Novel prmt5 inhibitors and pharmaceutical compositions, uses thereof, and processes for preparing thereof

Abstract

This document describes compounds having Formula I, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds of this invention can be used to inhibit PRMT5 activity and can be used in the treatment of proliferative disorders, metabolic diseases, and blood disorders. Compounds having Formula I have the following structures:

Description

[Previous Technology]

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

[0002] 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 the configurational transition 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 dysplasia, metabolic disorders, and blood disorders.

[0003] Homozygous loss of tumor suppressor genes is a key driver of cancer, typically leading to the incidental loss of passenger genes located in the genome adjacent to the tumor suppressor. These passenger gene deletions can create therapeutically manageable 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). The elevated MTA levels driven by MTAP loss selectively compete with SAM for binding to PRMT5, leaving the methyltransferase in a sub-dual gene state, vulnerable to further PRMT5 inhibition. Multiple genome-wide drop-out screening of shRNAs 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]

[0004] In one aspect, the present invention provides a compound I having formula I, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing; wherein R1, R2, and the nitrogen atom to which they are attached form a five-, six-, or seven-membered ring, the five-, six-, or seven-membered ring being saturated or partially saturated, and comprising 0, 1, or 2 additional identical or different heteroatoms selected from O, N, or S, wherein the S atom may be substituted with one or two side oxygen groups as desired; wherein the ring formed by R1, R2, and the nitrogen atom to which they are attached may be substituted with 0, 1, 2, or 3 R3s; In each case, R3 is selected from the same or different C1-6 alkyl, halogenated, C1-6 haloalkyl, -OC1-6 alkyl, -OC1-6 haloalkyl, -C(O)C1-6 alkyl, -C(O)C1-6 haloalkyl, -C(O)OC1-6 alkyl, -C(O)OC1-6 haloalkyl, and five- or six-membered rings, which may be saturated, partially saturated, or aromatic, and contain 0, 1, or 2 identical or different heteroatoms selected from O, N, and S, wherein the ring may be substituted by one, two, or three Ra as desired; wherein Ra is selected from halogenated, -CN, C1-6 alkyl, C1-6 haloalkyl, pentafluorohydrosulfide, -OC1-3 alkyl, and -OC1-3 haloalkyl in each case; wherein R is selected from the tricycles of formula IA and IB: IA and IB, wherein it is a single bond or a double bond. X1, X2, X6, X7, and X8 are each selected from N and C that are substituted as desired, wherein the substituents may be selected from C1-3 alkyl groups in each case; wherein X1 and X2 cannot both be N, and X6 and X7, as well as X7 and X8, cannot both be N; wherein if X1 is C, it may be halogenated as desired; X3, X4, and X5 are each selected from C, O, N, and S that are substituted as desired, wherein the substituents may be selected from C1-3 alkyl groups and C1-3 alkyl (OH), wherein the alkyl groups may be halogenated as desired.

[0005] In one aspect, the present invention provides a compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R may be a tricyclic ring having formula IA. In one embodiment, the present invention provides a compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R may be or

[0006] In one embodiment, X1 may be C. In another embodiment, X1 may be halogenated. In one embodiment, the halogenation may be fluorine. In another embodiment, the halogenation may be chlorine.

[0007] In another embodiment, X1 may be N.

[0008] In one embodiment, R2 and R1, and the nitrogen atom to which they are attached, may form a six-membered ring, which may be saturated or partially saturated, and may contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, wherein the six-membered ring is or, wherein R3 is a five-membered 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 be substituted with one, two, or three Ra as desired; and Ra is identical or different in each case, and is selected from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl.

[0009] In one embodiment, the present invention provides a compound having formula IA, wherein R3 may be phenyl, pyridyl, pyridyl or pyrimidyl, and may be substituted by one or more Ra as desired;

[0010] In one embodiment, R3 is a phenyl group, and in another embodiment, R3 is a tert-hydroxyl group.

[0011] In one embodiment, Ra is selected from C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl. In another embodiment, Ra is CF3.

[0012] In another embodiment, R2 and R1, and the nitrogen atom to which they are attached, may form a six-membered ring, which may be saturated or partially saturated, and may contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, wherein the six-membered ring is or, wherein R3 is a five-membered 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 be substituted with one, two, or three Ra as desired; and Ra is identical or different in each case, and is selected from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl.

[0013] In one embodiment, the present invention provides a compound having formula IA, wherein R3 may be phenyl, pyridyl, pyridyl or pyrimidinyl, and may be substituted by one or more Ra as needed;

[0014] In one embodiment, R3 is a phenyl group, and in another embodiment, R3 is a tert-hydroxyl group.

[0015] In one embodiment, Ra is selected from C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl. In another embodiment, Ra is CF3.

[0016] The present invention further provides a compound having formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R may be independently or.

[0017] In one embodiment, X1 may be C. In another embodiment, X1 may be halogenated. In one embodiment, the halogenation may be fluorine. In another embodiment, the halogenation may be chlorine.

[0018] In another embodiment, X1 may be N.

[0019] In one embodiment, R2 and R1, and the nitrogen atom to which they are attached, may form a six-membered ring, which may be saturated or partially saturated, and may contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, wherein the six-membered ring is or, wherein R3 is a five-membered 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 be substituted with one, two, or three Ra as desired; and Ra is identical or different in each case, and is selected from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl.

[0020] In one embodiment, the present invention provides a compound having formula IA, wherein R3 may be phenyl, pyridyl, pyridyl or pyrimidinyl, and may be substituted by one or more Ra as desired;

[0021] In one embodiment, R3 is a phenyl group, and in another embodiment, R3 is a tert-hydroxyl group.

[0022] In one embodiment, Ra is selected from C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl. In another embodiment, Ra is CF3.

[0023] In another embodiment, R2 and R1, and the nitrogen atom to which they are attached, may form a six-membered ring, which may be saturated or partially saturated, and may contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, wherein the six-membered ring is or, wherein R3 is a five-membered 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 be substituted with one, two, or three Ra as desired; and Ra is identical or different in each case, and is selected from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl.

[0024] In one embodiment, the present invention provides a compound having formula IA, wherein R3 may be phenyl, pyridyl, pyridyl or pyrimidinyl, and may be substituted by one or more Ra as needed;

[0025] In one embodiment, R3 is a phenyl group, and in another embodiment, R3 is a tert-hydroxyl group.

[0026] In one embodiment, Ra is selected from C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl. In another embodiment, Ra is CF3.

[0027] In one aspect, the R system has a tricyclic ring of formula IB: IB, wherein the system consists of a single or double bond, and X1, X2, X6, X7 and X8 are selected in each case from N and C that are substituted as desired, wherein the substituents are selected from C1-3 alkyl; wherein X1 and X2 cannot both be N, and X6 and X7 and X7 and X8 cannot both be N; further, wherein if X1 is C, it can be halogenated as desired; X3, X4 and X5 are selected in each case from C, O, N and S that are substituted as desired, wherein the substituents are selected from C1-3 alkyl and C1-3 alkyl (OH), wherein the alkyl can be halogenated as desired.

[0028] The present invention provides a compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R has the formula IB, wherein R is selected from , and .

[0029] In one embodiment, R2 and R1, and the nitrogen atom attached to them, can form a six-membered ring, which may be saturated or partially saturated, and may contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, wherein the six-membered ring system is...

[0030] Wherein, R3 is 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 be substituted by one, two, or three Ra as needed; and

[0031] Ra is the same or different in each case and is selected from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl and -OC1-3 haloalkyl.

[0032] In one embodiment, the present invention provides a compound having formula IA, wherein R3 may be phenyl, pyridyl, pyridyl or pyrimidinyl, and may be substituted by one or more Ra as needed;

[0033] In one embodiment, R3 is a phenyl group, and in another embodiment, R3 is a tert-hydroxyl group.

[0034] In one embodiment, Ra is selected from C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl. In another embodiment, Ra is CF3.

[0035] In another embodiment, R2 and R1, and the nitrogen atom to which they are attached, can form a six-membered ring, which may be saturated or partially saturated, and may contain 0, 1, or 2 additional heteroatoms selected from O, N, or S, wherein the six-membered ring system is...

[0036] Wherein, the R3 system consists of 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 be substituted by one, two, or three Ra atoms as desired; and

[0037] Ra is the same or different in each case and is selected from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl and -OC1-3 haloalkyl.

[0038] In one embodiment, the present invention provides a compound having formula IA, wherein R3 may be phenyl, pyridyl, pyridyl or pyrimidinyl, and may be substituted by one or more Ra as desired;

[0039] In one embodiment, R3 is a phenyl group, and in another embodiment, R3 is a tert-hydroxyl group.

[0040] In one embodiment, Ra is selected from C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl. In another embodiment, Ra is CF3.

[0041] The present invention includes all possible combinations of the aspects and embodiments disclosed above.

[0042] In one aspect, the present invention provides compounds, tautomers thereof, stereoisomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is selected from: (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-pyrinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-pyrinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(6-ethoxy-3-pyridinyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyrolinyl)-5-methyl-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridinyl)-5-methyl-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl ...4-c][1,7] acetyl-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(6-ethoxy-3-pyridyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-pyridine-8-yl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((2R,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)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]quinoline-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-terpinel)-4-hydroxylinyl) methyl ketone, ((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, ((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, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aR,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aR,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-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]quinoline-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]quinoline-8-yl)((3R,3aS,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrolo-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aS,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrolo-1(4H)-yl) methyl ketone, ((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, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidyl) 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-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,[4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-uraninyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-uraninyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-uraninyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(6-ethoxy-3-pyridinyl)-4-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-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]quinoline-8-yl)((3S,3aS,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aS,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((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, ((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, ((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]quinoline-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-hydroxy)-5-methyl-4-hydroxylinyl) 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-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-Dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-tertyl)-4-tertyl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl) ((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acety ...3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl) methyl ketone,4-c][1,7] acetyl-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-pyridine) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyridine) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyridine) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-pyridinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)((1R,3S)-1-oxy-3-(4-(trifluoromethyl)phenyl)-4-thiopyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)((1S,3S)-1-oxy-3-(4-(trifluoromethyl)phenyl)-4-thiopyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazine) methyl ketone, ...7] nitridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]nitridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]nitridin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)-2-phenylthio)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4,5-dichloro-2-phenylthio)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-phenylthio)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(6-(2-propyloxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)7] pyridin-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-pyridine) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridine) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridine) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2-propyloxy)-3-pyridyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-tertyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-oxo-linyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxo-azino-cycloheptane-4-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxo-azino-cycloheptane-4-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thio-arinyl)methylthione, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thio-arinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thio-arinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)7] acetyl-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyridine-8-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridyl)-4-pyridine-8-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(5-(trifluoromethyl)-2-phenylthio)-4-pyridine-8-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(2-propyloxy)-3-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-terpinel)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-hydroxylinyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridine)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-(6-methoxy-3-pyridine)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-pyridineyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, ...7] pyridin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)pyrimin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]pyrimin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyridin-2-yl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R,5S)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-(6-methyl-3-pyridinyl)pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyridin-2-yl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S,5R)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[racemic-(3S)-3-(6-cyclopropyl-3-pyridinyl)pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)-[racemic-(3S)-3-[5-(trifluoromethyl)-2-pyridyl] thiolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thiolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)(3R)-3-(4-(trifluoromethyl)phenyl)-4-thiolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)8] nitridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8]nitridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]hydroxylin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyridyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyridyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyridyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl thiophene, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl thiophene, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl thiophene, (4-amino-1,3-dihydrofurano[3,4-c]quinolinyl) methyl thiophene[4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tertyl)-4-terlinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-terlinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-terlinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]hydroxylin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]hydroxylin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,(4-c)quinoline-8-yl)-[(3R)-3-(3-chlorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3R)-3-(4-chlorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl] siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl] siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl) siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl) siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl] siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,(4-c)quinoline-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl] pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl] pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl] pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3R)-3-(6-methyl-3-pyridyl)pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-(2-chlorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-(3-bromophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-(3-fluorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-bromophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-fluorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-methoxyphenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(6-bromoda-3-yl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone,[4-c]quinoline-8-yl)-[racemic-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-phenylpyrimidin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-pyrimidin-2-ylpyrolin-4-yl] methyl ketone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyridine-8-yl, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) ...7] pyridine-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridine)-4-pyrolinyl) 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-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-hydroxylinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacrylyl) 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-hydroxylinyl) methyl ketone, (4-amino-2,3-dihydrofurano[3,2-c][1,7]pyrrolidinyl) methyl ketone, (4-amino-3,3-dimethyl-1H-furano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-siloxane) methyl ketone, (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]siloxane-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-siloxane) methyl ketone, (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethoxy ...S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone,[4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-pyridinyl)-5-methyl-4-hydroxylyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,[4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(6-ethoxy-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) 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-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-pyrolinyl) 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-pyrolinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-Dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridyl)-4-hydroxylinyl) 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]quinoline-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacrylyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-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-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4 ...phenyl)-1H-pyrazolo[4,3-c]quinoline-8-yl)(3R)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]quinoline-8-yl)(3R)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]quinoline-8-yl)(3R)[3-c]quinoline-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3 ...5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolinyl)[4-c]quinoline-8-yl)((3R)-3-(6-ethoxy-3-tertyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-pyrrolidyl) 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-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-Dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-tertyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) 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]quinoline-8-yl)((4S)-3,3-Dimethyl-4-(4-methylphenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) 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]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-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-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylinyl) methyl ketone, (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-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-((5-(trifluoromethyl)-2-pyridyl)oxy)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-fluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tert-yl)-4-hydroxylyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl ...3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-hydroxylyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3S)-3-(6-(trifluoromethyl)-3-tert-yl)-4-[3-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) 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-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-2,3-dihydrofurano[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrrolidone), (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-pyrrolidone) ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl ...4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(4-(trifluoromethyl)phenyl)-[4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-aminoimidazo[1,2-a]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-aminobenzhizo[2,3-c]quinoline-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-aminobenzhizo[2,3-c]quinoline-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]uranin-4-yl] methyl ketone, (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]uranin-4-yl] methyl ketone, (5-amino-1,4-dihydro-2H-piperano[3,4-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-uraninyl) methyl ketone, (5-aminobenzo[c][2,6]azinyl-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-uraninyl) methyl ketone, (5-aminopyridino[4,3-c][1,7]pyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (5-aminopyrimidino[4,5-c][1,7]pyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (5-aminopyrimidino[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7] acetylin-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7] acetylin-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (R)-(4-amino-1,3-dihydrofuran[3,4-c][1,7] acetylin-8-yl)(3-(4-(pentafluoro-16-hydrothio)phenyl)hydroxylinyl) methyl ketone, (R)-(4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)phospholino) ketone, (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]phospholin-8-yl)(3-(4-(pentafluoro-16-hydrothio)phenyl)phospholino) ketone, [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,[4-c]quinoline-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl] kilotin-4-yl] methyl ketone, [(3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl] kilotin-4-yl] methyl ketone, 1-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl)-1-piperyl) ethyl ketone, 4-((3R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)carbonyl)-3-holylinyl)benzonitrile, 4-((3R,5S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)carbonyl)-5-methyl-3-holylinyl)benzonitrile, 4-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)carbonyl)-3-holylinyl)benzonitrile, 4-((3S,5R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]quinoline-8-yl)carbonyl)-5-methyl-3-hydroxylinyl)benzonitrile, 4-chloro-6-[racemic-(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)quinoline-3-yl]pyridine-3-carboxynitrile, 6-[(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)quinoline-3-yl]pyridine-3-carboxynitrile, 6-[(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl) pyridine-3-carboxylonite, methyl(3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, methyl(3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, Tri-butyl(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]idine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, and tri-butyl(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]idine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate.

[0043] In one aspect, the present invention provides the following compositions: (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7] acetidyl-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridine)-5-methyl-4-pyrolinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]quinolino-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-tertyl)-4-pyrinyl) ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolino-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridine)-5-methyl-4-pyrolinyl) ketone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrolinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]siloxane-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) ketone; [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]quinolin-4-yl] ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]quinolin-4-yl] ketone;(4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl) ketone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tertyl)-4-hydroxylyl) ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(trifluoromethyl)-3-terpinel)-4-pyrrolidyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone; and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyrrolidyl-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]pyrrolidyl-4-yl] methyl ketone.

[0044] 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 tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer is selected from ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0045] 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.

[0046] The present invention also provides a method for treating cancer, the method comprising administering to a subject an effective amount of the compound of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer may be ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0047] 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 an effective amount of such compound to a subject. In one aspect, the cancer may be ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0048] 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 is selected from ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0049] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and requests.

Implementation Method

[0051] Definition

[0052] 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. Such compounds disclosed herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), mirror-image isomers, or non-mirror-image isomers. Therefore, any chemical structure having a relative configuration within (all or part of) the scope of this specification encompasses all possible mirror-image and stereoisomers of the compounds shown, including stereoisomeric pure forms (e.g., geometric pure forms, mirror-image pure forms, or non-mirror-image pure forms) and mixtures of mirror-image and stereoisomers. Mixtures of mirror-image and stereoisomers may be separated into component mirror-image or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0053] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds; racemic, mirror-image, non-mirror-image, geometric, and individual isomers are all intended to be covered within the scope of the present invention. Furthermore, configurational 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 configurational isomers.

[0054] 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 substantially be free of mirror-image isomers of the compound. A stereoisomerically pure compound having two chiral centers will substantially be free of other non-mirror-image isomers 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 3% of other stereoisomers of the compound. If the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, then that structure or part thereof should be interpreted as encompassing all its stereoisomers. Bonds drawn with wavy lines indicate that both stereoisomers are encompassed. Do not confuse this with wavy lines drawn perpendicular to the bonds, indicating the attachment points of groups to the rest of the molecule.

[0055] As 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 structural 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 into another, some compounds may exist as mixtures at room temperature, while others may be separated in tautomer or other forms. Examples of other tautomers related to the compounds of the present invention are those having a pyridone group (pyridyl group) (wherein hydroxypyridinium is a tautomer) and compounds having a ketone group (wherein enol tautomers are tautomers). Examples of these are shown below.

[0056] The compounds disclosed herein include, but are not limited to, compounds having Formula I and all of their pharmaceutically acceptable forms. Pharmaceutically acceptable forms of the compounds described herein include pharmaceutically acceptable salts, solvates, crystalline forms (including polymorphs and cage compounds), chelates, non-covalent complexes, precursors, and mixtures thereof. In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term "compound" encompasses not only the compound itself but also its pharmaceutically acceptable salts, its solvates, its chelates, its non-covalent complexes, its precursors, and any mixtures of the foregoing. In some embodiments, the term "compound" encompasses the compound itself, its pharmaceutically acceptable salts, tautomers of the compound, pharmaceutically acceptable salts of tautomers, and ester precursors (e.g., (C1-C4) alkyl esters). In other embodiments, the term "compound" encompasses the compound itself, its pharmaceutically acceptable salts, its tautomers, and pharmaceutically acceptable salts of tautomers.

[0057] 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, camphor sulfonic acid, isothiolic acid, mucilage, gentian acid, isonicotinic acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, o-aminobenzoic acid, salicylic acid). Acid addition salts formed with phenylacetic acid, 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., benzylsulfonic 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 sugar), lysine, and procaine); and salts formed internally. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (ed.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. Salts having non-pharmaceutical-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.

[0058] 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.

[0059] The compounds of the present invention may also contain naturally occurring or non-natural proportions of atomic isotopes on one or more atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). 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 the present invention are intended to be covered within the scope of the present invention. For example, if a variable is referred to or shown as H, this means that the variable may also be deuterium (D) or tritium (T).

[0060] "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, tributyl), etc. In some embodiments, the alkyl group comprises 1 to 20 carbon atoms. In some embodiments, the alkyl group comprises 1 to 10 carbon atoms or 1 to 6 carbon atoms; however, in other embodiments, the alkyl group comprises 1 to 4 carbon atoms. In still other embodiments, the alkyl group comprises 1 or 2 carbon atoms. Branched alkyl groups comprise 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 can be referred to as (C1-C6) alkyl groups, and alkyl groups having 1 to 4 carbon atoms can be referred to as (C1-C4) alkyl groups. This nomenclature can also be used for alkyl groups with different numbers of carbon atoms. "Alkyl" also includes cycloalkyl, where the carbon atoms are arranged in a ring. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] "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 the 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., propenyl, propenyl-2-yl, propenyl-2-yl (allyl), and propenyl-2-yl); butenyl (e.g., butenyl, butenyl-2-yl, 2-methyl-propenyl, butenyl, butenyl, butenyl-2-yl, butenyl-1,3-dienyl, and butenyl-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. An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C2-C6) alkenyl group. "Alkenyl" also includes cycloalkenyl. A cycloalkenyl refers to an alkenyl group consisting of three or more carbon atoms linked together by at least one carbon-carbon double bond to form a structural ring. Examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexyl.

[0062] "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.

[0063] "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. An alkoxy group containing 1 to 6 carbon atoms may be named -O-(C1-C6)alkyl or -O-(C1-C6 alkyl) group. In some embodiments, the alkoxy group may contain 1 to 4 carbon atoms and may be named -O-(C1-C4)alkyl or -O-(C1-C4 alkyl) group.

[0064] "Aryl" refers to a monovalent aromatic hydrocarbon group obtained by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, such as benzene. Aryl also encompasses 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, the aryl group comprises 6 to 10 carbon atoms. Such groups may be referred to as C6-C10 aryl groups. However, aryl does not in any way encompass or overlap with heteroaryl groups as separately defined below. Therefore, 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.

[0065] "Carbonyl" refers to the group -C(O), which can also be called the -C(=O) group.

[0066] "Carboxyl group" refers to the group -C(O)OH, which can also be called -C(=O)OH.

[0067] "Cyano" refers to the group -CN.

[0068] "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, groups 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 called (C3-C8)cycloalkyl, cycloalkyl groups with 3 to 7 ring members can be called (C3-C7)cycloalkyl, and cycloalkyl groups with 4 to 7 ring members can be called (C4-C7)cycloalkyl. In some embodiments, the cycloalkyl group may be a (C3-C10) cycloalkyl group, a (C3-C8) cycloalkyl group, a (C3-C7) cycloalkyl group, a (C3-C6) cycloalkyl group, or a (C4-C7) cycloalkyl group, and such groups may be referred to as C3-C10 cycloalkyl groups, C3-C8 cycloalkyl groups, C3-C7 cycloalkyl groups, C3-C6 cycloalkyl groups, or C4-C7 cycloalkyl groups using alternative language.

[0069] "Heterocyclic group" refers to a cyclic group comprising at least one saturated, partially unsaturated, cyclic ring. A heterocyclic group comprises 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 the bicyclic heterocyclic group may 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 may be attached to the remainder of the molecule on a 5-membered ring or a 6-membered ring.

[0070] In some embodiments, the heterocyclic group comprises 5 to 10 ring members, wherein 1, 2, 3, or 4, or 1, 2, or 3, 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 3-7 member heterocyclic groups, when the ring comprises only 3 members, there is only 1 ring atom that is a heteroatom, and when the ring comprises 4 members, there are 1 or 2 heteroatoms. 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, acrylane, tetrahydroazolinium, imidazoline, sulfadiazine, piperidine, hydrogenated pyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinine ring, tetrahydrofuran, tetrahydropiperan, benzimidazolone, pyridone, etc. Heterocyclic groups may 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-piperanyl, 3,4-dihydro-2H-piperanyl, 2,5-dihydro-1H-pyrroleyl, 2,3-dihydro-1H-pyrroleyl, 1H-azirinyl, 1,2-dihydroazetenyl, etc. The substituted heterocyclic group also includes a ring system substituted with one or more side-oxygen (=O) or oxide (-O-) substituents, such as piperidinyl N-oxide, succinyl-N-oxide, 1-side-oxy-1-thiosuccinyl, pyridinone, benzimidazolone, benzo[d] succinyl-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-imidazoline-2(3H)-keto, 1,1-side-oxy-1-thiosuccinyl, etc.

[0071] The term "comprising" means open-ended, that is, all-encompassing and non-restrictive. It may be used synonymously with "having" or "including" herein. "Comprising" is intended to include each and every specified or described component or one or more elements without excluding any other component or element.

[0072] "Disease" means any disease, disorder, symptom, or indication.

[0073] "Halogen" or "halogen" refers to a fluorine, chlorine, bromine or iodine group.

[0074] "Halogenated alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen. Therefore, the term "halogenated alkyl" includes monohalogenated alkyl (an alkyl group substituted with one halogen atom) and polyhalogenated alkyl (an alkyl group substituted with two or more halogen atoms). Representative "halogenated alkyl" groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Unless otherwise stated, the term "per-halogenated alkyl" means an alkyl group in which every hydrogen atom is replaced by a halogen atom. For example, the term "per-halogenated alkyl" includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, etc.

[0075] "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, of aromatic, monocyclic, bicyclic, and tricyclic rings, containing one or more (e.g., 1, 2, 3, or 4), or in some embodiments, 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the remaining ring atoms are carbon. In a monocyclic heteroaryl group, the monocyclic ring 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 a 5- to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic 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, alkanoline, furan, imidazole, indazole, indole, indole, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isobenzoxazole, alkanoline, diazole, alkanoline, pteridine, phenanthridine, phenanthidine, phenanthroline, phenanthridine, phthaloline, pteridine, purine, pyridine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrole, quinazoline, quinoline, quinoline, quinoline, tetrazolium, thiadiazole, thiazole, benzylthionine, 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 benzenesulfide, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, succinate, tetrazolium, and pyridine.

[0076] "Pharmaceutical acceptable" means generally accepted for use in animals (more particularly in humans).

[0077] "Pharmaceutical acceptable salt" means a salt of a compound that is pharmaceutically acceptable and has the pharmacological activity of the desired parent compound.

[0078] "Pharmaceutically acceptable excipients" refers to a broad range of ingredients that can be combined with the compounds or salts of the present invention to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, mediators, anti-adhesives, lubricants, disintegrants, flavoring agents, coating agents, adhesives, sweeteners, lubricants, adsorbents, preservatives, etc.

[0079] "Stereoisomers" refers to isomers whose constituent atoms are arranged differently in space. Stereoisomers that are mirror images of each other and are optically active are called "mirror image isomers", and stereoisomers that are not mirror images of each other and are optically active are called "non-mirror image isomers".

[0080] "Subject" includes mammals and humans. The terms "human" and "subject" are used interchangeably in this document.

[0081] A "therapeutic effective amount" means an amount of 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 as necessary to produce a therapeutic or preventive response in the subject. Therefore, a "therapeutic effective amount" is not limited to the amount in a single capsule or tablet but may contain more than one capsule or tablet, as prescribed by a qualified physician or healthcare provider. A "therapeutic effective amount" may 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 is obvious to those skilled in the art or can be determined by routine experimentation.

[0082] “Treatment” or “treatment” for any disease or disorder means preventing or improving a disease, disorder, or at least one clinical symptom of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one clinical symptom of a disease or disorder, reducing the development of a disease, disorder, or at least one clinical symptom of a disease or disorder, or reducing the risk of developing a disease or disorder or at least one clinical symptom of a disease or disorder. “Treatment” or “treatment” also means suppressing a 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 cannot be identified by the subject. Furthermore, “treating” or “treatment” means delaying the onset of a disease or disorder, or at least its symptoms, in a subject who may be exposed to or predisposed to having a disease or disorder (even if the subject has not yet experienced or displayed symptoms of a disease or disorder).

[0083] In some aspects, the compound can be in the form of a salt. Such salts can be anhydrous or can associate with water to form hydrates. In some embodiments, the compound can be in a neutral form, either basic or acidic.

[0084] A pharmaceutical composition is also provided, comprising a compound as described in any 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 such examples, the compound as described in any of the foregoing 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 once-daily or QD oral administration, and in some such formulations it is a tablet, wherein the effective amount of the active ingredient ranges from 1 mg to 100 mg, 5 mg to 80 mg, 10 mg to 50 mg, or 15 mg to 30 mg.

[0085] In some aspects, the subject is a mammal. In some such aspects, the mammal is a rodent. In other aspects, the mammal is a dog. In still other embodiments, the subject is a primate, and in some such embodiments, the subject is a human.

[0086] Pharmaceutical compositions or formulations for administration of the compounds of the present invention may conventionally exist in unit dose form and may be prepared by any method well known in the art. All methods include the step of associating the active ingredient with a carrier constituting one or more auxiliary components. Typically, the pharmaceutical composition is prepared by the following steps: uniformly 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 pharmaceutical composition in an amount sufficient to produce the desired effect on the course or symptoms of the disease.

[0087] 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. In still other embodiments, the compounds of the present invention are not administered orally.

[0088] 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 diseases.

[0089] 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 one of the compounds described herein (e.g., a compound having formula I or a pharmaceutically acceptable salt thereof). In some aspects, the effective amount is a therapeutically effective amount. In some aspects, the effective amount is a preventatively 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).

[0090] 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 the treatment or mitigation of the severity of a disease in which one or more known PRMT5s play a role.

[0091] In some respects, this article provides a method for inhibiting PRMT5 activity in a subject 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.

[0092] In another aspect, the compounds contemplated by the present invention can be used to treat proliferative disorders, such as cancer. In some embodiments, the compounds described herein can be used to treat lymphoma. In some embodiments, the lymphoma is mantle cell lymphoma (MCL). In some embodiments, the lymphoma is acute myeloid lymphoma (AML). In some embodiments, the 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. The 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, also referred to herein as "triple-negative breast cancer".

[0093] 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.

[0094] In one embodiment, the compounds of the present invention can be used to treat pancreatic cancer.

[0095] 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.

[0096] In another respect, the cancer can be GBM. In another respect, the cancer can be mesothelioma. In one respect, the cancer can be bladder cancer. In another respect, the cancer can be esophageal cancer. In another respect, the cancer can be melanoma. In another respect, the cancer can be DLBCL, HNSCC, or bile duct cancer.

[0097] In some respects, one or more of the compounds described herein may be used to treat any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, such as PRMT5-responsive cancer.

[0098] In one aspect, 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 of the compounds described herein may be used to treat p53-positive cancers. In some aspects, a larger amount of one or more of the compounds described herein may be needed to treat p53-negative cancers (e.g., p53-ineffective cancers) than is needed to treat p53-positive cancers.

[0099] In some aspects, this disclosure provides a method for identifying a subject with cancer that is sensitive to treatment with a PRMT5 inhibitor. 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 cancer that is sensitive to treatment with a PRMT5 inhibitor. Thus, in some embodiments, a subject with p53-positive cancer is identified as a subject being treated with a PRMT5 inhibitor. In some embodiments, the method further includes administering a composition containing a PRMT5 inhibitor to the subject.

[0100] 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.

[0101] "Sample" means any biological sample derived from the 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 blot, or any combination thereof.

[0102] 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, angiosarcoma). 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), etc. Cancers include: adenocarcinoma, Ewing's sarcoma, eye cancers (e.g., intraocular melanoma, retinoblastoma), common eosinophilic leukemia, 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, protozoan B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as protozoan 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); or a mixture of one or more of the leukemias / lymphomas 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 carcinoma). Myelodysplastic syndromes (MDS), mesothelioma, myelodysplastic disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloablative myelogenesis of unknown cause (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilia (HES)), neuroblastoma, neurofibromatosis (e.g., neurofibromatosis (NF) type 1 or Type 2, 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 testicular 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).

[0103] 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 in a histone protein) or DNA methylation (e.g., epigenetic DNA methylation, such as methylation of CpG sites). In some implementations, 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).

[0104] Some methods of the present invention include administering the compounds of the present invention and additional therapeutic agents (i.e., therapeutic agents other than the compounds of the present invention). Therefore, the compounds of the present invention can be used in combination with at least one other therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, antibiotics, antiemetics, antidepressants, antifungals, anti-inflammatory agents, antitumor agents, antiviral agents, cytotoxic agents, and other anticancer agents, immunomodulators, alpha-interferon, beta-interferon, alkylating agents, hormones, and interferons. In one embodiment, the present invention covers administering additional therapeutic agents for treating subjects suffering from chronic heart failure or hypertension.

[0105] As described above, some methods of the present invention include administering the compound of the present invention and additional therapeutic agents (i.e., therapeutic agents other than the compound of the present invention). In some embodiments, the present invention covers administering additional therapeutic agents for treating a subject together with an acceptable salt thereof, its tautomer, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, and additional therapeutic agents (e.g., inhibitors of the hyperpolarization initiation current). In some embodiments, the method of use may include two or more additional therapeutic agents.

[0106] 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. Examples

[0107] Unless otherwise stated in the intermediate section, all materials are obtained from market suppliers and are ready for use without further purification.

[0108] The following abbreviations are used to refer to various reagents, solvents, or instruments: AcOH Acetic acid aq or aq. Water-based Boc Tertiary butoxycarbonyl CLND Nitrogen chemiluminescence detection CMPI 2-Chloro-1-methylpyridine cationic iodide DAD Diode array detector DCE 1,2-Dichloroethane DCM dichloromethane DEA Diethylamine DIAD Diisopropyl azodicarbonate DMA or DMAc N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO dimethyl monoxide dppf 1,1'-Bis(diphenylphosphine)ferrocene EDC·HCl or EDCI 3-((ethylimino)methyleneamino)-N,N-dimethylpropyl-1-amine chloride ESI or ES Electro-injection Et Ethyl Et2O Diethyl ether EtOH ethanol EtOAc Ethyl acetate g gram h Hour HPLC High-pressure liquid chromatography HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine cation 3-oxide hexafluorophosphate HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N′,N′-Tetramethylurea hexafluorophosphate HOAt 1-Hydroxy-7-azabenzotriazole iPr Isopropyl iPr2NEt or DIPEA N-Ethyldiisopropylamine (Hünig's base) LC MS, LCMS, LC-MS or LC / MS Liquid chromatography-mass spectrometry LG Detachable radicals (e.g., halogens, methanesulfonates, trifluoromethanesulfonates) LiHMDS Lithium bis(trimethylsilicon)amine m / z mass-to-charge ratio Me methyl MeCN / ACN Acetonitrile MeOH methanol Met Metals used for cross-coupling (e.g., MgX, ZnX, SnR3, SiR3, B(OR)2) mg mg min minute mL milliliters MS mass spectrometry MsCl Methyl sulfonate MTBE Tertiary butyl methyl ether NMP 1-Methyl-2-pyrrolidone n-BuLi n-Butyllithium NMR Nuclear magnetic resonance Pd2(dba)3 Tris(dibenzylacetone)dipalladium(0) Pd(dppf)Cl2·DCM [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) complexed with DCM Pd(PPh3)4 Tetra(triphenylphosphine)palladium(0) Ph Phenyl PG or Prot. group Protecting group Prep Preparative PyBrOP Tripyrrolidine hexafluorophosphate rbf round-bottom flask RP-HPLC Reverse-phase high-pressure liquid chromatography RT or rt room temperature RT Duration of stay RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl sat. or sat'd saturation SFC Supercritical fluid chromatography t-BuOH Tertiary butanol TEA or Et3N Triethylamine TEOS Tetraethyl orthosilicate TFA Trifluoroacetic acid THF Tetrahydrofuran TBTU N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)ureatetrafluoroborate TOF Flight time UHPLC Ultra-high performance liquid chromatography Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan General synthesis scheme:

[0109] 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, a chiral SFC can be used to separate stereoisomers, in which case stereochemistry is arbitrarily assigned to each isomer.

[0110] Method B: Compound I can be prepared by reacting acetic acid IC and a secondary amine IB in a solvent (e.g., THF, dichloroisocyanuric acid, DCM, or DCE) in the presence of a base (e.g., Et3N, DIPEA, or pyridine). Alternatively, compound I can be prepared by reacting acetic acid IC and a secondary amine IB in pyridine in the presence of DMAP. If a racemic amine or acid is used in Method B, chiral SFC can be used to separate stereoisomers, in which case stereochemistry is arbitrarily partitioned to each isomer. Analytical U / HPLC

[0111] The following equipment is used for analytical UHPLC: Waters Acquity system equipped with Acquity BEH C18 (1.7 µm, 2.1 x 50 mm), featuring a linear gradient in a binary solvent system, using a flow rate of 0.5 mL / min and DAD, at ambient temperature, for MS detection of SQDI. The linear gradient used is (H2O / CH3CN / HCO2H (95 / 5 / 0.1% to 0 / 100 / 0.1%)). Agilent Infinity I / II-TOF6230B / CLND Antek 8060, equipped with Acquity BEH C18 (1.7 µm, 2.1 x 50 mm), featuring a linear gradient in a binary solvent system, using a flow rate of 0.75 mL / min, combined with DAD. The linear gradient used is (H2O / MeOH / HCO2H (95 / 5 / 0.1% to 0 / 100 / 0.1%)). Preparative HPLC

[0112] The following equipment was used for preparative HPLC: a Shimadzu Nexera X2 equipped with a Merck Chromolith SpeedROD RP-18E (5 µm, 10 x 100 mm) with a linear gradient for 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%)). Intermediates

[0113] Intermediate 1: 6-(difluoromethoxy)-3-carboxaldehyde

[0114] Step 1. In a vial, add 3-chloro-6-(difluoromethoxy)palladium (675 mg, 3.74 mmol), sodium carbonate (1190 mg, 11.2 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (274 mg, 0.374 mmol). Then add 1,4-dichlorophenoxyacetic acid (16.8 mL) and water (1.87 mL), followed by vinylboric acid ester (1.73 g, 1.90 mL, 11.2 mmol). Bubble the resulting mixture under nitrogen for 15 min, then heat to 80°C. After 15 h, cool the mixture to 23°C and transfer it 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% in heptane 3:1 EtOAc: EtOH) to give 3-(difluoromethoxy)-6-vinylpyrrolidone (573 mg, 3.33 mmol, 89% yield) as a light brown solid. m / z (ESI): 173.2 [M+H]+.

[0115] Step 2. In a vial, add 3-(difluoromethoxy)-6-vinyl tartar (573 mg, 3.33 mmol), acetone (7.93 mL), and water (1.59 mL). Add potassium (VI) osmium tetroxide dihydrate (123 mg, 0.333 mmol) to the resulting solution, followed by 4-methylphosphonoline 4-oxide (1.37 g, 11.7 mmol), and stir the resulting mixture 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% EtOAc : EtOH in heptane 3:1) to give 1-(6-(difluoromethoxy)-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]+.

[0116] Step 3. In a vial, add 1-(6-(difluoromethoxy)-3-yl)ethane-1,2-diol (300 mg, 1.45 mmol) and tetrahydrofuran (13.4 mL). Add sodium 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 H2O (10 mL), transfer it to a separatory funnel containing CH2Cl2 (20 mL) and brine (20 mL), and extract with CH2Cl2 (2 x 20 mL). 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% in heptane 3:1 EtOAc: EtOH) to give 6-(difluoromethoxy)-3-carboxaldehyde (1,217 mg, 1.25 mmol, 86% yield) as a clear oil. m / z (ESI): 175.2 [M+H]+. Intermediate 2: 6-cyclopropoxy-3-carboxaldehyde

[0117] Step 1. Sodium hydride (60% dispersion in mineral oil, 1.556 g, 38.9 mmol) and tetrahydrofuran (31.1 mL) were placed in a round-bottom flask. 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 dropwise to the tetrahydrofuran solution (8.0 mL), and the reaction mixture was stirred at 23°C for 1 h. 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-methylpyrazine (308.5 mg, 2.054 mmol, 26.4% yield), a pale yellow oil. m / z (ESI): 151.2 [M+H]+.

[0118] Step 2. 3-Cyclopropoxy-6-methylcarboxaldehyde (308.5 mg, 2.054 mmol), selenium dioxide (365 mg, 3.29 mmol), and 1,4-dicarboxylic acid (8.22 mL) were added to 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 diatomaceous earth mat (30 mL of 3:1 EtOAc: EtOH precipitate), 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-cyclopropoxycarboxaldehyde-3-carboxaldehyde (2,111.7 mg, 0.680 mmol, 33.1% yield) as an orange oil. m / z (ESI): 165.1 [M+H]+. Intermediate 3: 6-ethoxy-3-carboxaldehyde

[0119] 3-Chloro-6-methylpyrazine (1.00 g, 7.78 mmol, Combi Blocks) 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 crude residue was purified by rapid chromatography (0 to 100% EtOAc : EtOH in heptane 3:1) to give 3-ethoxy-6-methyl thiazoline (1.07 g, 7.72 mmol, 99% yield) as a pale yellow oil. m / z (ESI): 139.15 [M+H]+.

[0120] 3-ethoxy-6-methylcarboxaldehyde (1.07 g, 7.72 mmol), selenium dioxide (1.37 g, 12.3 mmol), and 1,4-dicarboxaldehyde (30.9 mL) were placed in 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 mat (30 mL of 3:1 EtOAc: EtOH precipitate), 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-ethoxy-6-methylcarboxaldehyde (3,332.7 mg, 2.187 mmol, 28% yield) as a pale yellow solid. ¹H NMR (400 MHz, chloroform-d) δ ppm 10.26 (d, J = 0.8 Hz, ¹H), 7.96 (d, J = 9.1 Hz, ¹H), 7.08 (dd, J = 9.0, 0.9 Hz, ¹H), 4.75 (q, J = 7.0 Hz, ²H), 1.52 (t, J = 7.2 Hz, ³H); m / z (ESI): 153.1 [M+H]+. This pathway can be applied to other non-commercial aldehyde intermediates listed in Table 1.

[0121] Intermediate 4-6: 3-(6-methoxy-3-yl)-5-methylporphyrin:

[0122] Step 1. In an oven-dried vial, 4 μg molecular sieve (2.00 g, 2.64 mmol), dichloromethane (10.6 mL), and 6-methoxy-3-carboxaldehyde (365 mg, 2.64 mmol, Enamine) were placed. 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 (using 20 mL of dichloromethane as a precipitate), and the filtrate was concentrated under vacuum to give (E)-1-(6-methoxy-3-yl)-N-(1-((tributyltinyl)methoxy)propyl-2-yl)methylimine as a brown oil. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.55 (s, ¹H), 8.10 (d, J = 9.0 Hz, ¹H), 7.00 (dd, J = 9.2, 0.6 Hz, ¹H), 4.20 (s, ³H), 3.62–3.81 (m, ³H), 3.38–3.49 (m, ²H), 1.18–1.69 (m, ²⁰H), 0.76–1.01 (m, ¹⁸H). This substance was used in subsequent steps without further purification.

[0123] Step 2. In a vial, oven-dried copper(II) trifluoromethanesulfonate (191 mg, 0.528 mmol), (4S,4'S)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydroacetazole) (88 mg, 0.264 mmol), (4R,4'R)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydroacetazole) (88 mg, 0.264 mmol), and hexafluoroisopropanol (4 mL) were added. The resulting mixture was stirred at 23°C for 7 h. The mixture was then added via syringe to a solution of (E)-1-(6-methoxy-3-yl)-N-(1-((tributyltinyl)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 a 30% aqueous solution of NH4OH and brine (1:1, 10 mL) and stirred vigorously at 23°C for 1 h. The mixture was transferred to a separatory funnel containing 20 mL of CH2Cl2 and 20 mL of brine, 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-methoxy-3-yl)-5-methylthioline (4,337 mg, 1.611 mmol, 61% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.50 (d,J= 9.1 Hz, 1 H), 6.97 (d,J= 9.1 Hz, 1 H), 4.27 - 4.38 (m, 1 H), 4.14 (s, 3 H), 4.07 (dd,J= 11.0, 3.3 Hz, 1 H), 3.81 - 3.92 (m, 1 H), 3.41 (t,J= 10.7 Hz, 1 H), 3.07 - 3.25 (m, 2 H), 1.92 (br s, 1 H), 1.07 (d,J= 6.0 Hz, 3 H); m / z(ESI): 210.1 [M+H]+.

[0124] Step 3. The 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-methoxy-3-yl)-5-methylpyrrolidone (5, 150.7 mg, >99% ee), and the second elution peak was arbitrarily designated as (3R,5S)-3-(6-methoxy-3-yl)-5-methylpyrrolidone (6, 152.7 mg, >99% ee).

[0125] The racemic amines summarized in Table 1 are prepared in a manner similar to that described above for amine 4. [Table 1] intermediate structure name m / z(ESI): [M+H] + 7 3-Methyl-5-(5-(trifluoromethoxy)pyridin-2-yl) α-line 263.1 8 3-(6-ethoxypyridin-3-yl)-5-methylpyridine 232.2 9 3,3-Dimethyl-5-(4-(trifluoromethyl)phenyl)oline 260.1 10 3-(6-ethoxy-3-yl)porphyrin 210.1 11 3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methylpiperidine 280.0 12 3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methylpiperidine 264.1 13 3-(6-ethoxypyridin-3-yl) α-line 209.2 14 3-(6-chloropyridin-3-yl)-5-methylpyrrolidone 312.0 15 3-(6-(difluoromethoxy)-3-yl)-5-methylphyll 246.0 16 2,3-Dimethyl-5-(5-(trifluoromethyl)pyridin-2-yl)oline 261.1 17 3-(4,5-Dichlorophenylthio-2-yl)O-line 238.2 18 3-(5-(trifluoromethyl)phenylthio-2-yl) α-line 238.0 19 3-(4-(trifluoromethyl)phenylthio-2-yl) α-line 238.0 20 2-Methyl-5-(5-(trifluoromethyl)pyridin-2-yl)oline 247.1 twenty one 6-(α-lin-3-yl)nicotinamide 190.1 twenty two 3-(5-bromopyridin-2-yl)oline 243.1, 245.1 twenty three 3-(6-bromoda-3-yl)oline 244.0, 246.0 twenty four 3-(5-chloropyridin-2-yl)oline 199.1 25 3-(6-(trifluoromethyl)-3-yl) ... 234.1 26 3-(6-Methoxy-3-yl)porphyrin 196.1 27 3-(6-(trifluoromethoxy)pyridin-3-yl) α-line 249.1 28 2,2-Dimethyl-5-(5-(trifluoromethyl)pyridin-2-yl)oline 261.1 29 3-(6-(trifluoromethyl)pyridin-3-yl)oline 233.2 30 3-(4-(2,2,2-trifluoroethyl)phenyl)α-line 246 31 3-(4-(pentafluoro-16-hydrothio)phenyl) α-line 290.1 32 Racemic-cis-(3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)oline 288.0 33 3-(4-(trifluoromethyl)phenyl)-1,4-oxonium heterocycloheptanane 246.2 34 3-(2-Chlorophenyl)O-line 198.2 35 3-(pyrimidin-2-yl)pyroline 166.3 36 4-Chloro-6-(α-lin-3-yl)nicotinamide 224.0 37 3-(6-cyclopropylpyridin-3-yl) α-line 205.1 38 3-(4-(difluoromethoxy)phenyl)oline 230.2 39 3-(3-Chlorophenyl)O-line 198.1 40 3-(4-Chlorophenyl)O2-line 198.2

[0126] The chiral amines summarized in Table 2 are prepared in a manner similar to that used for amines 5 and 6 described above. Chiral SFC is performed on racemic amines to provide mirror-isomerically pure amines (>99% ee). [Table 2] intermediate Structure SFC conditions m / z(ESI): [M+H] + 41 Chiralpak AD column (150 × 20 mm, 5 µm), with a mobile phase of 80% liquid CO2 and 20% MeOH containing 0.2% Et2NH, at a flow rate of 80 mL / min. 224.2 42 Chiral Technologies IG column (250 × 21 mm, 5 µm) with a mobile phase of 85% liquid CO2 and 15% CH3CN, used at a flow rate of 65 mL / min. 262.0 43 Chiral Technologies IG column (250 × 21 mm, 5 µm), with a mobile phase of 70% liquid CO2 and 30% CH3CN, used at a flow rate of 80 mL / min. 246.25 44 Chiralcel AD-H column (250 × 21 mm, 5 µm), with a mobile phase of 85% liquid CO2 and 15% MeOH containing 0.2% Et3N, was used at a flow rate of 80 mL / min. 247.15 45 Chiral Technologies AD column (250 × 21 mm, 5 µm), with a mobile phase of 90% liquid CO2 and 10% MeOH containing 0.2% Et3N, used at a flow rate of 80 mL / min. 247.15 46 IG column, mobile phase consisting of 60% liquid CO2 and 40% MeOH with DEA. 233.0 47 The second peak was constructed using two Chiral Technologies IG columns (250 x 21 mm, 5 mm each) with a mobile phase of 90% liquid CO2 and 10% MeOH with 0.2% TEA, at a flow rate of 70 mL / min. 282.0 48 Chiralpak AD column (250 x 21 mm, 5 μm), mobile phase of 90% liquid CO2 and 10% methanol with 0.2% TEA, flow rate of 80 mL / min. 290.1 49 A ChiralPak IG column (250 × 4.6 mm, 5 µm) was used with a mobile phase of 90% liquid CO2 and 10% MeOH with 0.2% DEA at a flow rate of 3 mL / min. 331.1 50 SFC Chiralpak AD-H column (250 x 21 mm, 5 µm), with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% TEA, at a flow rate of 100 mL / min. 234.1 51 The SFC Chiral Technologies IG column (250 x 21 mm, 5 mm) was used with a mobile phase of 50% liquid CO2 and 50% MeOH with 0.2% TEA at a flow rate of 55 mL / min. 246.3 52 SFC Chiralpak AD column (21 x 150 mm, 5 µm), with a mobile phase of 80% liquid CO2 and 20% MeOH containing 0.2% diethylamine, at a flow rate of 80 mL / min. 248.1 53 SFC Chiralpak AD column (21 x 150 mm, 5 µm), with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% diethylamine, at a flow rate of 80 mL / min. 232.2 54 SFC Chiralpak AD column (250 x 21 mm, 5 µm), with a mobile phase of 85% liquid CO2 and 15% MeOH with 0.2% TEA, at a flow rate of 80 mL / min. 278.2 55 An SFC Chiralpak IG column (21 x 150 mm, 5 µm) was used with a mobile phase of 65% liquid CO2 and 35% MeOH containing 0.2% diethylamine at a flow rate of 80 mL / min. 292.2 56 SFC Chiral Technologies OJ column (250 x 21 mm, 5 mm), with a mobile phase of 90% liquid CO2 and 10% MeOH with 0.2% TEA, at a flow rate of 80 mL / min. 236.2 Intermediate 57: 2-(4-bromophenyl)-4,4-difluoropiperidine

[0127] Step 1. As described in Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2016, 55, 9676-9: At room temperature, via syringe, vigorously stirred mixture of 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) and 4-(dimethylamino)pyridine (0.048 g, 0.396 mmol, Sigma-Aldrich Corporation) in DCM (25 mL) was added dropwise to the mixture. mL, 4.35 mmol, Sigma-Aldrich. The resulting mixture was stirred at room temperature for 17 h. The crude mixture was loaded directly onto a silicone 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-di-side-oxyisoindoline-2-yl)-4,4-difluoropiperidine-1,2-dicarboxylate as a white solid (1.45 g, 2.65 mmol, 66.8% yield). 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)+.

[0128] Step 2. The 25-mL reaction vessel containing nickel chloride hexahydrate(ii) (50.3 mg, 0.212 mmol, Sigma-Aldrich) and 1,10-xorphine (70.3 mg, 0.212 mmol, Combi-Blocks Inc.) was evacuated, then backfilled with argon (3X), and then 4.10 mL of N,N-dimethylformamide was introduced. 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-(tributyl)-2-(4,5,6,7-tetrachloro-1,3-di-sideoxyisoindoline-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 under nitrogen at room temperature 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. The volume was reduced, and the crude residue was loaded onto a silicone 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 a 215 nm UV channel) to yield 290 mg of impure tertiary butyl 2-(4-bromophenyl)-4,4-difluoropiperidine-1-carboxylate as a colorless film. This was used directly for the next step without further purification. m / z (ESI): 398.0 and 400.0 (M+Na)+.

[0129] 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 tributyl 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 silicone pre-column (25 g) and subjected to combi-fast 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 the impure desired product 57, which was dissolved in DCM / MeOH and loaded onto a silicone pre-column (25 g) and subjected to combi-fast column chromatography using a 12-g ISCO gold column (eluted with (EtOH / EtOAc, 1 / 3, v / v) / heptane (0 to 80%), monitored at a 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). ¹H NMR (chloroform-d, 400 MHz) δ 7.48 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4 Hz), 3.82 (br d, 1H, J = 11.7 Hz), 3.23 (tdd, 1H, J = 2.6, 5.3, 12.1 Hz), 2.9–3.0 (m, 1H), 2.1–2.3 (m, 2H), 1.7–2.0 (m, 3H). ¹⁹F 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]+.

[0130] The racemic amines in Table 3 are prepared in a manner similar to that described above for amine 57. [Table 3] intermediate structure name m / z(ESI): [M+H] + 58 2-(4-Bromophenyl)-4,4-Difluoropiperidine 276.0 and 278.0 59 3-(4-bromophenyl)oline 242.0 and 244.0 60 4,4-Difluoro-2-(4-(trifluoromethyl)phenyl)piperidine 266.0 61 4,4-Difluoro-2-(4-(trifluoromethoxy)phenyl)piperidine 282.2 Intermediate 100: 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid.

[0131] Step 1. Add methyl 4-amino-3-bromobenzoate (4 g, 17.39 mmol, Combibloc) and bis(diphenylphosphine)diboron (8.83 g, 34.8 mmol, Frontier Scientific, Inc.) in 1,4-diphenylphosphine (58.0 mL) to a 150-mL round-bottom flask. 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 minutes. Then add [1,1'-bis(diphenylphosphine)ferrocene]palladium(ii) dichloride (1.420 g, 1.739 mmol, Strem Chemicals, Inc.) in combination with dichloromethane. The reaction was then stirred at 100°C. After 18 h, the reaction was cooled, and the solid was filtered under vacuum and washed with DCM. The mother liquor was then concentrated to give a semi-solid residue. DCM was added, and the resulting solid was collected by vacuum filtration. The mother liquor was concentrated again, and the procedure 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). 1H NMR (400 MHz, chloroform-d) δ ppm 8.33 (d, J = 2.1 Hz, 1 H), 7.90 (dd, J = 8.6, 2.2 Hz, 1 H), 6.57 (d, J = 8.5 Hz, 1 H), 5.20 (br s, 2 H), 3.87 (s, 3 H), 1.37 (s, 12 H).

[0132] Step 2. DIPEA (0.943 mL, 5.40 mmol) was added to a stirred solution of 4-side-oxytetrahydrofuran-3-carboxynitrile (0.500 g, 4.50 mmol) in dichloromethane (5.00 mL), and the reaction mixture was cooled to -78°C. Then, trifluoromethanesulfonic anhydride (0.760 mL, 4.50 mmol) was added dropwise at -78°C for 1 min, and the reaction mixture was stirred at the same temperature for 15 min. After the reaction was complete, the reaction mixture was diluted with water, the organic layer was separated, washed with brine (2 x 10 mL), dried over sodium sulfate, and concentrated to give crude 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (1.05 g, 4.32 mmol, 96% yield), which was used in the next step without further purification.

[0133] 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 then 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]+. 1H NMR (400 MHz, TFA-d) δ ppm 8.59 - 8.67 (2H, m), 7.97 (1H, d, J = 9.3 Hz), 5.94 (2H, t, J = 3.5 Hz), 5.65 (2H, t, J = 3.4 Hz), 4.24 (3H, s). Note: For some heterocyclic rings, Pd(dppf)Cl2 is used instead of Pd(PPh3)4.

[0134] 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 ester (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]+. 1H NMR (400 MHz, DMSO-d) δ ppm 12.83 (1H, s), 7.88 - 8.30 (2H, m), 7.59 (1H, d, J = 8.8 Hz), 7.02 (2H, s), 5.40 (2H, t, J = 3.5 Hz), 5.03 (2H, t, J = 3.6 Hz).

[0135] The acids in Table 4 are prepared in a manner similar to that described for intermediate 100. [Table 4] Intermediate number Chemical structure name m / z(ESI): [M+H] + 101 4-amino-1,3-dihydrofurano[3,4-c][1,8] acetidine-8-carboxylic acid 232.1 102 4-Amino-1,3-dihydrofurano[3,4-c][1,7] acetidine-8-carboxylic acid 232.0 103 4-Amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 264.9 104 4-Amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 249.0 105 4-Amino-3,3-dimethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 259.1 106 4-amino-3-methylisoazolo[4,5-c]quinoline-8-carboxylic acid 244.0 107 4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylic acid 243.1 108 6-Amino-7,8,9,10-Tetrahydrophenanthridine-2-carboxylic acid 243.2 109 5-Aminobenzo[c][2,6] acetidine-9-carboxylic acid 240.1 110 5-Aminopyrido[4,3-c][1,7]pyridin-9-carboxylic acid 241.1 111 5-Aminopyrimidine[4,5-c]quinoline-9-carboxylic acid 241.2 112 5-Aminopyrimidine[4,5-c][1,7] acetylated-9-carboxylic acid 241.1 113 4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylic acid 261.1 114 6-Amino-8,9-dihydro-7H-cyclopentane[c][1,7] acetidine-2-carboxylic acid 230.0 115 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 261.0 116 4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7] acetidine-8-carboxylic acid 244.0 117 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 243.0 118 4-Amino-1,3-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 257.0 119 4-Amino-7-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 245.2 120 4-Amino-7-methoxy-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 261.0 121 4-Amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 257.0 122 4-Amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylic acid 257.1 123 4-Amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]pyridine-8-carboxylic acid 258.0 124 4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylic acid 476.9 125 4-Aminoimidazo[1,2-a]quinoline-8-carboxylic acid 228.9 126 4-Amino-2,3-dihydrofurano[3,2-c][1,7] acetidine-8-carboxylic acid 232.2 127 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 243.1 128 4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7] acetidine-8-carboxylic acid 258.0 (Me ester) No acidic substances were observed. 129 4-Amino-7-fluoro-2,3-dihydrofurano[3,2-c]quinoline-8-carboxylic acid 249.1 130 4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 277.0 131 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 310.9 Intermediate 132: 6-amino-8,9-dihydro-7H-cyclopentane[c][1,8] acetidine-2-carboxylic acid.

[0136] Step 1. Cool a mixture of methyl 2-sideoxycyclopentane 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) to -78°C and add trifluoromethanesulfonic anhydride (7.03 mL, 7.03 mmol, Sigma-Aldrich). After the addition is complete, stir the mixture at -78°C for 5 min, then remove the dry ice bath and stir at room temperature. After 15 min, the mixture was concentrated to obtain a quantitative yield of methyl 2-(((trifluoromethyl)hydrothio)oxy)cyclopent-1-ene-1-carboxylate as a pale yellow solid, and used as is. m / z (ESI): 275 [M+H]+.

[0137] Step 2. A mixture of methyl 2-(((trifluoromethyl)hydrothio)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-dichloromethane / 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 a methyl 6-sideoxy-6,7,8,9-tetrahydro-5H-cyclopentadienyl[c][1,8] acetidine-2-carboxylate in quantitative yield as a light gray solid. m / z (ESI): 245 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.93 - 12.58 (m, ¹H), 8.96 (d, J = 2.1 Hz, ¹H), 8.33 (d, J = 2.1 Hz, ¹H), 3.89 (s, ³H), 3.13 (br t, J = 7.6 Hz, ²H), 2.78 (br t, J = 7.3 Hz, ²H), 2.08 - 2.18 (m, ²H).

[0138] Step 3. A mixture of methyl 6-sideoxy-6,7,8,9-tetrahydro-5H-cyclopentan[c][1,8] acetidine-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-cyclopentan[c][1,8] acetidine-2-carboxylate in quantitative yield as a yellow solid. m / z(ESI): 263 [M+H]+.

[0139] Step 4. Add DIPEA (2.79 g, 3.77 mL, 21.58 mmol, Aldrich) to a suspension of methyl 6-chloro-8,9-dihydro-7H-cyclopenta[c][1,8] acetyl-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). Heat the resulting mixture at 90°C overnight. Cool the reaction to room temperature, dilute with water, wash with saturated NH4Cl, and extract 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-cyclopenta[c][1,8] acetidine-2-carboxylate (2.18 g, 5.54 mmol, 77% yield) as a yellow solid, and used as is. m / z (ESI): 394 [M+H]+.

[0140] Step 5. Add NaOH (10 mL, 10.00 mmol) to a solution of methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentan[c][1,8] acetidine-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 1M HCl. Filter off the pale yellow precipitate and dry it azeotropically with toluene to give 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentan[c][1,8] acetidine-2-carboxylate as a yellow solid (1.44 g, 3.46 mmol, 62.5% yield). m / z(ESI): 380.2 [M+H]+.

[0141] The acids in Table 5 are prepared in a manner similar to that described for intermediate 132. [Table 5] Intermediate number Chemical structure name m / z(ESI): [M+H] + 133 4-Aminophenylthio[2,3-c]quinoline-8-carboxylic acid 395.0 134 6-Aminophenanthridine-2-carboxylic acid 389.2 135 4-((4-methoxybenzyl)amino)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 351.0 136 4-((2,4-dimethoxybenzyl)amino)-2,3-dihydro-1H-cyclopentan[c]quinoline-8-carboxylic acid 379.2 137 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,8]pyridine-8-carboxylic acid 382.2 138 4-((4-methoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7] acetidine-8-carboxylic acid 352.2 139 5-((2,4-dimethoxybenzyl)amino)benzo[c][2,6] acetidine-9-carboxylic acid 390.2 140 4-((4-methoxybenzyl)amino)-3-methylisoazolo[4,5-c]quinoline-8-carboxylic acid 364.1 141 5-((2,4-dimethoxybenzyl)amino)pyrimido[4,5-c]quinoline-9-carboxylic acid 391.2 142 4-((4-methoxybenzyl)amino)-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-carboxylic acid 363.0 143 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 381.1 144 4-((4-methoxybenzyl)amino)-2,3-dihydrofurano[3,2-c]quinoline-8-carboxylic acid 351.2 145 5-((4-methoxybenzyl)amino)-1,4-dihydro-2H-piperano[3,4-c]quinoline-9-carboxylic acid 365.1 Intermediate 146: 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid

[0142] Step 1: At room temperature under a N2 atmosphere, methyl 2-hydroxyacetate (42.4 mL, 555 mmol, 1.0 equivalent) was added to a suspension of sodium hydride (11.10 g, 278 mmol, 0.5 equivalent, 60% in mineral oil) in anhydrous tetrahydrofuran (250 mL). The mixture was slowly added to the reaction mixture (E)-but-2-acrylonitrile (54.5 mL, 666 mmol, 1.0 equivalent) 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 in hexane as the eluent to give 2-methyl-4-sideoxytetrahydrofuran-3-carboxynitrile (22 g, 176 mmol, 32% yield) as a brown solid. Rf of the product: 0.3 (in 50% ethyl acetate in hexane) m / z (ESI, negative): 124.3 [M-1]. ¹H NMR (400 MHz, chloroform-d): δ ppm 4.40 - 4.27 (m, 2 H), 4.26 - 4.19 (m, 1 H), 3.24 - 2.99 (m, 1 H), 1.61 (dd, J = 18.6, 6.2 Hz, 3 H).

[0143] 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-sideoxytetrahydrofuran-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. The crude material was used in the next step without further purification. Rf of the product: 0.5 (40% ethyl acetate in hexane). m / z: 257.1 [non-ionized].

[0144] Step 3: Under a nitrogen atmosphere, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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. The reaction was indicated to be complete by LCMS. The reactants were concentrated under reduced pressure to give a crude product. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 50% ethyl acetate containing hexane as the eluent to give a brown solid methyl 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate (25 g, 97 mmol, 71% yield). Product Rf: 0.3 (100% ethyl acetate). m / z: 259.2 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 8.11 (d,J= 2.0 Hz, 1H), 8.00 (dd,J= 8.8, 2.0 Hz, 1H), 7.58 (d,J= 8.8 Hz, 1H), 6.87 (s, 2H), 4.11 (q,J= 5.3 Hz, 1H), 3.87 (s, 2H), 3.17 (d,J= 5.3 Hz, 3H), 1.41 (d,J= 5.9 Hz, 3H).

[0145] Step 4: Lithium hydroxide (9.64 g, 403 mmol, 4.0 equivalent) 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 equivalent) in tetrahydrofuran (130 mL), methanol (78 mL), and water (52 mL), and the mixture was stirred at 75°C for 4 h. The reaction was indicated by LCMS to be 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 as a grayish-white solid (17.5 g, 71.6 mmol, 71% yield). Product Rf: 0.1 (100% ethyl acetate). m / z: 245.1 [M+H]+ 1H NMR (TFA, 400 MHz): δ (ppm) 8.68 (t,J= 6.2 Hz, 2H), 8.01 (dd,J= 9.1, 4.2 Hz, 1H), 6.15 (s, 1H), 5.94 (m, 2H), 1.86 (t,J= 5.4 Hz, 3H)

[0146] 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. Stereochemically, the fractions were randomly allocated.

[0147] Separation Information: Keywords value 1 instrument SFC 200 2 column ChiralPak-IC (250 x 30 mm, 5 µ) 3 mobile phase Liquid CO2 : 0.5% DEA in methanol (40 : 60) 4 Flow rate 100 mL / min 5 pressure drop 130 bar 6 BPR 100 bar 7 UV detector wavelength 210 nm 8 Dissolve Dissolve 14.0 g of 2% DEA in 280 mL of methanol. 9 Test injection 2.5 mL, 1.5 mL, 1.8 mL 10 deal with NA 11 Injection volume 2.0 mL 12 Cycle time 4.14 min

[0148] The acids in Table 6 are prepared in a manner similar to that described for intermediate 146. [Table 6] acid SFC conditions m / z(ESI): [M+H] + Chiralpak IG-3 column, (50 × 4.6 mm ID, 3 um) Liquid CO2 : MeOH (0.05% isopropylamine, v / v); 95 : 5 → 1 : 1; 3 min gradient 246.0 The SFC CHIRALPAK IG column (250 x 50 mm, 10 µm) was used with a mobile phase of 75% liquid CO2 and 25% MeOH with 0.3% NH4OH at a flow rate of 200 mL / min. 263.1 Intermediate 151: 4-amino-3-((benzyloxy)methyl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid

[0149] Step 1: At -78°C, potassium tributoxide (1 M solution in THF; 732 mL, 732 mmol, 1.1 equivalent) was added to a stirred solution of diethyl(cyanomethyl)phosphonate (130 g, 732 mmol, 1.1 equivalent) in tetrahydrofuran (2000 mL), and the mixture was stirred for 30 min. At -78°C, 2-(benzyloxy)acetaldehyde (100 g, 666 mmol, 1.0 equivalent) 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 solvent to give 4-(benzyloxy)but-2-acrylonitrile (100.6 g, 87% yield) as a colorless oil. Rf of the product: 0.5 (30% ethyl acetate in hexane). m / z: 174.1 [M+H]+. ¹H NMR (chloroform-d, 400 MHz): δ (ppm) 7.47 - 7.32 (m, 5H), 6.80-6.62 (m, 1H), 5.77-5.72 (m, 1H), 4.59 (d, J = 2.8 Hz, 2H), 4.18-4.16 (m, 2H). Proton NMR showed a mixture of isomers.

[0150] 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-acrylonitrile (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 containing petroleum ether as the precipitate to give 2-((benzyloxy)methyl)-4-sideoxytetrahydrofuran-3-carboxynitrile (9.2 g, 14% yield) as a colorless oil. Rf of the product: 0.2 (80% ethyl acetate in hexane). LCMS (ESI, positive) m / z: 232.0 [M+H]+. ¹H NMR (400 MHz, 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).

[0151] Step 3: At -78°C under a N2 atmosphere, trifluoromethanesulfonic anhydride (6.75 mL, 40.1 mmol, 1.6 equivalent) and DIPEA (8.76 mL, 50.2 mmol, 2.0 equivalent) were added to a stirred solution of 2-((benzyloxy)methyl)-4-sideoxytetrahydrofuran-3-carboxynitrile (5.8 g, 25.08 mmol, 1.0 equivalent) 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 a brine solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was washed with diethyl ether (200 mL) and filtered. The organic layer was concentrated under reduced pressure to give 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. Rf of the product: 0.4 (40% ethyl acetate in hexane).

[0152] Step 4: At room temperature, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate (5.8 g, 20.93 mmol, 1.0 equivalent) and potassium carbonate (8.68 g, 62.8 mmol, 3.0 equivalent) were added 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 gas 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 containing petroleum ether as the solvent 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). Rf of the product: 0.2 (100% ethyl acetate in hexane). LCMS (ESI, cation / anion) m / z: 365.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d,J= 2.0 Hz, 1H), 8.01 (dd,J= 8.9, 2.0 Hz, 1H), 7.59 (d,J= 8.8 Hz, 1H), 7.34 - 7.20 (m, 5H), 6.91 (br s, 2H), 5.49 (dq,J= 5.6, 3.6, 2.7 Hz, 1H), 5.44 - 5.32 (m, 2H), 4.56 - 4.44 (m, 2H), 3.90 - 3.73 (m, 5H).

[0153] 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. Intermediate 152: 4-aminoimidazo[1,2-a]quinoline-8-carboxylic acid

[0154] 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 (silicon dioxide, 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]+.

[0155] 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 then recrystallized using EtOAc to give methyl 4-aminoimidazo[1,2-a]quinoline-8-carboxylate (350 mg, 1.45 mmol, 44% yield) as a pale yellow solid. m / z: 243.1 [M+H]+.

[0156] 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]quinoline-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 as a precipitate was formed, which was filtered and washed with diethyl ether to give 4-aminoimidazo[1,2-a]quinoline-8-carboxylic acid (480 mg, 2.10 mmol, 78% yield) as a grayish-white solid. m / z: 228.9 [M+H]+. Intermediate 153: 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0157] Step 1: At room temperature, bromine (5.01 mL, 97.0 mmol, 3.0 equivalent) and sodium acetate (10.6 g, 130 mmol, 4.0 equivalent) were added to a solution of ethyl 5-methyl-1H-pyrazole-4-carboxylate (5.00 g, 32.4 mmol, 1.0 equivalent, 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]+.

[0158] Step 2: At 0°C, DHP (2.26 mL, 24.7 mmol, 1.2 equivalent) and toluenesulfonic acid (0.78 g, 4.12 mmol, 0.2 equivalent) 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 substance. The crude material was purified by chromatography (silicone, 40% ethyl acetate in hexane) to give ethyl 3-bromo-5-methyl-1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazole-4-carboxylate (4.80 g, 15.1 mmol, 73.5% yield) as a colorless, viscous liquid. m / z: 314.9, 317.0 [M+H]+.

[0159] Step 3: Ethyl 3-bromo-5-methyl-1-(tetramethyl-1,3,2-dioxaneborane-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-dioxaneborane-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-piperan-2-yl)-1H-pyrazole-4-carboxylate.

[0160] At room temperature and under nitrogen, 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-piperan-2-yl)-1H-pyrazole-4-carboxylate (600 mg, 1.55 mmol, 1.0 equivalent) in 1,4-dimethylamine (9.60 mL) and water (2.40 mL), 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 (silicone, 5% MeOH in DCM) to yield pure methyl 4-hydroxy-3-methyl-1-(tetrahydro-2H-piperan-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]+

[0161] Step 4: Then, trifluoromethanesulfonic anhydride (992 mg, 3.52 mmol, 2.0 equivalent) and DIPEA (921 µL, 5.27 mmol, 3.0 equivalent) were added to a stirred solution of methyl 4-hydroxy-3-methyl-1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (600 mg, 1.76 mmol, 1.0 equivalent) in dichloromethane (3.00 mL), and the reaction mixture was maintained at 30°C–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-piperan-2-yl)-4-(((trifluoromethyl)hydrothio)oxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate.

[0162] DIPEA (332 µL, 1.90 mmol, 3.0 equivalent) was added to a stirred solution of crude methyl 3-methyl-1-(tetrahydro-2H-piperan-2-yl)-4-(((trifluoromethyl)hydrothio)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 (silicone, 50% EtOAc: hexane) to give pure methyl 4-((4-methoxybenzyl)amino)-3-methyl-1-(tetrahydro-2H-piperan-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]+

[0163] Step 5: A solution of methyl 4-((4-methoxybenzyl)amino)-3-methyl-1-(tetrahydro-2H-piperan-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]+.

[0164] Step 6: Then, lithium hydroxide monohydrate (4.02 g, 96.0 mmol, 7.0 equivalent) was added to a stirred solution of methyl 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid ester (3.50 g, 13.7 mmol, 1.0 equivalent) in tetrahydrofuran (35.0 mL), methanol (35.0 mL), and water (35.0 mL) at room temperature, 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]+. Intermediate 154: Lithium hydroxide 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate

[0165] Step 1. Dissolve 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-dioxaneborane-2-yl)-1h-pyrazole-4-carboxylonitrile (1.10 g, 4.70 mmol, Annamin), and methyl 4-amino-5-bromo-2-(trifluoromethyl)benzoate (0.700 g, 4.70 mmol, Sigma-Aldrich). The sample (2.349 mmol, Combibloc) was suspended in a degassed mixture of water (1.0 mL) and 1,4-dichlorophenoxyacetic acid (5.0 mL) and stirred overnight at 60°C, followed by stirring at 90°C for 18 h. Volatile substances 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 yield methyl 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (0.63 g, 1.94 mmol, 83% yield) as a light brown solid. m / z (ESI): 324.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 - 8.76 (m, 1 H), 8.33 - 8.37 (m, 1 H), 7.87 - 7.92 (m, 1 H), 7.54 - 7.61 (m, 2 H), 4.41 - 4.46 (m, 3 H), 3.92 (s, 3 H). 19F NMR (376 MHz, DMSO-d6) δ ppm -58.06.

[0166] 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]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H), 8.27 (s, 1 H), 7.68 (s, 1 H), 7.03 (br s, 2 H), 4.38 (s, 3 H). 19F NMR (376 MHz, DMSO-d6) δ ppm -57.47. Example

[0167] Example 300: Preparation of (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(pyrimidin-2-yl)pyrolino)methyl ketone

[0168] Add 3-(pyrimidin-2-yl)phospholine (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-dimethylacetylamine (6.0 mL) to a 50-mL round-bottom flask. Then add tripyridine phosphonium hexafluorophosphate (0.56 g, 1.21 mmol, Sigma-Aldrich) and triethylamine (0.61 g, 0.9 mL, 6.05 mmol, Sigma-Aldrich) to the reaction mixture. Stir the mixture at room temperature for 2 h. Concentrate the reaction mixture under vacuum. The crude material was adsorbed onto a silicone stopper and purified by chromatography using an Interchim (15 μm) silicone column (40 g) (0–35% MeOH gradient elution in DCM). The product was collected and then purified by reverse-phase HPLC: purification was performed using 0.1% NH4OH in H2O (A) and ACN (B) as the mobile phase on an XBridge column (19 x 100 mm, 5 µm). This yielded a white solid (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(pyrimidin-2-yl)oline) methyl ketone (0.120 g, 0.318 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (br d,J= 4.6 Hz, 2 H), 7.61 (br s, 2 H), 7.46 (t,J= 4.8 Hz, 2 H), 6.68 (br s, 2 H), 5.51 - 5.69 (m, 1 H), 5.37 (br s, 2 H), 5.00 (br s, 3 H), 4.63 (br s, 1 H), 4.18 - 4.37 (m, 1 H), 3.87 - 3.97 (m, 1 H), 3.66 - 3.79 (m, 1 H), 3.54 - 3.62 (m, 1 H). m / z(ESI): 378.1 [M+H]+.

[0169] The examples in Table 7 were prepared using the amide coupling reagent shown in the table in a manner similar to that described above for Example 300. [Table 7] Example structure name Coupling reagents m / z (ESI): [M+H) + 301 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone CMPI 493.0 302 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone CMPI 493.1 303 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone CMPI 459.2 304 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone CMPI 477.0 305 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone CMPI 473.2 306 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-pyrinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-pyrinyl)methyl ketone CMPI 450.2 307 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyrinyl)methyl ketone CMPI 474.0 308 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrinyl)methyl ketone CMPI 474.0 309 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone CMPI 477.0 310 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone CMPI 440.1 311 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone CMPI 426.1 312 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone CMPI 439.1 313 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone CMPI 443.1 314 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone CMPI 476.0 315 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl) methyl ketone CMPI 458.0 316 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-pyrinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-pyrinyl) methyl ketone CMPI 473.0 317 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone CMPI 472.1 318 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyrinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone CMPI 458.2 319 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-tert-yl)-5-methyl-4-tert-yl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-tert-yl)-5-methyl-4-tert-yl) methyl ketone CMPI 436.2 320 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) methyl ketone CMPI 437.2 321 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone CMPI 450.2 322 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-tert-yl)-5-methyl-4-tert-yl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone CMPI 470.2 323 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(6-(2-propyloxy)-3-pyridinyl)-4-pyrinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(2-propyloxy)-3-pyridinyl)-4-pyrinyl)methyl ketone CMPI 436.2 324 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone CMPI 441.1 325 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(6-ethoxy-3-tertyl)-4-pyrinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-ethoxy-3-tertyl)-4-pyrinyl)methyl ketone CMPI 437.2 326 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) methyl ketone CMPI 451.2 327 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone CMPI 454.2 328 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-pyrinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-pyrinyl) methyl ketone CMPI 493.0 329 ((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-hydroxylinyl)methyl ketone and ((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-hydroxylinyl)methyl ketone CMPI 506.0 330 ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl)methyl ketone and ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl)methyl ketone CMPI 507.0 331 ((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-hydroxylinyl) methyl ketone and ((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-hydroxylinyl) methyl ketone CMPI 490.1 332 ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl)methyl ketone and ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone CMPI 491.1 333 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl)methyl ketone CMPI 476.0 334 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone CMPI 477.0 335 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]siloxane-4-yl]methyl ketone HATU 460.0 336 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 508.0 337 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone and ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 509.0 338 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone and ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 459.0 339 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone HATU 460.1 340 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrinyl)methyl ketone HATU 460.2 341 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone HATU 478.1 342 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone HATU 480.1 343 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone HATU 459.2 344 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone HATU 479.1 345 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-pyrinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone HATU 479.1 346 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone HATU 512.0 347 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone HATU 496.0 348 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 462.1 349 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 463.1 350 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone HATU 496.1 351 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone HATU 463.1 352 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone HATU 463.1 353 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone HATU 479.0 354 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone HATU 459.2 355 ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone and ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 477.1 356 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 477.1 357 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-pyrinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrinyl)methyl ketone HATU 460.0 358 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone HATU 493.0 359 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyrinyl) methyl ketone HATU 476.1 360 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(2-chlorophenyl)phosphono-4-yl]methyl ketone PyBroP 410.2 361 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone PyBroP 390.2 362 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(o-tolyl)oline-4-yl] methyl ketone PyBroP 390.2 363 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-fluorophenyl)phosphono-4-yl]methyl ketone PyBroP 394.2 364 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(3-fluorophenyl)phosphono-4-yl]methyl ketone PyBroP 394.2 365 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-methoxyphenyl)phosphono-4-yl]methyl ketone PyBroP 406.2 366 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(3-bromophenyl)phosphono-4-yl]methyl ketone PyBroP 454.0 367 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-bromophenyl)phosphono-4-yl]methyl ketone PyBroP 454.1 and 456.0 368 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidinyl] methyl ketone PyBroP 488.0 and 490.0 369 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridyl)-4-hydroxylyl)methyl ketone PyBroP 455.2 370 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl) methyl ketone PyBroP 471.2 371 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone PyBroP 457.2 372 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone PyBroP 473.1 373 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone PyBroP 492.0 374 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone PyBroP 476.1 375 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone PyBroP 509.0 376 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl)methyl ketone PyBroP 475.1 377 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone PyBroP 489.2 378 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone PyBroP 493.0 379 ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyrinyl)methyl ketone and ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrinyl)methyl ketone PyBroP 490.0 380 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrinyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrinyl)methyl ketone PyBroP 490.0 381 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-pyrinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-pyrinyl) methyl ketone PyBroP 459.0 382 (4-amino-3,3-dimethyl-1H-furano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]siloxane-4-yl]methyl ketone PyBroP 488.2 383 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-hydroxylinyl)methyl ketone PyBroP 461.0 384 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-hydroxylinyl) methyl ketone PyBroP 477.1 385 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-hydroxylinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-hydroxylinyl) methyl ketone PyBroP 461.1 386 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone PyBroP 479.0 387 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone PyBroP 463.2 388 4-((3R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)carbonyl)-3-hydroxylinyl)benzonitrile and 4-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)carbonyl)-3-hydroxylinyl)benzonitrile PyBroP 402.2 389 4-((3R,5S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)carbonyl)-5-methyl-3-hydroxylinyl)benzonitrile and 4-((3S,5R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)carbonyl)-5-methyl-3-hydroxylinyl)benzonitrile PyBroP 416.2 390 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone PyBroP 475.2 391 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-tertyl)-4-tertyl)methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-tert-yl)-4-tert-yl)methyl ketone PyBroP 456.1 392 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-tertyl)-4-terlinyl) methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-tertyl)-4-tertyl)methyl ketone PyBroP 440.2 393 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-tertyl)-4-tertyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-tertyl)-4-tertyl)methyl ketone PyBroP 436.2 394 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-pyrinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-pyrinyl) methyl ketone PyBroP 444.1 395 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-phenylhexahydrocyclopenta[b]pyrrole-1(2H)-yl)methyl ketone TBTU 414.2 396 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(4-(4-chlorophenyl)-2-cyclopropylpyrrolidin-1-yl)methyl ketone TBTU 448.2 397 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl)methyl ketone TBTU 430.2 398 ((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 TBTU 448.2 399 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aS,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl)methyl ketone TBTU 430.2 400 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aS,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl)methyl ketone TBTU 414.2 401 ((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 TBTU 414.2 402 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-bromophenyl)-4-methylpyrrolidin-1-yl)methyl ketone TBTU 465.8 and 467.8 403 (4-aminoimidazo[1,2-a]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl)methyl ketone HATU 442.1 404 (4-amino-2,3-dihydrofurano[3,2-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 445.2 405 (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone HATU 455.9 406 (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone HATU 456.9 407 (4-amino-7-fluoro-2,3-dihydrofurano[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 462.1 408 (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone HATU 426.0 409 (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylyl)methyl ketone HATU 506.0 410 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxyl) methyl ketone HATU 507.0 411 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylyl)methyl ketone HATU 524.0 412 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl)methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methyl ketone TBTU 447.1 413 (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone TBTU 470.2 414 (4-amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone TBTU 470.2 415 (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone TBTU 471.2 416 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 515.0 417 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 517.2 418 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 535.8 419 (4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 548.2 420 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone TBTU 473.8 421 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone TBTU 429.2 422 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 432.2 423 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone TBTU 433.2 424 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methyl ketone TBTU 436.9 425 (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 440.9 426 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 441.9 427 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 444.9 428 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone TBTU 445.9 429 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 447.9 430 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 448.2 431 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolidyl)methyl ketone and ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolidyl)methyl ketone TBTU 450.8 432 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methyl ketone and (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone TBTU 455.9 433 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone and (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone TBTU 457.9 434 ((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 and ((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-pyrrolidyl) methyl ketone TBTU 458.2 435 ((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 TBTU 458.9 436 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone TBTU 458.2 437 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 458.9 438 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone TBTU 460.9 439 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 460.9 440 (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 460.9 441 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone and (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 462.8 442 (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone TBTU 461.8 443 (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 474.9 444 (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone TBTU 476.9 445 (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 and (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 TBTU 486.9 446 (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 TBTU 506.9 447 (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 514.2 448 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 515.2 449 (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 TBTU 522.9 450 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone TBTU 532.2 451 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-pyrolinyl) methyl ketone TBTU 457.1

[0170] Examples 452 and 453: ((R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]azin-8-yl)((S)-3-(4-(trifluoromethyl)phenyl)zolino) methyl ketone and ((S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]azin-8-yl)((S)-3-(4-(trifluoromethyl)phenyl)zolino) methyl ketone

[0171] A mixture of (S)-3-(4-(trifluoromethyl)phenyl)oline (0.079 g, 0.342 mmol, PharmaBlock Science, Nanjing, China), 4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] ethidium-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]+.

[0172] 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 (ee > 99%) at 39.7 mg and peak 2 (ee 99.8%) at 40.5 mg. Peak partitioning was determined by SFC using an OJ column (with 25% MeOH containing 0.2% TEA). Stereochemical partitioning was arbitrary.

[0173] Peak 1: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.73 - 8.92 (m, 1 H), 7.84 (s, 1 H), 7.59 - 7.81 (m, 4 H), 6.98 (br s, 2 H), 5.57 - 5.79 (m, 1 H), 5.42 - 5.50 (m, 1 H), 5.35 - 5.40 (m, 1 H), 5.22 - 5.34 (m, 1 H), 4.38 - 4.58 (m, 1 H), 3.69 - 3.94 (m, 3 H), 3.57 (br s, 1 H), 3.17 (d,J= 5.0 Hz, 1 H), 1.33 - 1.48 (m, 3 H).

[0174] Peak 2: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.71 - 8.97 (m, 1 H), 7.82 - 7.86 (m, 1 H), 7.59 - 7.82 (m, 4 H), 6.98 (br s, 2 H), 5.63 - 5.80 (m, 1 H), 5.46 (br s, 1 H), 5.25 - 5.41 (m, 2 H), 4.23 - 4.59 (m, 1 H), 3.71 - 3.99 (m, 3 H), 3.56 (br s, 1 H), 3.17 (d,J= 5.0 Hz, 1 H), 1.41 (br d,J = 6.2 Hz, 3 H).

[0175] 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 used in Examples 452 and 453 above. [Table 8] Example Structure Name Coupling reagents m / z(ESI): [M+H + SFC conditions 454 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone HATU 509.0 Peak 1, Chiral Technologies OJ column (250 x 21 mm, 5 µm), mobile phase of 75% liquid CO2 and 25% MeOH with 0.2% TEA, flow rate of 80 mL / min. 455 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]siloxane-4-yl]methyl ketone PyBroP 444.4 Peak 1, Chiral Technologies AZ column (250 x 21 mm, 5 µm), mobile phase of 50% liquid CO2 and 50% MeOH with 0.2% TEA, flow rate of 50 mL / min. 456 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]siloxane-4-yl]methyl ketone PyBroP 444.4 The second peak was constructed using a Chiral Technologies AZ column (250 x 21 mm, 5 µm) with a mobile phase of 50% liquid CO2 and 50% MeOH with 0.2% TEA at a flow rate of 50 mL / min. 457 (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)(3-(4-(pentafluoro-16-hydrothio)phenyl) pyroline) methyl ketone TBTU 503.8 Peak 1, Chiral Technologies IC column (250 x 21 mm, 5 mm), mobile phase 65% liquid CO2 and 35% MeOH with 0.2% TEA, flow rate 80 mL / min. 458 (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)(3-(4-(pentafluoro-16-hydrothio)phenyl) pyroline) methyl ketone TBTU 503.8 The second peak was observed using a Chiral Technologies IC column (250 x 21 mm, 5 mm), with a mobile phase of 65% liquid CO2 and 35% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 459 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-pyrinyl)methyl ketone PyBrOP 474.00 and 476.00 Peak 1, Chiralpak AD column (21 x 150 mm, 5 μm), mobile phase 55% liquid CO2 and 45% methanol with 0.2% diethylamine, flow rate 80 ml / min. 460 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-hydroxylinyl) methyl ketone PyBroP 491.00 and 493.00 Peak 1, (S,S) Whelk-O 1 column (21 x 250 mm), mobile phase 60% liquid CO2 and 40% MeOH with 0.2% diethylamine, flow rate 80 ml / min 461 ((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 TBTU 416.2 Peak 1, Chiralpak AD column (21 x 150 mm, 5 μm), mobile phase 65% liquid CO2 and 35% methanol with 0.2% diethylamine, flow rate 80 ml / min. 462 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone TBTU 420.1 Peak 1, Chiralcel OJ column (30 x 250 mm, 5 μm), mobile phase 75% liquid CO2 and 25% MeOH with 0.2% diethylamine, flow rate 80 ml / min. 463 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone TBTU 420.1 The second peak was observed on a Chiralcel OJ column (30 x 250 mm, 5 μm) with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% diethylamine at a flow rate of 80 ml / min. 464 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-3,3-dimethyl-4-(4-methylphenyl)-1-pyrrolidinyl)methyl ketone TBTU 420.2 The second peak was observed on a Chiralcel OJ column (2 x 25 cm, 5 μm) with a mobile phase of 80% liquid CO2 and 20% methanol containing 0.1% triethylamine at a flow rate of 70 mL / min. 465 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidinyl)methyl ketone TBTU 424.1 The second peak was observed on a Chiralcel OJ column (2 x 25 cm, 5 μm) with a mobile phase of 80% liquid CO2 and 20% methanol containing 0.1% triethylamine at a flow rate of 70 mL / min. 466 ((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 TBTU 424.9 Peak 1, Chiralcel OD column (21 x 250 mm, 5 μm), mobile phase 75% liquid CO2 and 25% MeOH with 0.2% DEA, flow rate 80 ml / min. 467 ((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 TBTU 424.9 The second peak was observed on a Chiralcel OD column (21 x 250 mm, 5 μm) with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% DEA at a flow rate of 80 ml / min. 468 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 446.8 The second peak was observed on a Chiralcel OJ column (21 x 250 mm, 5 μm) with a mobile phase of 75% liquid CO2 and 25% methanol containing 0.2% diethylamine at a flow rate of 80 ml / min. 469 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methyl ketone TBTU 472.9 Peak 1, Chiralcel OD column (2 x 25 cm, 5 μm), mobile phase 70% liquid CO2 and 30% methanol with 0.1% diethylamine, flow rate 60 mL / min. 470 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl)methyl ketone TBTU 472.9 The second peak was observed on a Chiralcel OD column (2 x 25 cm, 5 μm) with a mobile phase of 70% liquid CO2 and 30% methanol containing 0.1% diethylamine at a flow rate of 60 mL / min. 471 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone TBTU 474.9 Peak 1, Chiralpak IC column (2 x 15 cm, 5 μm), mobile phase 60% liquid CO2 and 40% methanol with 0.1% diethylamine, flow rate 55 mL / min. 472 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone TBTU 474.9 The second peak was observed using a Chiralpak IC column (2 x 15 cm, 5 μm) with a mobile phase of 60% liquid CO2 and 40% methanol containing 0.1% diethylamine at a flow rate of 55 mL / min. 473 (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 TBTU 474.8 The second peak was observed on a Chiralcel OJ column (21 x 250 mm, 5 μm) with a mobile phase of 75% liquid CO2 and 25% methanol containing 0.2% diethylamine at a flow rate of 80 ml / min. 474 (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 TBTU 475.0 Peak 1, Chiralpak IC column (2 x 15 cm, 5 μm), mobile phase 60% liquid CO2 and 40% methanol with 0.1% diethylamine, flow rate 55 mL / min. 475 (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 TBTU 475.0 The second peak was observed using a Chiralpak IC column (2 x 15 cm, 5 μm) with a mobile phase of 60% liquid CO2 and 40% methanol containing 0.1% diethylamine at a flow rate of 55 mL / min. 476 (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 TBTU 476.0 Peak 1, Whelk-OS, S column (250 x 21 mm, 5 μm), mobile phase 60% liquid CO2 and 40% methanol with 0.2% TEA, flow rate 80 mL / min. 477 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl)methyl ketone TBTU 478.8 The second peak was observed on a Chiral Technologies OJ column (250 x 21 mm, 5 mm), with a mobile phase of 80% liquid CO2 and 20% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 478 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidinyl)methyl ketone TBTU 483.9 / 485.8 (1 : 1) The second peak was observed on a Chiralcel OJ column (2 x 25 cm, 5 μm) with a mobile phase of 80% liquid CO2 and 20% methanol containing 0.1% triethylamine at a flow rate of 70 mL / min. 479 Methyl(3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidone carboxylate TBTU 504.2 Peak 1, Chiralcel OJ column (21 x 400 mm), mobile phase 80% liquid CO2 and 20% methanol with 0.2% diethylamine, flow rate 60 ml / min 480 Methyl(3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate TBTU 504.2 The second peak was observed on a Chiralcel OJ column (21 x 400 mm) with a mobile phase of 80% liquid CO2 and 20% methanol containing 0.2% diethylamine at a flow rate of 60 ml / min.

[0176] Examples 483 and 484: (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone

[0177] Step 1. Add bromotripyrrolidone hexafluorophosphate (0.203 g, 0.436 mmol, Arch Corporations, New Jersey) to a solution of 2-(4-(trifluoromethyl)phenyl)piperidine (0.100 g, 0.436 mmol, Arch Corporations, New Jersey), 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7] phosphonium-8-carboxylate (0.273 g, 0.654 mmol) and 1,1'-dimethyltriethylamine (0.564 g, 0.762 mL, 4.36 mmol, Sigma-Aldrich) in DMF (4 mL), and heat the resulting mixture at 50°C for 30 min. The reaction mixture was cooled to room temperature, diluted with water and saturated NaHCO3, and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was then subjected to silica gel chromatography in heptane at 0–50% (3:1 EtOAc / EtOH) to give a pale yellow solid (4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl) methyl ketone. m / z (ESI): 593 [M+H]+.

[0178] 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]diphenidyl-8-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone 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 at 0–50% (3:1 EtOAc / EtOH) to give a grayish-white solid (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl) methyl ketone (0.042 g, 0.095 mmol, 21.76% yield). m / z (ESI): 443 [M+H]+.

[0179] Step 2. The compound was purified by preparative SFC using a Chiral Technologies AS 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 a 13.5 mg peak (ee > 99%) and a 13 mg peak (ee > 99%) with arbitrary stereochemical partitions. Peak 1: (R)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone (481, 0.013 g, 0.029 mmol). White solid. m / z (ESI): 443 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 - 8.99 (m, 1 H), 7.73 - 7.86 (m, 3 H), 7.57 - 7.67 (m, 2 H), 7.03 (br s, 2 H), 5.38 (br s, 2 H), 5.05 (br s, 2 H), 3.64 - 3.91 (m, 1 H), 2.35 - 2.46 (m, 2 H), 1.86 - 2.01 (m, 1 H), 1.29 - 1.72 (m, 5 H). Peak 2: (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone (482, 0.011 g, 0.025 mmol). White solid. m / z (ESI): 443 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 - 8.98 (m, 1 H), 7.74 - 7.84 (m, 3 H), 7.62 (br d,J= 7.9 Hz, 2 H), 7.03 (br s, 2 H), 5.39 (br d,J= 2.9 Hz, 2 H), 5.05 (br s, 2 H), 3.72 - 3.87 (m, 1 H), 2.36 - 2.45 (m, 2 H), 1.85 - 2.04 (m, 1 H), 1.31 - 1.72 (m, 5 H).

[0180] Example 483: (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,8]monidin-8-yl)(3-(4-(trifluoromethyl)phenyl)oline) methyl ketone. Example 483 was prepared in a racemic manner similar to that of compound 481 above. m / z(ESI): 445.1 [M+H]+

[0181] Example 484: (5-amino-2,4-dihydro-1H-piperano[3,4-c]quinoline-9-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]oline-4-yl]methyl ketone. Example 484 was prepared in a racemic manner similar to that of compound 481 above. m / z(ESI): 474.0 [M+H]+ The following examples were prepared in a manner similar to that described for Examples 481 and 482. [Table 9] Example structure name m / z(ESI): [M+H + SFC conditions 485 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]phosphono-4-yl]methyl ketone 445.0 Peak 1, Chiral Technologies AD column (150 x 21 mm, 5 mm), mobile phase of 60% liquid CO2 and 40% MeOH with 0.2% TEA, flow rate of 80 mL / min. 486 (4-amino-1,3-dihydrofurano[3,4-c][1,7]diazin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]phospholin-4-yl]methyl ketone 445.0 The second peak was constructed using a Chiral Technologies AD column (150 x 21 mm, 5 mm), with a mobile phase of 60% liquid CO2 and 40% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 487 (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]siloxane-4-yl]methyl ketone 458.0 Peak 1, Chiral Technologies OJ column (250 x 21 mm, 5 mm), mobile phase of 70% liquid CO2 and 30% MeOH with 0.2% TEA, flow rate of 80 mL / min. 488 (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]siloxane-4-yl]methyl ketone 458.0 The second peak was constructed using a Chiral Technologies OJ column (250 x 21 mm, 5 mm), with a mobile phase of 70% liquid CO2 and 30% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 489 (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone 456.0 Peak 1, Chiral Technologies AS column (250 x 21 mm, 5 mm), mobile phase of 65% liquid CO2 and 35% MeOH with 0.2% TEA, flow rate of 80 mL / min. 490 (4-aminophenylthio[2,3-c]quinolin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone 456.0 The second peak was constructed using a Chiral Technologies AS column (250 x 21 mm, 5 mm), with a mobile phase of 65% liquid CO2 and 35% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. .

[0182] Example 491: (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-methoxy-3-yl)-5-methyl-3-lino) methyl ketone

[0183] Step 1. Add 4 M HCl (1.62 mL, 6.49 mmol) in 1,4-dicarboxylic acid to a stirred suspension of 4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-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 it with toluene (2 x 5 mL). Resuspend the obtained crude substance in dichloromethane (20.0 mL), cool to 0°C, and treat with oxalic acid (2.0 M in CH2Cl2, 4.33 mL, 8.65 mmol), followed by treatment with DMF (5 drops). Rinse 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] acetidine-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]+.

[0184] Step 2. In a vial, (3S,5R)-3-(6-methoxy-3-yl)-5-methylthioline (35.9 mg, 0.172 mmol), 4-amino-1,3-dihydrofurano[3,4-c][1,7]acetidine-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 resulting crude residue was purified by rapid chromatography (0 to 100% EtOAc : EtOH in heptane 3:1) to give (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-methoxy-3-yl)-5-methyl-3-yl) methyl ketone (59.8 mg, 0.142 mmol, 83% yield) as a grayish-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 9.03 (br s, 1 H), 7.94 (br s, 1 H), 7.72 (br d,J= 7.1 Hz, 1 H), 6.99 (d,J= 9.2 Hz, 1 H), 5.97 (d,J= 3.8 Hz, 1 H), 5.50 (t,J= 3.7 Hz, 2 H), 5.29 - 5.44 (m, 1 H), 5.15 - 5.23 (m, 2 H), 4.97 (s, 2 H), 4.37 - 4.65 (m, 1 H), 4.17 (s, 3 H), 3.68 - 3.99 (m, 3 H), 1.05 (d,J= 7.1 Hz, 3 H); m / z(ESI): 423.25 [M+H]+.

[0185] The following examples were prepared in a manner similar to that described for Example 491. [Table 10] Example structure name m / z(ESI): [M+H + 492 4-Chloro-6-[racemic-(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl) pyridine-3-carboxynitrile 436.0 493 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-phenyllin-4-yl]methyl ketone 376.1 494 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[racemic-(3S)-3-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl] methyl ketone 446.0 495 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[racemic-(3S)-3-(6-cyclopropyl-3-pyridinyl)phosphono-4-yl] methyl ketone 418.2 496 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone 442.2 497 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone and (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone 456.1 498 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone 472.1 499 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone and (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone 457.1 500 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(6-bromoda-3-yl)phosphono-4-yl] methyl ketone 454.0, 456.0 501 (5-aminopyridino[4,3-c][1,7]pyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone 454.1 502 (5-aminopyrimidino[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone 454.0 503 (5-aminobenzo[c][2,6]azir-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone 453.1 504 (5-aminopyrimidino[4,5-c][1,7]pyrimidin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrinyl)methyl ketone 455.1 505 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl)methyl ketone 491.00 and 493.00 506 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]phospholin-4-yl]methyl ketone 461.0 507 (4-amino-1,3-dihydrofurano[3,4-c][1,8]diazin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]phospholin-4-yl]methyl ketone 461.0 508 (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone 458.0 509 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone 459.0 510 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone 494.0 511 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone 495.0 512 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3R)-3-(6-methyl-3-pyridyl)phosphono-4-yl] methyl ketone 391.2 513 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]siloxane-4-yl]methyl ketone 445.0 514 (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7] acetylin-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone 459.0 515 (6-amino-8,9-dihydro-7H-cyclopentadienyl[c][1,7]pyridin-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone 458.2 516 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-pyrinyl)methyl ketone 444.2 517 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl) methyl ketone 489.2 518 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone 474.2 519 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl) methyl ketone 489.2 520 (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrolinyl) methyl ketone 472.2 521 (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone 456.2 522 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone 460.2 523 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone 458.8 524 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrinyl)methyl ketone 459.8 525 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone 475.2 526 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone 476.1 527 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone 458.1 528 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone 462.1 529 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone 478.0 530 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone 508.0 531 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone 488.1 532 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone 504.1 533 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methyl ketone 469.9 534 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone 486.0 535 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) methyl ketone 437.2 536 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl)methyl ketone 488.2 537 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone 450.1 538 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone 434.2 539 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone 452.2 540 (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone 440.2 541 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl)methyl ketone and (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone 459.1 542 (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl)methyl ketone and (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl)methyl ketone 463.2 543 (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl)methyl ketone and (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone 475.2 544 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone 532.0 545 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-fluorophenyl)-4-hydroxylyl)methyl ketone 424.1 546 (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone 489.9 547 (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone 507.9 548 (4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone 523.8 549 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tert-yl)-4-pyrinyl)methyl ketone 446.8 550 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-tert-yl)-5-methyl-4-pyrinyl) methyl ketone 449.2 551 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone 452.2 552 ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-tertyl)methyl ketone 454.2 553 (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-tert-linyl)methyl ketone 456.0 554 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-pyrinyl) methyl ketone 459.1 555 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-tert-yl)-4-pyrinyl)methyl ketone 461.1 556 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-tert-linyl)methyl ketone 474.1 557 (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-tert-linyl)methyl ketone 474.1 558 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone 475.1 559 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl)methyl ketone 475.2 560 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tert-yl)-4-tert-linyl) methyl ketone 476.1 561 (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-linyl) methyl ketone 488.2 562 ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-tert-yl)methyl ketone 490.2 563 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-tert-yl)-4-pyrinyl) methyl ketone 491.1 564 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-tert-yl)-4-pyrinyl) methyl ketone 505.2 565 ((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-tert-yl)-4-tert-ylinyl) methyl ketone 536.2

[0186] Examples 566 and 567: (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl) pyroline) methyl ketone and (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)((3S,5R)-3-isobutyl-5-(4-(trifluoromethyl)phenyl) pyroline) methyl ketone.

[0187] A mixture of 4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidine-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) iodine (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 reverse-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] acetylin-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl) pyroline) 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). The submitted sample of 70 mg 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 isolated from the dissolved sample and then arbitrarily designated as the cis-mirror isomer (4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)((3S,5R)-3-isobutyl-5-(4-(trifluoromethyl)phenyl)oline)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] acetylin-8-yl)((3R,5S)-3-isobutyl-5-(4-(trifluoromethyl)phenyl) pyroline) methyl ketone 3 (peak 2, chiral column) (21 mg, 0.041 mmol, 22% yield).1H NMR (400 MHz, methanol-d4) δ ppm 9.14 (s, 1 H), 8.10 (br s, 1 H), 7.88 - 8.00 (m, 2 H), 7.62 - 7.76 (m, 2 H), 5.76 - 5.99 (m, 1 H), 5.47 - 5.63 (m, 2 H), 5.24 (t,J= 3.9 Hz, 2 H), 4.62 - 4.88 (m, 1 H), 3.82 - 4.08 (m, 4 H), 1.13 - 1.35 (m, 2 H), 1.00 - 1.08 (m, 1 H), 0.25 (br d,J= 1.5 Hz, 6H). m / z(ESI): 501.0 [M+H]+.

[0188] The examples in Table 11 were prepared in a manner similar to that described for Examples 566 and 567. [Table 11] Example structure name m / z(ESI): [M+H + SFC conditions 568 [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]silolin-4-yl]methyl ketone 474 Peak 1, Chiral Tech OJ column (250 x 21 mm, 5 μm), mobile phase 65% liquid CO2 and 35% MeOH with 0.2% TEA, flow rate 80 mL / min. 569 [(3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]silolin-4-yl]methyl ketone 474 The second peak was observed on a Chiral Tech OJ column (250 x 21 mm, 5 μm) with a mobile phase of 65% liquid CO2 and 35% MeOH containing 0.2% TEA at a flow rate of 80 mL / min. 570 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl]methyl ketone 445.2 Peak 1: Chiral Tech AD column (250 x 21 mm, 5 μm), mobile phase of 60% liquid CO2 and 40% MeOH with 0.2% TEA, flow rate of 80 mL / min. 571 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl]methyl ketone 445.2 The second peak was observed on a Chiral Tech AD column (250 x 21 mm, 5 μm) with a mobile phase of 60% liquid CO2 and 40% MeOH containing 0.2% TEA at a flow rate of 80 mL / min. 572 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)phosphono-4-yl]methyl ketone 455 Peak 1, Chiral Tech OJ column (250 x 21 mm, 5 μm), mobile phase 50% liquid CO2 and 50% MeOH with 0.2% TEA, flow rate 60 mL / min 573 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)phosphono-4-yl]methyl ketone 455 The second peak was observed on a Chiral Tech OJ column (250 x 21 mm, 5 μm) with a mobile phase of 50% liquid CO2 and 50% MeOH containing 0.2% TEA at a flow rate of 60 mL / min. 574 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl]methyl ketone 459.2 Peak 1, Chiral Tech OD column (250 x 21 mm, 5 mm), mobile phase 85% liquid CO2 and 15% MeOH with 0.2% TEA, flow rate 80 mL / min 575 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2S,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl]methyl ketone 459.2 The second peak was observed on a Chiral Tech OD column (250 x 21 mm, 5 mm), with a mobile phase of 85% liquid CO2 and 15% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 576 6-[(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl) pyridine-3-carboxynitrile 402.2 Peak 1, Chiral Tech OJ column (250 x 21 mm, 5 mm), mobile phase 50% liquid CO2 and 50% MeOH with 0.2% TEA, flow rate 50 mL / min 577 6-[(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl) pyridine-3-carboxynitrile 402.2 The second peak was observed on a Chiral Tech OJ column (250 x 21 mm, 5 mm), with a mobile phase of 50% liquid CO2 and 50% MeOH containing 0.2% TEA, at a flow rate of 50 mL / min. 578 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(3-chlorophenyl)phospholin-4-yl]methyl ketone 410 Peak 1, Chiral Tech AD column (250 x 21 mm, 5 μm), mobile phase 73% liquid CO2 and 27% MeOH with 0.2% TEA, flow rate 80 mL / min. 579 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl)phosphono-4-yl]methyl ketone 410.1 The second peak was observed on a Chiral Tech AD column (250 x 21 mm, 5 μm) with a mobile phase of 73% liquid CO2 and 27% MeOH containing 0.2% TEA at a flow rate of 80 mL / min. 580 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(4-chlorophenyl)phosphono-4-yl]methyl ketone 410.2 Peak 1, Chiral Tech AD column (250 x 21 mm, 5 μm), mobile phase 65% liquid CO2 and 35% MeOH with 0.2% TEA, flow rate 80 mL / min 581 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl)phosphono-4-yl]methyl ketone 410.2 The second peak was observed on a Chiral Tech AD column (250 x 21 mm, 5 μm) with a mobile phase of 65% liquid CO2 and 35% MeOH containing 0.2% TEA at a flow rate of 80 mL / min. 582 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl] methyl ketone 459.2 Peak 1, Chiral Tech OJ column (250 x 21 mm, 5 μm), mobile phase 70% liquid CO2 and 30% MeOH with 0.2% TEA, flow rate 80 mL / min. 583 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl] methyl ketone 459.2 The second peak was observed on a Chiral Tech OJ column (250 x 21 mm, 5 μm) with a mobile phase of 70% liquid CO2 and 30% MeOH containing 0.2% TEA at a flow rate of 80 mL / min. 584 (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl)methyl ketone 456.2 The second peak was determined using a Chiral Technologies IC column (250 x 21 mm, 5 mm) with a mobile phase of 65% liquid CO2 and 35% MeOH containing 0.2% TEA at a flow rate of 80 mL / min. Peak partitioning was determined by SFC using an IC column containing 35% MeOH. 585 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl]methyl ketone 473.9 Peak 1, Chiral Technologies AD column (250 x 21 mm, 5 mm), mobile phase 82% liquid CO2 and 18% MeOH with 0.2% TEA, flow rate 80 mL / min 586 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl]methyl ketone 473.9 The second peak was observed using a Chiral Technologies AD column (250 x 21 mm, 5 mm), with a mobile phase of 82% liquid CO2 and 18% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 587 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl]methyl ketone 473.9 Peak 1, Chiralpak AS-H column (250 x 21 mm, 5 μm), mobile phase 85% liquid CO2 and 15% MeOH + TEA, flow rate 80 mL / min. 588 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl]methyl ketone 473.9 The second peak was observed on a Chiralpak AS-H column (250 x 21 mm, 5 μm) with a mobile phase of 85% liquid CO2 and 15% MeOH + TEA at a flow rate of 80 mL / min. 589 Tributyl(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate 544.2 Peak 1, Chiralcel OJ-H column, mobile phase 70% liquid CO2 and 30% MeOH. 590 Tributyl(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate 544.2 The second peak was observed on a Chiralcel OJ-H column with a mobile phase of 70% liquid CO2 and 30% MeOH. 591 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]phosphono-4-yl]methyl ketone 461.1 Peak 1, Chiralcel OJ-H column, mobile phase: 60% liquid CO2 and 40% MeOH. 592 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]phosphono-4-yl]methyl ketone 461.1 The second peak was observed on a Chiralcel OJ-H column with a mobile phase of 60% liquid CO2 and 40% MeOH. 593 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tert-yl)-4-tert-linyl)methyl ketone 446.1 The second peak, on a ChiralPak OD-H column, showed a mobile phase of 60% liquid CO2 and 40% iPrOH with 0.5% DEA. 594 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylyl)methyl ketone 473.3 The second peak was observed on a ChiralPak OD-H column with a mobile phase of 70% liquid CO2 and 30% MeOH. 595 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thiopyrinyl) methyl ketone or (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thio-linyl) methyl ketone 461.1 The second peak was observed on a ChiralPak IC column with a mobile phase of 60% liquid CO2 and 40% MeOH. 596 (4-amino-1,3-dihydrofurano[3,4-c][1,7]idin-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazine) ketone or (4-amino-1,3-dihydrofurano[3,4-c][1,7]idin-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazine) ketone 444.1 The second peak, Lux C3 column, with a mobile phase of 60% liquid CO2 and 40% MeOH containing 0.5% DEA. 597 (4-amino-1,3-dihydrofurano[3,4-c][1,7]ardin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane-4-yl) methyl ketone or (4-amino-1,3-dihydrofurano[3,4-c][1,7]ardin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane-4-yl) methyl ketone 459.1 The second peak was observed on a Chiralpak IC column with a mobile phase of 60% liquid CO2 and 40% MeOH. 598 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone 479 Peak 1, Chiral Technologies AS column (250 x 21 mm, 5 mm), mobile phase 75% liquid CO2 and 25% MeOH with 0.2% TEA, flow rate 80 mL / min 599 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]methyl ketone 479 The second peak was observed using a Chiral Technologies AS column (250 x 21 mm, 5 mm), with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 600 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]methyl ketone 495 Peak 1, Chiral Technologies AS column (250 x 21 mm, 5 mm), mobile phase 80% liquid CO2 and 20% MeOH with 0.2% TEA, flow rate 80 mL / min 601 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]methyl ketone 495 The second peak was constructed using a Chiral Technologies AS column (250 x 21 mm, 5 mm), with a mobile phase of 80% liquid CO2 and 20% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 602 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl)methyl ketone 491.00 and 493.00 Peak 1, Chiral Technologies OJ column (250 x 21 mm, 5 mm), mobile phase of 85% liquid CO2 and 15% MeOH with 0.2% TEA, flow rate of 80 mL / min. 603 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone 458 Peak 1, Chiralcel AS-H column (250 x 21 mm, 5 μm), mobile phase 80% liquid CO2 and 20% MeOH + TEA, flow rate 80 mL / min. 604 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl)methyl ketone 459 Peak 1, Chiral Technologies AS column (250 x 21 mm, 5 mm), mobile phase of 80% liquid CO2 and 20% MeOH with 0.2% TEA, flow rate of 80 mL / min. 605 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)phosphono-4-yl]methyl ketone 391.2 The second peak was constructed using a Chiral Technologies OJ column (250 x 21 mm, 5 mm), with a mobile phase of 70% liquid CO2 and 30% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 606 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)phosphono-4-yl]methyl ketone 391.2 Peak 1, Chiral Technologies OJ column (250 x 21 mm, 5 mm), mobile phase of 70% liquid CO2 and 30% MeOH with 0.2% TEA, flow rate of 80 mL / min. 607 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)phosphono-4-yl]methyl ketone 392.2 Peak 1, Regis (S,S) Whelk-01 column (250 x 21 mm, 5 mm), mobile phase of 70% liquid CO2 and 30% MeOH with 0.2% TEA, flow rate of 80 mL / min. 608 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)phosphono-4-yl]methyl ketone 392.2 The second peak was observed using a Regis (S,S) Whelk-01 column (250 x 21 mm, 5 mm), with a mobile phase of 70% liquid CO2 and 30% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 609 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]pyrolin-4-yl]methyl ketone 445 Peak 1, Chiral Technologies ID column (250 x 21 mm, 5 mm), mobile phase of 60% liquid CO2 and 40% MeOH with 0.2% TEA, flow rate of 70 mL / min. 610 (R)-(4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)phospholino) ketone 445 The second peak was observed on a Chiral Technologies ID column (250 x 21 mm, 5 mm) with a mobile phase of 60% liquid CO2 and 40% MeOH with 0.2% TEA, at a flow rate of 70 mL / min. 611 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrolin-4-yl]methyl ketone 447 For the second peak, ChromegaChiral CC4 column (250 x 21 mm, 5 μm) and Chiralcel OJ-H column (250 x 21 mm, 5 μm) were used, with a mobile phase of 65% liquid CO2 and 35% MeOH + TEA, and a flow rate of 80 mL / min. 612 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrolin-4-yl]methyl ketone 447 For the first peak, ChromegaChiral CC4 column (250 x 21 mm, 5 μm) and Chiralcel OJ-H column (250 x 21 mm, 5 μm) were used, with a mobile phase of 65% liquid CO2 and 35% MeOH + TEA, and a flow rate of 80 mL / min. 613 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyrrolidone-2-yl]pyrrolidone-4-yl]methyl ketone 447 Peak 1, Chiral Technologies OJ column (250 x 21 mm, 5 mm), mobile phase of 75% liquid CO2 and 25% MeOH with 0.2% TEA, flow rate of 80 mL / min. 614 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyrrolidone-2-yl]pyrrolidone-4-yl]methyl ketone 447 The second peak was constructed using a Chiral Technologies OJ column (250 x 21 mm, 5 mm), with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 615 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-(trifluoromethyl)-2-phenylthio)-4-pyrinyl) methyl ketone 451.2 Peak 1, Chiral Technologies OX column (250 x 21 mm, 5 mm), mobile phase of 65% liquid CO2 and 35% MeOH with 0.2% TEA, flow rate of 80 mL / min. 616 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-phenylthio)-4-pyrinyl)methyl ketone 451.2 Peak 1, Chiral Technologies IC column (250 x 21 mm, 5 mm), mobile phase 70% liquid CO2 and 30% MeOH with 0.2% TEA, flow rate 80 mL / min 617 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-phenylthio)-4-pyrinyl) methyl ketone 451.2 The second peak was observed using a Chiral Technologies IC column (250 x 21 mm, 5 mm), with a mobile phase of 70% liquid CO2 and 30% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min. 618 (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4,5-dichloro-2-phenylthio)-4-pyrinyl)methyl ketone 451.4 Peak 1, Chiral Technologies OJ column (250 x 21 mm, 5 mm), mobile phase 60% liquid CO2 and 40% MeOH with 0.2% TEA, flow rate 60 mL / min 619 ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-pyrinyl)methyl ketone 474.8 The second peak was observed on a Chiralcel OJ-H column with a mobile phase of 80% liquid CO2 and 20% MeOH + TEA, at a flow rate of 80 mL / min. 620 (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 470.2 Peak 1, SFC, using Chiralcel OJ, 2 x 25 cm, 5 μm, mobile phase of 75% liquid CO2 and 25% methanol with 0.1% diethylamine, at a flow rate of 60 mL / min. 621 (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 470.2 The second peak, SFC, was observed using Chiralcel OJ, 2 x 25 cm, 5 μm, with a mobile phase of 75% liquid CO2 and 25% methanol containing 0.1% diethylamine, at a flow rate of 60 mL / min. 622 (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-hydroxylinyl) methyl ketone 473.00 and 475.00 The second peak was observed on a Chiral Technologies OJ column (250 x 21 mm, 5 mm), with a mobile phase of 75% liquid CO2 and 25% MeOH containing 0.2% TEA, at a flow rate of 80 mL / min.

[0189] Example 623: (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)((3S)-1-oxy-3-(4-(trifluoromethyl)phenyl)thio-lino) methyl ketone.

[0190] 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]pyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)thio-lino) methyl ketone (30 mg, 0.065 mmol) in 1.5 mL of DCM. The mixture was stirred for 2 h at room temperature (LCMS showed the formation of a mixture of uranium and uranium ions), 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]diphenyl-8-yl)((3S)-1-oxo-3-(4-(trifluoromethyl)phenyl)thio-lino)methyl ketone 2,2,2-trifluoroacetate (2 mg, 3.39 µmol, 5.2% yield). m / z (ESI): 476.9 [M+H]+. 19F NMR (methanol-d4, 376 MHz) δ -64.16 (s, 3F), -77.26 (s, 3F). ¹H NMR (methanol-d⁴, 400 MHz) 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).

[0191] Example 624: (S)-1-(4-(4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidine-8-carbonyl)-3-(4-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl-1-one.

[0192] 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]pyridin-8-yl)(2-(4-(trifluoromethyl)phenyl)piperazine-1-yl) ketone (50 mg, 0.113 mmol) in 1.5 mL of DCM at 0°C, followed by the addition of triethylamine (31.7 µL, 0.226 mmol, SIGMA Aldrich). The mixture was stirred for 20 min at 0°C, then stirred for 10 min at room temperature, and then partitioned between 1 mL of 0.5 N NaOH and 10 mL of DCM. The organic phase was washed with 1 mL of brine, concentrated, and the residue purified by RP-HPLC (10%–90% CH3CN in water mediated by 0.1% TFA) to give (S)-1-(4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]acetidine-8-carbonyl)-3-(4-(trifluoromethyl)phenyl)piperazine-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]+. 19F NMR (DMSO-d6, 376 MHz) δ -60.88 (s, 3F), -74.63 (s, 6F). 1H-NMR is a mixture of rotational isomers (1 / 3 ratio). 1H NMR (DMSO-d6, 400 MHz) δ 9.00 (br s, 0.75H), 8.86 (br s, 0.25H), 7.97 (m, 2H), 7.78 (m, 3H), 7.63 (m, 2H), 5.86 (br s, 0.75H), 5.64 (br s, 0.25H), 5.42 (br s, 1.5H), 5.37 (br s, 0.5H), 5.09 (br s, 2H), 3.8-4.0 (m, 6H), 2.8-3.0 (m, 2H), 1.96 (br s, 3H).

[0193] Example 625: (S)-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)phosphino)methylthione

[0194] 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) oxylino) methyl ketone (70 mg, 0.158 mmol) in 1 mL of THF was microwaved at 95°C for 6 h in a sealed glass tube. RP-HPLC purification of the crude mixture (10%–90% CH3CN in water mediated by 0.1% TFA) yielded a yellow solid (S)-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)oline)methylthione 2,2,2-trifluoroacetate (69.7 mg, 0.122 mmol, 77% yield). m / z (ESI): 460.3 [M+H]+. 19F NMR (methanol-d4, 376 MHz) δ -64.14 (s, 3F), -77.05 (s, 3F). 1H NMR (400 MHz, methanol-d4) δ ppm 7.91 (m, 1 H), 7.69 - 7.83 (m, 3 H), 7.64 (m, 1 H), 7.51 (br s, 1 H), 7.05 (br s, 1 H), 5.52 (br s, 2 H), 5.20 (br s, 2 H), 4.90 - 5.06 (m, 2 H), 4.73 (m, 1 H), 4.11 (m, 1 H), 3.89 (m, 1 H), 3.81 (m, 1 H), 3.71 (m, 1 H).

[0195] Example 626: (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl)methylthionone. Example 626 was prepared in the same manner as Example 625. m / z(ESI): 461.10 [M+H]+ HCT116 proliferation activity

[0196] HCT116 MTAP invalid and WT cells were inoculated in 96-well tissue culture plates in RPMI 1640 medium + 10% fetal bovine serum. The plates were incubated overnight at 37°C and 5% CO2. Cells were then treated with 8- or 9-spot serial dilutions of compounds (maximum concentrations of 1 μM or 10 μM, 1:3 serial dilution steps were used) as well as DMSO-only controls. In the presence of drug, cells were incubated for 6 days. The effect on cell viability was measured using the CellTiter-Glo® luminescent cell viability assay (Promega) according to the manufacturer’s recommendations. The analysis plate is read on the EnVisionTM multi-label reader using the ultra-sensitive light-emitting module. IC50 values ​​were calculated using GraphPad Prism v 5.01 using a symmetric S-shaped dose-response least squares fit (Hill slope fixed at −1 and top constraint of 100%) or dose-response curves with GeneData Screener using a 4-parameter logistic model.

[0197] Alternatively, compounds can be analyzed in a 384-well plate format:

[0198] The compounds (compounds with 22-point serial dilutions, using the highest concentration of 10 μM or 50 μM, 1:2 serial dilution steps) were pre-spotted on 384-well plates as well as DMSO-only control. HCT116 MTAP-null and WT cells were then inoculated as above, and 6 days later, the effect on cell viability was measured using the CellTiter-Glo® luminescent cell viability assay (Ploe McGrath Corporation). The analysis plates were read as above, and the IC50 values ​​were calculated using a 4-parameter logistic model using GeneData Screener to fit a dose-response curve. The reported IC50 indicates the value of the curve passing through 50% of the control.

[0199] All published documents as well as patent applications cited in this specification are hereby incorporated by reference in their entirety and for all purposes as if each separate public document or patent application was specifically and solely specified as incorporated by reference and each literature was adequately stated in its entirety. Notwithstanding the fact that the foregoing invention has been described in considerable detail by way of exposition and examples for the purpose of clear understanding, it is readily clear to those familiar with the technology that certain variations and modifications may be made to the invention without departing from the spirit or scope of the scope of the appended patent application, according to the imparted content of the invention. [Brief explanation of the diagram]

[0050] None [Biomaterial Storage]

[0201] None

Claims

1. A compound I having formula I, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing: wherein R1, R2, and the nitrogen atom to which they are attached form a five- or six-membered ring, the five- or six-membered ring being saturated or partially saturated, and comprising 0, 1, or 2 additional identical or different heteroatoms selected from O, N, or S, wherein the S atom is optionally substituted with one or two side oxygen groups; wherein the ring formed by R1, R2, and the nitrogen atom to which they are attached can be substituted with 0, 1, 2, or R3; In each case, R3 is selected from C1-6 alkyl, halogenated, C1-6 haloalkyl, -OC1-6 alkyl, -OC1-6 haloalkyl, -C(O)C1-6 alkyl, -C(O)C1-6 haloalkyl, -C(O)OC1-6 alkyl, -C(O)OC1-6 haloalkyl, 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 be substituted with one or more Ra as desired, wherein Ra is selected in each case from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, pentafluorohydrosulfide, -OC1-3 alkyl, and -OC1-3 haloalkyl; wherein R is selected from the tricycles of formula IA and IB: IA and IB, wherein it is a single bond or a double bond. X1 and X2 are each selected from N and C, wherein X1 and X2 cannot both be N; and if X1 is C, it can be substituted with C1-3 alkyl or halogen as desired; X6, X7 and X8 are each independently selected from N and C as desired, wherein the substituents on N and C are independently selected from C1-3 alkyl; X6 and X7 and X7 and X8 cannot both be N; X3, X4 and X5 are each selected from O, S, C as desired and N as desired, wherein the substituents on C and N are independently selected from C1-3 alkyl and C1-3 alkyl (OH), wherein the alkyl can be substituted with halogen as desired.

2. The compound as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is a tricyclic IA having the formula IA.

3. The compound as claimed in claim 2, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is a series of , , or .

4. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of claims 1 to 3, wherein X1 is C, a halogenated C, or N.

5. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of claims 1 to 3, wherein X1 is N.

6. The compound as claimed in claim 4, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is a series.

7. A pharmaceutically acceptable salt of the compound as claimed in claim 1, its tautomers, its stereoisomers, or any of the foregoing, wherein R is a tricyclic IB of formula IB and X1, X2, X6, X7, and X8 are as defined in claim 1.

8. The compound as claimed in claim 7, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1 is N, X7 is N, or both X1 and X7 are N.

9. A compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any of claims 1 to 3, 7 and 8, wherein R1, R2 and the nitrogen atom to which they are attached form a six-membered ring, which may be saturated or partially saturated and contains 0, 1 or 2 additional heteroatoms selected from O, N or S.

10. The compound of claim 9, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein the six-membered ring system is , , or .

11. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, 7 and 8, wherein R3 is independently selected in each case from C1-6 alkyl, halogenated, and five- or six-membered rings, which may be saturated, partially saturated, or aromatic, and contains 0, 1, or 2 heteroatoms selected from O, N, and S.

12. The compound as claimed in claim 11, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3 is phenyl, pyridyl, tert-yl, or pyrimidinyl, which is substituted with one or more Ra as desired.

13. A compound as claimed in claim 12, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein the ring system formed by R1, R2 and the nitrogen atom to which they are attached, wherein Ra is as defined in claim 1.

14. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of claims 1 to 3, 7 and 8, wherein Ra is selected in each case from halogenated, CN, C1-6 alkyl, C1-6 haloalkyl, -OC1-3 alkyl, and -OC1-3 haloalkyl.

15. The compound of claim 14, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ra is in each case a C1-6 haloalkyl or -OC1-3 haloalkyl.

16. The compound of claim 15, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein the ring system is formed by R1, R2, and the nitrogen atom to which they are attached.

17. A compound, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from: (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-pyrinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-pyrinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R)-3-(6-ethoxy-3-pyridinyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(3,5-difluorophenyl)-5-methyl-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyrolinyl)-5-methyl-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-chloro-3-pyridinyl)-5-methyl-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridinyl)-5-methyl-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl ...7] acetyl-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrolinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(6-ethoxy-3-pyridyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(3,5-difluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyridinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-pyridine-8-yl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((2R,4R)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((2R,4S)-4-(4-chlorophenyl)-2-cyclopropyl-1-pyrrolidinyl)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]quinoline-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-ethoxy-3-terpinel)-4-hydroxylinyl) methyl ketone, ((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, ((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, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aR,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aR,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-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]quinoline-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]quinoline-8-yl)((3R,3aS,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrolo-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,3aS,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrolo-1(4H)-yl) methyl ketone, ((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, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4R)-3,4-diphenyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-(4-chlorophenyl)-4-hydroxy-1-pyrrolidyl) 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-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-ethoxy-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,[4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-uraninyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-uraninyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-uraninyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(6-ethoxy-3-pyridinyl)-4-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,6aR)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,6aS)-3-phenylhexahydrocyclopentan[b]pyrrole-1(2H)-yl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aR,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-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]quinoline-8-yl)((3S,3aS,7aR)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,3aS,7aS)-3-phenylhexahydropiperano[4,3-b]pyrrole-1(4H)-yl) methyl ketone, ((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, ((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, ((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]quinoline-8-yl)((3S,4R)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3-(4-bromophenyl)-4-methyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,4S)-3,4-diphenyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-hydroxy)-5-methyl-4-hydroxylinyl) 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-hydroxylinyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-Dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyrolinyl) ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4R)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-tertyl)-4-tertyl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3R)-4-amino-7-fluoro-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-tertyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl) ((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acety ...3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl) methyl ketone,4-c][1,7] acetyl-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-pyridine) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyridine) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyridine) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-pyridinyl) methyl ketone, ((3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)((1R,3S)-1-oxy-3-(4-(trifluoromethyl)phenyl)-4-thiopyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)((1S,3S)-1-oxy-3-(4-(trifluoromethyl)phenyl)-4-thiopyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)((2S)-2-(4-(trifluoromethyl)phenyl)-1-piperazinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((2R)-2-(4-(trifluoromethyl)phenyl)-1-piperazine) methyl ketone, ...7] nitridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]nitridin-8-yl)((3R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]nitridin-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)-2-phenylthio)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4,5-dichloro-2-phenylthio)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-phenylthio)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(6-(2-propyloxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)7] pyridin-8-yl)((3R,5S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-pyridine) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridine) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridine) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyridinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-pyridyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(2-propyloxy)-3-pyridyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-methyl-5-(6-(3,3,3-trifluoropropoxy)-3-tertyl)-4-pyrinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-(difluoromethoxy)-3-fluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-oxo-linyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-1,4-oxo-azino-cycloheptane-4-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1,4-oxo-azino-cycloheptane-4-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thio-arinyl)methylthione, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-thio-arinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thio-arinyl)methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(4-bromo-2,6-difluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylinyl)7] acetyl-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyridine-8-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridyl)-4-pyridine-8-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]acetyl-8-yl)((3S)-3-(5-(trifluoromethyl)-2-phenylthio)-4-pyridine-8-yl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(2-propyloxy)-3-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-terpinel)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(4-(difluoromethoxy)-3-fluorophenyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-hydroxylinyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridinyl)-5-methyl-4-pyridinyl) ketone5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridine)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-(6-methoxy-3-pyridine)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(2-propyloxy)-3-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridinyl)-4-pyridineyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2R)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethoxy)phenyl]-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(2S)-4,4-difluoro-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, ...7] pyridin-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)pyrimin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]pyrimin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R)-3-[5-(trifluoromethyl)pyridin-2-yl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3R,5S)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-(6-methyl-3-pyridinyl)pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S)-3-[5-(trifluoromethyl)pyridin-2-yl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[(3S,5R)-3-isobutyl-5-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridin-8-yl)-[racemic-(3S)-3-(6-cyclopropyl-3-pyridinyl)pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)-[racemic-(3S)-3-[5-(trifluoromethyl)-2-pyridyl] thiolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8] acetylin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-thiolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)(3R)-3-(4-(trifluoromethyl)phenyl)-4-thiolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetylin-8-yl)8] nitridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c][1,8]nitridin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]hydroxylin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(difluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyridyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyridyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyridyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(2,2,2-trifluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-(difluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl thiophene, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl thiophene, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl thiophene, (4-amino-1,3-dihydrofurano[3,4-c]quinolinyl) methyl thiophene[4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tertyl)-4-terlinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-4-terlinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-terlinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-pyrolinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((5S)-2,2-dimethyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5R)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]hydroxylin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]hydroxylin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2S,5R)-2-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(2R,5S)-2-methyl-5-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,(4-c)quinoline-8-yl)-[(3R)-3-(3-chlorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3R)-3-(4-chlorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3R)-3-(5-bromo-2-pyridyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3R)-3-(6-methyl-3-pyridyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl] siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R)-3-[6-(trifluoromethoxy)-3-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3R,5S)-3-methyl-5-[4-(trifluoromethoxy)phenyl] siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(3-chlorophenyl) siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(4-chlorophenyl) siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(5-bromo-2-pyridyl)siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-(6-methyl-3-pyridyl)siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl] siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[6-(trifluoromethoxy)-3-pyridyl]siloxane-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,(4-c)quinoline-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl] pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5R)-3-methyl-5-[4-(trifluoromethoxy)phenyl] pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5R)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl] pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(2R)-2-(4-bromophenyl)-4,4-difluoro-1-piperidinyl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3R)-3-(6-methyl-3-pyridyl)pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-(2-chlorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-(3-bromophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-(3-fluorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-bromophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-fluorophenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(4-methoxyphenyl)uranin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(6-bromoda-3-yl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[racemic-(3S)-3-(p-tolyl)phospholin-4-yl] methyl ketone,[4-c]quinoline-8-yl)-[racemic-(3S)-3-[6-(trifluoromethyl)-3-pyridyl]pyrolin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-phenylpyrimidin-4-yl] methyl ketone, (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[racemic-(3S)-3-pyrimidin-2-ylpyrolin-4-yl] methyl ketone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c][1,8]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyridine-8-yl, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridine-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c][1,7]pyridin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) ...7] pyridine-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridine)-4-pyrolinyl) 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-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrolinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-hydroxylinyl) methyl ketone, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacrylyl) 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-hydroxylinyl) methyl ketone, (4-amino-2,3-dihydrofurano[3,2-c][1,7]pyrrolidinyl) methyl ketone, (4-amino-3,3-dimethyl-1H-furano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]siloxane-4-yl] methyl ketone, (4-amino-3,7-dimethyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-siloxane) methyl ketone, (4-amino-3-methyl-1H-pyrazolo[4,3-c][1,7]siloxane-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-siloxane) methyl ketone, (4-amino-3-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethoxy ...S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone,[4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(difluoromethoxy)-2-pyridinyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl) methyl ketone, (4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-pyridinyl)-5-methyl-4-hydroxylyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,[4-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(6-ethoxy-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) 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-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,4S)-3-ethyl-4-(4-methylphenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-pyrolinyl) 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-pyrolinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-Dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-pyridyl)-4-hydroxylinyl) 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]quinoline-8-yl)((3S,5R)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridinyl)-4-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacrylyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-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-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4 ...phenyl)-1H-pyrazolo[4,3-c]quinoline-8-yl)(3R)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]quinoline-8-yl)(3R)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]quinoline-8-yl)(3R)[3-c]quinoline-8-yl)((3R,4S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-chloro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(2-(trifluoromethyl)-4-pyridinyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R)-3-(6-(difluoromethoxy)-3 ...5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3R)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolinyl)[4-c]quinoline-8-yl)((3R)-3-(6-ethoxy-3-tertyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-pyrrolidyl) 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-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-(6-ethoxy-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(2-(trifluoromethyl)-4-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-Dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(5-bromo-3-fluoro-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-(6-ethoxy-3-tertyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tertyl)-5-methyl-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-chloro-3-pyridyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethoxy)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((3S,5R)-3-methyl-5-(6-(trifluoromethyl)-3-pyridyl)-4-hydroxylinyl) 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]quinoline-8-yl)((4S)-3,3-Dimethyl-4-(4-methylphenyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-bromophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4S)-4-(4-fluorophenyl)-3,3-dimethyl-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) 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]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-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-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylinyl) methyl ketone, (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-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-((5-(trifluoromethyl)-2-pyridyl)oxy)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoroethyl)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)benzyl)-1-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenoxy)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-fluorophenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-1-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(5-(trifluoromethyl)-2-pyridinyl)-4-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-pyridinyl)-4-pyrrolidinyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(6-(trifluoromethyl)-3-tert-yl)-4-hydroxylyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl ...3S,5R)-3-(6-(difluoromethoxy)-3-tert-yl)-5-methyl-4-hydroxylyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3S)-3-(6-(trifluoromethyl)-3-tert-yl)-5-[3-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4R)-3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) 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-pyrrolidyl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-(5-(trifluoromethyl)-2-pyridyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)(3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-tetrahydroacryl) methyl ketone, (4-amino-7-fluoro-2,3-dihydrofurano[3,2-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrrolidone), (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidinyl) ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-4-pyrrolidone) ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-hydroxylinyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tert-yl ...4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(6-(difluoromethoxy)-3-tert-yl)-4-hydroxyl) methyl ketone, (4-amino-7-fluoro-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)(3S)-3-(4-(trifluoromethyl)phenyl)-[4-c]quinoline-8-yl)((3S,5R)-3-(6-methoxy-3-tertyl)-5-methyl-4-pyrolinyl) methyl ketone, (4-aminoimidazo[1,2-a]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) methyl ketone, (4-aminobenzhizo[2,3-c]quinoline-8-yl)-[(2R)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-aminobenzhizo[2,3-c]quinoline-8-yl)-[(2S)-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] methyl ketone, (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(3R)-3-[4-(trifluoromethyl)phenyl]uranin-4-yl] methyl ketone, (4-aminobenzothio[2,3-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]uranin-4-yl] methyl ketone, (5-amino-1,4-dihydro-2H-piperano[3,4-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-uraninyl) methyl ketone, (5-aminobenzo[c][2,6]azinyl-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-uraninyl) methyl ketone, (5-aminopyridino[4,3-c][1,7]pyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (5-aminopyrimidino[4,5-c][1,7]pyridin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (5-aminopyrimidino[4,5-c]quinolin-9-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) methyl ketone, (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7] acetylin-2-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridyl)-4-hydroxylinyl) methyl ketone, (6-amino-8,9-dihydro-7H-cyclopentan[c][1,7] acetylin-2-yl)((3S)-3-(4-(trifluoromethoxy)phenyl)-4-hydroxylinyl) methyl ketone, (R)-(4-amino-1,3-dihydrofuran[3,4-c][1,7] acetylin-8-yl)(3-(4-(pentafluoro-16-hydrothio)phenyl)hydroxylinyl) methyl ketone, (R)-(4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(6-(trifluoromethyl)pyridin-3-yl)phospholino) ketone, (S)-(4-amino-1,3-dihydrofurano[3,4-c][1,7]phospholin-8-yl)(3-(4-(pentafluoro-16-hydrothio)phenyl)phospholino) ketone, [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,[4-c]quinoline-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl] kilotin-4-yl] methyl ketone, [(3S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl] kilotin-4-yl] methyl ketone, 1-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl)-1-piperyl) ethyl ketone, 4-((3R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)carbonyl)-3-holylinyl)benzonitrile, 4-((3R,5S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)carbonyl)-5-methyl-3-holylinyl)benzonitrile, 4-((3S)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]monidin-8-yl)carbonyl)-3-holylinyl)benzonitrile, 4-((3S,5R)-4-((4-amino-1,3-dihydrofurano[3,4-c][1,7]quinoline-8-yl)carbonyl)-5-methyl-3-hydroxylinyl)benzonitrile, 4-chloro-6-[racemic-(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)quinoline-3-yl]pyridine-3-carboxynitrile, 6-[(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)quinoline-3-yl]pyridine-3-carboxynitrile, 6-[(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl) pyridine-3-carboxylonite, methyl(3R,4S)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, methyl(3S,4R)-1-((4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)carbonyl)-4-(4-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxylate, Tri-butyl(3R)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]idine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, and tri-butyl(3S)-4-(4-amino-1,3-dihydrofurano[3,4-c][1,7]idine-8-carbonyl)-3-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate.

18. The compound of claim 17, 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] acetidyl-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-pyrolinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7] acetidyl-8-yl)((3S,5R)-3-(6-(cyclopropyloxy)-3-pyridine)-5-methyl-4-pyrolinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]quinolino-8-yl)((3R,5S)-3-methyl-5-(6-(2,2,2-trifluoroethoxy)-3-tertyl)-4-pyrinyl) ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolino-8-yl)((3S,5R)-3-(6-ethoxy-3-tertyl)-5-methyl-4-pyrinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyridine-8-yl)((3S,5R)-3-(6-(difluoromethoxy)-3-pyridine)-5-methyl-4-pyrolinyl) ketone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((3S)-3-(4-(pentafluoro-λ~6~-hydrothio)phenyl)-4-pyrolinyl) ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]pyrolin-4-yl] ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S,5S)-3-methyl-5-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S)-3-[6-(trifluoromethyl)-3-pyridyl]siloxane-4-yl] methyl ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)-[(3S)-3-[5-(trifluoromethyl)-2-pyridyl]siloxane-4-yl] methyl ketone; ((3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c][1,7]quinolin-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylinyl) ketone; [(3R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinolin-8-yl]-[(3S)-3-[4-(trifluoromethoxy)phenyl]quinolin-4-yl] ketone; (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)-[(3S)-3-[4-(trifluoromethoxy)phenyl]quinolin-4-yl] ketone;(4-amino-3-methyl-3H-pyrazolo[3,4-c]quinoline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)-2-pyridinyl)-4-hydroxylyl) ketone; (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(4-(trifluoromethyl)phenyl)-4-hydroxylyl) ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(difluoromethoxy)-3-tertyl)-4-hydroxylyl) ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3S)-3-(6-(trifluoromethyl)-3-terpinel)-4-pyrrolidyl) methyl ketone; (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((3R)-3-(4-(trifluoromethyl)phenyl)-1-pyrrolidyl) methyl ketone; and (4-amino-1,3-dihydrofurano[3,4-c][1,7]pyrrolidyl-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]pyrrolidyl-4-yl] methyl ketone.

19. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the preceding claims, wherein the compound is (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]urin-4-yl] methyl ketone.

20. A free base of (4-amino-1,3-dihydrofurano[3,4-c][1,7]diazin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]urin-4-yl] methyl ketone.

21. A pharmaceutically acceptable salt of (4-amino-1,3-dihydrofurano[3,4-c][1,7]diazin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]urin-4-yl] methyl ketone.

22. A pharmaceutical composition comprising a compound as described in any one of claims 1-19, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, a free base as described in claim 20, or a pharmaceutically acceptable salt as described in claim 21, and at least one pharmaceutically acceptable excipient.

23. The compound, tautomer, stereoisomer, or pharmaceutically acceptable salt of any of claims 1-19, the free base of claim 20, the pharmaceutically acceptable salt of claim 21, or the pharmaceutical composition of claim 22, which is used as a medicine.

24. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of claims 1 to 19, the free base of claim 20, the pharmaceutically acceptable salt of claim 21, or the pharmaceutical composition of claim 22, which is used to treat cancer.

25. Use of a compound, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 19, a free base as described in claim 20, a pharmaceutically acceptable salt as described in claim 21, or a pharmaceutical composition as described in claim 22, for the preparation of a medicament for the treatment of cancer.

26. The use as described in claim 25, wherein the cancer is selected from ovarian cancer, lung cancer, HNSCC, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, biliary tract cancer, pancreatic cancer, or bladder cancer.

27. The use as described in claim 26, wherein the cancer is lung cancer.

28. The use as described in claim 26, wherein the cancer is pancreatic cancer.

29. A method for synthesizing (4-amino-1,3-dihydrofurano[3,4-c][1,7]diphenyl-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]oline-4-yl] methyl ketone, its tautomers or pharmaceutically acceptable salts thereof, comprising converting the tautomers or pharmaceutically acceptable salts thereof into the form of the tautomers or pharmaceutically acceptable salts thereof.