred at room temperature for 17 h. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-fast column chromatography using a 40-g ISCO gold column (eluted with EtOAc / heptane (17 min from 10% to 70%)) to give 1-(tert-butyl)2-(4,5,6,7-tetrachloro-1,3-dioxoisoindololin-2-yl)4,4-difluoropiperidine-1,2-dicarboxylate (1.45 g, 2.65 mmol, 66.8% yield) as a white solid. 1 ¹H 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) + .

[0612] Step 2. A 25-mL reaction vessel containing nickel chloride (ii) hexahydrate (50.3 mg, 0.212 mmol, Sigma-Aldrich) and 1,10-phenanthroline (70.3 mg, 0.212 mmol, Combi-Blocks Inc.) was evacuated, then backfilled with argon (3X), followed by the introduction of 4.10 mL of N,N-dimethylformamide. The resulting mixture was stirred at room temperature under argon for 2.5 h, resulting in a green solution. Separately, a 250-mL single-necked reaction vessel containing 1-(tert-butyl)-2-(4,5,6,7-tetrachloro-1,3-dioxoisoindoline-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, backfilled with nitrogen (3X), and then 1,4-dioxane (41 mL) was introduced. The resulting mixture was stirred at room temperature under nitrogen for 2 min, and then triethylamine (1071 mg, 1.487 mL, 10.58 mmol, Sigma-Aldrich) was added. The resulting mixture was stirred at room temperature for 5 min, and then introduced into the previously prepared catalyst solution via a syringe under nitrogen. The resulting mixture was immediately placed in an oil bath preheated to 90 °C and stirred for 17 h. Volume was reduced, and the crude residue was loaded onto a silica pre-column (25 g) and subjected to combi-fast column chromatography using a 24-g ISCO gold column (eluting with MeOH / DCM (20 min from 0 to 5%), monitored at 215 nm UV channel) to yield 290 mg of impure tert-butyl-2-(4-bromophenyl)-4,4-difluoropiperidine-1-carboxylate as a colorless film. This was used directly in the next step without further purification. m / z (ESI): 398.0 and 400.0 (M+Na) + .

[0613] Step 3. At room temperature, 2,2,2-trifluoroacetic acid (88 mg, 4.0 mL, 0.771 mmol, Aldrich) was added to a stirred solution of tert-butyl 2-(4-bromophenyl)-4,4-difluoropiperidine-1-carboxylate (290 mg, 0.771 mmol, from the impurity of Step 2) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 h. The volatiles were removed under vacuum, and the residue was loaded onto a silica gel pre-column (25 g) and subjected to combi-rapid column chromatography using a 12-g ISCO gold column (eluted with 20% MeOH (containing 0.5% ammonium hydroxide) / DCM (12 min from 1% to 20%)) to give an impure desired product 57, which was dissolved in DCM / MeOH and loaded onto a silica gel pre-column (25 g) and subjected to combi-rapid column chromatography using a 12-g ISCO gold column (eluted with (EtOH / EtOAc, 1 / 3, v / v) / heptane (0 to 80%), monitored at 215 nm UV channel) to give 2-(4-bromophenyl)-4,4-difluoropiperidine (142 mg, 0.514 mmol, 49% yield in two steps) as a colorless film (57). 1 ¹H NMR (chloroform-d, 400MHz) δ 7.48 (d, 2H, J = 8.4Hz), 7.26 (d, 2H, J = 8.4Hz), 3.82 (br d, 1H, J = 11.7Hz), 3.23 (tdd, 1H, J = 2.6, 5.3, 12.1Hz), 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] + .

[0614] The racemic amines in Table 3 are prepared in a manner similar to that described above for amine 57.

[0615] Table 3

[0616]

[0617] Intermediate 100: 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid.

[0618]

[0619] Step 1. Add methyl 4-amino-3-bromobenzoate (4 g, 17.39 mmol, Combilot) and bis(pinacol)diboron (8.83 g, 34.8 mmol, Frontier Scientific, Inc.) in 1,4-dioxane (58.0 mL). Then add potassium acetate (5.12 g, 52.2 mmol, Sigma-Aldrich) to the solution and degas the mixture by bubbling with argon for 5 min. Then add [1,1'-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride (1.420 g, 1.739 mmol, Strem Chemicals, Inc.) in combination with dichloromethane. The reaction is then stirred at 100 °C. After 18 h, the reaction is cooled and the solid is filtered under vacuum and washed with DCM. The mother liquor is then concentrated to give a semi-solid residue. DCM was added, and the resulting solid was collected by vacuum filtration. The mother liquor was concentrated again, and this step was repeated. The desired gray solid methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate was isolated (2.6 g, 9.38 mmol, 54.0% yield). m / z (ESI): 196.1 [M+H] + (boric acid). 1 ¹H NMR (400MHz, chloroform-d) δppm 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).

[0620] Step 2. Add DIPEA (0.943 mL, 5.40 mmol) to a stirred solution of 4-oxotetrahydrofuran-3-carboxynitrile (0.500 g, 4.50 mmol) in dichloromethane (5.00 mL), and cool the reaction mixture to -78 °C. Then, add trifluoromethanesulfonic anhydride (0.760 mL, 4.50 mmol) dropwise at -78 °C for 1 min, and stir the reaction mixture at the same temperature for 15 min. After the reaction is complete, dilute the reaction mixture with water, separate the organic layer, wash with brine (2 x 10 mL), dry with sodium sulfate, and concentrate to give crude 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (1.05 g, 4.32 mmol, 96% yield), which is used in the next step without further purification.

[0621] Step 3. Under nitrogen purging, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate (9.12 g, 32.9 mmol), K₂CO₃ (17.05 g, 123 mmol), and Pd(PPh₃)₄ (4.75 g, 4.11 mmol) were added to a stirred solution of 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (10 g, 41.1 mmol) in 1,4-dioxane (200 mL) and water (20.00 mL). The reaction mixture was then heated at 80 °C for 16 h. The reaction mixture was concentrated and diluted with ethyl acetate (50 mL) and water (50 mL), and stirred at room temperature for 30 min. The resulting solid was then filtered and washed with ethyl acetate (50 mL) and 2% MeOH in DCM (50 mL), and then dried under vacuum to give methyl 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate as a gray solid (6.6 g, 27.0 mmol, 65.7% yield). m / z (ESI): 245.3 [M+H] + . 1 ¹H NMR (400MHz, TFA-d) δppm 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 heterocyclic rings, Pd(dppf)Cl₂ is used instead of Pd(PPh₃)₄.

[0622] Step 4. LiOH (11.77 g, 491 mmol) was added to a stirred solution of methyl 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (30 g, 123 mmol) in water (300 mL):tetrahydrofuran (300 mL):methanol (300 mL), and the reaction mixture was heated at 75 °C for 3 h. The reaction mixture was concentrated, and 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-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (28 g, 122 mmol, 99% yield) as a grayish-white solid. m / z (ESI): 231.2 [M+H] + . 1 H NMR (400MHz, DMSO-d) δppm 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).

[0623] The acids in Table 4 are prepared in a manner similar to that described for intermediate 100.

[0624] Table 4

[0625]

[0626]

[0627]

[0628]

[0629] Intermediate 132: 6-amino-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylic acid.

[0630]

[0631] Step 1. A mixture of methyl 2-oxocyclopentane carboxylate (1.0 g, 0.877 mL, 7.03 mmol, Matrix Scientific) and 1,1'-dimethyltriethylamine (1.000 g, 1.352 mL, 7.74 mmol, Sigma-Aldrich) in DCM (15 mL) was cooled to -78 °C, and trifluoromethanesulfonic anhydride (7.03 mL, 7.03 mmol, Sigma-Aldrich) was added. After addition, the mixture was stirred at -78 °C for 5 min, then the dry ice bath was removed and the mixture was 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 pale yellow solid in quantitative yield, used as is. m / z (ESI): 275 [M+H] + .

[0632] Step 2. A mixture of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-en-1-carboxylate (1.982 g, 7.23 mmol), (2-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (1.70 g, 8.67 mmol), tripotassium phosphate (3.78 g, 21.69 mmol, Acros), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(ii) dichloride (0.177 g, 0.217 mmol, Strem Chemicals Ltd.) in dichloromethane in 1,4-dioxane / water (10 / 0.60 mL) was heated at 80 °C for 1 h. When the reaction was complete, it was allowed to reach room temperature and diluted with EtOAc. A precipitate corresponding to the desired product was formed. The precipitate was filtered and washed with EtOAc to produce methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,8]naphthyl-2-carboxylate in quantitative yield as a light gray solid. m / z(ESI): 245[M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 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).

[0633] Step 3. A mixture of methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,8]naphthyl-2-carboxylate (1.76 g, 7.21 mmol) in POCl3 (24.68 g, 15 mL, 161 mmol, Aldrich) was heated to reflux for 30 min. Once the reaction was complete, it was carefully added to a cold, saturated aqueous solution of NaHCO3 to alkalize the reaction. After stirring for 15 min, the mixture was extracted with EtOAc, and the combined organic matter was concentrated to give methyl 6-chloro-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate as a yellow solid in quantitative yield. m / z (ESI): 263 [M+H] + .

[0634] Step 4. DIPEA (2.79 g, 3.77 mL, 21.58 mmol, Aldrich) was added to a suspension of methyl 6-chloro-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate (1.89 g, 7.19 mmol) in DMSO (15 mL), followed by (2,4-dimethoxyphenyl)methylamine (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 organic compounds were dried over Na₂SO₄, filtered, and concentrated to give methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate (2.18 g, 5.54 mmol, 77% yield) as a yellow solid, and used as is. m / z (ESI): 394 [M+H] + .

[0635] Step 5. Add 10 mL of NaOH (10.00 mmol) to a solution of methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate (2.18 g, 5.54 mmol) in THF / MeOH (10 / 10 mL), and heat the resulting solution at 70 °C for 2 h. When the reaction is complete, allow it to reach room temperature and acidify with 10 mL of 1 M HCl. Filter off the pale yellow precipitate and azeotropically dry it to toluene to give 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate as a yellow solid (1.44 g, 3.46 mmol, 62.5% yield). m / z (ESI): 380.2 [M+H] + .

[0636] Intermediate 138: 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylic acid.

[0637]

[0638] Step 1. A mixture of 3-furanic 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) 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 the mixture was 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, used as is. m / z (ESI): 277 (M+H) + .

[0639] 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), tripotassium phosphate (4.44 g, 25.5 mmol, Acros Corporation), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(ii) dichloride (0.347 g, 0.425 mmol, Strem Chemicals Ltd.) in dichloromethane in 1,4-dioxane / water (20 / 1.20 mL) was heated at 90 °C for 1 h. The mixture was then allowed to reach room temperature and diluted with EtOAc. A precipitate corresponding to the desired product was formed. This precipitate was filtered and washed with EtOAc. A gray solid, methyl 4-oxo-1,3,4,5-tetrahydrofurano[3,4-c][1,7]naphthyl-8-carboxylate, was obtained. m / z(ESI): 247(M+H) + Theoretical yield was taken into account.

[0640] Step 3. A mixture of methyl 4-oxo-1,3,4,5-tetrahydrofurano[3,4-c][1,7]naphthyl-8-carboxylate (2.0 g, 8.12 mmol) and POCl3 (32.9 g, 20 mL, 215 mmol, Aldrich) was heated to reflux for 3 h. The reaction was allowed to reach room temperature and carefully added to cold saturated NaHCO3 to alkalize the reaction. After stirring for 15 min, the mixture was extracted with EtOAc, and the combined organic matter was concentrated to give methyl 4-chloro-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate. m / z (ESI): 265 (M+H) + Theoretical yield was taken into account.

[0641] Step 4. Add DIPEA (3.15 g, 4.26 mL, 24.37 mmol, Aldrich) to a mixture of methyl 4-chloro-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate (2.15 g, 8.12 mmol) in DMSO (20 mL), followed by (2,4-dimethoxyphenyl)methylamine (1.630 g, 1.464 mL, 9.75 mmol, Aldrich). Heat the resulting mixture at 90 °C overnight. Allow the reaction to reach room temperature, dilute with water, and extract with EtOAc. The combined organic compounds were analyzed by silica gel chromatography in heptane at a concentration of 0-30% 3:1 EtOAc / EtOH to yield a brown solid, methyl 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate (0.500 g, 1.264 mmol, 15.57% yield). m / z (ESI): 396 (M+H) + .

[0642] Step 5. Add NaOH (5.0 mL, 5.00 mmol, EDM) to a solution of methyl 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate (0.500 g, 1.264 mmol) in THF / MeOH (10 / 10 mL), and heat the resulting solution at 70 °C for 2 h. Then, allow the reaction to reach room temperature and acidify with 1 M HCl (5 mL). Concentrate the resulting mixture and azeotropically dry it to toluene to give 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate as a brown solid. m / z (ESI): 382 (M+H) + Theoretical yield was taken into account.

[0643] The acids in Table 5 are prepared in a manner similar to that described for intermediates 132 and 138.

[0644] Table 5

[0645]

[0646]

[0647]

[0648] Intermediate 146: 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid

[0649]

[0650] Step 1: At room temperature under a nitrogen atmosphere, methyl 2-hydroxyacetate (42.4 mL, 555 mmol, 1.0 equivalence) was added to a suspension of sodium hydride (11.10 g, 278 mmol, 0.5 equivalence, 60% in mineral oil) in anhydrous tetrahydrofuran (250 mL). The mixture was then slowly added to the reaction mixture (E)-but-2-acrylonitrile (54.5 mL, 666 mmol, 1.0 equivalence) 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 approximately 1 and extracted with dichloromethane (2 x 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 with hexane as the eluent to give 2-methyl-4-oxotetrahydrofuran-3-carboxynitrile (22 g, 176 mmol, 32% yield) as a brown solid. The R of the product... f : 0.3 (in hexane, 50% ethyl acetate) m / z (ESI, negative): 124.3 [M-1]. 1 ¹H NMR (400MHz, chloroform-d): δppm 4.40-4.27 (m, 2H), 4.26-4.19 (m, 1H), 3.24-2.99 (m, 1H), 1.61 (dd, J = 18.6, 6.2Hz, 3H).

[0651] Step 2: At -78°C, DIPEA (69.8 mL, 400 mmol, 2.0 equivalent) and trifluoromethanesulfonic anhydride (47.1 mL, 280 mmol, 1.4 equivalent) were added to a stirred solution of 2-methyl-4-oxotetrahydrofuran-3-carboxynitrile (25.0 g, 200 mmol, 1.0 equivalent) in dichloromethane (500 mL), and the mixture was stirred for 15 min at the same temperature. The reaction mixture was quenched by the slow addition of water (250 mL) and extracted with dichloromethane (2 x 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 and filtered in diethyl ether. The mother liquor was concentrated under reduced pressure to give 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (35.0 g, crude) as a light brown adduct. This crude substance was used in the next step without further purification. R of the product f : 0.5 (40% ethyl acetate in hexane). m / z: 257.1 [non-ionizing].

[0652] Step 3: Under a nitrogen atmosphere, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate (37.7 g, 136 mmol, 1.0 equivalent) and tripotassium phosphate (87 g, 408 mmol, 3.0 equivalent) were added to a stirred solution of 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (35 g, 136 mmol, 1.0 equivalent) in 1,4-dioxane (1400 mL) and water (70.0 mL). The reaction mixture was degassed with nitrogen for 15 min, then PdCl2(dppf)-DCM adduct (9.96 g, 13.61 mmol, 0.1 equivalent) was added, and the reaction mixture was heated at 90 °C for 16 h. LC-MS indicated that the reaction was complete. The reactants were 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 with hexane as the eluent to give methyl 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate as a brown solid (25 g, 97 mmol, 71% yield). Product R f 0.3 (100% ethyl acetate). m / z: 259.2 [M+H] +1 H NMR (400MHz, DMSO-d6): δ8.11(d,J=2.0Hz,1H),8.00(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.8Hz,1H ), 6.87 (s, 2H), 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).

[0653] Step 4: Lithium hydroxide (9.64 g, 403 mmol, 4.0 equivalence) was added to a stirred solution of methyl 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate (26.0 g, 101 mmol, 1.0 equivalence) in tetrahydrofuran (130 mL), methanol (78 mL), and water (52 mL), and the mixture was stirred at 75 °C for 4 h. LCMS indicated 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 with concentrated HCl (pH 6 to 6.5). 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 a grayish-white solid. Product R f 0.1 (100% ethyl acetate). m / z: 245.1 [M+H] + 1HNMR (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)

[0654] Step 5: Chiral SFC separation: 44.5 g of racemic 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid was separated by chiral SFC to obtain 14 g of each isomer. Stereochemistry was arbitrary.

[0655] Separate information:

[0656]

[0657]

[0658] The acids in Table 6 are prepared in a manner similar to that described for intermediate 146.

[0659] Table 6

[0660]

[0661] Intermediate 151: 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid

[0662]

[0663] Step 1: At -78°C, potassium tert-butoxide (1M solution in THF; 732 mL, 732 mmol, 1.1 equivalents) was added to a stirred solution of diethyl(cyanomethyl)phosphonate (130 g, 732 mmol, 1.1 equivalents) in tetrahydrofuran (2000 mL), and the mixture was stirred for 30 min. At -78°C, 2-(benzyloxy)acetaldehyde (100 g, 666 mmol, 1.0 equivalents) was added to the reaction mixture, and the mixture was heated 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 × 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 containing petroleum ether as the eluent to give 4-(benzyloxy)but-2-ene acrylonitrile (100.6 g, 87% yield) as a colorless oil. The product's R... f 0.5 (30% ethyl acetate in hexane). m / z: 174.1 [M+H] +. 1 ¹H NMR (chloroform-d, 400MHz): 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 showed a mixture of isomers.

[0664] Step 2: At room temperature, methyl 2-hydroxyacetate (22.03 mL, 289 mmol, 1.0 equivalent) was added to a stirred solution of potassium tert-butoxide (1 M solution in THF; 289.0 mL, 289 mmol, 1.0 equivalent) in tetrahydrofuran (260 mL), and the mixture was heated to 50 °C under a nitrogen atmosphere. 4-(benzyloxy)but-2-enonitrile (50.0 g, 289 mmol, 1.0 equivalent) was added, and the mixture was stirred at the same temperature for 4 h. The reaction was monitored by TLC. The reaction temperature was increased to 70 °C, and the mixture was 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 x 200 mL), acidified with concentrated HCl (until pH approximately 1-2), and then extracted with DCM (2 x 500 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 26% ethyl acetate with petroleum ether as the eluent to give 2-((benzyloxy)methyl)-4-oxotetrahydrofuran-3-carboxynitrile (9.2 g, 14% yield) as a colorless oil. The product's R... f 0.2 (80% ethyl acetate in hexane). LCMS (ESI, positive) m / z: 232.0 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 7.41–7.28 (m, 5H), 4.83–4.60 (m, 2H), 4.52 (dd, J = 11.8, 6.6 Hz, 1H), 4.33 (dd, J = 17.0, 9.0 Hz, 1H), 4.11–3.89 (m, 2H), 3.82–3.68 (m, 2H).

[0665] Step 3: At -78°C under a N2 atmosphere, trifluoromethanesulfonic anhydride (6.75 mL, 40.1 mmol, 1.6 equivalence) and DIPEA (8.76 mL, 50.2 mmol, 2.0 equivalence) were added to a stirred solution of 2-((benzyloxy)methyl)-4-oxotetrahydrofuran-3-carboxynitrile (5.8 g, 25.08 mmol, 1.0 equivalence) in dichloromethane (116 mL), and the mixture was stirred for 10 min. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was washed with diethyl ether (200 mL) and filtered. The organic layer was concentrated under reduced pressure to give 7.65 g of 5-((benzyloxy)methyl)-4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate, a light brown liquid, which was used as is in the next step. The product's R... f : 0.4 (40% ethyl acetate in hexane).

[0666] Step 4: At room temperature, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yltrifluoromethanesulfonate (7.65 g, 20.93 mmol, 1.0 equivalent) and potassium carbonate (8.68 g, 62.8 mmol, 3.0 equivalent) were added to a stirred solution of 5-((benzyloxy)methyl)-4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (7.65 g, 20.93 mmol, 1.0 equivalent) in 1,4-dioxane (232 mL) and water (11.60 mL). The reaction mixture was purged with N2 for 15 min, and then Pd(PPh3)4 (1.209 g, 1.046 mmol, 0.05 equivalent) was added. The reaction mixture was heated at 80 °C for 16 h. 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 with petroleum ether as eluent to give 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate as a grayish-white solid (4.4 g, 58% yield). The product's R... f 0.2 (in 100% ethyl acetate in hexane). LCMS (ESI, cation / anion) m / z: 365.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.12(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).

[0667] Ester 151 was treated with LiOH in THF (similar to step 4 of intermediate 146), and the crude lithium salt of 151 was used in the amide coupling reaction.

[0668] Intermediate 152: 4-Aminoimidazo[1,2-a]quinoxaline-8-carboxylic acid

[0669]

[0670] Step 1: At room temperature, DIPEA (2.35 mL, 13.43 mmol, 2.5 equivalents) was added to a stirred suspension of methyl 3-fluoro-4-nitrobenzene (1.07 g, 5.37 mmol, 1.00 equivalent) and 1H-imidazolium-2-carboxynitrile (0.500 g, 5.37 mmol, 1.0 equivalent) in dimethyl sulfoxide (5.00 mL), and the reaction mixture was stirred for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain a crude product, which was 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-nitrobenzene ester (1.20 g, 4.41 mmol, 82% yield) as a pale brown solid. m / z: 273.1 [M+H] + .

[0671] Step 2: At room temperature, acetic acid (0.946 mL, 16.53 mmol, 5.0 equivalent) and iron powder (1.85 g, 33.1 mmol, 10.0 equivalent) were added to a stirred solution of methyl 3-(2-cyano-1H-imidazol-1-yl)-4-nitrobenzene (0.900 g, 3.31 mmol, 1.0 equivalent) in tetrahydrofuran (10.0 mL) and water (2.00 mL). The reaction mixture was stirred for 16 hours. The reaction mixture was then diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The organic layer was then concentrated, and the residue was recrystallized using EtOAc to give methyl 4-aminoimidazo[1,2-a]quinoxaline-8-carboxylate (350 mg, 1.45 mmol, 44% yield) as a pale yellow solid. m / z: 243.1 [M+H] + .

[0672] Step 3: At 0 °C, lithium hydroxide monohydrate (0.450 g, 10.7 mmol, 4.0 equivalent) was added to a suspension of methyl 4-aminoimidazo[1,2-a]quinoxaline-8-carboxylic acid ester (0.650 g, 2.68 mmol, 1.0 equivalent) in a mixture of tetrahydrofuran (12.0 mL), methanol (4.00 mL), and water (4.00 mL). The reaction mixture was then heated to 60 °C for two hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was diluted with water and acidified to pH 6 with 1.50 N HCl solution. A grayish-white solid precipitate was formed, which 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 a grayish-white solid. m / z: 228.9 [M+H] + .

[0673] Intermediate 153: 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0674]

[0675] Step 1: At room temperature, bromine (5.01 mL, 97.0 mmol, 3.0 equivalence) and sodium acetate (10.6 g, 130 mmol, 4.0 equivalence) were added to a solution of ethyl 5-methyl-1H-pyrazole-4-carboxylate (5.00 g, 32.4 mmol, 1.0 equivalence, Combibloc) in acetic acid (100 mL). The reaction mixture was 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] + .

[0676] Step 2: At 0 °C, DHP (2.26 mL, 24.7 mmol, 1.2 equivalents) and toluenesulfonic acid (0.78 g, 4.12 mmol, 0.2 equivalents) were added to a stirred solution of ethyl 3-bromo-5-methyl-1H-pyrazole-4-carboxylate (4.80 g, 20.6 mmol, 1.0 equivalent) in dichloromethane (15 mL). The resulting reaction mixture was stirred for 16 h until complete. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aqueous brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude substance was purified by chromatography (silica gel, 40% ethyl acetate in hexane) to give ethyl 3-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate as a colorless, viscous liquid (4.80 g, 15.1 mmol, 73.5% yield). m / z: 314.9, 317.0 [M+H] + .

[0677] Step 3: Ethyl 3-bromo-5-methyl-1-(tetramethyl-1,3,2-dioxane-2-yl)benzoate (7.34 g, 26.5 mmol, 1.2 equivalents, LabNetwork) was added to a stirred solution of methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-pyrazole-4-carboxylate (7.00 g, 22.1 mmol, 1.0 equivalents) and tripotassium phosphate (9.36 g, 44.1 mmol, 2.0 equivalents) in 1,4-dioxane (112 mL) and water (28.0 mL), and the mixture was purged with nitrogen for 10 min at room temperature. Then, Pd(amphos)Cl2 adduct (0.781 g, 1.10 mmol, 0.05 equivalents) was 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 give 7.00 g of crude ethyl 5-(2-amino-5-(methoxycarbonyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate.

[0678] DBU (2.00 mL, 13.3 mmol, 12 equivalents) was added 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 equivalent) in 1,4-dioxane (9.60 mL) and water (2.40 mL) at room temperature under nitrogen atmosphere, 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 obtain a crude product. The crude product was purified by column chromatography (silica gel, 5% MeOH in DCM) to yield 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] +

[0679] Step 4: 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 equivalent) in dichloromethane (3.00 mL) was added. Trifluoromethanesulfonic anhydride (992 mg, 3.52 mmol, 2.0 equivalent) and DIPEA (921 μL, 5.27 mmol, 3.0 equivalent) were then 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.

[0680] DIPEA (332 μL, 1.90 mmol, 3.0 equivalent) was added to a stirred solution of 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 equivalent) in N,N-dimethylacetamide (2.00 mL). Then (4-methoxyphenyl)methylamine (130 mg, 0.950 mmol, 1.5 equivalent) was 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 obtain a crude product. The crude product was purified by column chromatography (silica gel, 50% EtOAc:hexane) 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] +

[0681] 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 equivalent) in trifluoroacetic acid (28.0 mL) was heated at 90 °C for 12 h. 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] + .

[0682] Step 6: At room temperature, methyl 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (3.50 g, 13.7 mmol, 1.0 equivalent) was added to a stirred solution of tetrahydrofuran (35.0 mL), methanol (35.0 mL), and water (35.0 mL). Lithium hydroxide monohydrate (4.02 g, 96.0 mmol, 7.0 equivalent) was then added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water, and a solid precipitate 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] + .

[0683] Intermediate 154: Lithium hydroxide 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate

[0684]

[0685] Step 1. Add K3PO4·H2O (1.08 g, 4.70 mmol, Sigma-Aldrich), X-Phos (0.08 g, 0.16 mmol, Sigma-Aldrich), (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), 1-methyl-5- (4,4,5,5-Tetramethyl-1,3,2-dioxane-2-yl)-1h-pyrazol-4-carboxylonitrile (1.10 g, 4.70 mmol, Annamin) and methyl 4-amino-5-bromo-2-(trifluoromethyl)benzoate (0.700 g, 2.349 mmol, Combilot) were suspended in a degassed mixture of water (1.0 mL) and 1,4-dioxane (5.0 mL) and stirred overnight at 60 °C, followed by stirring at 90 °C for 18 h. The volatiles were removed under vacuum, and the crude product was purified by silica gel column chromatography (0 to 5% MeOH / DCM + 0.5% NH3 / MeOH) to produce methyl 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate as a light brown solid (0.63 g, 1.94 mmol, 83% yield). m / z (ESI): 324.8 [M+H] + . 1H NMR (400MHz, DMSO-d6) δppm 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) δppm-58.06.

[0686] 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) were suspended in methanol (3.0 mL), H₂O (3.0 mL), and THF (3.0 mL) and stirred at 50 °C for 2 hours. The volatiles of the crude mixture were removed under vacuum, and the light brown solid was co-evaporated twice with DCM, followed by co-evaporation with toluene, to give lithium hydroxide 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (585 mg, 1.720 mmol, 91% yield), which was used in subsequent steps without further purification. m / z (ESI): 310.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 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) δppm-57.47.

[0687] Example

[0688] Example 300: Preparation of (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(pyrimidin-2-yl)morpholino)methyl ketone

[0689]

[0690] 3-(pyrimidin-2-yl)morpholine (35, 0.20 g, 1.21 mmol) and 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (100, 0.33 g, 1.45 mmol) in N,N-dimethylacetamide (6.0 mL) were added to the reaction mixture. Tripyrrolidine bromophosphonium hexafluorophosphate (0.56 g, 1.21 mmol, Sigma-Aldrich) and triethylamine (0.61 g, 0.9 mL, 6.05 mmol, Sigma-Aldrich) were then added to the reaction mixture. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by chromatography using an Interchim (15 μm) silica gel column (40 g) (eluted with a 0–35% MeOH gradient in DCM). The product was collected and then purified by reversed-phase HPLC: purification was performed using 0.1% NH4OH in H2O (A) and ACN (B) as the mobile phase and an XBridge column (19 x 100 mm, 5 μm). This yielded (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(pyrimidin-2-yl)morpholino) methyl ketone as a white solid (0.120 g, 0.318 mmol, 26% yield). 1 H NMR (400MHz, DMSO-d6) δppm 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] + .

[0691] The examples in Table 7 were prepared using the amide coupling reagents shown in the table in a manner similar to that described above for Example 300.

[0692] Table 7

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748] Examples 452 and 453: ((R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((S)-3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone and ((S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((S)-3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone

[0749]

[0750] A mixture of (S)-3-(4-(trifluoromethyl)phenyl)morpholine (0.079 g, 0.342 mmol, PharmaBlock Science, Nanjing, China), 4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate (0.125 g, 0.444 mmol, acid 149), HATU (0.169 g, 0.444 mmol, Combibloc), 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 aqueous solutions of EtOAc and Na2CO3. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel chromatography: 0–100% EtOAc / EtOH (3 / 1) in heptane. A racemic product was obtained as a grayish-white solid (0.108 g, 69%). m / z (ESI): 459 [M+H] + .

[0751] 100 mg of the racemic product was purified by preparative SFC using a Chiral Technologies OJ column (250 x 21 mm, 5 mm) (mobile phase: 75% liquid CO2 and 25% MeOH with 0.2% TEA, flow rate: 80 mL / min) to produce peak 1 at 39.7 mg (ee >99%) and peak 2 at 40.5 mg (ee 99.8%). Peak partitioning was determined by SFC using an OJ column (with 25% MeOH containing 0.2% TEA). Stereochemical partitioning was arbitrary.

[0752] Peak 1: 1H NMR(500MHz,DMSO-d6)δppm 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).

[0753] Peak 2: 1 H NMR(500MHz,DMSO-d6)δppm 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).

[0754] The examples in Table 8 were prepared using the amide coupling reagents and purification conditions shown in the table, in a manner similar to those described above for Examples 452 and 453.

[0755] Table 8

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765] Examples 481 and 482: (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methyl ketone

[0766]

[0767] Step 1: Add bromotripyrroleylphosphonium hexafluorophosphate (0.202 g, 0.432 mmol, Sigma-Aldrich) to a solution of 3-(4-(trifluoromethyl)phenyl)morpholine (0.100 g, 0.432 mmol, Annamin), 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylate (138) (0.271 g, 0.649 mmol) and 1,1'-dimethyltriethylamine (0.559 g, 0.755 mL, 4.32 mmol, Sigma-Aldrich) in DMF (4 mL), and heat the resulting mixture at 50 °C for 30 min. Allow the reaction to reach room temperature, dilute with water and saturated NaHCO3, and extract with EtOAc (3x). Dry the combined organics in Na2SO4, filter, and concentrate. The residue was then subjected to silica gel chromatography in heptane at a concentration of 0-50% 3:1 EtOAc / EtOH to yield a pale yellow solid (4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone (0.160 g, 0.269 mmol, 62.2% yield). m / z (ESI): 595 (M+H) + .

[0768] TFA (14.80 g, 10 mL, 130 mmol, Aldrich) was added to a solution of (4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7]-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) ketone (0.160 g, 0.269 mmol, 62.2% yield) in DCM (2 mL), 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 organic compounds were concentrated and analyzed by silica gel chromatography in heptane at a concentration of 0-50% 3:1 EtOAc / EtOH to yield a grayish-white solid as a TFA salt, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone (0.078 g, 0.140 mmol, 32.3% yield). m / z (ESI): 445 (M+H) + .

[0769] Step 2: (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone and (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone

[0770] (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methyl ketone 2,2,2-trifluoroacetate was prepared using a preparative SFC via Chiral Technologies. AD column (150x21mm, 5mm) (mobile phase: 60% liquid CO2 and 40% MeOH with 0.2% TEA, flow rate: 80 mL / min) separation yielded peak 1, (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone (ee >99%), and peak 2, (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone (ee 99.28%). Peak partitioning was determined by SFC using AD column (60% liquid CO2 and 40% MeOH with 0.2% TEA) and absolute stereochemistry was arbitrary.

[0771] Peak 1: (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methyl ketone (481), a white solid. m / z (ESI): 445 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δppm 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(brs,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) δppm-60.90 (br s, 3F).

[0772] Peak 2: (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methyl ketone (482), a white solid. m / z (ESI): 445 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 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,3F).

[0773] Example 483: Racemic-(4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone

[0774]

[0775] Example 483 was prepared in a racemic manner similar to that of compound 481 described above. m / z (ESI): 445.1 [M+H] +

[0776] Example 484: (5-amino-2,4-dihydro-1H-pyrano[3,4-c]quinoline-9-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone

[0777]

[0778] Example 484 was prepared using commercially enantiomeric pure (3S)-3-[4-(trifluoromethoxy)phenyl]morpholine hydrochloride (NetChem, CAS No. 1391448-60-4) in a racemic manner similar to that of compound 481 above. m / z (ESI): 474.0 [M+H] +

[0779] The following examples are prepared in a manner similar to that described for examples 481 and 482.

[0780] Table 9

[0781]

[0782]

[0783]

[0784] Example 491: (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholino) methyl ketone

[0785]

[0786] Step 1. Add 4M HCl (1.62 mL, 6.49 mmol) in 1,4-dioxane to a stirred suspension of 4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylic acid (500 mg, 2.163 mmol) in CH2Cl2 (10.0 mL), and stir the resulting suspension at room temperature for 30 min. Concentrate the mixture under reduced pressure and then co-evaporate with toluene (2 x 5 mL). Resuspend the obtained crude material in dichloromethane (20.0 mL), cool to 0 °C, and treat with oxaloyl chloride (2.0 M in CH2Cl2, 4.33 mL, 8.65 mmol), followed by treatment with DMF (5 drops). Purge the reaction vessel with nitrogen and stir the reaction mixture overnight at room temperature under nitrogen. After 16 h, the reaction mixture was concentrated under reduced pressure, and the resulting crude residue was washed with heptane (30 mL) and dried under vacuum to give 4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carbonyl chloride hydrochloride as a brown solid (463 mg, 1.62 mmol, 75% yield); after quenching the aliquots with MeOH, the m / z (ESI) of the corresponding methyl ester was observed to be 246.1 [M+H]. + .

[0787] Step 2. In a vial, (3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholine (35.9 mg, 0.172 mmol), 4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carbonyl chloride hydrochloride (63.8 mg, 0.223 mmol), and dichloromethane (3.43 mL) were added. N,N-diisopropylethylamine (111 mg, 150 μL, 0.858 mmol) was added to the resulting suspension, and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding saturated NaHCO3 aqueous solution (10 mL), transferred to a separatory funnel containing brine (10 mL) and CH2Cl2 (20 mL), and extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude residue was purified by rapid chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to give (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-methoxypyridazin-3-yl)-5-methylmorpholino) methyl ketone as a grayish-white solid (59.8 mg, 0.142 mmol, 83% yield). 1 H NMR (400MHz, chloroform-d) δppm 9.03(br s,1H),7.94(brs,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] + .

[0788] The following examples are prepared in a manner similar to that described for example 491.

[0789] Table 10

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810] Examples 566 and 567: (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino) methyl ketone.

[0811]

[0812] A mixture of 4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidine-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 according to the procedure described in Bode, JW et al.; Org. Lett. [Organic Chemistry Communications]; 2014, pp. 1236-1239) was stirred in THF (1.9 mL) for 4.5 h. The reaction was then concentrated, and the residue was dissolved in DMSO and purified by reversed-phase preparative HPLC (C18, 10% to 100% MeCN:water (+0.1% TFA)) to give racemic (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methyl ketone (2,2,2-trifluoroacetate) (80 mg, 0.055 mmol, 49% yield). This racemic mixture was then subjected to chiral separation. The sample was purified by SFC using a Chiralpak IC column (250 x 21 mm, 5 μm) (modified with 25% MeOH + TEA at a flow rate of 100 mL / min). 70 mg of the submitted sample was dissolved in 10 mL of MeOH:DCM 1:1 (7 mg / mL). Peak 1 (16.7 mg, ee > 99%, chemical purity > 99%) and peak 2 (20.6 mg, ee > 99%, chemical purity > 99%) were separated from the dissolved sample and then arbitrarily designated as the cis-enantiomer (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidium-8-yl)((3S,5R)-3-isobutyl-5-(4-(trifluoromethyl)) (Phenyl)morpholino)methyl ketone 2 (peak 1, chiral column) (17 mg, 0.033 mmol, 17% yield) and (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)morpholino)methyl ketone 3 (peak 2, chiral column) (21 mg, 0.041 mmol, 22% yield). 1H NMR (400MHz, methanol-d4) δppm 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] + .

[0813] The examples in Table 11 were prepared in a manner similar to that described for examples 566 and 567.

[0814] Table 11

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829] Example 623: (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-1-oxy-3-(4-(trifluoromethyl)phenyl)thiomorpholino) methyl ketone.

[0830]

[0831] At room temperature, 3-chloroperoxybenzoic acid (36.5 mg, 0.163 mmol, Sigma-Aldrich) was added to a solution of (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)(3-(4-(trifluoromethyl)phenyl)thiomorpholino) ketone (30 mg, 0.065 mmol) in 1.5 mL of DCM. The mixture was stirred at room temperature for 2 h (LCMS showed the formation of a mixture of sulfones and sulfoxides), 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% 0.1% TFA-mediated CH3CN in water) to give a grayish-white solid (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-1-oxo-3-(4-(trifluoromethyl)phenyl)thiomorpholino)methyl ketone 2,2,2-trifluoroacetate (2 mg, 3.39 μmol, 5.2% yield). m / z (ESI): 476.9 [M+H] + . 19 F NMR (methanol-d4, 376MHz) δ -64.16 (s, 3F), -77.26 (s, 3F). 1 ¹H 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 = 3.9 Hz, 2H), 4.05 (dd, J = 5.4, 13.2 Hz, 1H), 3.45 (m, 3H), 3.13 (m, 2H).

[0832] Example 624: (S)-1-(4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidium-8-carbonyl)-3-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl-1-one.

[0833]

[0834] At 0 °C, acetic anhydride (13.81 mg, 0.135 mmol, Sigma-Aldrich) was added to a solution of (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(2-(4-(trifluoromethyl)phenyl)piperazin-1-yl) methyl ketone (50 mg, 0.113 mmol) in 1.5 mL of DCM, followed by the addition of triethylamine (31.7 μL, 0.226 mmol, Sigma-Aldrich). The mixture was stirred at 0 °C for 20 min, followed by stirring at room temperature for 10 min, and then partitioned between 1 mL of 0.5 NNaOH 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% 0.1% TFA-mediated CH3CN in water) to give (S)-1-(4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidium-8-carbonyl)-3-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl-1-one bis(2,2,2-trifluoroacetate) as a brown solid (55 mg, 0.077 mmol, 68.4% yield). 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 is a mixture of rotational isomers (1 / 3 ratio). 1 H NMR(DMSO-d6,400MHz)δ9.00(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).

[0835] Example 625: (S)-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methylthione

[0836]

[0837] A mixture of Lawesson's reagent (63.8 mg, 0.158 mmol, Aldrich) and (S)-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methylthione (70 mg, 0.158 mmol) in 1 mL of THF was microwaved at 95 °C for 6 h in a sealed glass tube. The crude mixture (10%–90% 0.1% TFA-mediated CH3CN in water) was purified by RP-HPLC to give (S)-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methylthione 2,2,2-trifluoroacetate as a yellow solid (69.7 mg, 0.122 mmol, 77% yield). m / z(ESI): 460.3 [M+H] + . 19 F NMR (methanol-d4, 376MHz) δ -64.14 (s, 3F), -77.05 (s, 3F). 1 H NMR (400MHz, methanol-d4) δppm 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).

[0838] Example 626: (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)meththione

[0839]

[0840] Example 626 was prepared in the same manner as Example 625. m / z(ESI): 461.10 [M+H] +

[0841] HCT116 proliferation activity

[0842] To evaluate the selective antiproliferative activity of the compounds of this invention in cells lacking MTAP expression, an HCT-116 allogeneic cell line pair was used, one of which was engineered to knock out two MTAP alleles. Cell viability was then assessed in both the parental HCT-116 cell line and the MTAP-nulling cell line after 6 days of treatment with the compounds of this invention. The selective antiproliferative activity in the MTAP-nulling cell line demonstrates the ability of PRMT5 to synergistically inhibit MTAP and suppress the growth of cancer cells lacking MTAP.

[0843] HCT116MTAP-ineffective and WT cells were seeded in 96-well tissue culture plates in RPMI 1640 medium plus 10% fetal bovine serum. The plates were incubated overnight at 37°C and 5% CO2. Cells were then treated with 8- or 9-point serially diluted compounds (using the highest concentration of 1 μM or 10 μM, 1:3 serial dilution steps) and a control of DMSO only. Cells were incubated for 6 days in the presence of the drug. Use according to the manufacturer's recommendations. The effect of luminescent cell viability assay (Promega) on cell viability was measured. The analysis plate was read on an EnVision™ multi-label reader using an ultrasensitive luminescence module. IC50 was calculated by fitting the dose-response curve using GraphPad Prism v 5.01 with a symmetric sigmoid dose-response least-squares fit (with a fixed Hill slope of -1 and a top constraint of 100%) or by fitting the dose-response curve using a 4-parameter logistic model with GeneData Screener. 50 value.

[0844] Alternatively, compounds can be analyzed using a 384-well plate format:

[0845] The compound (serially diluted 22 times, using the highest concentration of 10 μM or 50 μM, 1:2 serial dilution steps) and a control of DMSO alone were pre-spotted into 384-well plates. Then, HCT116MTAP null and WT cells were seeded as above, and after 6 days, CellTiter- The effect of luminescent cell viability assay (Promega) on cell viability was measured. The analysis panel was read as above, and the IC50 was calculated using a 4-parameter logistic model fitted to the dose-response curve using GeneData Screener. 50 Value. Reported IC 50 This indicates the value of the curve after a 50% control.

[0846] Table 12. HCT116-MTAP ineffectiveness and WT cell line proliferation

[0847]

[0848]

[0849]

[0850]

[0851]

[0852] All publications and patent applications cited in this specification are incorporated herein by reference in their entirety, and for all purposes, as each individual publication or patent application is precisely and individually indicated as incorporated by reference, and each document is fully set forth in its entirety. Although the foregoing invention has been described in considerable detail by way of illustration and example for the purposes of clarity, it will be readily apparent to those skilled in the art, based on the teachings of the invention, that certain changes and modifications may be made to the invention without departing from the spirit or scope of the appended claims.

Claims

1. A compound having Formula I I Its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing: Where R 1 R 2 They form five- or six-membered rings with the nitrogen atoms to which they are attached. These five- or six-membered rings may be saturated or partially saturated and contain 0, 1 or 2 additional heteroatoms selected from O, N or S, which may be the same or different heteroatoms, wherein the S atom may optionally be replaced by one or two oxo groups. Among them, R 1 R 2 The rings formed by the nitrogen atoms to which they are attached can have 0, 1, 2, or 3 R atoms. 3 replace; Where R 3 In each case, select C. 1-6 Alkyl, Halogenated, C 1-6 Halogenated alkyl groups, -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 The alkyl halide and a five- or six-membered ring, which may be saturated, partially saturated, or aromatic, and contains 0, 1, or 2 identical or different heteroatoms selected from O, N, and S, wherein the ring may optionally be separated by one or more R atoms. a replace, Where R a In each case, it is selected from halogen, CN, C. 1-6 Alkyl, C 1-6 Halogenated alkyl, pentafluorosulfonyl, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups; Where R is a three-ring selected from formulas IA and IB: IA and ONE, in Is it a single or double bond? X1 and X2 are each selected from N and C, respectively, where X1 and X2 cannot both be N; and if X1 is C, it can be arbitrarily selected by C. 1-3 Alkyl or halogenated substitutions; X6, X7, and X8 are each independently selected from optionally substituted N and optionally substituted C, wherein the substituents on N and C are independently selected from C. 1-3 alkyl; X6 and X7, as well as X7 and X8, cannot both be N at the same time; X3, X4, and X5 are each selected from O, S, optionally substituted C, and optionally substituted N, wherein these substituents on C and N are independently selected from C. 1-3 Alkyl and C 1-3 Alkyl-OH, wherein the alkyl group may optionally be halogenated.

2. The compound of claim 1, its tautomers, its stereoisomers, or the pharmaceutically acceptable salt of claim 1, wherein... a) R is 、 、 or ;or b) R is a three-ring structure with the formula IB. ONE, Where X 1 It is N and X 7 It is N.

3. The compound of claim 2, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing. Where X1 is C, which is optionally halogenated, or Where X1 is N.

4. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of claims 1-3, wherein R 1 R 2 They form a six-membered ring with the nitrogen atoms to which they are attached. The six-membered ring may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms selected from O, N or S.

5. The compound of claim 4, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein the six-membered ring is , , or .

6. The compound of claim 5, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein the six-membered ring is or .

7. The compound of claim 5 or 6, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 Selected independently from C in each case 1-6 Alkyl, halogenated, and five- or six-membered rings, which may be saturated, partially saturated, or aromatic, and contain 0, 1, or 2 heteroatoms selected from O, N, and S.

8. The compound of claim 7, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 It is phenyl, pyridyl, pyridazinyl, or pyrimidinyl, optionally with one or more R... a replace.

9. The compound of claim 8, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a In each case, it is selected from halogen, CN, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups.

10. The compound of claim 8 or 9, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 It was R a Substituted phenyl, wherein R a It is C 1-6 Halogenated alkyl groups.

11. The compound of claim 10, wherein R a In every case, it is C. 1-6 Halogenated alkyl or -OC 1-3 Halogenated alkyl groups.

12. The compound of claim 11, wherein... yes .

13. Selected from the following compounds, their tautomers, stereoisomers of any of the foregoing, or pharmaceutically acceptable salts of any of the foregoing: (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2R,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2S,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((2S,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aR,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aR,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aR,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,7aR)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,3aS,7aS)-3-phenylhexahydropyrano[4,3-b]pyrrole-1(4H)-yl)methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,4R)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-azacyclobutane) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((1R,3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((1S,3S)-1-oxido-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4,5-dichloro-2-thiophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(5-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-Amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane-4-yl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane-4-yl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)meththione, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thiomorpholino) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-(trifluoromethyl)-2-thiophenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3R,5S)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyrazin-2-yl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S,5R)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[racemic-(3S)-3-(6-cyclopropyl-3-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[racemic-(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-morpholinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)meththione, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone, (4-Amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone, (4-Amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(3-chlorophenyl)morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(4-chlorophenyl)morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methyl ketone, (4-Amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl)morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl)morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl]methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3R)-3-(6-methyl-3-pyridyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(2-chlorophenyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(3-bromophenyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(3-fluorophenyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-bromophenyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-fluorophenyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-methoxyphenyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(6-bromopyridazin-3-yl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(o-tolyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-phenylmorpholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-pyrimidin-2-ylmorpholin-4-yl]methyl ketone, (4-Amino-1,7-Dimethyl-1H-pyrazolo[4,3-c][1,8]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-Amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-2,3-dihydrofurano[3,2-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-Amino-3,3-dimethyl-1H-furano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, (4-Amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-morpholinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-Amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (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) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridinyl)-1-azacyclobutane) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-Amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-morpholinyl) methyl ketone, (4-Amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-Amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-3,3-dimethyl-4-(4-methylphenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-azacyclobutane) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-yl) methyl ketone, (4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((1S,5R)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-yl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl) methyl ketone, (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) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-((5-(trifluoromethyl)-2-pyridinyl)oxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-fluorophenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (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) methyl ketone, (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) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4S)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-azacyclobutane) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-azacyclobutane) methyl ketone, (4-amino-7-fluoro-2,3-dihydrofurano[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-Amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-4-morpholinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-Amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone, (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) methyl ketone, (4-Aminoimidazo[1,2-a]quinoxalin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (4-Aminothio[2,3-c]quinolin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone, (4-Aminothio[2,3-c]quinolin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone, (4-Aminothio[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (4-Aminothio[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methyl ketone, (5-amino-1,4-dihydro-2H-pyrano[3,4-c]quinoline-9-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholino)methyl ketone, (5-Aminobenzo[c][2,6]naphthid-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl)methyl ketone, (5-Aminopyrido[4,3-c][1,7]naphthid-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (5-aminopyrimidino[4,5-c][1,7]naphthid-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholino)methyl ketone, (5-aminopyrimidino[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone, (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7]naphthid-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone, (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7]naphthid-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-morpholinyl) methyl ketone, (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(pentafluoro-16-thioalkyl)phenyl)morpholino)methyl ketone, (R)-(4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)morpholino)methyl ketone, (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)(3-(4-(pentafluoro-16-thioalkyl)phenyl)morpholino)methyl ketone, [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, [(3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl]methyl ketone, 1-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl)-1-piperazinyl)acetone, 4-((3R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-3-morpholino)benzonitrile, 4-((3R,5S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-5-methyl-3-morpholino)benzonitrile, 4-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-3-morpholino)benzonitrile, 4-((3S,5R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)carbonyl)-5-methyl-3-morpholino)benzonitrile, 4-Chloro-6-[racemic-(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)morpholino-3-yl]pyridine-3-carboxynitrile, 6-[(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)morpholino-3-yl]pyridine-3-carboxynitrile, 6-[(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)morpholino-3-yl]pyridine-3-carboxynitrile, Methyl(3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, Methyl(3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, tert-butyl(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidium-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, and tert-Butyl(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate.

14. The compound of claim 13, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from: (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone; (4-Amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone; [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone; (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone; and (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone.

15. The compound of claim 11, or a pharmaceutically acceptable salt of any of the preceding claims, wherein the compound is selected from: (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridazinyl)-5-methyl-4-morpholinyl) methyl ketone; (4-Amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-sulfonyl)phenyl)-4-morpholinyl) methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]morpholin-4-yl] methyl ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone; [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]morpholin-4-yl] methyl ketone; (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-morpholinyl) methyl ketone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-morpholinyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridazinyl)-4-morpholinyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-pyridazinyl)-4-morpholinyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone; and (4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone.

16. (4-Amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone: Free base.

17. (4-Amino-1,3-dihydrofurano[3,4-c][1,7]naphthid-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methyl ketone: Pharmaceutically acceptable salts.

18. Use of the compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of claims 1 to 17 in the preparation of a medicament, wherein the medicament is used in a method of treating cancer, the method comprising administering to a subject an effective amount of the compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of claims 1 to 17.

19. The use as described in claim 18, wherein the cancer is selected from ovarian cancer, lung cancer, HNSCC, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, pancreatic cancer, or bladder cancer.

20. The use as described in claim 18, wherein the cancer is lung cancer.

21. The use as described in claim 18, wherein the cancer is pancreatic cancer.

22. A pharmaceutical composition comprising a compound as described in any one of claims 1-17, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

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