tricyclo-amide-bicyclo prmt5 inhibitors

CN117062816BActive Publication Date: 2026-10-09AMGEN INC
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Patent Information

Application Number
CN202280024792.9
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Priority Date
2021-02-04
Filing Date
2022-02-03
Publication Date
2026-10-09
Estimated Expiration
2042-02-03

AI Technical Summary

Technical Problem

然而，PRMT5是一种已知的细胞必需基因，并且条件性PRMT5敲除和siRNA敲低研究表明，重大负担(例如，全血细胞减少症、不育症、骨骼肌损失、心脏肥大)可能与在正常组织中抑制PRMT5相关

Benefits of technology

[0580]本发明的其他目的、特征和优点对于本领域技术人员来说将从以下描述和权利要求中变得清楚。

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Abstract

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

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 145,634, filed on February 4, 2021. Background Technology

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

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

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

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

[0007]

[0008] Its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing; wherein R is a tricyclic ring independently selected from formula IA:

[0009]

[0010] in Is it a single bond or a double bond?

[0011] X 1and X 2 In each case, the N and C are independently selected, with the substituents being selected independently from C. 1-3 alkyl;

[0012] Where X 1 and X 2 It cannot be N at the same time;

[0013] Where X 1 It is C, which can be halogenated or halogenated C by choice. 1-3 Alkyl or -CN substituted;

[0014] X 3 X 4 and X 5 In each case, the C, O, and N are independently selected from those that are optionally substituted, wherein these substituents are independently selected from C. 1-3 Alkyl and C 1-3 Alkyl (OH), wherein the alkyl group may optionally be halogenated;

[0015] Where R 1 It is a double ring independently selected from formulas IB, IC, and ID, which is optionally controlled by R. 4 replace;

[0016]

[0017] Where X 6 In each case, the choices are independently selected from O and C;

[0018] Where X 7 In each case, N and C are selected independently;

[0019] Where R 2 In each case, the C that is optionally replaced is selected independently. 1-6 Alkyl or optionally substituted C 1-6 cycloalkyl, wherein these substituents are selected from -CN or C 1-6 cycloalkyl;

[0020] Where R 3 Selected independently from C in each case 1-6 Alkyl, C 1-6 cycloalkyl, halogenated, C 1-6 Haloalkyl, -S(=O)2C 1-6 Alkyl group, -S(O)(NH)C 1-6 Alkyl, -S(O)(NC 1-3 Alkyl)C 1-6 Alkyl, -CN, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(=O)-OC1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Halogenated alkyl groups, 3,6-dihydro-2H-pyranyl groups, and pentafluorosulfuryl groups;

[0021] Where R 4 Selected independently from C in each case 1-6 Alkyl, halogenated and C 1-6 Halogenated alkyl groups.

[0022] In one aspect, the present invention provides a compound, its tautomer, its stereoisomer, or any of the foregoing, a pharmaceutically acceptable salt thereof, wherein R is...

[0023]

[0024] In other respects, X 1 It can be C, optionally replaced by halogenation.

[0025] On the other hand, X 1 It can be N.

[0026] On the other hand, X 3 C can be arbitrarily replaced.

[0027] This invention provides a pharmaceutically acceptable salt of a compound, its tautomer, its stereoisomer, or any of the foregoing, wherein R may be...

[0028]

[0029] On the one hand, X 1 It can be C that has been halogenated.

[0030] This invention provides that R can be

[0031]

[0032] On one hand, X1 can be C, optionally replaced by halogenation.

[0033] This invention provides a pharmaceutically acceptable salt of a compound, its tautomers, its stereoisomers, or any of the foregoing, wherein R 1 It could be IB. On the other hand, R 1 It could be an IC. On the other hand, R... 1 It can be an ID.

[0034] In one aspect, the present invention discloses compounds, their tautomers, their stereoisomers, or any of the foregoing, wherein R 3 C can be selected independently in each case.1-6 Alkyl, halogenated and C 1-6 Haloalkyl. On the other hand, R 3 It can be selected independently of -S(=O)2C in each case. 1-6 Alkyl groups and -CN.

[0035] This invention also discloses the compounds therein, their tautomers, their stereoisomers, or pharmaceutically acceptable salts of any of the foregoing, wherein R 1 It can be R 4 replace.

[0036] On the one hand, R 4 It can be halogenated.

[0037] In one aspect of the invention, R 3 It can be independently selected from methyl, ethyl and cyclopropyl.

[0038] This invention provides a pharmaceutically acceptable salt of a compound, its tautomers, its stereoisomers, or any of the foregoing, wherein the compound is selected from:

[0039] 4-Amino-N-cyclopropyl-7-fluoro-1-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0040] 4-Amino-N-((3R)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0041] 4-Amino-N-((3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0042] 4-Amino-N-methyl-N-((3S)-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0043] (3R)-4-amino-N,3-dimethyl-N-((3S)-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0044] (1R)-4-amino-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0045] (1S)-4-amino-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0046] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0047] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0048] 4-Amino-N-(cyanomethyl)-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0049] 4-Amino-N-(cyanomethyl)-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0050] 4-Amino-N-((3S)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0051] 4-Amino-N-((3R)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0052] (3R)-4-amino-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0053] 4-Amino-7-fluoro-N-methyl-N-((3R)-5-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0054] 4-Amino-7-fluoro-N-methyl-N-((3S)-5-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0055] 4-Amino-N-((5R)-6,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0056] 4-Amino-N-((5S)-6,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0057] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0058] 4-Amino-N-((5R)-6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0059] 4-Amino-N-((5S)-6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0060] 4-Amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0061] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((3S)-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0062] 4-Amino-7-cyano-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0063] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrothieno[3,4-c]quinoline-8-carboxamide,

[0064] 5-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)benzo[c][2,6]naphthidine-9-carboxamide,

[0065] 5-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)pyrimido[4,5-c]quinoline-9-carboxamide,

[0066] 5-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)benzo[c][2,6]naphthidine-9-carboxamide,

[0067] 5-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)pyrido[4,3-c][1,7]naphthyl-9-carboxamide,

[0068] 5-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)pyrimido[4,5-c][1,7]naphthyl-9-carboxamide,

[0069] 4-Amino-7-fluoro-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide,

[0070] 4-Amino-N,1-Dimethyl-N-((3R)-5-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0071] 4-Amino-N,1-Dimethyl-N-((3S)-5-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0072] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0073] 4-Amino-N-ethyl-1-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0074] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0075] 4-Amino-N-((3S)-4-chloro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0076] 4-Amino-N-((3R)-4-chloro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0077] 4-Amino-N-((5R)-6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0078] 4-Amino-N-((5S)-6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0079] 4-Amino-N-((3S)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0080] 4-Amino-N-((3S)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0081] 4-Amino-N-((3R)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0082] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0083] 4-Amino-N-ethyl-1-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0084] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0085] 4-Amino-N,1-Dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0086] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0087] 4-Amino-7-fluoro-N,1-dimethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0088] 4-Amino-N-ethyl-7-fluoro-1-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0089] 4-Amino-N-ethyl-7-fluoro-1-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0090] 4-Amino-N-((5R)-6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0091] 4-Amino-N-((5S)-6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0092] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0093] 4-Amino-7-chloro-N,1-dimethyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0094] 4-Amino-N,1,7-Trimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0095] 4-Amino-N,1,7-Trimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,8]naphthidine-8-carboxamide,

[0096] 4-Amino-N-((3S)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c][1,8]naphthyl-8-carboxamide,

[0097] 4-Amino-N,1-Dimethyl-7-(trifluoromethyl)-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0098] 4-Amino-6-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0099] 4-Amino-N,3-dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0100] 4-Amino-N,3-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c][1,7]naphthidine-8-carboxamide,

[0101] 4-Amino-N,3-dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c][1,7]naphthyl-8-carboxamide,

[0102] 4-Amino-7-fluoro-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0103] 4-Amino-7-fluoro-N,3-dimethyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0104] 4-Amino-7-fluoro-N,3-dimethyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0105] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0106] 4-Amino-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0107] 4-Amino-N,1,3-trimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0108] 4-Amino-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0109] 4-Amino-N,1,3-trimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0110] 4-Amino-N,1,3-trimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0111] 4-Amino-7-fluoro-N,1,3-trimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0112] 4-Amino-7-fluoro-N,1,3-trimethyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0113] (3R)-4-amino-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N,3-dimethyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0114] (3R)-4-amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0115] (3S)-4-amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0116] 4-Amino-7-fluoro-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0117] 4-Amino-N-(7-bromoisocyanate-4-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0118] 4-Amino-7-chloro-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0119] 4-Amino-7-chloro-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0120] 4-Amino-7-chloro-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0121] 4-Amino-N,7-Dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0122] 4-Amino-N-methyl-7-(trifluoromethyl)-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0123] 5-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)benzo[c][2,6]naphthyl-9-carboxamide,

[0124] 5-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)pyrimido[4,5-c]quinoline-9-carboxamide,

[0125] 5-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)pyrido[4,3-c][1,7]naphthyl-9-carboxamide,

[0126] 5-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)pyrimido[4,5-c][1,7]naphthyl-9-carboxamide,

[0127] 4-Amino-N-((5S)-2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0128] 4-Amino-N-((5R)-2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0129] 4-Amino-N-((5S)-2-ethoxy-5,8-dihydro-6H-pyrano[3,4-d]pyrimidin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0130] 4-Amino-N,1-Dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0131] 4-Amino-N-(7-bromoisocyanate-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0132] 4-Amino-N,1-Dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0133] 4-Amino-N,1-Dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0134] 4-Amino-7-fluoro-N,1-dimethyl-N-((4R)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0135] 4-Amino-7-fluoro-N,1-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0136] 4-Amino-7-fluoro-N,1-dimethyl-N-((4R)-7-(trifluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0137] 4-Amino-7-fluoro-N,1-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0138] 4-Amino-7-fluoro-N,1-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0139] 4-Amino-7-fluoro-N,1-dimethyl-N-((4R)-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0140] 4-Amino-7-chloro-N,1-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0141] 4-Amino-7-chloro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0142] 4-Amino-7-chloro-N,1-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c][1,8]naphthidine-8-carboxamide,

[0143] 4-Amino-N,1,7-Trimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0144] 4-Amino-N-((5S)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0145] 4-Amino-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c][1,8]naphthidine-8-carboxamide,

[0146] 4-Amino-N,1,7-Trimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c][1,8]naphthidine-8-carboxamide,

[0147] 4-Amino-N,1,7-Trimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,8]naphthyl-8-carboxamide,

[0148] 4-Amino-N,1-Dimethyl-7-(trifluoromethyl)-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0149] 4-Amino-N,1-Dimethyl-7-(trifluoromethyl)-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0150] 4-Amino-N,3-Dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c][1,7]naphthyl-8-carboxamide,

[0151] 4-Amino-N-ethyl-7-fluoro-3-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0152] 4-Amino-7-fluoro-N,3-dimethyl-N-((4R)-7-(trifluoromethoxy)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0153] 4-Amino-7-fluoro-N,3-dimethyl-N-((4S)-7-(trifluoromethoxy)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0154] 4-Amino-N-ethyl-3,7-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0155] 4-Amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0156] 4-Amino-N,1,3-trimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0157] 4-Amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0158] 4-Amino-N,1,3-trimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0159] 4-Amino-N,1,3-trimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0160] 4-Amino-7-fluoro-N,1,3-trimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0161] 4-Amino-7-fluoro-N,1,3-trimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0162] 2-Amino-3-iodo-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-6-quinoline carboxamide,

[0163] 4-Amino-N,1,7-trimethyl-N-((5R)-2-(trifluoromethyl)-5,6,7,9-tetrahydrooxohepyn[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0164] 4-Amino-N,1,7-trimethyl-N-((5S)-2-(trifluoromethyl)-5,6,7,9-tetrahydrooxohepyn[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0165] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0166] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0167] 4-Amino-N-methyl-N-((3S)-6-nitro-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0168] 4-Amino-N-methyl-N-((3R)-6-nitro-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0169] 4-Amino-N-(~2~H_3_)methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0170] 4-Amino-N-(~2~H_3_)methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0171] 4-Amino-N-methyl-N-((3S)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0172] 4-Amino-N-methyl-N-((3R)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0173] 4-Amino-N-((3S)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0174] 4-Amino-N-((3R)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0175] 4-Amino-N-methyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0176] 4-Amino-N-methyl-N-((3R)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0177] 4-Amino-N-((3S)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0178] 4-Amino-N-((3R)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0179] (3R)-4-amino-N-((3S)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N,3-dimethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0180] (3R)-4-amino-N-((3R)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N,3-dimethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0181] 4-Amino-N-((3S)-6-chloro-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0182] 4-Amino-N-((3R)-6-chloro-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0183] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0184] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0185] 4-Amino-N-(~2~H_3_)methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0186] 4-Amino-N-(~2~H_3_)methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0187] 4-Amino-N-methyl-N-((3S)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0188] 4-Amino-N-methyl-N-((3R)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0189] 4-Amino-N-methyl-N-((1R)-5-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0190] 4-Amino-N-methyl-N-((1S)-5-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0191] 4-Amino-N-methyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0192] 4-Amino-N-methyl-N-((3R)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0193] 4-Amino-N-((3S)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0194] 4-Amino-N-((3R)-6-bromo-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0195] 4-Amino-N-((3S)-6-chloro-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0196] 4-Amino-N-((3R)-6-chloro-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0197] 4-Amino-7-fluoro-N-methyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0198] 4-Amino-7-fluoro-N-methyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0199] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0200] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0201] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0202] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0203] 4-Amino-7-fluoro-N-((3S)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0204] 4-Amino-7-fluoro-N-((3R)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0205] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0206] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0207] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0208] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0209] 4-Amino-7-chloro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0210] 4-Amino-7-chloro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0211] 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0212] 4-Amino-N,1-Dimethyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0213] 4-Amino-N-ethyl-1-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0214] 4-Amino-N,1-Dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0215] 4-Amino-N,1-Dimethyl-N-((3R)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0216] 4-Amino-N-((1R)-5-bromo-2,3-dihydro-1H-inden-1-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0217] 4-Amino-N-((1S)-5-bromo-2,3-dihydro-1H-inden-1-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0218] 4-Amino-N-((5R)-2-bromo-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0219] 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0220] 4-Amino-N-ethyl-1-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0221] 4-Amino-N-((3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0222] 4-Amino-N-((3R)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0223] 4-Amino-7-fluoro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0224] 4-Amino-7-fluoro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0225] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0226] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0227] 4-Amino-7-fluoro-N,1-dimethyl-N-((3R)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0228] 4-Amino-7-fluoro-N-((3S)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0229] 4-Amino-7-fluoro-N-((3R)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0230] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0231] 4-Amino-7-fluoro-N,1-dimethyl-N-((3R)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0232] 4-Amino-7-chloro-N,1-dimethyl-N-((5R)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0233] 4-Amino-7-chloro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0234] 4-Amino-7-chloro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0235] 4-Amino-7-chloro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0236] 4-Amino-7-chloro-N,1-dimethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0237] 4-Amino-7-fluoro-N,3-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0238] 4-Amino-7-fluoro-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0239] 4-Amino-7-fluoro-N,1,3-trimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0240] 4-Amino-7-fluoro-N,1,3-trimethyl-N-((3R)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0241] 4-Amino-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0242] (3R)-4-amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N,3-dimethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0243] (3R)-4-amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N,3-dimethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0244] (3R)-4-amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0245] (3R)-4-amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0246] 4-Amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0247] 4-Amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0248] 4-Amino-7-fluoro-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0249] 4-Amino-7-fluoro-N-methyl-N-((4R)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0250] 4-Amino-7-chloro-N-((5S)-2-cyano-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0251] 4-Amino-7-chloro-N-((5R)-2-cyano-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0252] 4-Amino-7-chloro-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0253] 4-Amino-7-chloro-N-((4R)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0254] 4-Amino-7-chloro-N-methyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0255] 4-Amino-N-((4S)-8-fluoro-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0256] 4-Amino-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0257] 4-Amino-N-((4S)-7,8-difluoro-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0258] 4-Amino-N-((5S)-2-ethoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0259] 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-5-quinolinyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0260] 4-Amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0261] 4-Amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0262] 4-Amino-N,1-Dimethyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0263] 4-Amino-N,1-Dimethyl-N-((1S,4R)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0264] 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0265] 4-Amino-N-((4R)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0266] 4-Amino-N-((5S)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0267] 4-Amino-N-((5R)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0268] 4-Amino-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0269] 4-Amino-N-((4R)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0270] 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0271] 4-Amino-N-((5S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0272] 4-Amino-N-((5R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0273] 4-Amino-7-fluoro-N-((4S)-8-fluoro-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0274] 4-Amino-7-fluoro-N-((4R)-8-fluoro-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0275] 4-Amino-7-fluoro-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0276] 4-Amino-7-fluoro-N-((4R)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0277] 4-Amino-7-fluoro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-5-quinolinyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0278] 4-Amino-7-fluoro-N,1-dimethyl-N-((4S)-7-(trifluoromethoxy)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0279] 4-Amino-7-fluoro-N,1-dimethyl-N-((4R)-7-(trifluoromethoxy)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0280] 4-Amino-7-fluoro-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0281] 4-Amino-7-fluoro-N-((4R)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0282] 4-Amino-N-((5R)-7,7-dimethyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro-5-quinolinyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0283] 4-Amino-N-((5S)-7,7-dimethyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro-5-quinolinyl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0284] 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0285] 4-Amino-N-((4R)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1,7-trimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0286] 4-Amino-N-((5S)-2-ethoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0287] 4-Amino-7-fluoro-N,3-dimethyl-N-((5R)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-5-quinolinyl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0288] 4-Amino-7-fluoro-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0289] 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-5,6,7,9-tetrahydrooxohepyn[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0290] 4-Amino-7-chloro-N-cyclopropyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0291] 4-Amino-7-chloro-N-cyclopropyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0292] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0293] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0294] 4-Amino-N-methyl-N-((3S)-6-(S-methylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0295] 4-Amino-N-((3S)-6-((R)-N,S-dimethylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0296] 4-Amino-N-((3S)-6-((S)-N,S-dimethylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0297] 4-Amino-N-cyclopropyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0298] 4-Amino-N-cyclopropyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0299] 4-Amino-N-((3R)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0300] 4-Amino-N-((3S)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0301] 4-Amino-N-ethyl-N-(6-(trifluoromethyl)-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0302] 4-Amino-N-((3S)-5,6-difluoro-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0303] 4-Amino-N-((3R)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0304] 4-Amino-N-((3S)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0305] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0306] 4-Amino-N-((3S)-6-((R)-N,S-dimethylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0307] 4-Amino-N-((3S)-6-((S)-N,S-dimethylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0308] 4-Amino-N-methyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0309] 4-Amino-N-((3R)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0310] 4-Amino-N-((3S)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0311] 4-Amino-N-((3R)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0312] 4-Amino-N-((3S)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0313] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0314] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0315] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0316] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0317] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(S-methylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0318] 4-Amino-N-((3S)-6-((R)-N,S-dimethylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0319] 4-Amino-N-((3S)-6-((S)-N,S-dimethylsulfonylimino)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0320] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(2-propanesulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0321] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(2-propanesulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0322] 4-Amino-N-((3R)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0323] 4-Amino-N-((3S)-6-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0324] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0325] (3R)-4-amino-N-cyclopropyl-7-fluoro-3-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0326] (3R)-4-amino-7-fluoro-3-methyl-N-(2-propyl)-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0327] (3R)-4-amino-7-fluoro-3-methyl-N-(2-propyl)-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0328] (3R)-4-amino-N-cyclobutyl-7-fluoro-3-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0329] (3R)-4-amino-N-cyclobutyl-7-fluoro-3-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0330] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0331] 4-Amino-N-((3S)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0332] 4-Amino-N-((3S)-5,6-difluoro-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0333] 4-Amino-N-((3S)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0334] 4-Amino-N-((3R)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0335] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0336] 4-Amino-N-((3R)-6-bromo-2,3-dihydro-1-benzothiophene-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0337] 4-Amino-N-((3S)-6-bromo-2,3-dihydro-1-benzothiophene-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0338] 4-Amino-7-chloro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0339] 4-Amino-7-chloro-N,1-dimethyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0340] 4-Amino-N-((3R)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0341] 4-Amino-N-((3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0342] 4-Amino-N-((3S)-5,6-dichloro-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0343] 4-Amino-N-((3R)-6-bromo-2,3-dihydro-1-benzothiophene-3-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0344] 4-Amino-N-((3S)-6-bromo-2,3-dihydro-1-benzothiophene-3-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0345] 4-Amino-7-chloro-N,3-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0346] 4-Amino-7-chloro-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0347] 4-Amino-7-chloro-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0348] 4-Amino-7-chloro-N,3-dimethyl-N-((3S)-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0349] (3R)-4-amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0350] 4-Amino-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0351] 4-Amino-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0352] 4-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0353] 4-Amino-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0354] 4-Amino-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0355] 4-Amino-7-fluoro-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0356] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0357] 4-Amino-7-chloro-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0358] 4-Amino-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N,3-dimethyl[1,2]oxazolo[4,5-c]quinoline-8-carboxamide,

[0359] 4-Amino-N,3-Dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)[1,2]oxazolo[4,5-c]quinoline-8-carboxamide,

[0360] 4-Amino-N,1-Dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0361] 4-Amino-N,1-Dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0362] 4-Amino-N-ethyl-1-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0363] 4-Amino-N-ethyl-1-methyl-N-((5R)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0364] 4-Amino-N-cyclopropyl-1-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0365] 4-Amino-1-methyl-N-(2-methylpropyl)-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0366] 4-Amino-1-methyl-N-(2-methylpropyl)-N-((5R)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0367] 4-Amino-7-fluoro-N,1-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0368] 4-Amino-7-fluoro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0369] 4-Amino-N-ethyl-7-fluoro-1-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0370] 4-Amino-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0371] 4-Amino-N,3-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0372] 4-Amino-N,3-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0373] 4-Amino-N,3-Dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0374] 4-Amino-7-fluoro-N-((5S)-2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0375] 4-Amino-7-fluoro-N,3-dimethyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0376] 4-Amino-7-fluoro-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0377] 4-Amino-N-cyclopropyl-7-fluoro-3-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0378] 4-Amino-7-fluoro-3-methyl-N-(2-methylpropyl)-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0379] 4-Amino-7-fluoro-3-methyl-N-(2-methylpropyl)-N-((5R)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0380] 4-Amino-7-chloro-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0381] 4-Amino-N,3,7-trimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0382] 4-Amino-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1,3-trimethyl-1H-pyrazolo[4,3-c][1,7]naphthidine-8-carboxamide,

[0383] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0384] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0385] 4-Amino-N-((3S)-6-methoxy-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0386] 4-Amino-N-((3R)-6-methoxy-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0387] 4-Amino-N-((3S)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0388] 4-Amino-N-methyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0389] 4-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0390] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0391] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0392] 4-Amino-N-methyl-N-((1R)-5-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0393] 4-Amino-N-methyl-N-((1S)-5-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0394] 4-Amino-N-ethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0395] 4-Amino-N-ethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0396] (4S,6R)-4-(3-chloro-5-fluorophenyl)-1-(2-hydroxyethyl)-6-(3-methylphenyl)-2-piperidinone,

[0397] N-(6,8-dichloro-2-(3-chloro-4-(1,2,4-oxadiazol-5-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoroacetamide,

[0398] (3R)-4-amino-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0399] (3R)-4-amino-N,3-dimethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0400] (3R)-4-amino-N-ethyl-3-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0401] (3R)-4-amino-N-ethyl-3-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0402] 4-Amino-N-((3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0403] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0404] 4-Amino-N-ethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0405] 4-Amino-N-ethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0406] 4-Amino-N-((3S)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0407] 4-Amino-N-((3R)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0408] 4-Amino-N-cyclopropyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0409] 4-Amino-N-((3S)-6-chloro-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0410] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0411] 4-Amino-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0412] 4-Amino-N-((3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0413] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0414] 4-Amino-7-fluoro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0415] 4-Amino-N-cyclopropyl-7-fluoro-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0416] 4-Amino-N-cyclopropyl-7-fluoro-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0417] 4-Amino-N-(cyclopropylmethyl)-7-fluoro-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0418] 4-Amino-N-(cyclopropylmethyl)-7-fluoro-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0419] 4-Amino-7-chloro-N-methyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0420] 4-Amino-7-chloro-N-methyl-N-((5S)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0421] 4-Amino-7-chloro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0422] 4-Amino-7-chloro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0423] 4-Amino-7-chloro-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0424] 4-Amino-7-chloro-N-methyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0425] 4-Amino-7-chloro-N-methyl-N-((3S)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0426] 4-Amino-7-chloro-N-methyl-N-((3R)-6-(methylsulfonyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0427] 4-Amino-7-chloro-N-((3S)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0428] 4-Amino-7-chloro-N-((3R)-4-fluoro-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0429] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0430] 4-Amino-N-((3S)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0431] 4-Amino-N-((3R)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0432] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0433] 4-Amino-7-fluoro-N,1-dimethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0434] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0435] 4-Amino-7-fluoro-N,1-dimethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0436] 4-Amino-N,3-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0437] 4-Amino-N,3-dimethyl-N-((3R)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0438] 4-Amino-N-((3S)-6-(difluoromethoxy)-2,3-dihydro-1-benzofuran-3-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0439] 4-Amino-N-methyl-N-((4R)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0440] 4-Amino-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0441] 4-Amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0442] 4-Amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0443] 4-Amino-N-((4S)-7-methoxy-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0444] 4-Amino-N-methyl-N-((4S)-6-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0445] 4-Amino-N-methyl-N-((4R)-6-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0446] 4-Amino-N-methyl-N-((4R)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0447] 4-Amino-N-methyl-N-((4S)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0448] 4-Amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0449] 4-Amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0450] 4-Amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0451] 4-Amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,8]naphthidine-8-carboxamide,

[0452] 4-Amino-7-fluoro-N-methyl-N-((4S)-7-(methylsulfonyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0453] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((4S)-7-(methanesulfonyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0454] 4-Amino-N-(cyclopropylmethyl)-1-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0455] 4-Amino-N-(cyclopropylmethyl)-1-methyl-N-((5R)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0456] 4-Amino-N-((4S)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0457] 4-Amino-N-((4R)-7-cyano-3,4-dihydro-1H-2-benzopyran-4-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0458] 4-Amino-N-((4S)-7,8-difluoro-3,4-dihydro-1H-2-benzopyran-4-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0459] 4-Amino-N-((4R)-7,8-difluoro-3,4-dihydro-1H-2-benzopyran-4-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0460] 4-Amino-7-fluoro-N,1-dimethyl-N-((8S)-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0461] 4-Amino-7-fluoro-N,1-dimethyl-N-((4S)-7-(methylsulfonyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0462] 4-Amino-N,3-dimethyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0463] 4-Amino-N,3-dimethyl-N-((1R,4R)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0464] 4-Amino-N,3-dimethyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0465] 4-Amino-N,3-dimethyl-N-((1S,4R)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0466] 4-Amino-N-((4S)-7,8-difluoro-3,4-dihydro-1H-2-benzopyran-4-yl)-7-fluoro-N,3-dimethyl-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0467] 4-Amino-7-fluoro-N,3-dimethyl-N-((8S)-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0468] 4-Amino-N-(cyclopropylmethyl)-7-fluoro-3-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-pyrazolo[3,4-c]quinoline-8-carboxamide,

[0469] 4-Amino-N-((4S)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0470] 4-Amino-N-((4R)-7-bromo-3,4-dihydro-1H-2-benzopyran-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0471] 4-Amino-N-((3S)-6-cyclopropyl-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0472] 4-Amino-N-((3R)-6-cyclopropyl-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0473] 4-Amino-N-((3S)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0474] 4-Amino-N-((3R)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0475] 2-Methyl-2-propane 4-((3R)-3-(((4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)carbonyl)(methyl)amino)-2,3-dihydro-1-benzofuran-6-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate,

[0476] 2-Methyl-2-propane 4-((3S)-3-(((4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)carbonyl)(methyl)amino)-2,3-dihydro-1-benzofuran-6-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate,

[0477] 4-Amino-N-((3S)-6-cyclopropyl-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0478] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-methyl-1H-pyrrolo-3-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0479] 4-Amino-N-((3S)-6-(1-cyclohexen-1-yl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0480] 4-Amino-N-((3S)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0481] 4-Amino-N-((3S)-6-(4,4-difluoro-1-cyclohexen-1-yl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0482] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0483] (3R)-4-amino-N-((4S)-7-cyclopropyl-3,4-dihydro-1H-2-benzopyran-4-yl)-N-ethyl-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0484] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0485] 4-Amino-N,1-Dimethyl-N-((1R)-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0486] 4-Amino-N,1-Dimethyl-N-((5S)-2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0487] 4-Amino-N,1-Dimethyl-N-((3S)-6-(3-oxetane)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0488] 4-Amino-N-((3S)-6-(3-furanyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0489] 4-Amino-N,1-Dimethyl-N-((3S)-6-(4-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0490] 4-Amino-N,1-Dimethyl-N-((3S)-6-(3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0491] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0492] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0493] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0494] 4-Amino-N,1-Dimethyl-N-((3S)-6-(5-methyl-3-furanyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0495] 4-Amino-N,1-Dimethyl-N-((3S)-6-(3-methyl-1,2-oxazol-5-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0496] 4-Amino-N-((3S)-6-(5,6-dihydro-2H-pyran-3-yl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0497] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1,3-thiazo-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0498] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-methyl-5-pyrimidinyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0499] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-oxo-1,2-dihydro-5-pyrimidinyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0500] 4-Amino-N-((3S)-6-(6-fluoro-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0501] 4-Amino-N-((3S)-6-(1-ethyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0502] 4-Amino-N-((3S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0503] 4-Amino-N-((3S)-6-(3,5-difluorophenyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0504] 4-Amino-N-((3S)-6-(2,6-difluoro-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0505] 4-Amino-N-((3S)-6-(2,3-difluoro-4-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0506] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0507] 4-Amino-N,1-Dimethyl-N-((3S)-6-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0508] 4-Amino-N,1-Dimethyl-N-((3S)-6-(6-(methylcarbamoyl)-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0509] N-((3S)-6-(6-acetamido-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0510] 4-Amino-N,1-Dimethyl-N-((3S)-6-(6-(trifluoromethyl)-2-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0511] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-(trifluoromethyl)-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0512] 4-Amino-N,1-Dimethyl-N-((3S)-6-(4-(trifluoromethyl)-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0513] 4-Amino-N,1-Dimethyl-N-((3S)-6-(5-(trifluoromethyl)-3-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0514] 4-Amino-N,1-Dimethyl-N-((3S)-6-(5-(trifluoromethyl)-2-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0515] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0516] 4-Amino-N,1-Dimethyl-N-((3S)-6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0517] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-(trifluoromethyl)-1,3-thiazo-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0518] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-(trifluoromethyl)-1,3-thiazo-5-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0519] 4-Amino-N-((3S)-6-(2,2-difluoro-1,3-benzo[4,3-c]quinoline-8-carboxamide,

[0520] 4-Amino-N,1-Dimethyl-N-((3S)-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0521] 4-Amino-N-((3S)-6-(3-(difluoromethoxy)-5-fluorophenyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0522] 4-Amino-N-((3S)-6-(2-fluoro-5-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0523] 4-Amino-N-((3S)-6-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0524] 4-Amino-N,1-Dimethyl-N-((3S)-6-(2-(2,2,2-trifluoroethoxy)-4-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0525] 4-Amino-N,1-Dimethyl-N-((4S)-7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0526] 4-Amino-N,1-Dimethyl-N-((4R)-7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0527] 4-Amino-7-fluoro-N-methyl-N-((4R)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0528] 4-Amino-7-fluoro-N-methyl-N-((4S)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0529] 4-Amino-7-fluoro-N-methyl-N-((3S)-6-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0530] 4-Amino-N,1-Dimethyl-N-((3S)-6-(4-(pentafluoro-λ~6~-thioalkyl)phenyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0531] 4-Amino-N,1-Dimethyl-N-((4S)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0532] 4-Amino-N,1-Dimethyl-N-((4R)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0533] 4-Amino-N-((3S)-6-methoxy-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0534] 4-Amino-N-((3S)-6-(cyclopropyloxy)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0535] 4-Amino-N-((3S)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0536] 4-Amino-N-((3S)-6-ethoxy-2,3-dihydro-1-benzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0537] 4-Amino-N-((3S)-6-ethoxy-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0538] 4-Amino-N-((3S)-6-(cyclobutoxy)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0539] 4-Amino-N,1-Dimethyl-N-((3S)-6-(3-oxetanebutyryloxy)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0540] 4-Amino-N-((3S)-6-(2-methoxyethoxy)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0541] 4-Amino-N,1-Dimethyl-N-((5S)-2-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0542] 4-Amino-N,1-Dimethyl-N-((1R)-5-methyl-2,3-dihydro-1H-inden-1-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0543] 4-Amino-N-((1R)-2,3-dihydro-1H-inden-1-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0544] 4-Amino-N-((1S)-2,3-dihydro-1H-inden-1-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0545] 4-Amino-N,1-Dimethyl-N-((5R)-2-methyl-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0546] 4-Amino-N,1-Dimethyl-N-((5S)-2-methyl-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0547] 4-Amino-N,1-Dimethyl-N-((3S)-6-methyl-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0548] 4-Amino-N-((5S)-2-cyclopropyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0549] Methyl(3S)-3-(((4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)carbonyl)(methyl)amino)-2,3-dihydro-1-benzofuran-6-carboxylate,

[0550] 4-Amino-N-((3S)-6-(hydroxymethyl)-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0551] 4-Amino-N-((3S)-6-chloro-2,3-dihydro-1-benzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0552] 4-Amino-N,1-Dimethyl-N-((3S)-6-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0553] N-((3R)-6-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-4-amino-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide and

[0554] N-((3S)-6-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-2,3-dihydro-1-benzofuran-3-yl)-4-amino-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide.

[0555] This invention provides a compound, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from: 4-amino-7-chloro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0556] 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0557] 4-Amino-N-((5S)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0558] 4-Amino-7-chloro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0559] 4-Amino-7-fluoro-N-methyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0560] (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0561] 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0562] 4-Amino-N,1-Dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0563] 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide,

[0564] 4-Amino-7-fluoro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0565] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0566] 4-Amino-7-chloro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0567] 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0568] 4-Amino-N-((5S)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0569] 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0570] (3R)-4-amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide,

[0571] 4-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide,

[0572] 4-Amino-7-fluoro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide,

[0573] 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide,

[0574] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide and

[0575] 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.

[0576] The present invention further provides a method for treating cancer, the method comprising administering to a subject an effective amount of the compound of the present invention, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer is selected from lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer. In another aspect, the lung cancer may be non-small cell lung cancer (NSCLC).

[0577] 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.

[0578] The present invention also provides a method for preparing a medicament for treating cancer, the method comprising administering to a subject an effective amount of the compound of the present invention, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, the cancer may be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, cholangiocarcinoma, melanoma, gastric cancer, pancreatic cancer, or bladder cancer. In one aspect, the lung cancer may be non-small cell lung cancer (NSCLC). The present invention also provides the compound of the present invention, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing for use in a method of treating cancer, the method comprising administering to a subject an effective amount of such compound. In one aspect, the cancer may be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, cholangiocarcinoma, or bladder cancer. In one aspect, the lung cancer may be non-small cell lung cancer (NSCLC).

[0579] The present invention also provides the use of the compounds of the present invention, their tautomers, their stereoisomers, or pharmaceutically acceptable salts of any of the foregoing in the preparation of a medicament for treating cancer. In one aspect, the cancer may be lung cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, or bladder cancer. In another aspect, the lung cancer may be non-small cell lung cancer (NSCLC).

[0580] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. Detailed Implementation

[0581] definition

[0582] As used herein, if any variable appears more than once in a chemical formula, its definition for each occurrence is independent of its definition for each subsequent occurrence. If a chemical structure and chemical name conflict, the chemical structure will determine the identity of the compound. These compounds disclosed herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double-bonded isomers (i.e., geometric isomers), enantiomers, or diastereomers. Therefore, any chemical structure having a relative configuration within (all or part of) the scope of this specification as described covers all possible enantiomers and stereoisomers of the compounds shown, including pure stereoisomeric forms (e.g., geometrically pure forms, enantiomeric pure forms, or diastereomeric pure forms) as well as mixtures of enantiomers and mixtures of stereoisomers. Mixtures of enantiomers and stereoisomers can be resolved into enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0583] Some compounds of this invention may possess asymmetric carbon atoms (optical centers) or double bonds; racemic, enantiomers, diastereomers, geometric isomers, and various isomers are all intended to be covered within the scope of this invention. Furthermore, rotation-restricted isomers and mixtures thereof (such as those resulting from restricted rotation around two aromatic or heteroaromatic rings bonded to each other) are intended to be covered within the scope of this 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 that different rotation-restricted isomers are separated and isolated.

[0584] As used herein and unless otherwise stated, the terms "stereoisomer" or "stereoisopure" mean a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisopure compound having one chiral center will be substantially free of its mirror-image enantiomers. A stereoisopure compound having two chiral centers will be substantially free of its other diastereomers. A typical stereoisomeric pure compound comprises, by weight, more than about 80% of one stereoisomer of the compound and less than about 20% of other stereoisomers of the compound, more preferably more than about 90% of one stereoisomer of the compound and less than about 10% of other stereoisomers of the compound, even more preferably more than about 95% of one stereoisomer of the compound and less than about 5% of other stereoisomers of the compound, and most preferably more than about 97% of one stereoisomer of the compound and less than about 3% of other stereoisomers of the compound. If the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, the structure or part thereof should be interpreted as encompassing all its stereoisomers. Bonds drawn with wavy lines indicate that both stereoisomers are encompassed. This should not be confused with wavy lines drawn perpendicular to the bonds, indicating the attachment points of groups to the rest of the molecule.

[0585] As is known to those skilled in the art, certain compounds of the present invention can exist in one or more tautomeric forms. Because a chemical structure can only be used to represent one tautomeric form, it should be understood for convenience that references to compounds having a given structural formula include tautomeric forms of the structure represented by that formula. Depending on the compound, some compounds may exist primarily in one form rather than another. Furthermore, depending on the compound and the energy required to convert one tautomeric form to another, some compounds may exist as mixtures at room temperature, while others may be isolated in tautomeric or other forms. Examples of other tautomeric forms associated with the compounds of the present invention are those having a pyridone group (pyridyl group) (where hydroxypyridine is a tautomeric form) and compounds having a ketone group (having an enol tautomeric form). Examples of these are shown below.

[0586]

[0587] 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 inclusion compounds), chelates, non-covalent complexes, prodrugs, 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 prodrugs, 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 prodrugs (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.

[0588] Pharmaceutically acceptable salts of the compounds of the present invention include those with inorganic acids (e.g., hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and with organic acids (e.g., tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, camphorsulfonic acid, isothiosulfonic acid, mucoic acid, gentianic acid, isonicotinic acid, gluconic acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylethylamine, etc.). Acid addition salts formed with acids, mandelic acid, methylene dihydroxynaphthyl acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid, sulfurous acid, alginic acid, galacturonic acid, and arylsulfonic acids (e.g., benzenesulfonic acid and p-toluenesulfonic acid); base addition salts formed with alkali metals and alkaline earth metals and organic bases (e.g., N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), lysine, and procaine); and salts formed internally. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. Salts having non-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.

[0589] 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.

[0590] This invention discloses compounds that may also contain naturally occurring or non-natural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as, for example, tritium (3H), iodine-125 (125I), or carbon-14 (14C). Radiolabeled compounds can be used as therapeutic or preventative agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the compounds of this invention, whether or not they are radioactive, are intended to be covered within the scope of this invention. For example, this invention also includes compounds containing deuterium (D) or tritium (T).

[0591] "Alkyl" refers to a saturated branched or straight-chain monovalent hydrocarbon group derived 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 (such as propyl-1-yl and propyl-2-yl), butyl (such as butyl-1-yl, butyl-2-yl, 2-methyl-propyl-1-yl, 2-methyl-propyl-2-yl, tert-butyl, etc.). In some embodiments, the alkyl group comprises 1 to 20 carbon atoms. In some embodiments, the alkyl group comprises 1 to 10 carbon atoms or 1 to 6 carbon atoms, while 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 comprise 3 to 7 carbon atoms, or in some embodiments, 3 to 6 carbon atoms. Alkyl groups having 1 to 6 carbon atoms may be referred to as (C1-C6) alkyl groups, and alkyl groups having 1 to 4 carbon atoms may be referred to as (C1-C4) alkyl groups. This nomenclature can also be used for alkyl groups with different numbers of carbon atoms.

[0592] "Alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond, derived by removing a hydrogen atom from a single carbon atom of a parent olefin. This group may be Z- or E- (cis or trans) with respect to one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl groups; propenyl groups such as propyl-1-en-1-yl, propyl-1-en-2-yl, propyl-2-en-1-yl (allyl), and propyl-2-en-2-yl; butenyl groups such as buten-1-en-1-yl, buten-1-en-2-yl, 2-methyl-propyl-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, and buten-1,3-dien-2-yl; and so on. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, and in other embodiments, it has 2 to 6 carbon atoms. Alkenyl groups having 2 to 6 carbon atoms can be called (C2-C6) alkenyl groups.

[0593] "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.

[0594] "Alkoxy" refers to the group -OR, where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. A typical alkoxy group contains 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms in the R group. Alkoxy groups containing 1 to 6 carbon atoms may be designated as -O-(C1-C6)alkyl or -O-(C1-C6 alkyl) groups. In some embodiments, the alkoxy group may contain 1 to 4 carbon atoms and may be designated as -O-(C1-C4)alkyl or -O-(C1-C4 alkyl) groups.

[0595] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. Aryl groups encompass monocyclic carbocyclic aromatic rings, such as benzene. Aryl groups also encompass bicyclic carbocyclic aromatic ring systems, where each of these rings is aromatic, such as naphthalene. Aryl groups can therefore include fused ring systems, where each ring is a carbocyclic aromatic ring. In some embodiments, aryl groups contain 6 to 10 carbon atoms. Such groups may be referred to as C6-C. 10Aryl groups. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined separately below. Thus, as defined herein, 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.

[0596] "Carbonyl" refers to the group -C(O), and can also be called the -C(=O) group.

[0597] "Carboxyl group" refers to the group -C(O)OH, which can also be called -C(=O)OH.

[0598] "Cyano" refers to the group -CN.

[0599] "Cycloalkyl" refers to a saturated cyclic alkyl group derived 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, a cycloalkyl group having 3 to 8 ring members can be called (C3-C8)cycloalkyl, a cycloalkyl group having 3 to 7 ring members can be called (C3-C7)cycloalkyl, and a cycloalkyl group having 4 to 7 ring members can be called (C4-C7)cycloalkyl. In some embodiments, the cycloalkyl group can be (C3-C8)cycloalkyl. 10 )cycloalkyl, (C3-C8)cycloalkyl, (C3-C7)cycloalkyl, (C3-C6)cycloalkyl, or (C4-C7)cycloalkyl groups, and these can be referred to in alternative language as C3-C 10 Cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4-C7 cycloalkyl groups.

[0600] A "heterocyclic group" is a cyclic group comprising at least one saturated, partially unsaturated, cyclic ring. A heterocyclic group contains at least one heteroatom as a ring member. Typical heteroatoms include O, S, and N, and can be chosen independently. Heterocyclic groups include monocyclic and bicyclic ring systems. A bicyclic heterocyclic group comprises at least one non-aromatic ring having at least one heteroatom ring member, which may be fused to a cycloalkyl ring or to an aromatic ring, wherein the aromatic ring may be a carbocyclic ring or may contain one or more heteroatoms. The attachment point of a bicyclic heterocyclic group can be on a non-aromatic cyclic ring containing at least one heteroatom or on another ring of the heterocyclic group. For example, a heterocyclic group obtained by removing a hydrogen atom from one of the following 9-membered heterocyclic compounds can be attached to the remainder of the molecule on a 5-membered ring or a 6-membered ring.

[0601]

[0602] 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- to 7-membered heterocyclic groups, only 1 ring atom is a heteroatom when the ring comprises only 3 members, and 1 or 2 heteroatoms are contained when the ring comprises 4 members. In some embodiments, the heterocyclic group comprises 3 or 4 ring members, wherein 1 is a heteroatom selected from O, S, or N. In other embodiments, the heterocyclic group comprises 5 to 7 ring members, wherein 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclic groups include, but are not limited to, groups derived from epoxides, aziridines, aziridines, imidazolides, morpholines, piperazines, piperidines, hydrogenated pyrimidines, 1,4,5,6-tetrahydropyrimidines, pyrazolidines, pyrrolidines, quinine rings, tetrahydrofurans, tetrahydropyrans, benzimidazolones, pyridones, etc. Heterocyclic groups can be fully saturated, but may also contain one or more double bonds. Examples of such heterocyclic groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrroleyl, 2,3-dihydro-1H-pyrroleyl, 1H-azirinyl, 1,2-dihydroaziridine, etc. Substituted heterocyclic groups also include those oxidized (=O) or oxidized (-O) by one or more oxo groups. - ) ring systems substituted with substituents, such as piperidinyl N-oxide, morpholino-N-oxide, 1-oxo-1-thiomorpholino, pyridinone, benzimidazolone, benzo[d]oxazol-2(3H)-keto, 3,4-dihydroisoquinoline-1(2H)-keto, indoline-keto, 1H-imidazo[4,5-c]pyridin-2(3H)-keto, 7H-purine-8(9H)-keto, imidazoline-2-keto, 1H-imidazo-2(3H)-keto, 1,1-dioxo-1-thiomorpholino, etc.

[0603] The term “comprising” is intended to be open-ended, meaning it covers all and is not restrictive. It may be used synonymously with “having” or “including” herein. “Comprising” is intended to include every indicated or referenced component or element without excluding any other component or element.

[0604] "Disease" means any disease, disorder, symptom, or indication.

[0605] "Halogen" or "halogen" refers to a fluorine, chlorine, bromine, or iodine group.

[0606] "Haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen. Therefore, the term "haloalkyl" includes monohaloalkyl (an alkyl group substituted with one halogen atom) and polyhaloalkyl (an alkyl group substituted with two or more halogen atoms). Representative "haloalkyl" groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Unless otherwise stated, the term "perhaloalkyl" means an alkyl group in which every hydrogen atom is replaced by a halogen atom. For example, the term "perhaloalkyl" includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, etc.

[0607] "Heteroaryl" refers to a monovalent heteroaryl group obtained by removing a hydrogen atom from a single atom of a parent heteroaryl ring system. Heteroaryl groups typically comprise 5 to 14 members, but more typically 5 to 10 members, and are monocyclic, bicyclic, or tricyclic aromatic, containing one or more (e.g., 1, 2, 3, or 4) heteroatoms, or in some embodiments, 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the remaining ring atom is carbon. In a monocyclic heteroaryl group, the monocycle is aromatic and contains at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may comprise 5 or 6 ring members and may contain 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom, wherein one or more heteroatoms are independently selected from O, S, or N. In a bicyclic aromatic ring, both rings are aromatic. In a bicyclic heteroaryl group, at least one ring must contain a heteroatom, but both rings do not necessarily need to contain heteroatoms, although this is permissible. For example, the term "heteroaryl" includes 5- to 7-membered heteroaryl rings fused to a carbocyclic aromatic ring or fused to another heteroaryl ring. In a tricyclic aromatic ring, all three rings are aromatic, and at least one ring contains at least one heteroatom. For fused, bicyclic, and tricyclic heteroaryl ring systems (where only one ring contains one or more heteroatoms), the attachment point can be on the ring containing at least one heteroatom or on the carbocyclic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. A heteroaryl does not cover or overlap with an aryl group as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, zoline, furan, imidazole, indazole, indole, indoleazine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthidine, oxadiazole, oxazole, pteridine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrrole, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, etc. In some embodiments, the heteroaryl group may be a 5- to 20-membered heteroaryl group, for example, a 5- to 14-membered or a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group may be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazolium, and pyrazine.

[0608] “MTAP” refers to mammalian methylthioadenosine phosphorylase.

[0609] "Pharmaceutical acceptable" means that it is generally accepted for use in animals, and more specifically for use in humans.

[0610] "Pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the pharmacological activity of the desired parent compound.

[0611] "Pharmaceutically acceptable excipients" refers to a broad range of ingredients that can be combined with the compounds or salts of this invention to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, mediators, anti-adhesives, flow aids, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0612] “PRMT5” refers to mammalian protein arginine N-methyltransferase 5 (PRMT5).

[0613] "PRMT5 inhibitors" are compounds that inhibit or negatively regulate all or part of the activity of the PRMT5 enzyme.

[0614] "MTA-cooperative PRMT5 inhibitors" are compounds that inhibit or negatively regulate all or part of the PRMT5 enzyme activity in cells with elevated MTA levels, either in vitro or in vivo, in the presence of bound MTA.

[0615] "Stereoisomers" refer to isomers whose constituent atoms are arranged differently in space. Stereoisomers that are mirror images of each other and are optically active are called "enantiomers", while stereoisomers that are not mirror images of each other and are optically active are called "diastereomers".

[0616] The term “subject” includes mammals and humans. The terms “human” and “subject” are used interchangeably in this document.

[0617] "Therapeutic effective amount" means the amount of a compound that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect that disease, disorder, or symptom. As those skilled in the art will recognize, this amount is generally not limited to a single dose but may include multiple doses over a significant period of time, such as when a therapeutic or preventative response is required in the subject. Therefore, "therapeutic effective amount" is not limited to the amount in a single capsule or tablet but may include more than one capsule or tablet, as prescribed by a qualified physician or healthcare provider. "Therapeutic effective amount" can vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given case, the appropriate amount will be obvious to those skilled in the art or can be determined by routine experiments.

[0618] "Treating" or "treatment" for any disease or disorder means preventing or improving the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the risk of acquiring the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the development of the disease, disorder, or at least one clinical symptom of the disease or disorder, or reducing the risk of developing the disease or disorder or at least one clinical symptom of the disease or disorder. "Treating" or "treatment" also means suppressing the disease or disorder physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of bodily parameters), or both, or suppressing at least one bodily parameter that is not identifiable by the subject. Furthermore, "treating" or "treatment" means delaying the onset of the disease or disorder, or at least its symptoms, in a subject who may be exposed to or predisposed to having the disease or disorder (even if the subject has not yet experienced or displayed symptoms of the disease or disorder).

[0619] Pharmaceutical compositions are also provided comprising a compound as described in any one of the examples, or a pharmaceutically acceptable salt thereof, its tautomers, pharmaceutically acceptable salts of tautomers, stereoisomers of any of the foregoing, or mixtures thereof, and at least one pharmaceutically acceptable excipient, carrier, or diluent. In some examples, the compound as described in any of these aspects, or a pharmaceutically acceptable salt thereof, its tautomers, pharmaceutically acceptable salts of tautomers, stereoisomers of any of the foregoing, or mixtures thereof, are present in an amount effective for treating PRMT5-dependent cancers. In some aspects, the pharmaceutical composition is formulated for oral delivery, while in other embodiments, the pharmaceutical composition is formulated for intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for oral administration once daily or QD, and in some such formulations is a tablet, wherein the effective amount of the active ingredient is in the range of 1 mg to 1000 mg.

[0620] 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.

[0621] Pharmaceutical compositions or formulations for administering the compounds of the present invention can conventionally be present in unit dose form and can be prepared by any method well known in the art. All methods involve the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, pharmaceutical compositions are prepared by the following steps: homogenizing and tightly associating 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 the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0622] 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.

[0623] The compounds of the present invention, their pharmaceutically acceptable salts, their tautomers, pharmaceutically acceptable salts of the tautomers, stereoisomers of any of the foregoing, or mixtures thereof, can be used to treat a variety of ailments.

[0624] The compounds and compositions described herein are generally used to inhibit PRMT5. In some aspects, a method of treating a PRMT5-mediated disorder in a subject is provided, the method comprising administering to a subject requiring treatment an effective amount of a compound described herein (e.g., a compound having formula I or a pharmaceutically acceptable salt thereof). In some aspects, this effective amount is a therapeutically effective amount. In some aspects, this effective amount is a prophylacticly effective amount. In some aspects, the subject has a PRMT5-mediated disorder (e.g., cancer, such as lymphoma, breast cancer, or pancreatic cancer). In other aspects, the subject is susceptible to a PRMT5-mediated disorder (e.g., cancer, such as lymphoma, breast cancer, or pancreatic cancer).

[0625] As used herein, the term "PRMT5-mediated disorder" means any disease, disorder, or other pathological condition in which PRMT5 is known to play a role. Therefore, in some respects, this disclosure relates to treating or alleviating the severity of diseases in which one or more PRMT5s are known to play a role.

[0626] In some respects, this article provides a method for inhibiting PRMT5 activity in subjects in need, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound having Formula I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0627] This invention provides methods for treating cancers and other disorders caused by homozygous loss of the chromosome 9p21 gene locus (carrying the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A)). In one aspect, the invention covers methods for treating MTAP (methylthioadenosine phosphorylase)-ineffective cancers and tumors. In some embodiments, these types of cancer exhibit accumulation of the MTAP substrate methylthioadenosine (MTA).

[0628] The methods for treating PRMT5 impairment covered by this invention preferentially target PRMT5 in MTAP-ineffective tumors without impairing PRMT5 in normal tissue (MTAP WT). The compounds of this invention therefore contain MTA-cooperative small molecule inhibitors that preferentially target the MTA-binding state of PRMT5 enriched in MTAP-ineffective tumor cells, while providing an improved therapeutic index exceeding that of normal cells (where MTAP is intact and MTA levels are low).

[0629] In other aspects, compounds cooperating with the PRMT5 inhibitor MTA of this invention can be used to treat proliferative disorders, such as cancer. In some embodiments, the cancer compounds described herein can be used to treat pancreatic cancer. In some aspects, the cancer compounds described herein can be used to treat multiple myeloma (MM). In another embodiment, the cancer compounds described herein can be used to treat breast cancer. Breast cancer may be estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-). In another embodiment, the breast cancer may be HER2-negative. In some embodiments, the breast cancer is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative, and is also referred to herein as "triple-negative breast cancer".

[0630] In other respects, 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.

[0631] In one embodiment, the compounds of the present invention can be used to treat pancreatic cancer.

[0632] 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.

[0633] In other respects, cancer can be glioblastoma (GBM). In other respects, cancer can be mesothelioma. In one respect, cancer can be bladder cancer. In another respect, cancer can be esophageal cancer. In other respects, cancer can be melanoma. In another respect, cancer can be DLBCL, HNSCC, or bile duct cancer.

[0634] In some respects, one or more of the compounds described herein can be used to treat any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, such as PRMT5-responsive cancer.

[0635] On the one hand, cancers lacking p53 (e.g., p53-ineffective cancers) are less sensitive to PRMT5 inhibition than p53-positive cancers. Therefore, PRMT5-responsive cancers can be p53-positive cancers. The term "p53-positive" refers to cancers that do not lack p53 expression and / or activity. In some embodiments, one or more compounds described herein may be used to treat p53-positive cancers. In some aspects, larger quantities of one or more compounds described herein may be needed to treat p53-negative cancers (e.g., p53-ineffective cancers) than those needed to treat p53-positive cancers.

[0636] In some aspects, this disclosure provides methods for identifying subjects with cancers that are sensitive to treatment with PRMT5 inhibitors. In some embodiments, the method includes obtaining a sample from the subject; detecting the presence of p53; and if p53 is present in the sample, identifying the subject as having cancers sensitive to treatment with PRMT5 inhibitors. Thus, in some embodiments, subjects with p53-positive cancers are identified as subjects treated with PRMT5 inhibitors. In some embodiments, the method further includes administering a composition comprising a PRMT5 inhibitor to the subject.

[0637] 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.

[0638] "Sample" means any biological sample derived from a subject, including but not limited to cells, tissue samples, bodily fluids (including but not limited to mucus, blood, plasma, serum, urine, saliva, and semen), cancer cells, and cancerous tissue. The presence of p53 in a sample can be detected by any suitable method for detecting p53 nucleic acid or protein, such as nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, or any combination thereof.

[0639] It should be understood that, in some respects, one or more of the compounds described herein can be used to treat other types of cancer, including but not limited to acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, and angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma). Sarcoma), appendiceal cancer, benign monoclonal gammopathy, biliary tract tumors (e.g., bile duct cancer), bladder cancer, brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumors, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's sarcoma). Cancers include adenocarcinoma, Ewing's sarcoma, eye cancers (e.g., intraocular melanoma, retinoblastoma), common eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancers (e.g., squamous cell carcinoma of the head and neck), oral cancers (e.g., oral squamous cell carcinoma (OSCC)), pharyngeal cancers (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic system cancers (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML)). 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, etc. Hematologic disorders (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Cezari syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); and mixtures of one or more of the above-described leukemia / lymphomas.And multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immune-mediated amyloidosis, renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS), mast cell hyperplasia (e.g., generalized mast cell hyperplasia) Myelodysplastic syndromes (MDS), mesothelioma, myelodysplastic disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myelopathic myelogenesis of unknown cause (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)), neuroblastoma, neurofibromatosis (e.g., neurofibromatosis (NF) type 1) Type 2 or schwannoma); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget's disease of the penis and scrotum), pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma), Basal cell carcinoma (BCC), small bowel cancer (e.g., appendix cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovial tumor, testicular cancer (e.g., seminoma, embryonal testis carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva).

[0640] In some aspects, a method of treating a subject's cancer includes administering to the subject a composition comprising a PRMT5 inhibitor, wherein treatment with the PRMT5 inhibitor inhibits tumor growth of the cancer by more than about 25%, more than about 50%, more than about 75%, or more than about 90% (e.g., 25%-50%, 50%-75%, 75%-90%, or 90%-100%). In some embodiments, a method of treating a subject's cancer includes administering to the subject a composition comprising a PRMT5 inhibitor, wherein methylation of the cancer is reduced by more than about 50%, more than about 75%, or more than about 80% (e.g., 50%-75%, 50%-80%, 80%-90%, 80%-100%, or 90%-100%). Methylation refers to protein methylation, such as histone methylation (e.g., methylation of one or more lysine and / or arginine residues in a histone protein) or DNA methylation (e.g., epigenetic DNA methylation, such as methylated CpG sites). In some embodiments, the methyl labeling level of a cell is a measure of the degree of histone methylation in that cell (e.g., at one or more specific lysine and / or arginine sites).

[0641] The invention is further described with reference to the following examples, which are intended to illustrate the claimed invention but not to limit it in any way.

[0642] Example

[0643] Unless otherwise stated, all materials were obtained from commercial suppliers and are ready for use without further purification.

[0644] The following abbreviations are used to refer to various reagents, solvents, or instruments:

[0645]

[0646]

[0647]

[0648] General synthesis scheme:

[0649] Method A

[0650]

[0651] Method A-SFC

[0652]

[0653] Method B

[0654]

[0655] Method B-SFC

[0656]

[0657] Method A: Compound I can be prepared by reacting acid IA and secondary amine IB-1 in a solvent (e.g., DMF or DMAc) in the presence of a base (e.g., Et3N or DIPEA) and an activating agent (e.g., HATU or PyBrOP). If a racemic amine or acid is used in method A, chiral SFC can be used to separate stereoisomers, in which case stereochemistry is arbitrarily assigned to each isomer.

[0658] Method B: Compound I can be prepared by reacting an acyl chloride IC with a secondary amine IB in a solvent (e.g., THF, dioxane, DCM, or DCE) in the presence of a base (e.g., Et3N, DIPEA, or pyridine). Alternatively, compound I can be prepared by reacting an acyl chloride IC with a secondary amine IB in pyridine in the presence of DMAP. If a racemic amine or acid is used in method B, a chiral SFC can be used to separate stereoisomers, in which case the stereochemistry is arbitrarily assigned to each isomer.

[0659] Analytical U / HPLC

[0660] The following instruments were used for analytical UHPLC: A Waters Acquity system equipped with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) with a binary solvent system linear gradient, used at a flow rate of 0.5 mL / min with DAD, at ambient temperature, for MS detection of SQDI. The linear gradient used was (H₂O / CH₃CN / HCO₂H (95 / 5 / 0.1% to 0 / 100 / 0.1%)). An Agilent Infinity I / II-TOF6230B / CLND Antek 8060 equipped with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) with a binary solvent system linear gradient, used at a flow rate of 0.75 mL / min with DAD. The linear gradient used was (H₂O / MeOH / HCO₂H (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0661] Preparative HPLC

[0662] The following equipment was used for preparative HPLC: a Shimadzu Nexera X2 equipped with a Merck ChromolithSpeedROD RP-18E (5 μm, 10 x 100 mm) with a linear gradient in a binary solvent system, using flow rates between 4 mL / min and 7 mL / min and UV detection at 254 nm, combined with MS detection on a Shimadzu LCMS-2020. The linear gradient used was (H₂O / MeOH / HCO₂H (95 / 5 / 0.1% to 0 / 100 / 0.1%)).

[0663] intermediate

[0664] Intermediate 1: N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridine-5-amine

[0665]

[0666] Acetic acid (1.120 g, 1.076 mL, 18.64 mmol, Sigma-Aldrich) was added to a stirred mixture of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-one (1.50 g, 7.46 mmol, Angel Pharmatech) and aminomethane (2 M solution in THF) (9.32 mL, 18.64 mmol, Sigma-Aldrich Corporation) in DCM (7 mL). The resulting mixture was stirred at rt for 10 min, and then sodium triacetoxyborohydride (2.055 g, 9.69 mmol, Sigma-Aldrich Corporation) was added in a single batch as a solid. The resulting mixture was stirred at rt for 42 h. The reaction was quenched with methanol. The volatiles were removed under vacuum and the residue was alkalized with ammonium hydroxide at 0 °C. It was then directly loaded onto a silica gel pre-column (25 g) and purified by combi-flash column chromatography (elution with MeOH (containing 0.5% ammonium hydroxide) / DCM (0 to 20%) on a 24-g ISCO gold column (2x elution) to give N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-amine (1) (1.40 g, 6.48 mmol, 87% yield) as a dark solid. m / z (ESI): 217.20 (M+H) + . 1H NMR (chloroform-d, 400MHz) δ7.78 (d, 1H, J = 7.7Hz), 7.52 (d, 1H, J = 7.7Hz), 4.26 (t, 1H, J = 6 .9Hz),3.1-3.2(m,1H),3.0-3.1(m,1H),2.5-2.6(m,4H),1.9-2.0(m,1H),1.31(br s,1H). 19 F NMR (chloroform-d, 376 MHz) δ -67.39 (s, 3F).

[0667] The following amines in Table 1 are prepared in a manner similar to that described for intermediate 1.

[0668] Table 1

[0669]

[0670]

[0671] Intermediate 11: N-methyl-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridine-3-amine

[0672]

[0673] Step 1. Under nitrogen atmosphere, sodium borohydride (0.950 g, 25.1 mmol, Sigma-Aldrich) as a solid was added in a single step to an ice-cooled solution of 6-(trifluoromethyl)furano[2,3-b]pyridin-3(2H)-one (3.000 g, 14.77 mmol, eNovation) in tetrahydrofuran (25 mL) and MeOH (20 mL). The resulting mixture was stirred at 0 °C for 20 min and then at ambient temperature for 15 min. Volatile substances were removed under vacuum, and the residue was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 16%) on a 40-g ISCO gold column) to give 6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-ol as a colorless oil (2.65 g, 12.92 mmol, 87% yield). m / z (ESI): 206.20 (M+H) + . 1H NMR (chloroform-d, 400MHz) δ7.89 (d, 1H, J = 7.3Hz), 7.32 (d, 1H, J = 7.5Hz), 5.51 (br d,1H,J=2.7Hz), 4.75(dd,1H,J=7.1,10.9Hz), 4.57(dd,1H,J=3.1,10.9Hz), 2.41(br d,1H,J=7.1Hz). 19 F NMR (chloroform-d, 376 MHz) δ -67.96 (s, 3F).

[0674] Step 2. Under nitrogen atmosphere, over a period of 15 min, slowly add a solution of diisopropyl azodicarbonate (1.346 g, 6.34 mmol), bis(Boc)amine (1.446 g, 6.65 mmol, Oakwood Products), and triphenylphosphine (1.745 g, 6.65 mmol, Sigma-Aldrich) in THF (20 mL) to a stirred, ice-cooled solution over nitrogen atmosphere. Stir overnight at nitrogen atmosphere. Volatile substances were removed, and the crude residue was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 1%) on a 40-g ISCO gold column) to give an impure product. This product was dissolved in DCM and loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with EtOAc / heptane (0 to 40%) on a 40-g ISCO gold column) to give an impure N,N-bis(Boc)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridine-3-amine (1.75 g, 4.33 mmol, 68% yield) as a white solid. m / z (ESI): 426.80 (M+Na) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.67 (d, 1H, J = 7.7 Hz), 7.25 (d, 1H, J = 7.5 Hz), 6.17 (dd, 1H, J = 5.5, 10.3 Hz), 4.8–4.9 (m, 1H), 4.70 (dd, 1H, J = 5.4, 10.0 Hz), 1.40 (s, 18H). 19 F NMR (chloroform-d, 376 MHz) δ -67.95 (s, 3F).

[0675] Step 3. A mixture of N,N-bis(Boc)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridine-3-amine (3.65 g, 9.03 mmol) and lithium bromide (2.352 g, 27.1 mmol, Sigma-Aldrich) in 250 mL RBF in acetonitrile (55 mL) was stirred at 58 °C for 18 h. Volatile substances were removed, and the crude residue was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (on a 40-g ISCO gold column, eluted with MeOH / DCM (0 to 8%) (3x)) to give an impure tert-butyl(6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)carbamate (1.46 g, 4.80 mmol, 53% yield) as a white solid, which was used in the next step without further purification. m / z (ESI): 326.95 (M+Na) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.84 (br d, 1H, J = 7.3 Hz), 7.29 (d, 1H, J = 7.5 Hz), 5.50 (br d, 1H, J = 2.1 Hz), 4.7–5.1 (m, 2H), 4.44 (dd, 1H, J = 4.7, 10.3 Hz), 1.48 (s, 9H). 19 F NMR (chloroform-d, 376 MHz) δ -67.98 (s, 3F).

[0676] Step 4. Under nitrogen atmosphere, sodium hydride (60% in mineral oil, 307 mg, 7.68 mmol, Sigma-Aldrich) was added in two portions to a stirred solution of tert-butyl(6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)carbamate (935 mg, 3.07 mmol) in THF (20 mL) for 5 min. The resulting mixture was stirred at 0 °C for 15 min, and then iodomethane (872 mg, 0.383 mL, 6.15 mmol, Sigma-Aldrich) was slowly added dropwise via syringe. The resulting mixture was stirred at 0 °C for 15 min and then stirred at rt for 1 h. The reaction was cooled in an ice-water bath and then quenched with MeOH (3 mL). The volatiles were removed under vacuum and the residue was dissolved in DCM / MeOH, loaded onto a silica gel pre-column (25 g), and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 2%) on a 24-g ISCO gold column) to give tert-butylmethyl (6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)carbamate (10) (950 mg, 2.98 mmol, 97% yield) as an almost colorless oil, which was cured at rt after standing. m / z (ESI): 340.90 (M+Na) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.71 (br d, 1H, J = 7.3 Hz), 7.30 (d, 1H, J = 7.3 Hz), 5.5–6.4 (m, 1H), 4.79 (dd, 1H, J = 9.5, 10.3 Hz), 4.3–4.6 (m, 1H), 2.5–2.8 (m, 3H), 1.49 (br s, 9H). 19 F NMR (chloroform-d, 376 MHz) δ -67.95 (s, 3F).

[0677] Step 5. 2,2,2-Trifluoroacetic acid (1.039 g, 3.0 mL, 9.11 mmol, Sigma-Aldrich) was added dropwise to an ice-cold solution of tert-butylmethyl (6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)carbamate (10) (1.160 g, 3.64 mmol) in a stirred DCM (20 mL) via syringe. The resulting mixture was stirred at rt for 2 h. Volatile substances were removed under vacuum, and the residue was dissolved in DCM / MeOH and ammonium hydroxide (0.4 mL) and loaded onto a silica gel pre-column (25 g). The mixture was subjected to combi-flash column chromatography (eluting on a 24-g ISCO gold column with MeOH (containing 0.5% ammonium hydroxide) / DCM (1% to 20%) (2x)) to give N-methyl-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-amine (11) (625 mg, 2.86 mmol, 79% yield) as a light brown film, with an overall yield of approximately 20% (through 5 steps). m / z (ESI): 219.10 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.78 (d, 1H, J = 7.3 Hz), 7.0–7.4 (m, 1H), 4.7–4.8 (m, 1H), 4.4–4.6 (m, 2H), 2.48 (s, 3H), 1.3–1.6 (m, 1H). 19 F NMR (chloroform-d, 376 MHz) δ -67.92 (s, 3F).

[0678] Intermediate 12: N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0679]

[0680] Step 1. Add di-tert-butyl dicarbonate (0.473 g, 2.166 mmol, TCI America) to an ice-cooled solution of 6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.440 g, 2.166 mmol, eNovation) and triethylamine (0.219 g, 0.304 mL, 2.166 mmol, Sigma-Aldrich) in DCM (8 mL) with stirring. Stir the resulting mixture at 0 °C for 15 min and then at rt for 2 days. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with EtOAc / heptane (0 to 60%) on a 24-g ISCO gold column) to give tert-butyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate as a grayish-white solid (630 mg, 2.077 mmol, 96% yield). m / z (ESI): 303.10 (M+H) + . 1 H NMR (chloroform-d, 400MHz) δ7.45 (d, 1H, J = 7.9Hz), 7.20 (d, 1H, J = 7.7Hz), 7.08 (s, 1H), 5.42 (br s, 1H), 4.86 (br d,1H,J=3.1Hz), 4.75(dd,1H,J=8.3,9.9Hz), 4.40(dd,1H,J=4.5,10.1Hz), 1.48(s,9H). 19 FNMR (chloroform-d, 376 MHz) δ -62.52 (s, 3F).

[0681] Step 2. Under nitrogen atmosphere, 60% sodium hydride in mineral oil (65.3 mg, 1.632 mmol, Sigma-Aldrich) was added to an ice-cooled solution of tert-butyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (330 mg, 1.088 mmol) in THF (5 mL) with stirring. The resulting mixture was stirred at 0 °C for 15 min, and then methyl iodoform (154 mg, 0.154 mL, 1.088 mmol, Sigma-Aldrich) was added via syringe. The resulting mixture was stirred at 0 °C for 15 min and then stirred at ambient temperature for 16 h. The reaction mixture was cooled again in an ice bath and then quenched with MeOH. Volatile substances were removed under vacuum, and the residue was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with EtOAc / heptane (0 to 40%) on a 12-g ISCO gold column) to give tert-butylmethyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (340 mg, 1.072 mmol, 98% yield) as a colorless oil, which was used in the next step without further purification. m / z (ESI): 340.15 (M+Na) + .

[0682] Step 3. Add 2,2,2-trifluoroacetic acid (122 mg, 2.0 mL, 1.072 mmol, Sigma-Aldrich) to a stirred solution of tert-butylmethyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (340 mg, 1.072 mmol) in DCM (2 mL). Stir the resulting mixture at rt for 2 h. Remove the volatiles under vacuum. Carefully alkalize the residue with ammonium hydroxide (0.5 mL). The crude residue was directly loaded onto a silica gel pre-column (25 g) (previously coated with a layer of Na₂CO₃) and subjected to combi-flash column chromatography (eluting on a 12-g ISCO gold column with MeOH (containing 0.5% ammonium hydroxide) / DCM (1 to 20%)) to give N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (12) as a colorless oil (140 mg, 0.645 mmol, 60.2% yield). Note that the low yield is due to material loss during rotary evaporation caused by its high volatility. It was later found that no higher than 32 °C was the optimal temperature for processing the compound without loss. 1¹H NMR (chloroform-d, 400 MHz): δ 7.43 (d, ¹H, J = 7.7 Hz), 7.18 (d, ¹H, J = 7.7 Hz), 7.07 (s, ¹H), 4.6–4.7 (m, ¹H), 4.4–4.5 (m, 2H), 2.46 (s, 3H). m / z (ESI): 218.20 (M+H) + .

[0683] Step 4. The racemic mixture was separated by a preparative SFC (using two Chiral Technologies IG columns (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 60 mL / min) to produce (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (13) as peak 1, wherein ee > 99% and (R)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (14) as peak 2, wherein ee > 99%.

[0684] The following amine intermediates in Table 2 were prepared in a manner similar to that described for intermediate 12. The chiral amines in Table 2 were synthesized from the corresponding chiral primary amines (intermediate 25, from (3S)-6-bromo-2,3-dihydro-3-benzofuranamine, CAS#1228568-69-1).

[0685] Table 2

[0686]

[0687]

[0688] Intermediate 27: 3-(methylamino)-2,3-dihydrobenzofuran-6-carboxynitrile

[0689]

[0690] Step 1. Di-tert-butyl dicarbonate (2.039 g, 9.34 mmol, TCI USA) was added to an ice-cold solution of 6-bromo-2,3-dihydrobenzofuran-3-amine (2.000 g, 9.34 mmol, Aurum Pharmatech) and triethylamine (1.040 g, 1.444 mL, 10.28 mmol, Sigma-Aldrich) in DCM (14 mL). The resulting mixture was stirred at 0 °C for 15 min, and then at rt for 48 h. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 4%) on a 40-g ISCO gold column) to give tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate as a grayish-white solid (2.79 g, 8.88 mmol, 95% yield). m / z (ESI): 335.95 and 338.05 (M+Na) + . 1 H NMR (chloroform-d, 400MHz) δ7.20 (d, 1H, J = 7.9Hz), 7.06 (dd, 1H, J = 1.7, 7.9Hz), 7.01 (d, 1H, J = 1.7Hz), 5.32 (br s, 1H), 4.82 (br s, 1H), 4.70 (dd, 1H, J = 8.2, 10.0Hz), 4.36 (dd, 1H, J = 4.2, 10.0Hz), 1.47 (s, 9H).

[0691] Under nitrogen atmosphere, sodium hydride (60% in mineral oil, 0.279 g, 6.97 mmol, Aldrich) was added in two equal fractions to an ice-cooled solution of tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (1.46 g, 4.65 mmol) in THF (18 mL) under stirring. The resulting mixture was stirred at 0 °C for 15 min, and then methyl iodoform (0.660 g, 0.289 mL, 4.65 mmol, Sigma-Aldrich) was added via syringe. The resulting mixture was stirred at 0 °C for 15 min and then stirred at ambient temperature for 2 days. The reaction mixture was cooled in an ice bath and then quenched with MeOH. Volatile substances were removed under vacuum, and the residue was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 2%) on a 24-g ISCO gold column) to give tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (26) as a colorless oil (1.55 g, 4.72 mmol, 102% yield). m / z (ESI): 350.05 and 352.00 (M+Na)+ . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.0–7.2 (m, 2H), 7.01 (d, 1H, J = 1.5 Hz), 5.6–6.2 (m, 1H), 4.63 (br t, 1H, J = 9.6 Hz), 4.39 (br dd, 1H, J = 3.4, 10.1 Hz), 2.55 (br s, 3H), 1.50 (s, 9H).

[0692] Step 2. Copper cyanide (218 mg, 2.437 mmol, Sigma-Aldrich) was added to a stirred solution of tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.609 mmol) in NMP (3.5 mL). The container was sealed and subjected to microwave conditions (135 °C for 4 h). The crude product was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (on a 24 g ISCO gold column, eluted with MeOH / DCM (25 min from 0 to 1%)) to give 240 mg of an impure mixture of tert-butyl(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate and unreacted starting material as an almost colorless oil, which was used in the next step without further purification. m / z (ESI): 365.00 (M+Na) + .

[0693] Under rt, via syringe, 2,2,2-trifluoroacetic acid (366 mg, 3 mL, 3.21 mmol, Sigma-Aldrich) was added to a stirred solution of a mixture of tert-butyl(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (220 mg, 0.802 mmol) and tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (263 mg, 0.802 mmol) (240 mg of total weight of impurities) in DCM (6 mL). The resulting mixture was stirred under rt for 1 h. Volatile substances were removed to give an oily crude mixture of 3-(methylamino)-2,3-dihydrobenzofuran-6-carboxynitrile (27) and its brominated counterpart (produced from tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate). The crude mixture was diluted in MeOH / DCM and filtered through a solid sodium carbonate layer to remove residual acid. The filtrate was then concentrated under vacuum. The crude product, 3-(methylamino)-2,3-dihydrobenzofuran-6-carboxynitrile, was used in the next step. m / z (ESI): 197.00 (M+Na) + .

[0694] Intermediate 29: 3-(methylamino)-2,3-dihydrobenzofuran-6-carboxynitrile

[0695]

[0696] Step 1. Add 2.5 mL of dimethyl sulfoxide to a mixture of tert-butyl(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (26) (330 mg, 1.005 mmol), sodium methanesulfonate (205 mg, 2.011 mmol, TCI, USA), sodium (S)-pyrrolidine-2-carboxylate (55.1 mg, 0.402 mmol, Combi-Blocks), and ketone iodide (i) (38.3 mg, 0.201 mmol, Sigma-Aldrich). Purge the resulting solution with nitrogen for 10 min, then seal and expose to microwave radiation (at 90 °C for 16 h). The crude product was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH (containing 0.5% ammonium hydroxide) / DCM (0 to 4%) on a 24-g ISCO gold column) to give tert-butylmethyl (6-(methanesulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate (28) as a colorless film (300 mg, 0.916 mmol, 91% yield). m / z (ESI): 350.05 (M+Na) + . 1 HNMR (chloroform-d, 400MHz) δ7.51 (dd, 1H, J = 1.6, 7.8Hz), 7.40 (br d, 1H, J = 7.7Hz), 7.36 (d, 1H, J = 1.5Hz), 5.7-6.2 (m, 1H), 4.70 (t, 1H, J = 9.8Hz), 4.46 (br dd,1H,J=3.8,9.8Hz),3.04(s,3H),2.55(br s,3H),1.48(s,9H).

[0697] Step 2. Under reflux, 2,2,2-trifluoroacetic acid (120 mg, 2.0 mL, 1.054 mmol, Sigma-Aldrich) was added to a stirred solution of tert-butylmethyl (6-(methanesulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate (28) (300 mg, 0.916 mmol) in DCM (8 mL). The resulting mixture was stirred under reflux for 1 h. Volatile substances were removed and the residue was dissolved in MeOH / DCM and ammonium hydroxide (0.4 mL). The crude residue was directly loaded onto a silica gel pre-column (25 g) (previously coated with a layer of sodium carbonate) and subjected to combi-flash column chromatography (eluting on a 24 g ISCO gold column with MeOH (containing 0.5% ammonium hydroxide) / DCM (2% to 20%)) to give N-methyl-6-(methanesulfonyl)-2,3-dihydrobenzofuran-3-amine (29) as a colorless oil (190 mg, 0.836 mmol, 91% yield). m / z (ESI): 228.00 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.4–7.6 (m, 2H), 7.34 (s, 1H), 4.6–4.7 (m, 1H), 4.4–4.5 (m, 2H), 3.02 (s, 3H), 2.44 (s, 3H), 1.40 (br s, 1H).

[0698] Intermediate 30: 6-(isopropylsulfonyl)-N-methyl-2,3-dihydrobenzofuran-3-amine

[0699]

[0700] Intermediate 30 was prepared in a manner similar to that of intermediate 29 described above, with m / z (ESI): 256.1 (M+H). + .

[0701] Intermediate 31: N-cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0702]

[0703] Step 1. A mixture of 2-hydroxy-4-(trifluoromethyl)benzaldehyde (2.00 g, 10.52 mmol, PharmaBlock), cyclopropylamine (1.201 g, 21.04 mmol, Acros), and anhydrous magnesium sulfate (5.06 g, 42.1 mmol, Sigma-Aldrich) in DCM (20 mL) was stirred at rt for 18 hours. The reaction mixture was filtered under gravity and the filtrate was concentrated to give (Z)-2-((cyclopropylimino)methyl)-5-(trifluoromethyl)phenol (2.1 g, 9.16 mmol, 87% yield) as a yellow solid. The product was used in the next step without further purification. m / z (ESI): 230.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δppm 12.98(br s,1H)8.83(s,1H)7.67(d,J=7.94Hz,1H)7.24(dd,J=7.94,1.05Hz,1H)7.1 7(s,1H)3.20(tt,J=6.85,3.40Hz,1H)0.98-1.09(m,2H)0.89-0.98(m,2H). 19 F NMR (376MHz, DMSO-d6) δppm-61.60 (s, 3F).

[0704] Step 2. Potassium tert-butoxide (1.297 g, 11.56 mmol, Sigma-Aldrich) was added dropwise to a suspension of trimethyl sulfoxide (2.54 g, 11.56 mmol, Sigma-Aldrich) in tetrahydrofuran (20 mL). The suspension was stirred at rt for 30 min and then treated dropwise with a solution of (Z)-2-((cyclopropylimino)methyl)-5-(trifluoromethyl)phenol (1.06 g, 4.62 mmol) in THF (4 mL). The resulting suspension was stirred at rt for 1 h and then at 50 °C for 3 h. The reaction was cooled to rt, and another 1 equivalent of potassium tert-butoxide (0.519 g, 4.62 mmol, Sigma-Aldrich) was added. The resulting suspension was stirred at rt for 12 h. The reaction mixture was filtered, and the filtrate was diluted with water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by column chromatography (using EtOAc / EtOH (3:1) (0-60%) in heptane) to give N-cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (31, 0.750 g, 3.08 mmol, 66.7% yield) as an oil. 1¹H NMR (400MHz, chloroform-d) δppm 7.46 (d, J = 7.73Hz, 1H) 7.19 (d, J = 7.59Hz, 1H) 7.08 (s, 1H) 4.56-4.68 (m, 2H) 4.49 (dd, J = 9.41, 3.76Hz, 1H) 2.26 (tt, J = 6.71, 3.42Hz, 1H) 1.75-2.06 (m, 1H) 0.50-0.55 (m, 2H) 0.41-0.46 (m, 2H). 19 F NMR (376MHz, chloroform-d) δppm -62.36 (s, 3F).

[0705] Step 3. N-Cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.750 g) was purified by preparative SFC (using a Chiral Technologies AD column (150 x 30 mm, 5 mm), with a mobile phase of 90% liquid CO2 and 10% MeOH containing 0.2% TEA, at a flow rate of 175 mL / min) to produce (S)-N-Cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (32) (0.413 g) as peak 1, where ee > 99%. 1 H NMR (400MHz, chloroform-d) δppm7.46 (d, J=7.67Hz, 1H) 7.19 (d, J=7.67Hz, 1H) 7.08 (s, 1H )4.61-4.68(m,1H)4.56-4.61(m,1H)4.47-4.51(m,1H)2.23-2.29(m,1H)1.59(br s,1H)0.42-0.56(m,4H). 19 F NMR (376MHz, chloroform-d) δppm -62.36 (s, 3F). (R)-N-cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (33) (0.314 g) was separated as peak 2, with ee of 98.56%. 1 H NMR (400MHz, chloroform-d) δppm 7.46(d,J=7.88Hz,1H)7.19(d,J=7.67Hz,1H)7.08(s,1H)4.56-4.68(m,2H)4.45-4.52(m,1H)2.26(tt,J=6.66,3.50Hz,1H)1.87(br s,1H)0.40-0.56(m,4H). 19 F NMR (376MHz, chloroform-d) δppm -62.36 (s, 3F).

[0706] The following amines in Table 3 are prepared in a manner similar to that described for intermediates 31-33.

[0707] Table 3

[0708]

[0709]

[0710] Intermediate 48: N,5-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-amine

[0711]

[0712] Step 1. Ethyl titanate (2.495 g, 2.495 mL, 10.94 mmol, Sigma-Aldrich) as a solid was added in a single step to a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (1.000 g, 4.97 mmol, Angel Pharmaceuticals) in 15 mL of THF in a 20 mL microwave reaction vessel, followed by the addition of 2-methylpropane-2-sulfinamide (0.603 g, 4.97 mmol, Sigma-Aldrich). The vessel was sealed and subjected to microwave irradiation (4 h, 70 °C). After cooling to rt, the crude reaction mixture was poured into brine (20 mL). The mixture was stirred vigorously for 15 min and then vacuum filtered through a diatomaceous earth layer. The filter cake was washed with EtOAc and the organic layer of the filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in DCM, loaded onto a silica gel pre-column (25 g), and subjected to combi-flash column chromatography (eluting with EtOAc / heptane (0 to 100%) on a 24-g ISCO gold column) to give (E)-2-methyl-N-(2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ylidene)propane-2-sulfinamide as a dark film (710 mg, 2.333 mmol, 46.9% yield). m / z (ESI): 327.0 (M+Na) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 8.19 (d, 1H, J = 7.9 Hz), 7.66 (d, 1H, J = 8.2 Hz), 3.5–3.7 (m, 1H), 3.35 (dd, 2H, J = 5.0, 7.3 Hz), 3.2–3.3 (m, 1H), 1.35 (s, 9H).

[0713] Step 2. Under a nitrogen atmosphere, methyl magnesium bromide (3.0 M in diethyl ether, 4.67 mL, 14.00 mmol, Sigma-Aldrich) was added via syringe to an ice-cold solution of (E)-2-methyl-N-(2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ylidene)propane-2-sulfinamide (710 mg, 2.333 mmol) in a stirred 15 mL DCM solution in a 250 mL single-necked round-bottom flask. The resulting mixture was stirred at 0 °C for 2 h and then heated to rt and stirred at rt overnight. The reaction was cooled in an ice-water bath, carefully quenched with ice-cold saturated ammonium chloride, and extracted with DCM (3x). The combined organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in DCM, loaded onto a silica gel pre-column (25 g), and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 5%) on a 40-g ISCO gold column) to give a single enantiomer, 2-methyl-N-(5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)propane-2-sulfinamide (100 mg, 0.312 mmol, 13.38% yield), as a dark film. m / z (ESI): 321.0 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.90 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 7.7 Hz), 3.50 (s, 1H), 3.2–3.3 (m, 1H), 3.0–3.1 (m, 1H), 2.52 (ddd, 1H, J = 7.0, 8.8, 13.5 Hz), 2.30 (ddd, 1H, J = 5.1, 8.4, 13.4 Hz), 1.65 (s, 3H), 1.2–1.3 (m, 8H). 19 F NMR (chloroform-d, 376 MHz) δ -67.45 (s, 3F).

[0714] Step 3. Under nitrogen atmosphere, sodium hydride (60% in mineral oil, 14.98 mg, 0.375 mmol, Sigma-Aldrich) was added to a stirred solution of 2-methyl-N-(5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)propane-2-sulfinamide (100 mg, 0.312 mmol) in THF (5 mL). The resulting mixture was stirred at 0 °C for 20 min, followed by slow dropwise addition of iodomethane (89 mg, 0.039 mL, 0.624 mmol, Sigma-Aldrich) via syringe. The resulting mixture was stirred at 0 °C for 2 h and then at ambient temperature for 3.5 h. The reaction was cooled in an ice-water bath and then quenched with MeOH (5 mL). Volatile substances were removed under vacuum, and the residue was dissolved in DCM / MeOH and loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 4%) on a 24-g ISCO gold column) to give N,2-dimethyl-N-(5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)propane-2-sulfinamide as a nearly colorless film (64 mg, 0.191 mmol, 61.3% yield). m / z (ESI): 335.0 (M+H) + . 1 ¹H NMR (chloroform-d, 400MHz) δ 7.82 (d, 1H, J = 7.9Hz), 7.53 (d, 1H, J = 7.9Hz), 3.2–3.3 (m, 1H), 3.0–3.1 (m, 1H), 2.62 (ddd, 1H, J = 6.7, 9.1, 13.7Hz), 2.46 (s, 3H), 2.10 (ddd, 1H, J = 5.3, 8.7, 13.7Hz), 1.65 (s, 3H), 1.22 (s, 9H). 19 F NMR (chloroform-d, 376 MHz) δ -67.44 (s, 3F).

[0715] Step 4. Under rt, hydrogen chloride in dioxane (4M solution, 3.0 mL, 12.00 mmol, Sigma-Aldrich) was added to a stirred solution of N,2-dimethyl-N-(5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)propane-2-sulfinamide (64 mg, 0.191 mmol) in MeOH (1.0 mL). The resulting mixture was stirred under rt for 0.5 h. The volatiles were removed to obtain crude N,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-amine (48), which was used directly in the next step. m / z (ESI): 231.20 (M+H) + .

[0716] Intermediate 49: 6,6-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridine-5-ol

[0717]

[0718] Step 1. Under nitrogen atmosphere, sodium hydride (60% in mineral oil, 298 mg, 7.46 mmol, Sigma-Aldrich) was added in a single, stirred, ice-cooled solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (600 mg, 2.98 mmol, Angel Pharma) in THF (8 mL). The resulting mixture was stirred at 0 °C for 25 min, and then methyl iodoform (889 mg, 0.390 mL, 6.26 mmol, Sigma-Aldrich) was added via syringe. The resulting mixture was stirred at 0 °C for 1.5 h and then at rt for 2 h. The mixture was poured into ice and saturated ammonium chloride aqueous solution and extracted with DCM (3x). The combined organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was dissolved in DCM, loaded onto a silica gel pre-column (25 g), and subjected to combi-flash column chromatography (eluting with MeOH / DCM (0 to 6%) on a 24-g ISCO gold column) to give 6,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-one (65 mg, 0.284 mmol, 9.51% yield) as an almost colorless film / solid. m / z (ESI): 230.20 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 8.21 (d, 1H, J = 7.9 Hz), 7.73 (d, 1H, J = 7.9 Hz), 3.22 (s, 2H), 1.33 (s, 6H). 19 F NMR (chloroform-d, 376 MHz) δ -68.00 (s, 3F).

[0719] Step 2. Add acetic acid (102 mg, 0.098 mL, 1.702 mmol, Sigma-Aldrich) to a stirred mixture of 6,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (65 mg, 0.284 mmol) and aminomethane (2.0 M solution in THF, 0.922 mL, 1.843 mmol, Sigma-Aldrich) in DCM (7 mL). Stir the resulting mixture at rt for 25 min, then add sodium triacetoxyborohydride (78 mg, 0.369 mmol, Sigma-Aldrich) as a solid in a single step. Stir the resulting mixture at rt overnight. MeOH (0.5 mL) was added to the mixture, and stirring was continued for 2 h. The mixture was then directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting on a 24 g ISCO gold column with MeOH / DCM (0 to 4%) and (MeOH containing 0.5% ammonium hydroxide) / DCM (2% to 20%)) to give impure N,6,6-trimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-amine (49) as a colorless film (10 mg, 0.041 mmol, 14.44% yield). m / z (ESI): 245.20 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.75 (d, 1H, J = 7.7 Hz), 7.49 (d, 1H, J = 7.7 Hz), 5.50 (br d, 1H, J = 2.3 Hz), 3.73 (s, 1H), 2.64 (s, 3H), 2.08 (s, 2H), 1.28 (s, 3H), 1.06 (s, 3H). 19 F NMR (chloroform-d, 376 MHz) δ -67.35 (s, 3F).

[0720] Intermediate 50: 6,6-difluoro-N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-amine

[0721]

[0722] Step 1. Under nitrogen atmosphere, a few drops of 2,2,2-trifluoroacetic acid (0.028 g, 0.249 mmol, Sigma-Aldrich) were added via syringe to a stirred mixture of 2-trifluoromethyl-6,7-dihydro-[1]piperidin-5-one (1.000 g, 4.97 mmol, Synnovator) and but-1-amine (0.436 g, 0.590 mL, 5.97 mmol, Sigma-Aldrich) in cyclohexane (50 mL). The flask was then fitted with a Dean-Stark condenser and the mixture was refluxed overnight. After cooling to rt, the crude mixture was poured into ice and saturated NaHCO3 aqueous solution and extracted with EtOAc (3x). The combined organic matter was washed with brine and dried over anhydrous sodium sulfate. Vacuum removal of volatiles yielded a colorless film-like substance, (Z)-5-(butyl-14-azanediol)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (1.00 g, 3.89 mmol, 78% yield), which was used in the next step without purification. m / z (ESI): 257.20 (M+H) + . 1 ¹H NMR (chloroform-d, 400MHz) δ 8.21 (d, 1H, J = 7.9Hz), 7.61 (d, 1H, J = 7.9Hz), 3.51 (t, 2H, J = 7.1Hz), 3.2–3.3 (m, 2H), 2.8–2.9 (m, 2H), 1.7–1.8 (m, 2H), 1.4–1.6 (m, 3H), 0.99 (t, 3H, J = 7.4Hz). 19 FNMR (chloroform-d, 376 MHz) δ -67.57 (s, 3F).

[0723] Step 2. Under nitrogen atmosphere, 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dionium tetrafluoroborate (2.478 g, 7.00 mmol, Sigma-Aldrich) in solid form was added in a single addition to a stirred mixture of (Z)-5-(butyl-14-azanediol)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (1.000 g, 3.50 mmol) and sodium sulfate (0.497 g, 3.50 mmol, Sigma-Aldrich) in MeCN (30 mL). The resulting mixture was heated to reflux overnight. After cooling to rt, HCl aqueous solution (37%) (3.0 mL) was added and the mixture was stirred at rt for 35 min. Volatiles were removed under vacuum. The residue was mixed with DCM and washed with ice-cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM (2x). The combined organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was loaded directly onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH / DCM (15 min from 0 to 4%) on a 24 g ISCO gold column) to give an impure 6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-one (410 mg, 1.729 mmol, 49.4% yield) as a brown solid. 1 H NMR (chloroform-d, 400MHz) δ 8.34 (d, 1H, J = 8.2Hz), 7.96 (d, 1H, J = 7.9Hz), 7.86 (d, 1H, J = 7.9Hz), 7.67 (d, 1H, J = 7.9Hz), 3.80 (t, 2H, J = 12.4Hz). 19 F NMR (chloroform-d, 376 MHz) δ -68.42 (s, 3F), -110.96 (s, 2F).

[0724] Step 3. Add acetic acid (263 mg, 0.253 mL, 4.39 mmol, Sigma-Aldrich) to a stirred mixture of 6,6-difluoro-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-one (260 mg, 1.096 mmol) and aminomethane (2.0 M solution in THF, 2.193 mL, 4.39 mmol, Sigma-Aldrich) in DCM (4 mL). Stir the resulting mixture at rt for 30 min, then add sodium triacetoxyborohydride (302 mg, 1.425 mmol, Sigma-Aldrich) as a solid in a single step. Stir the resulting mixture at rt for 2 days. MeOH (0.5 mL) was added to the mixture, and stirring was continued for 20 min. The mixture was then directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting on a 24 g ISCO gold column with 2x elution of MeOH containing 0.5% ammonium hydroxide / DCM (20 min from 0 to 6%)) to give impure 6,6-difluoro-N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-amine (50) (104 mg, 0.412 mmol, 37.6% yield) as a colorless film. m / z (ESI): 253.00 (M+H) + . 1 ¹H NMR (chloroform-d, 400 MHz) δ 7.88 (d, 1H, J = 7.7 Hz), 7.62 (d, 1H, J = 7.9 Hz), 4.3–4.4 (m, 1H), 3.5–3.7 (m, 2H), 2.71 (d, 3H, J = 1.0 Hz), 1.67 (br s, 1H). 19 F NMR (chloroform-d, 376MHz) δ -67.70 (s, 3F), -99.8–-97.2 (m, 1F), -112.08 (d, 1F, J = 233.2Hz).

[0725] Intermediates 51 and 52: methyl((S)-3-(methylamino)-2,3-dihydrobenzofuran-6-yl)(methylimino)-λ6-sulfanilamide and imino(methyl)((S)-3-(methylamino)-2,3-dihydrobenzofuran-6-yl)-λ6-sulfanilamide

[0726]

[0727] Step 1. A dried round-bottom flask was filled with tert-butyl(S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (500 mg, 1.591 mmol) and tetrahydrofuran (15.9 mL). The resulting solution was cooled to 0 °C and sodium hydride (60% dispersion in mineral oil, 115 mg, 2.86 mmol) was added in a single addition. The resulting mixture was stirred at 0 °C for 15 min, then methyl iodide (407 mg, 178 μL, 2.86 mmol) was added, and the mixture was heated to 23 °C. After 1 h, the reaction mixture was cooled to 0 °C and quenched by the slow addition of MeOH (5 mL). The solution was then heated to room temperature and concentrated under vacuum. The resulting crude residue was purified by rapid chromatography (0 to 50% 3:1 EtOAc:EtOH in heptane) to give tert-butyl(S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate as a clear oil (439.6 mg, 1.339 mmol, 84% yield). m / z (ESI): 352.0 (M+Na) + . 1 ¹H NMR (400MHz, chloroform-d) δppm 6.99–7.16 (m, 3H), 6.03 (br s, 1H), 4.65 (br t, J = 9.7Hz, 1H), 4.32–4.47 (m, 1H), 2.56 (br s, 3H), 1.45–1.53 (m, 9H).

[0728] Step 2. A round-bottom flask was filled with tert-butyl(S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (439.6 mg, 1.339 mmol) and tetrahydrofuran (13.4 mL). The resulting solution was rinsed with nitrogen, cooled to -78 °C, and n-butyllithium (729 μL, 1.473 mmol, 2.02 M in hexane) was added dropwise. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 30 min, followed by the dropwise addition of dimethyl disulfide (252 mg, 241 μL, 2.68 mmol). The reaction mixture was stirred at -78 °C. After 1 h, the reaction mixture was heated to 0 °C and quenched by the slow addition of H₂O (20 mL). The mixture was then transferred to a separatory funnel containing EtOAc (20 mL) and H₂O, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic compounds were dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude residue was purified by rapid chromatography (0 to 100% EtOAc in heptane) to give tert-butyl(S)-methyl(6-(methylthio)-2,3-dihydrobenzofuran-3-yl)carbamate as a clear oil (237.9 mg, 0.805 mmol, 60.1% yield). m / z (ESI): 318.2 (M+Na)+ . 1 ¹H NMR (400MHz, chloroform-d) δppm 7.09-7.21 (m, 1H), 6.80-6.88 (m, 1H), 6.76 (s, 1H), 5.67-6.22 (m, 1H), 4.56-4.69 (m, 1H), 4.39 (br dd, J=9.7, 3.1Hz, 1H), 2.56 (br s, 3H), 2.45-2.52 (m, 3H), 1.52 (s, 9H).

[0729] Step 3. A vial was filled with tert-butyl(S)-methyl(6-(methylthio)-2,3-dihydrobenzofuran-3-yl)carbamate (223.5 mg, 0.757 mmol) and methanol (1.51 mL). Ammonium carbamate (118 mg, 1.513 mmol) and diacetate iodobenzene (609 mg, 1.892 mmol) were added to the resulting solution. The mixture was stirred at 23 °C. After 30 min, the reaction mixture was concentrated under vacuum, and the resulting crude residue was purified by rapid chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to give tert-butylmethyl((3S)-6-(S-methylsulfonylimino)-2,3-dihydrobenzofuran-3-yl)carbamate (177.8 mg, 0.545 mmol, 72.0% yield) as a yellow oil. m / z (ESI): 327.1 (M+H) + .

[0730] Step 4. A vial was filled with tert-butylmethyl ((3S)-6-(S-methylsulfonylimino)-2,3-dihydrobenzofuran-3-yl)carbamate (178 mg, 0.545 mmol) and dichloromethane (5.45 mL). 2,2,2-trifluoroacetic acid (1.55 g, 1.04 mL, 13.6 mmol) was added to the resulting solution, and the reaction mixture was stirred at 23 °C. After 30 min, the reaction mixture was concentrated to dryness, and the resulting crude imino(methyl)((S)-3-(methylamino)-2,3-dihydrobenzofuran-6-yl)-λ 6 - Sulfamethoxazole (51) was used in subsequent steps without further purification. m / z (ESI): 227.2 (M+H) + .

[0731] Step 5. A round-bottom flask was filled with tert-butylmethyl ((3S)-6-(S-methylsulfonylimino)-2,3-dihydrobenzofuran-3-yl)carbamate (271.7 mg, 0.832 mmol) and dichloromethane (16.6 mL). The resulting solution was cooled to 0 °C, and a single addition of solid trimethyloxonium tetrafluoroborate (197 mg, 1.332 mmol) was made. The reaction vessel was then rinsed with nitrogen. The resulting mixture was then heated to 23 °C. After 1 h, the reaction mixture was cooled to 0 °C and quenched by the slow addition of H₂O (10 mL). The resulting two-phase mixture was then transferred to a separatory funnel containing DCM (20 mL), a saturated aqueous solution of Na₂CO₃ (20 mL), and brine (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting crude residue was purified by rapid chromatography (0 to 100% 3:1 EtOAc:EtOH in heptane) to give tert-butyl((3S)-6-(N,S-dimethylsulfonylimino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate as a clear oil (212 mg, 0.622 mmol, 74.7% yield). m / z (ESI): 341.2 (M+H) + .

[0732] Step 6. A vial was filled with tert-butyl((3S)-6-(N,S-dimethylsulfonylimino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (212 mg, 0.622 mmol) and dichloromethane (6.22 μL). 2,2,2-trifluoroacetic acid (1.77 g, 1.19 mL, 15.6 mmol) was added to the resulting solution, and the reaction mixture was stirred at 23 °C. After 2 h, the reaction mixture was concentrated to dryness, and the resulting crude methyl((S)-3-(methylamino)-2,3-dihydrobenzofuran-6-yl)(methylimino)-λ6-sulfanilamide (52) was used in subsequent steps without further purification. m / z (ESI): 241.2 (M+H) + .

[0733] Intermediate 53: (S)-N-methyl-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine

[0734]

[0735] Step 1. A mixture of tert-butyl(S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (0.3434 g, 1.046 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(trifluoromethyl)-1H-pyrazole (0.411 g, 1.569 mmol, Enamine) and toluene (10 mL) was purged with Ar, and then tripotassium phosphate monohydrate (0.723 g, 3.14 mmol, Sigma-Aldrich) and water (1.111 mL) were added. The mixture was stirred at rt for 10 min, and then tricyclohexylphosphine (0.059 g, 0.209 mmol, Strehm Chemicals) and palladium(II) acetate (0.023 g, 0.105 mmol, Sigma-Aldrich) were added. The mixture was stirred overnight at 90°C in a sealed vial. The crude product was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (using 0-60% EtOAc in heptane). Tert-butyl(S)-methyl(6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate was given as a grayish-white solid (0.300 g, 0.783 mmol, 74.8% yield). m / z (ESI): 384.1 (M+H) + .

[0736] Step 2. TFA (0.044 g, 0.030 mL, 0.392 mmol, Sigma-Aldrich) was added to a mixture of tert-butyl(S)-methyl(6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (0.0375 g, 0.098 mmol) and DCM (1 mL). The mixture was stirred overnight at rt and then concentrated under vacuum. The crude product was dissolved in 4 M HCl in dioxane to convert the TFA salt to an HCl salt and concentrated to dryness. (S)-N-methyl-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine (53) (0.028 g, 0.099 mmol, 101% yield) was given as a white solid. m / z (ESI): 306.1 (M+Na) + .

[0737] Intermediate 54: (S)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine

[0738]

[0739] Step 1. A mixture of tert-butyl(S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (0.3287 g, 1.002 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole (0.417 g, 2.003 mmol, Apollo), potassium carbonate (0.415 g, 3.00 mmol, Sigma-Aldrich), dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane adduct (0.095 g, 0.130 mmol, Strehm Chemicals), 1,4-dioxane (5 mL), and water (0.556 mL) was purged with Ar and then stirred overnight at 85 °C in a sealed vial. The crude product was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (using 0-60% EtOAc in heptane). Tert-butyl(S)-methyl(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate was given as a white solid (0.289 g, 0.877 mmol, 88% yield). m / z (ESI): 330, 352 (M+H) + . 1 H NMR (400MHz, chloroform-d) δppm 7.73(s,1H),7.58(s,1H),7.21(br d,J=7.7Hz,1H),7.04(dd,J=7.7,1.5Hz,1H),6.93(d,J=1.5Hz,1H),5.70-6.11(m,1H),4.62(br t,J=9.4Hz,1H),4.38(br dd,J=10.2,3.8Hz,1H),3.94(s,3H),2.57(br s,3H),1.54(s,6H),1.24(s,3H).

[0740] Step 2. Hydrogen chloride (4M in dioxane, 1.091 mL, 4.37 mmol, Sigma-Aldrich) was added to a mixture of tert-butyl(S)-methyl(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (0.2876 g, 0.873 mmol) in 1,4-dioxane (8 mL). MeOH (0.699 g, 0.883 mL, 21.83 mmol, Sigma-Aldrich) was added to dissolve the salt. Then 0.3 mL of HCl was added and the reaction was continued overnight, followed by concentration under vacuum. (S)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine hydrochloride (54) (0.227 g, 0.854 mmol, 98% yield) was given as a grayish-white solid. m / z (ESI): 230, 252 (M+Na) + .

[0741] Intermediates 56 and 57: (R)-N-methyl-7-(trifluoromethyl)isocyanate-4-amine and (S)-N-methyl-7-(trifluoromethyl)isocyanate-4-amine

[0742]

[0743] Step 1. Add potassium hydroxide (1.611 g, 28.7 mmol, Sigma-Aldrich) and tetrabutylammonium hydrogen sulfate (0.770 g, 2.267 mmol, Sigma-Aldrich) to a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (3.8552 g, 15.12 mmol, AA Blocks) in allyl bromide (1.829 g, 1.316 mL, 15.12 mmol, Sigma-Aldrich). Stir the mixture overnight at room temperature. Then add water (20 mL) and extract the aqueous layer with ethyl acetate (3–5 times). Wash the combined organic layers once with water and once with brine, then dry with magnesium sulfate, filter, and concentrate under vacuum to give the crude product. The crude product was separated as a yellow oil and purified by column chromatography (0-17% EA / heptane) to produce ((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene (4.3595 g, 14.77 mmol, 98% yield) as a clear oil. 1¹H NMR (400MHz, chloroform-d) δppm 7.80 (d, J = 1.5Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.37–7.47 (m, 1H), 6.00 (ddt, J = 17.2, 10.4, 5.6, 5.6Hz, 1H), 5.23–5.44 (m, 2H), 4.60 (s, 2H), 4.16 (dt, J = 5.6, 1.4Hz, 2H).

[0744] Step 2. Add cesium carbonate (5.78 g, 17.73 mmol, Sigma-Aldrich), triphenylphosphine (1.744 g, 6.65 mmol, Sigma-Aldrich), and palladium acetate (ii) (0.497 g, 2.216 mmol, Strehm Chemicals) to a solution of 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene (4.3595 g, 14.77 mmol) in N,N-dimethylformamide (87 mL), cesium carbonate (5.78 g, 17.73 mmol, Sigma-Aldrich), phosphine (1.744 g, 6.65 mmol, Sigma-Aldrich), and palladium acetate (ii) (0.497 g, 2.216 mmol, Strehm Chemicals) to the reaction mixture at 90 °C overnight, then filter and concentrate to remove most of the DMF. Add water and EtOAc and transfer the resulting two-phase mixture to a separatory funnel. Separate the layers and extract the aqueous phase with EtOAc. Wash the organic phase with brine. Dry the combined organic matter with anhydrous MgSO4, filter, and concentrate under reduced pressure. The resulting oil was purified by rapid column chromatography (0-25% EtOAc / heptane) to give 4-methylene-7-(trifluoromethyl)isocyanane (2.4102 g, 11.25 mmol, 76% yield), which was a yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δppm 7.79 (d, J = 8.4Hz, 1H), 7.45-7.52 (m, 1H), 7.31 (s, 1H), 5.73 (s, 1H), 5.16 (s, 1H), 4.85 (s, 2H), 4.48 (t, J = 1.3Hz, 2H).

[0745] Step 3. Add 2.4102 g (11.25 mmol) of 4-methylene-7-(trifluoromethyl)isocyanate in acetone (26.8 mL) and water (5.36 mL) to a 100 mL round-bottom flask. Then add potassium osmium tetroxide (vi) (0.415 g, 1.125 mmol, Sigma-Aldrich) followed by 4-methylmorpholine 4-oxide (4.61 g, 39.4 mmol, Sigma-Aldrich) to the reaction mixture. Stir the entire reaction mixture overnight under an inert (N2) atmosphere at rt. Quench the reaction mixture by adding solid sodium sulfite and stirring for 10 min. Partially concentrate the reaction mixture under vacuum, then dilute with EtOAc and brine. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic matter, dry over MgSO4, filter, and concentrate under vacuum. The crude residue was purified by column chromatography (eluting with a 0-100% EA gradient in heptane) to obtain 4-(hydroxymethyl)-7-(trifluoromethyl)isocyanan-4-ol (2.4765 g, 9.98 mmol, 89% yield). 1 H NMR (400MHz, chloroform-d) δppm 7.74 (d, J = 8.1Hz, 1H), 7.56 (br d,J=7.5Hz,1H),7.29(s,1H),4.85(s,2H),4.18(d,J=11.4Hz,1H),3.92(dd,J=11.1,6.7Hz,1H), 3.72(ddd,J=11.2,5.0,1.0Hz,1H),3.64(dd,J=11.3,1.1Hz,1H),2.76(s,1H),2.02-2.10(m,1H).

[0746] The diol was diluted with THF (36 mL), followed by sodium periodate (7.22 g, 33.8 mmol, Sigma-Aldrich), and then water (1.2 mL). The resulting reaction mixture was stirred under an inert (N2) atmosphere. After stirring overnight, the mixture was diluted with a mixture of EtOAc / heptane (1:1). The mixture was filtered through a diatomaceous earth mat, and the filtrate was collected and concentrated. The filtrate was treated with a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with a brine solution, dried over MgSO4, filtered through a diatomaceous earth mat, and concentrated under vacuum. The crude product was purified by column chromatography (eluting with a 0–20% EA / heptane gradient) to give 7-(trifluoromethyl)isocyanan-4-one (1.7116 g, 7.92 mmol, 70.4% yield) as a white solid. m / z (ESI): 216.8 (M+H) + , 1¹H NMR (400MHz, chloroform-d) δppm 8.19 (d, J = 8.1Hz, 1H), 7.71 (d, J = 8.1Hz, 1H), 7.54 (s, 1H), 4.97 (s, 2H), 4.44 (s, 2H).

[0747] Step 4. At 0 °C, sodium borohydride (0.296 g, 7.82 mmol, Sigma-Aldrich) was added in portions to a stirred solution of 7-(trifluoromethyl)isocyanate-4-one (1.300 g, 6.01 mmol) in methanol (20.05 mL). After stirring at this temperature for 15 min, the reaction mixture was allowed to rise to room temperature and stirred. After 20 min, MeOH was evaporated from the reaction mixture using a rotary evaporator. The reaction mixture was extracted three times with DCM and brine solution. The organic compounds were combined, dried over MgSO4, filtered, and the solvent was evaporated. The crude alcohol, 7-(trifluoromethyl)isocyanate-4-ol (1.312 g, 6.01 mmol, 100% yield), was used in the next step without further purification. 1 ¹H NMR (400MHz, chloroform-d) δppm 7.53-7.64 (m, 2H), 7.31 (s, 1H), 4.69-4.93 (m, 2H), 4.62 (dt, J = 9.7, 2.8Hz, 1H), 4.11 (dd, J = 11.9, 3.1Hz, 1H), 3.93 (dd, J = 11.9, 2.9Hz, 1H), 2.28-2.39 (m, 1H).

[0748] The crude alcohol was dissolved in DCM (20 mL) and stirred at 0 °C. At the same temperature and under a N2 atmosphere, methanesulfonyl chloride (0.827 g, 0.559 mL, 7.22 mmol, Sigma-Aldrich) was added dropwise via syringe, followed by triethylamine (0.791 g, 1.099 mL, 7.82 mmol, Sigma-Aldrich). The reaction mixture was stirred at the same temperature for 30 min, and then stirred again at room temperature for 30 min until the alcohol was exhausted. The reaction mixture was extracted with dichloromethane and water. The organic matter was combined and dried over MgSO4. The solvent was evaporated using a rotary evaporator, and the crude product 7-(trifluoromethyl)isocyanate-4-ylmethanesulfonate (1.782 g, 6.01 mmol, 100% yield) was separated as a white solid and used in the next step without further purification. 1¹H NMR (400MHz, chloroform-d) δppm 7.55-7.76 (m, 2H), 7.37 (s, 1H), 5.73 (t, J = 2.7Hz, 1H), 4.88-5.01 (m, 1H), 4.68-4.82 (m, 1H), 4.39 (dd, J = 13.2, 2.9Hz, 1H), 4.04 (dd, J = 13.1, 2.8Hz, 1H), 3.12 (s, 3H).

[0749] Sodium azide (0.782 g, 0.425 mL, 12.03 mmol, Sigma-Aldrich) was added to a solution of crude 7-(trifluoromethyl)isocyanate-4-ylmethanesulfonate (1.782 g, 6.01 mmol) in N,N-dimethylformamide (20.05 mL), and the mixture was stirred at rt for 2 h. After the reaction was complete, it was partially concentrated to remove DMF and extracted with EtOAc and brine. The organic compounds were combined and dried over MgSO4, and the solvent was evaporated using a rotary evaporator. The crude product was purified by silica gel column chromatography (0–40% EtOAc in n-heptane) to produce 4-azido-7-(trifluoromethyl)isocyanate as a clear oil (1.0389 g, 4.27 mmol, 71.0% yield). 1 H NMR (400MHz, chloroform-d) δppm 7.61(d,J=8.6Hz,1H),7.55(dd,J=8.2,1.0Hz,1H),7.38(s,1H),4.92(d,J=15.3 Hz,1H),4.79(d,J=15.5Hz,1H),4.19-4.33(m,2H),4.02(dd,J=11.9,2.9Hz,1H)

[0750] Step 5. Add anhydrous tetrahydrofuran (9698 μL) to solid-supported PPh3 (1.9 g, 4.11 mmol, Sigma-Aldrich) (2.15 mmol / g). Allow the mixture to stand for 5 min, then add a solution of 4-azido-7-(trifluoromethyl)isocyanate (500 mg, 2.056 mmol) in THF. Stir the suspension overnight at rt, then add iodomethane (1751 mg, 768 μL, 12.34 mmol, Sigma-Aldrich). Stir the mixture overnight at room temperature, filter, and wash the resin with anhydrous THF and DCM. Resuspend the resin in MeOH (2 mL) in rbf and add potassium hydroxide (254 mg, 4.52 mmol, Sigma-Aldrich). Stir the suspension at 65 °C for 4 h, cool to rt, filter, and wash the resin with DCM and MeOH. Combine the filtrate and washes and concentrate to dryness. The crude product was partitioned between DCM and aqueous NaHCO3, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain the amine. The crude material was adsorbed onto a silica gel stopper and purified by chromatography through a Biotage pre-packed silica gel column (eluting with a 0% to 100% EtOAc gradient in heptane) to produce N-methyl-7-(trifluoromethyl)isocyanane-4-amine (55,435.8 mg, 1.885 mmol, 92% yield). m / z (ESI): 232.2 (M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δppm 7.45–7.52 (m, 2H), 7.28 (s, 1H), 4.69–4.91 (m, 2H), 4.19 (dd, J = 11.8, 2.7Hz, 1H), 3.81 (dd, J = 11.8, 2.9Hz, 1H), 3.55 (br s, 1H), 2.54 (s, 3H).

[0751] Step 6. N-methyl-7-(trifluoromethyl)isocyanate-4-amine (435.8 mg) was purified by preparative SFC (using two Chiral Technologies IG columns (250 x 21 mm, 5 mm), mobile phase of 90% liquid CO2 and 10% MeOH containing 0.2% TEA, at a flow rate of 70 mL / min) to produce peak 1 at 138.2 mg with ee > 99% and peak 2 at 157.2 mg with ee 97.22%. Peak partitioning was determined by SFC using an IG column (with 10% MeOH and 0.2% TEA). Peak 1: (R)-N-methyl-7-(trifluoromethyl)isocyanate-4-amine (56, 138.2 mg, 0.598 mmol, 29.1% yield), m / z (ESI): 232.2 (M+H)+ . 1 ¹H NMR (400MHz, chloroform-d) δppm 7.45–7.52 (m, 2H), 7.28 (s, 1H), 4.69–4.91 (m, 2H), 4.19 (dd, J = 11.8, 2.7 Hz, 1H), 3.81 (dd, J = 11.8, 2.9 Hz, 1H), 3.55 (br s, 1H), 2.54 (s, 3H) Peak 2: (S)-N-methyl-7-(trifluoromethyl)isocyanane-4-amine (57, 157.2 mg, 0.680 mmol, 33.1% yield), m / z (ESI): 232.2 (M+H) + , 1 ¹H NMR (400MHz, chloroform-d) δppm 7.49 (s, 2H), 7.28 (s, 1H), 4.68–4.92 (m, 2H), 4.19 (dd, J = 11.6, 2.7Hz, 1H), 3.81 (dd, J = 11.8, 2.9Hz, 1H), 3.55 (br s, 1H), 2.53 (s, 3H)

[0752] The following amines in Table 4 are prepared in a manner similar to that described for intermediates 55-57.

[0753] Table 4

[0754]

[0755]

[0756] Intermediates 72 and 73: trans-N,1-dimethyl-7-(trifluoromethyl)isocyanate-4-amine and cis-N,1-dimethyl-7-(trifluoromethyl)isocyanate-4-amine

[0757]

[0758] Step 1.4 - Azide-1-methyl-7-(trifluoromethyl)isocyanane was prepared using the same method as intermediate 55 up to step 4. The crude 4-azido-1-methyl-7-(trifluoromethyl)isocyanane was purified by silica gel column chromatography (using 0-40% EtOAc in n-heptane). Peak 1 was determined to be the trans isomer by observing the crystal structure of the corresponding final analogue, and peak 2 was determined to be the cis isomer. Peak 1: trans-4-azido-1-methyl-7-(trifluoromethyl)isocyanane (141.4 mg, 0.550 mmol, 24.4% yield) 1¹H NMR (400MHz, chloroform-d) δppm 7.56–7.60 (m, 2H), 7.39 (s, 1H), 5.01 (q, J = 6.6 Hz, 1H), 4.45 (t, J = 5.3 Hz, 1H), 4.30 (dd, J = 11.7, 4.5 Hz, 1H), 3.86 (dd, J = 11.6, 6.4 Hz, 1H), 1.58 (d, J = 6.6 Hz, 3H) Peak 2: cis-4-azido-1-methyl-7-(trifluoromethyl)isocyanate (296.6 mg, 1.153 mmol, 51.5% yield) 1 ¹H NMR (400MHz, chloroform-d) δppm: 7.60 (d, J = 8.1 Hz, 1H), 7.44–7.52 (m, 2H), 4.85 (q, J = 6.6 Hz, 1H), 4.35 (dd, J = 12.1, 1.6 Hz, 1H), 4.13 (s, 1H), 3.96 (dd, J = 12.2, 2.3 Hz, 1H), 1.65 (d, J = 6.6 Hz, 3H)

[0759] Step 2. Perform the same procedure separately for both isomers; the following procedure applies to the cis isomer (peak 2). Add anhydrous tetrahydrofuran (5439 μL) to solid-supported PPh3 (1.07 g, 2.306 mmol, Sigma-Aldrich) (2.15 mmol / g). Allow the mixture to stand for 5 min, then add a solution of cis-4-azido-1-methyl-7-(trifluoromethyl)isocyanane (296.6 mg, 1.153 mmol) in THF. Stir the suspension overnight at rt, then add iodomethane (982 mg, 431 μL, 6.92 mmol, Sigma-Aldrich). Stir the mixture overnight at rt, filter, and wash the resin with THF and DCM. Resuspend the resin in MeOH (2 mL) and transfer to rbf, then add potassium hydroxide solution (142 mg, 2.54 mmol, Sigma-Aldrich) (2% in MeOH). The suspension was stirred overnight at 65°C, cooled to rt, filtered, and the resin was washed with DCM and MeOH. The filtrate and washings were combined and concentrated to dryness. The crude product was partitioned between DCM and aqueous NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to give the amine. The crude material was adsorbed onto a silica gel stopper and purified by chromatography through a Biotage pre-packed silica gel column (eluting with a 0% to 100% EtOAc gradient in heptane) to give the product, cis-N,1-dimethyl-7-(trifluoromethyl)isocyanane-4-amine (73) (213.1 mg, 0.869 mmol, 75% yield). m / z (ESI): 246.2 (M+H)+ . 1 ¹H NMR (400MHz, chloroform-d) δppm 7.41–7.53 (m, 2H), 7.33–7.39 (m, 1H), 4.79 (q, J = 6.4 Hz, 1H), 4.30 (dd, J = 11.8, 1.2 Hz, 1H), 3.68–3.79 (m, 2H), 3.46 (s, 1H), 2.54 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). Peak 1 was subjected to the same operation to produce trans-N,1-dimethyl-7-(trifluoromethyl)isocyanane-4-amine (72) (81.7 mg, 0.333 mmol, 60.6% yield). m / z (ESI): 246.2 (M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δppm 7.55-7.60 (m, 1H), 7.48-7.51 (m, 1H), 7.31 (s, 1H), 4.96 (q, J = 6.5Hz, 1H), 4.16 (dd, J = 11.5, 3.8Hz, 1H), 3.75-3.84 (m, 1H), 3.67-3.74 (m, 1H), 2.52 (s, 3H), 1.54 (d, J = 6.6Hz, 3H).

[0760] Intermediate 74: N-methyl-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-8-amine

[0761]

[0762] Step 1. Add allyl bromide (0.572 g, 0.411 mL, 4.73 mmol, Sigma-Aldrich), potassium hydroxide (0.504 g, 8.98 mmol, Sigma-Aldrich), and tetrabutylammonium hydrogen sulfate (0.241 g, 0.709 mmol, Sigma-Aldrich) to a solution of [2-chloro-5-(trifluoromethyl)-3-pyridyl]methanol (1.00 g, 1 mL, 4.73 mmol, Aurum Pharmatech LLC.) in dichloromethane (5 mL), to a solution of allyl bromide in dichloromethane (5 mL). Stir all the reaction mixtures overnight at rt. Dilute the reaction mixtures with DCM and water. Separate the layers and extract the aqueous layer with DCM (3x). Dry the combined organic extracts over MgSO4, filter, and concentrate under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-25% EtOAc gradient in heptane) to give 3-((allyloxy)methyl)-2-chloro-5-(trifluoromethyl)pyridine (1.116 g, 4.44 mmol, 94% yield), a pale yellow oil. m / z (ESI): 252.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 8.81(br s,1H),8.21(br s,1H),5.88-6.03(m,1H),5.15-5.37(m,2H),4.53-4.63(m,2H),4.09-4.17(m,2H).

[0763] Step 2. Add 3-((allyloxy)methyl)-2-chloro-5-(trifluoromethyl)pyridine (1.116 g, 4.44 mmol), triphenylphosphine (0.523 g, 1.996 mmol, Sigma-Aldrich), and cesium carbonate (1.734 g, 5.32 mmol, Sigma-Aldrich) in N,N-dimethylformamide (15 mL) to a dried 2-necked 100 mL round-bottom flask. Purge the reaction mixture with argon (gas) for 5 min, then add palladium(ii) acetate (0.149 g, 0.665 mmol, Sigma-Aldrich) to the reaction mixture. Stir and heat the resulting reaction mixture at 90 °C for 16 h. Cool the reaction mixture to rt and then filter through a diatomaceous earth pad. Collect the filtrate and then partially concentrate under vacuum (to remove most of the DMF). Dilute the residue with EtOAc and water. Extract the aqueous layer with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-20% EtOAc gradient in heptane) to give 8-methylene-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine (0.256 g, 1.190 mmol, 26.8% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 8.86 (s, 1H), 8.06 (s, 1H), 6.32 (d, J = 1.3Hz, 1H), 5.36 (d, J = 1.5Hz, 1H), 4.88 (s, 2H), 4.58 (s, 2H). m / z(ESI):216.0(M+H) + .

[0764] Step 3. Add potassium osmium tetroxide dihydrate (vi) (0.041 g, 0.112 mmol, Acros Organics) and 4-methylmorpholine 4-oxide (0.457 g, 3.90 mmol, Sigma-Aldrich) to a stirred solution of 8-methylene-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine (0.240 g, 1.115 mmol, acetone (5 mL) / water (1 mL)). Stir the resulting reaction mixture at rt for 1.5 h. Quench the reaction mixture by adding solid sodium sulfite (240 mg) and stirring for 10 min. Concentrate the reaction mixture partially under vacuum (to remove acetone). Dilute the residue with EtOAc and brine solution. Separate the layers and extract the aqueous layer with EtOAc (3x). Dry the combined organic extracts over MgSO4, filter, and concentrate under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-10% MeOH gradient in DCM) to give 8-(hydroxymethyl)-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-ol (0.270 g, 1.084 mmol, 97% yield). m / z (ESI): 250.0 (M+H) + .

[0765] The previous residue was diluted with THF (6 mL), and then sodium periodate (0.716 g, 3.35 mmol, Sigma-Aldrich) and water (0.2 mL) were added to the reaction mixture. The resulting mixture was stirred at rt for 16 h. The reaction mixture was diluted with a mixture of EtOAc:heptane (1:1). The heterogeneous mixture was filtered through a diatomaceous earth mat, and the filtrate was collected. The filtrate was treated with a saturated aqueous solution of NaHCO3, and the layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting in heptane with a 0-30% EtOAc:EtOH (3:1) gradient) to give 3-(trifluoromethyl)-5H-pyrano[4,3-b]pyridin-8(7H)-one (0.190 g, 0.875 mmol, 78% yield) as a grayish-white solid. m / z (ESI): 218.2 (M+H) + .

[0766] Step 4. Sodium borohydride (0.030 g, 0.787 mmol, Sigma-Aldrich) was added to a solution of 3-(trifluoromethyl)-5H-pyrano[4,3-b]pyridin-8(7H)-one (0.171 g, 0.787 mmol) in ethanol (4 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and saturated NH4Cl aqueous solution, and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum to give crude 3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-ol. This substance was used without further purification. m / z (ESI): 220.1 (M+H) + .

[0767] Step 5. Add 3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-ol (0.170 g, 0.776 mmol) in dichloromethane (2 mL) to a 50-mL round-bottom flask. Cool the mixture to 0 °C, then add methanesulfonyl chloride (0.107 g, 0.07 mL, 0.931 mmol, Sigma-Aldrich) followed by triethylamine (0.102 g, 0.14 mL, 1.008 mmol, Sigma-Aldrich) to the reaction mixture. Stir the reaction mixture at 0 °C for 15 min, then at rt for 30 min. Dilute the reaction mixture with DCM and a saline solution, then transfer the two phases to a separatory funnel. Extract the aqueous layer with DCM (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum to give 3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-yl methanesulfonate. This substance was used without further purification. m / z (ESI): 298.0 (M+H) + .

[0768] The previous residue was diluted with N,N-dimethylformamide (2 mL), and then sodium azide (0.101 g, 1.551 mmol, Sigma-Aldrich) was slowly added to the reaction mixture. The resulting reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with EtOAc and brine. The two phases were transferred to a separatory funnel and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0–25% EtOAc gradient in heptane) to give 8-azido-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine as a colorless oil (0.080 g, 0.328 mmol, 42.2% yield). m / z (ESI): 245.0 (M+H) + .

[0769] Step 6. Add 8-azido-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine (0.075 g, 0.307 mmol) in tetrahydrofuran (1 mL) to a 50-mL round-bottom flask. Then add triphenylphosphine (0.161 g, 0.614 mmol, Sigma-Aldrich) to the reaction mixture and stir at rt for 16 h. Dilute the reaction mixture with EtOAc and brine. Separate the layers and extract the aqueous layer with EtOAc (3x). Dry the combined organic extracts over MgSO4, filter, and concentrate under vacuum. m / z (ESI): 219.0 (M+H) + .

[0770] The previous residue was diluted with dichloromethane (1 mL), and then di-tert-butyl dicarbonate (0.101 g, 0.107 mL, 0.461 mmol, Oakwood Products) and triethylamine (0.093 g, 0.130 mL, 0.921 mmol, Sigma-Aldrich) were added. All reaction mixtures were stirred at rt for 16 h. The reaction mixtures were treated with a saturated aqueous solution of NaHCO3 and diluted with DCM. The layers were separated, and the aqueous layer was extracted with DCM (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-30% EtOAc gradient in heptane) to give tert-butyl(3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-yl) carbamate as a grayish-white solid (0.076 g, 0.239 mmol, 78% yield). m / z (ESI): 319.1 (M+H) + .

[0771] Step 7. Add tert-butyl (3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-yl) carbamate (0.070 g, 0.220 mmol) in tetrahydrofuran (1 mL) to a 50 mL round-bottom flask. Cool the mixture to 0 °C, then add sodium hydride (60% dispersion in mineral oil) (10.56 mg, 0.264 mmol, Oakwood Products) to the reaction mixture. Stir the resulting mixture at 0 °C for 2 h, then add methyl iodide (0.037 g, 0.04 mL, 0.264 mmol, Sigma-Aldrich) dropwise to the mixture. Stir the reaction mixture for another 20 min while maintaining the temperature at 0 °C, then stir it overnight at rt. Quench the reaction mixture with MeOH and concentrate it under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-25% EtOAc gradient in heptane) to obtain a colorless oily tert-butylmethyl (3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-yl)carbamate. m / z (ESI): 333.0 (M-BOC+H) + .

[0772] The previous residue was dissolved in dichloromethane (1 mL) and then treated with trifluoroacetic acid (0.251 g, 0.2 mL, 2.199 mmol, Sigma-Aldrich). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and then treated with a saturated aqueous solution of NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude N-methyl-3-(trifluoromethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-8-amine (74) was used without further purification. m / z (ESI): 233.0 (M+H) + .

[0773] Intermediate 75: 2-methoxy-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-amine

[0774]

[0775] Step 1. Under reflux, allyl bromide (0.476 mL, 5.50 mmol) was added to a stirred solution of (3-bromo-6-methoxypyridin-2-yl)methanol (1.0 g, 4.59 mmol) in tetrahydrofuran (20 mL). Then, under reflux, KOH (0.515 g, 9.17 mmol) was added, followed by tetrabutylammonium bisulfate (0.234 g, 0.688 mmol). The reaction mixture was stirred under reflux for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum to give a crude product. The crude product was purified by column chromatography (eluting with 10% EtOAc in petroleum ether) to give 2-((allyloxy)methyl)-3-bromo-6-methoxypyridinium (900 mg, 3.49 mmol, 76% yield) as a colorless oil. m / z (ESI): 258.1, 260.1 (M+H) + .

[0776] Step 2. Under reflux, cesium carbonate (379 mg, 1.162 mmol), palladium(II) acetate (43.5 mg, 0.194 mmol), and triphenylphosphine (127 mg, 0.484 mmol) were added to a stirred solution of 2-((allyloxy)methyl)-3-bromo-6-methoxypyridine (250 mg, 0.969 mmol) in N,N-dimethylformamide (2.5 mL), and the mixture was stirred at 90 °C for 30 min. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was then washed with water and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (230-400 mesh) (using 5% ethyl acetate in hexane as eluent) to give 2-methoxy-5-methylene-5,8-dihydro-6H-pyrano[3,4-b]pyridine as a yellow solid (90 mg, 0.508 mmol, 52.4% yield). m / z (ESI): 178.2 (M+H) + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.85 (d, J = 8.7 Hz, 1H), 6.65 (dq, J = 8.5, 0.9 Hz, 1H), 5.44 (d, J = 1.2 Hz, 1H), 5.00–4.97 (m, 1H), 4.76 (s, 2H), 4.43 (t, J = 1.2 Hz, 2H), 3.93 (s, 3H).

[0777] Step 3. Under rt, potassium osmium tetroxide (VI) (0.790 g, 2.144 mmol) was added to a stirred solution of 2-methoxy-5-methylene-5,8-dihydro-6H-pyrano[3,4-b]pyridine (3.8 g, 21.44 mmol) in a mixture of acetone (50 mL) and water (10 mL), followed by the addition of 4-methylmorpholine 4-oxide (8.79 g, 75 mmol), and the reaction mixture was stirred under rt for 16 h. The reaction mixture was quenched by adding solid sodium sulfite and the mixture was stirred for 10 min. The reaction mixture was partially concentrated under vacuum (to remove acetone), then diluted with ethyl acetate and extracted with ethyl acetate (3 x 100 mL), washed with water, dried over anhydrous Na2SO4 through an organic layer, and concentrated under vacuum to give crude 5-(hydroxymethyl)-2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-ol as a brown oil. m / z (ESI): 212.3 (M+H) + .

[0778] Sodium periodate (12.15 g, 56.8 mmol) was added to a stirred solution of 5-(hydroxymethyl)-2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-ol (4.8 g, 22.73 mmol) in tetrahydrofuran (100 mL) and water (20 mL) under rt, and the reaction mixture was stirred under rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude compound, which was purified by column chromatography (eluting with 20% EtOAc in petroleum ether) to give 2-methoxy-6H-pyrano[3,4-b]pyridin-5(8H)-one (2.6 g, 14.51 mmol, 63.9% yield) as a brownish-yellow solid. m / z (ESI): 180.1 (M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δ 8.17 (d, J = 8.6Hz, 1H), 6.76 (d, J = 8.6Hz, 1H), 4.86 (s, 2H), 4.36 (s, 2H), 4.02 (d, J = 1.2Hz, 3H).

[0779] Step 4. To a stirred solution of 2-methoxy-6H-pyrano[3,4-b]pyridin-5(8H)-one (2.0 g, 11.16 mmol) in trifluoroethanol (14.46 mL, 201 mmol), methylamine (27.9 mL, 55.8 mmol) in THF was added, and the reaction mixture was stirred at rt for 16 h. After 16 h, methanol (4.00 mL) was added at 0 °C, followed by sodium borohydride (2.111 g, 55.8 mmol). The reaction mixture was heated to rt and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, quenched with 10% sodium bicarbonate, and extracted with 10% MeOH in DCM. The combined organic layers were dried over sodium sulfate and concentrated. The crude substance was purified by column chromatography (eluting with 5% MeOH in DCM) to give 2-methoxy-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-amine (75) as a pale yellow liquid (1.5 g, 7.72 mmol, 69.2% yield). m / z (ESI): 195.1 (M+H) + .

[0780] The following amines in Table 5 are prepared in a manner similar to that described for intermediate 75.

[0781] Table 5

[0782]

[0783]

[0784] Intermediate 81: (R)-2-methoxy-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-amine

[0785]

[0786] Step 1. At 0 °C, sodium bicarbonate (0.811 g, 9.65 mmol) and Fmoc-OSu (3.26 g, 9.65 mmol) were added to a stirred solution of 2-methoxy-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (75) (1.25 g, 6.44 mmol) in 1,4-dioxane (12.50 mL) and water (12.50 mL). The reaction was heated to rt and stirred for 1 h. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography; the compound was eluted in 15% ethyl acetate in petroleum ether to yield 9H-fluorene-9-yl)methyl(2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)(methyl)carbamate as a racemic compound.

[0787] Step 2. Racemic 9H-fluorene-9-yl)methyl(2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)(methyl)carbamate was separated by chiral SFC (using a Chiralcel OD-H column (250 x 21 mm, 5 μm), with a mobile phase of 79% liquid CO2 and 21% MeOH containing 0.2% TEA, at a flow rate of 70 mL / min) to obtain 840 mg of each isomer. Peak 1 is the more potent isomer.

[0788] Step 3. At 0 °C, (9H-fluorene-9-yl)methyl(R)-(2-methoxy-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)(methyl)carbamate (840 mg, 2.017 mmol) and DBU (20% in THF, 1520 μL, 2.017 mmol) were added to a 100-mL round-bottom flask. The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete, the reaction mixture was diluted with water and extracted with 20% MeOH in DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography and the compound was eluted in 5% MeOH in DCM to give (R)-2-methoxy-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-amine (81) as a brown liquid (289 mg, 1.488 mmol, 73.8% yield). m / z (GCMS): 194.1. 1 H NMR (401MHz, DMSO-d6) δ7.69(d,J=8.4Hz,1H),6.69(d,J=8.4Hz,1H),4.53(q,J=16.0Hz,2H),3.8 9(dd,J=11.5,4.1Hz,1H),3.80(s,3H),3.77(d,J=3.7Hz,1H),3.52(t,J=3.9Hz,1H),2.30(s,3H).

[0789] The following amines in Table 6 are prepared in a manner similar to that described for intermediate 81, wherein the SFC conditions shown are used during step 2.

[0790] Table 6

[0791]

[0792]

[0793]

[0794] Intermediate 92: 5-(methylamino)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-2-carboxynitrile

[0795]

[0796] Step 1. 6H-pyrano[3,4-b]pyridin-5(8H)-one (80.0 mg, 0.536 mmol, 1.0 equivalent, Enamine) was dissolved in DCM (5.36 mL) and m-CPBA (93.0 mg, 0.536 mmol, 1.0 equivalent, Sigma-Aldrich) was added. The reaction was stirred overnight until complete and then diluted with water and DCM. The layers were separated and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organic layers were dried over MgSO4, and the crude product was purified by medium-pressure chromatography (silica, 0 to 100% EtOAc: heptane) to give 5-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridine 1-oxide (16.0 mg, 0.097 mmol, 18.1% yield). m / z (ESI): 166.0 (M+H) + .

[0797] Step 2. 5-O-5,8-dihydro-6H-pyrano[3,4-b]pyridine 1-oxide (16.0 mg, 0.097 mmol, 1.0 equivalence) was dissolved in dichloromethane (969 μL) and dimethylcarbamoyl chloride (17.8 μL, 0.194 mmol, 2.0 equivalence, Sigma-Aldrich) was added, followed by trimethylcyanosilane (26.0 μL, 0.194 mmol, 2.0 equivalence, Sigma-Aldrich). The resulting solution was stirred at rt for 4.5 days until near completion. The mixture was then directly loaded onto a column for medium-pressure chromatography (silica gel, 0 to 75% EtOAc:heptane) to give 5-O-5,8-dihydro-6H-pyrano[3,4-b]pyridine-2-carboxynitrile (7.00 mg, 0.0400 mmol, 41.5% yield). m / z (ESI): 175.0 (M+H) + .

[0798] Step 3. 5-O-5,8-dihydro-6H-pyrano[3,4-b]pyridine-2-carboxynitrile (40.0 mg, 0.230 mmol, 1.0 equivalence) was dissolved in trifluoroethanol (1.53 mL), and methylamine (2.0 M in THF) (0.459 mL, 0.919 mmol, 4.0 equivalence, Sigma-Aldrich) was added. The solution was stirred overnight to form an imine. Sodium borohydride (21.7 mg, 0.574 mmol, 2.5 equivalence, Sigma-Aldrich) was then added, and the reaction was stirred for 45 minutes until complete. The reaction was then quenched by dropwise addition of water (10 mL), and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were then dried over Na₂SO₄. The crude product was then purified by medium-pressure chromatography (silica, 0 to 100% EtOAc:heptane to 40% to 100% (hold) (3:1 EtOAc:EtOH:heptane) to give 5-(methylamino)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-2-carboxynitrile (10 mg, 0.053 mmol, 23.0% yield). (92). m / z (ESI): 190.2 (M+H) + .

[0799] Intermediate 94: 4-(methylamino)isosourane-7-carboxynitrile

[0800]

[0801] Step 1. Add 7-bromo-N-methylisocyanate-4-amine (6) (0.130 g, 0.537 mmol, 1.0 equivalent) and di-tert-butyl dicarbonate (0.176 g, 0.805 mmol, 1.50 equivalent, Oakwood Products) in 1,2-dichloroethane (2.68 mL) to a 100-mL round-bottom flask. Then add triethylamine (0.163 g, 0.226 mL, 1.611 mmol, 3.0 equivalent, Sigma-Aldrich) to the reaction mixture and stir all the mixture at rt for 2 h. Dilute the reaction mixture with DCM (5 mL) and saturated NaHCO3 aqueous solution (5 mL). Separate the layers and extract the aqueous layer with DCM (3x). Dry the combined organic extracts over MgSO4, filter, and concentrate under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-20% EtOAc gradient in heptane) to give tert-butyl(7-bromoisocyanate-4-yl)(methyl)carbamate (93) as a grayish-white solid (0.181 g, 0.529 mmol, 99% yield). m / z (ESI): 342.0 (M+H) + . 1H NMR(400MHz,DMSO-d6)δppm 7.47(br d,J=8.2Hz,1H),7.39(s,1H),7.05-7.13(m,1H),4.93-5.24(m,1H),4.70-4.78 (m,1H),4.57-4.65(m,1H),3.85-4.00(m,2H),2.53-2.62(m,3H),1.46(s,9H).

[0802] Step 2. Fill a resealable glass vial with tert-butyl(7-bromoisocyanate-4-yl)(methyl)carbamate (0.075 g, 0.219 mmol, 1.0 equivalence) and potassium ferrocyanide trihydrate (0.370 g, 0.877 mmol, 4.0 equivalence, Toronto Research Chemicals) in a 1:1 mixture of 1,4-dioxane (1.10 mL) and water (1.10 mL). Purge the reaction mixture with argon (gas) for 5 min, then add xphos pd g3 (0.037 g, 0.044 mmol, 0.2 equivalence, Sigma-Aldrich) and potassium acetate (0.065 g, 0.657 mmol, 3.0 equivalence, Sigma-Aldrich). Stir and heat the resulting reaction mixture at 100 °C for six hours. The reaction mixture was diluted with EtOAc and then filtered through a diatomaceous earth pad. The filter cake was washed with MeOH:EtOAc (2:1) and the filtrate was collected. The combined organic matter was then concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-30% EtOAc gradient in heptane) to give tert-butyl(7-cyanoisocyanate-4-yl)(methyl)carbamate as a pale yellow oil (0.058 g, 0.201 mmol, 92% yield). m / z (ESI): 342.0 (M+H) + .

[0803] Step 3. Add tert-butyl(7-cyanoisocyanate-4-yl)(methyl)carbamate (0.058 g, 0.201 mmol) and trifluoroacetic acid (0.229 g, 0.150 mL, 2.011 mmol, Sigma-Aldrich) to a 50-mL round-bottom flask in dichloromethane (1.006 mL). Stir the resulting reaction mixture at rt for one hour. Concentrate the reaction mixture under vacuum. Use the crude 4-(methylamino)isocyanate-7-carboxynitrile (94) without further purification in the next synthetic step. m / z (ESI): 182.9 (M+H) + .

[0804] Intermediate 95: N-methyl-7-(methanesulfonyl)isocyanane-4-amine

[0805]

[0806] Step 1. A glass reaction vessel was filled with tert-butyl(7-bromoisocyanate-4-yl)(methyl)carbamate (93) (0.310 g, 0.906 mmol), sodium methanesulfonate (0.555 g, 5.43 mmol, TCI, USA), ketone(i) (0.035 g, 0.181 mmol, Alfa Aesar), sodium (s)-pyrrolidine-2-carboxylate (0.025 g, 0.181 mmol, Combilot), and tripotassium phosphate (0.385 g, 1.812 mmol, Acros Organics) in dimethyl sulfoxide (4.53 mL). The reaction vessel was evacuated and then backfilled with argon (3x). The vial was sealed, and the reaction mixture was stirred and heated at 100 °C for 16 h. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by silica gel column chromatography (eluting with a 0-50% EtOAc gradient in heptane) to give tert-butylmethyl (7-(methanesulfonyl)isocyano-4-yl)carbamate as a colorless oil (0.202 g, 0.592 mmol, 65.3% yield). m / z (ESI): 342.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 7.83 (dd, J=8.2, 1.7Hz, 1H), 7.74 (br s, 1H), 7.41 (br dd, J=16.6, 7.8Hz, 1H), 5.28 (br s,1H),4.69-4.90(m,2H),3.89-4.08(m,2H),3.21(s,3H),2.57-2.73(m,3H),1.29-1.53(m,9H).

[0807] Step 2. Add tert-butylmethyl (7-(methanesulfonyl)isocyanate-4-yl)carbamate (0.200 g, 0.586 mmol) and trifluoroacetic acid (0.668 g, 0.4 mL, 5.86 mmol, Sigma-Aldrich) to a 50-mL round-bottom flask in dichloromethane (6 mL). Stir the resulting reaction mixture at rt for 4 h. Concentrate the reaction mixture under vacuum. Use the crude N-methyl-7-(methanesulfonyl)isocyanate-4-amine (95) without further purification in the next synthetic step. m / z (ESI): 242.0 (M+H)+ .

[0808] Intermediate 96: Methyl 6-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)nicotinate

[0809]

[0810] Step 1. Methyl 6-amino-2-chloronicotinic acid ester (50.0 mg, 0.268 mmol, Oram Pharmaceuticals, Inc.) was dissolved in acetonitrile (1340 μL) and N-bromosuccinimide (52.5 mg, 0.295 mmol, Sigma-Aldrich, Inc.) was added. The reaction was stirred for two hours until complete. The solution was concentrated and then water (15 mL) was added. The solid was filtered and washed with water, then air-dried to give methyl 6-amino-5-bromo-2-chloronicotinic acid ester (48.5 mg, 0.183 mmol, 68.2% yield). m / z (ESI): 265.0, 267.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 8.16 (s, 1H), 7.14-7.88 (m, 2H), 3.78 (s, 3H).

[0811] Step 2. Methyl 6-amino-5-bromo-2-chloronicotinate (6.70 g, 25.2 mmol), bis(pinacolyl)diboron (7.69 g, 30.3 mmol, Sigma-Aldrich), 1,1'-bis(diphenylphosphino)ferrocene-palladium chloride (2.061 g, 2.52 mmol, Strem Chemicals), and potassium acetate (9.91 g, 101 mmol, Sigma-Aldrich) were added to a flask containing degassed dioxane (84 mL). The mixture was heated at 80 °C for 7.5 hours. The reaction mixture was cooled, filtered, and washed with ethyl acetate on a diatomaceous earth mat. The filtrate was then concentrated and purified by medium-pressure chromatography (silica, 0 to 50% EtOAc:hexane) to give methyl 6-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)nicotinate (96) (4.50 g, 14.40 mmol, 57.1% yield). m / z (ESI): 313.0 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δppm 8.14-8.25 (m, 1H), 3.78 (s, 3H), 1.32 (s, 12H).

[0812] Intermediate 97: 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid.

[0813]

[0814] Step 1. Add methyl 4-amino-3-bromobenzoate (4 g, 17.39 mmol, Combilot) and bis(pinacol)diboron (8.83 g, 34.8 mmol, Frontier Scientific) in 1,4-dioxane (58.0 mL). Add potassium acetate (5.12 g, 52.2 mmol, Sigma-Aldrich) to the solution and degas the mixture by bubbling with argon for 5 min. Then add [1,1'-bis(diphenylphosphine)ferrocene]palladium(ii) dichloride (1.420 g, 1.739 mmol, Strehm Chemicals) in combination with dichloromethane. The reaction is then stirred at 100 °C. After 18 h, the reaction is cooled, and the solid is filtered under vacuum and washed with DCM. The mother liquor is concentrated to give a semi-solid residue. DCM is added, and the resulting solid is collected by vacuum filtration. The mother liquor was concentrated again, and this step was repeated. The desired gray solid methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate was isolated (2.6 g, 9.38 mmol, 54.0% yield). m / z (ESI): 196.1 (M+H) + (Boric acid). 1 ¹H NMR (400MHz, chloroform-d) δppm 8.33 (d, J = 2.1Hz, 1H), 7.90 (dd, J = 8.6, 2.2Hz, 1H), 6.57 (d, J = 8.5Hz, 1H), 5.20 (br s, 2H), 3.87 (s, 3H), 1.37 (s, 12H).

[0815] Step 2. Add DIPEA (0.943 mL, 5.40 mmol) to a stirred solution of 4-oxotetrahydrofuran-3-carboxynitrile (0.500 g, 4.50 mmol) in dichloromethane (5.00 mL) and cool the reaction mixture to -78 °C. Then, at -78 °C, add trifluoromethanesulfonic anhydride (0.760 mL, 4.50 mmol) dropwise for 1 min while stirring the reaction mixture at the same temperature for 15 min. After the reaction is complete, dilute the reaction mixture with water, separate the organic layer, wash with brine (2 x 10 mL), dry with sodium sulfate, and concentrate to give crude 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (1.05 g, 4.32 mmol, 96% yield), which is used in the next step without further purification.

[0816] 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) + . 1 ¹H NMR (400MHz, TFA-d) δppm 8.59-8.67 (2H, m), 7.97 (1H, d, J = 9.3Hz), 5.94 (2H, t, J = 3.5Hz), 5.65 (2H, t, J = 3.4Hz), 4.24 (3H, s). Note: For some heterocycles in Table 7, Pd(dppf)Cl₂ is used instead of Pd(PPh₃)₄.

[0817] 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 then 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 (97) (28 g, 122 mmol, 99% yield) as a grayish-white solid. m / z (ESI): 231.2 (M+H) + . 1HNMR (400MHz, DMSO-d) δppm 12.83 (1H, s), 7.88-8.30 (2H, m), 7.59 (1H, d, J = 8.8Hz), 7.02 (2H, s), 5.40 (2H, t, J = 3.5Hz), 5.03 (2H, t, J = 3.6Hz).

[0818] The acids in Table 7 are prepared in a manner similar to that described for intermediate 97.

[0819] Table 7

[0820]

[0821]

[0822]

[0823]

[0824] Intermediate 129: 4-amino-7-cyano-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate

[0825]

[0826] Step 1. 4-Amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (103) (500 mg, 1.89 mmol, 1.0 equivalent) was slurried in EtOH (9.45 mL) and sulfuric acid (445 mg, 4.53 mmol, 2.4 equivalent, Sigma-Aldrich) was added. The reaction mixture was stirred under reflux for 2.5 days, then cooled, filtered, and washed with EtOH to give the desired sulfonate of the product. This salt was slurried in 2M ammonia in MeOH, then heated and concentrated. The residue was purified by medium-pressure chromatography (silica, 0 to 100% (3:1 EtOAc:EtOH):heptane) to give ethyl 4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid ester (235 mg, 0.803 mmol, 42.5% yield). m / z (ESI): 293.1 (M+H) + .

[0827] Step 2. Add methanesulfonate-(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (239 mg, 0.0301 mmol, 0.4 equivalents, Strehm Chemicals) and di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (1) to the reaction vial. 28 mg (0.0301 mmol, 0.4 equivalent, Strehm Chemicals), K4[Fe(CN)6].3H2O (159 mg, 0.376 mmol, 0.5 equivalent, Oakwood), and ethyl 4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate (220 mg, 0.752 mmol, 1 equivalent). The container was evacuated and backfilled with nitrogen (3x). Dioxane (1.25 mL) in water (1.25 mL) and 0.05 M KOAc (1.88 mL, 0.094 mmol, 0.125 equivalent, Sigma-Aldrich) were added to the reaction via syringe, and the reaction vial was stirred at 100 °C for 2.5 h. The reaction was cooled and then extracted between EtOAc (2 x 50 mL) and brine (30 mL). The combined organic layers were dried over magnesium sulfate, and the residue was purified by medium-pressure chromatography (silica, 0 to 100% (3:1 EtOAc:EtOH):heptane) (2x) to give ethyl 4-amino-7-cyano-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate (12.0 mg, 0.042 mmol, 5.64% yield). m / z (ESI): 284.1 (M+H) + .

[0828] Step 3. Lithium hydroxide monohydrate (3.56 mg, 0.085 mmol, 2.0 equivalent, Sigma-Aldrich) was added to a suspension of ethyl 4-amino-7-cyano-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate (12.0 mg, 0.042 mmol, 1.0 equivalent) in MeOH (0.15 mL), THF (0.15 mL), and water (0.15 mL). The mixture was heated to 60 °C for 18 hours and then cooled to rt. An additional 4.0 equivalent of LiOH was added and the reaction was stirred for another 2.5 hours. The organic solvent was removed under vacuum and the resulting aqueous solution was adjusted to pH 3 with 2N HCl solution. The resulting suspension was filtered, washed with water, and air-dried to give 4-amino-7-cyano-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate (129) (10.0 mg, 0.034 mmol, 81% yield). m / z (ESI): 256.2 (M+H) + .

[0829] Intermediate 130: 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentan[c][1,8]naphthyl-2-carboxylic acid.

[0830]

[0831] Step 1. A mixture of methyl 2-oxocyclopentane carboxylate (1.0 g, 0.877 mL, 7.03 mmol, Matrix Scientific) and 1,1'-dimethyltriethylamine (1.000 g, 1.352 mL, 7.74 mmol, Sigma-Aldrich) in DCM (15 mL) was cooled to -78 °C, and trifluoromethanesulfonic anhydride (7.03 mL, 7.03 mmol, Sigma-Aldrich) was added. After the addition was complete, the mixture was stirred at -78 °C for 5 min, then the dry ice bath was removed and the reaction mixture was stirred at rt. After 15 min, the mixture was concentrated to give methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate as a pale yellow solid in quantitative yield, used as is. m / z (ESI): 275 (M+H) + .

[0832] Step 2. A mixture of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-en-1-carboxylate (1.982 g, 7.23 mmol), (2-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (1.70 g, 8.67 mmol), tripotassium phosphate (3.78 g, 21.69 mmol, Acros Corporation), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.177 g, 0.217 mmol, Strem Chemicals) in dichloromethane in 1,4-dioxane / water (10 / 0.60 mL) was heated at 80 °C for 1 h. The reaction was allowed to complete and cooled to rt and diluted with EtOAc. A precipitate corresponding to the desired product was formed. The precipitate was filtered and washed with EtOAc to produce methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,8]naphthyl-2-carboxylate in quantitative yield as a light gray solid. m / z (ESI): 245 (M+H) + . 1H NMR (400MHz, DMSO-d6) δppm 11.93-12.58(m,1H),8.96(d,J=2.1Hz,1H),8.33(d,J=2.1Hz,1H),3.89(s,3H),3.13(br t,J=7.6Hz,2H),2.78(br t,J=7.3Hz,2H),2.08-2.18(m,2H).

[0833] Step 3. A mixture of methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,8]naphthyl-2-carboxylate (1.76 g, 7.21 mmol) in POCl3 (24.68 g, 15 mL, 161 mmol, Sigma-Aldrich) was heated to reflux for 30 min. After the reaction was complete, the reactants were carefully added to a cold, saturated aqueous solution of NaHCO3 to alkalize them. After stirring for 15 min, the mixture was extracted with EtOAc, and the combined organic matter was concentrated to give methyl 6-chloro-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate as a yellow solid in quantitative yield. m / z (ESI): 263 (M+H) + .

[0834] Step 4. DIPEA (2.79 g, 3.77 mL, 21.58 mmol, Sigma-Aldrich) was added to a suspension of methyl 6-chloro-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate (1.89 g, 7.19 mmol) in DMSO (15 mL), followed by (2,4-dimethoxyphenyl)methylamine (1.564 g, 1.405 mL, 9.35 mmol, Sigma-Aldrich). The resulting mixture was heated at 90 °C overnight. The reaction was cooled to room temperature, diluted with water, washed with saturated NH4Cl, and extracted with EtOAc. The combined organic compounds were dried over Na₂SO₄, filtered, and concentrated to give methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate (2.18 g, 5.54 mmol, 77% yield) as a yellow solid, and used as is. m / z (ESI): 394 (M+H) + .

[0835] Step 5. Add 1N NaOH (10 mL, 10.00 mmol) to a solution of methyl 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate (2.18 g, 5.54 mmol) in THF / MeOH (10 / 10 mL), and heat the resulting solution at 70 °C for 2 h. Cool the reaction mixture to rt and acidify with 10 mL of 1M HCl. A pale yellow precipitate forms, which is filtered off and azeotropically dried over toluene to give 6-((2,4-dimethoxybenzyl)amino)-8,9-dihydro-7H-cyclopentane[c][1,8]naphthyl-2-carboxylate salt (130) as a yellow solid (1.44 g, 3.46 mmol, 62.5% yield). m / z (ESI): 380.2 (M+H) + .

[0836] The intermediates in Table 8 are prepared in a manner similar to that described for intermediate 130. Intermediate 132 follows the same process up to step 4.

[0837] Table 8

[0838]

[0839] Intermediate 133: 4-amino-7-fluoro-3-methylisoxazolo[4,5-c]quinoline-8-carboxylic acid

[0840]

[0841] Step 1. At 100 °C, anisole (209 g, 1.93 mol, 210 mL) was added dropwise to a mixture of methyl 7-fluoro-4-((4-methoxybenzyl)amino)-3-methylisoxazolo[4,5-c]quinoline-8-carboxylate (132) (17.6 g, 44.6 mmol) in TFA (210 mL). The mixture was stirred at 100 °C for 12 hours, and then the reaction mixture was concentrated. The crude product was milled with MTBE (50.0 mL) at 25 °C for 20 min, filtered, and the filter cake was dried to give methyl 4-amino-7-fluoro-3-methylisoxazolo[4,5-c]quinoline-8-carboxylate (16.0 g, 43.0 mmol, 96.6% yield, TFA) as a white solid. m / z (ESI): 276.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 8.57 (d, J = 7.60 Hz, 1H), 7.92-7.88 (m, 1H), 7.43 (d, J = 12.8 Hz, 1H), 3.90 (s, 3H), 2.69 (s, 3H).

[0842] Step 2. At 20°C, LiOH·H₂O (2.93 g, 69.9 mmol) was added to a solution of methyl 4-amino-7-fluoro-3-methylisoxazolo[4,5-c]quinoline-8-carboxylate (16.0 g, 43.0 mmol, TFA) in THF (96.0 mL), MeOH (48.0 mL), and H₂O (48.0 mL). The mixture was stirred at 75°C for 2 hours, and then additional LiOH·H₂O (362 mg, 8.63 mmol) was added at 20°C, and the mixture was stirred at 75°C for 5 hours. The reaction mixture was filtered and the filter cake was dried. The crude product was milled with MeCN (120 mL) for 30 min at 20°C. The reaction mixture was filtered and the filter cake was dried to give 4-amino-7-fluoro-3-methylisoxazolo[4,5-c]quinoline-8-carboxylic acid (133) as a white solid (5.10 g, 19.5 mmol, 45.4% yield, 99.1% purity). m / z (ESI): 261.9 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 8.26 (d, J = 7.60 Hz, 1H), 7.12 (d, J = 1 Hz, 1H), 6.91 (s, 2H), 2.66 (s, 1H).

[0843] Intermediate 134: 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid

[0844]

[0845] Step 1. At room temperature under a N2 atmosphere, methyl 2-hydroxyacetate (42.4 mL, 555 mmol, 1.0 equivalence) was added to a suspension of sodium hydride (11.10 g, 278 mmol, 0.5 equivalence, 60% in mineral oil) in anhydrous tetrahydrofuran (250 mL). The mixture was then slowly added to the reaction mixture (E)-but-2-acrylonitrile (54.5 mL, 666 mmol, 1.0 equivalence) at 65 °C, and stirred at the same temperature for 2 h. The reaction mixture was cooled, quenched with 2N NaOH solution (250 mL), and extracted with diethyl ether (500 mL). The aqueous layer was acidified with concentrated HCl to adjust the pH to approximately 1 and extracted with dichloromethane (2 x 500 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (230-400 mesh) using 10% ethyl acetate with hexane as the eluent to give 2-methyl-4-oxotetrahydrofuran-3-carboxynitrile (22 g, 176 mmol, 32% yield) as a brown solid. m / z (ESI, negative): 124.3 (MH) - . 1 ¹H NMR (400MHz, chloroform-d): δppm 4.40-4.27 (m, 2H), 4.26-4.19 (m, 1H), 3.24-2.99 (m, 1H), 1.61 (dd, J = 18.6, 6.2Hz, 3H).

[0846] Step 2. At -78°C, DIPEA (69.8 mL, 400 mmol, 2.0 equivalent) and trifluoromethanesulfonic anhydride (47.1 mL, 280 mmol, 1.4 equivalent) were added to a stirred solution of 2-methyl-4-oxotetrahydrofuran-3-carboxynitrile (25.0 g, 200 mmol, 1.0 equivalent) in dichloromethane (500 mL) and stirred for 15 min at the same temperature. The reaction mixture was quenched by the slow addition of water (250 mL), and after reaching room temperature, it was extracted with dichloromethane (2 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was stirred and filtered in diethyl ether. The mother liquor was concentrated under reduced pressure to give 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (35.0 g, crude) as a light brown adduct. This crude substance was used in the next step without further purification. m / z (ESI): 257.1 [non-ionizing].

[0847] Step 3. Under a nitrogen atmosphere, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate (37.7 g, 136 mmol, 1.0 equivalent) and potassium 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, and then PdCl2(dppf)-DCM adduct (9.96 g, 13.61 mmol, 0.1 equivalent) was added. The reaction mixture was then heated at 90 °C for 16 h. The reactants were concentrated under reduced pressure to give the crude product. The crude residue was purified by silica gel column chromatography (60-120 mesh) using 50% ethyl acetate with hexane as the eluent to give methyl 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylate as a brown solid (25 g, 97 mmol, 71% yield). m / z (ESI): 259.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6): δ8.11(d,J=2.0Hz,1H),8.00(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.8Hz,1H ), 6.87 (s, 2H), 4.11 (q, J = 5.3Hz, 1H), 3.87 (s, 2H), 3.17 (d, J = 5.3Hz, 3H), 1.41 (d, J = 5.9Hz, 3H).

[0848] 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-dihydrofuran[3,4-c]quinoline-8-carboxylic acid (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 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 4-amino-3-methyl-1,3-dihydrofuran[3,4-c]quinoline-8-carboxylic acid (134) as a grayish-white solid (17.5 g, 71.6 mmol, 71% yield). m / z (ESI): 245.1 (M+H) + . 1H NMR (TFA, 400MHz): δ (ppm) 8.68 (t, J = 6.2Hz, 2H), 8.01 (dd, J = 9.1, 4.2Hz, 1H), 6.15 (s, 1H), 5.94 (m, 2H), 1.86 (t, J = 5.4Hz, 3H)

[0849] Step 5. Chiral SFC separation: 44.5 g of racemic 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid was separated by chiral SFC to obtain 14 g of each isomer. Stereochemistry was assigned arbitrarily. Peak 1 was designated as (S)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (135) and peak 2 was designated as (R)-4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (136).

[0850] Separate information:

[0851] 1 instrument SFC 200 2 column ChiralPak-IC (250x30mm, 5μm) 3 mobile phase <![CDATA[Liquid CO₂: 0.5% DEA in methanol (40:60)]]> 4 Flow rate 100mL / min 5 pressure drop 130 bar 6 BPR 100 bar 7 UV detector wavelength 210nm 8 Dissolve Dissolve 14.0g of 2% DEA in 280mL of methanol.

[0852] The acids in Table 9 are prepared in a manner similar to that described for intermediate 134.

[0853] Table 9

[0854]

[0855] Intermediate 143: 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0856]

[0857] Step 1. Add K3PO4·H2O (1.08 g, 4.70 mmol, Sigma-Aldrich), X-Phos (0.08 g, 0.16 mmol, Sigma-Aldrich), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.14 mg, 0.16 mmol, Sigma-Aldrich), 1-methyl-5-(4 4,5,5-Tetramethyl-1,3,2-dioxane-2-yl)-1h-pyrazol-4-carboxynitrile (1.10 g, 4.70 mmol, Enamine) and methyl 4-amino-5-bromo-2-(trifluoromethyl)benzoate (0.700 g, 2.349 mmol, Combilot) were suspended in a degassed mixture of water (1.0 mL) and 1,4-dioxane (5.0 mL) and stirred overnight at 60 °C, followed by stirring at 90 °C for 18 h. The volatiles were removed under vacuum, and the crude product was purified by silica gel column chromatography (0 to 5% MeOH / DCM + 0.5% NH3 / MeOH) to produce methyl 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate as a light brown solid (0.63 g, 1.94 mmol, 83% yield). m / z (ESI): 324.8 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 8.74 (s, 1H), 8.35 (s, 1H), 7.89 (s, 1H), 7.58 (bs, 2H), 4.45 (s, 3H), 3.91 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δppm-58.06.

[0858] 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 4-amino-1-methyl-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate lithium hydroxide (143) (585 mg, 1.720 mmol, 91% yield), which was used directly in subsequent steps without further purification. m / z (ESI): 310.9 (M+H) + .1 H NMR (400MHz, DMSO-d6) δppm 8.33 (s, 1H), 8.26 (s, 1H), 7.68 (s, 1H), 7.03 (br s, 2H), 4.38 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δppm-57.47.

[0859] Intermediate 144: 4-amino-6-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0860]

[0861] Intermediate 144 was prepared in a manner similar to that of intermediate 143 described above, with m / z (ESI): 261.0 (M+H). + .

[0862] Intermediate 145: Lithium 4-amino-1H-pyrazolo[4,3-c]quinoline-8-carboxylate

[0863]

[0864] Step 1. Methyl 4-amino-3-(4,4,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate (886 mg, 3.2 mmol), 5-bromo-1h-pyrazol-4-carboxynitrile (500 mg, 2.9 mmol), K3PO4 hydrate (2.68 g, 11.6 mmol), and Pd(amphos)Cl2 (144 mg, 0.20 mmol) were suspended in degassed water (2 mL) and 1,4-dioxane (8.00 mL) and stirred overnight at 90 °C, at which point an orange-beige solid was formed. Water (20 mL) was added, and the mixture was then cooled to rt and the precipitate was filtered to produce methyl 4-amino-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (230 mg, 0.949 mmol, 32.7% yield). m / z (ESI): 243.0 (M+H) + .

[0865] Step 2. Methyl 4-amino-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (230 mg, 0.95 mmol) and lithium hydroxide hydrate (80 mg, 1.90 mmol, Sigma-Aldrich) were suspended in water (0.6 mL), methanol (0.6 mL), and tetrahydrofuran (0.6 mL) and stirred at 50 °C for 90 min. Volatiles were removed under vacuum to produce lithium 4-amino-1H-pyrazolo[4,3-c]quinoline-8-carboxylate hydroxide (145) (240 mg, 0.930 mmol, 98% yield). m / z (ESI): 229.0 (M+H) + .

[0866] The following amines in Table 10 are prepared in a manner similar to that described for intermediate 145.

[0867] Table 10

[0868]

[0869]

[0870] Intermediate 150: 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0871]

[0872] Step 1. Under rt, bromine (5.01 mL, 97.0 mmol, 3.0 equivalence) and sodium acetate (10.6 g, 130 mmol, 4.0 equivalence) were added to a solution of ethyl 5-methyl-1H-pyrazole-4-carboxylate (5.00 g, 32.4 mmol, 1.0 equivalence, Combibloc) in acetic acid (100 mL). The reaction mixture was then stirred and heated for 16 h. The reaction was slowly quenched with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give pure crude ethyl 3-bromo-5-methyl-1H-pyrazole-4-carboxylate (4.80 g, 20.6 mmol, 63.5% yield). m / z: 230.8, 232.9 (M+H) + .

[0873] Step 2. At 0 °C, dihydropyran (2.26 mL, 24.7 mmol, 1.2 equivalents) and toluenesulfonic acid (0.78 g, 4.12 mmol, 0.2 equivalents) were added to a stirred solution of ethyl 3-bromo-5-methyl-1H-pyrazole-4-carboxylate (4.80 g, 20.6 mmol, 1.0 equivalent) in dichloromethane (15 mL). The resulting reaction mixture was stirred for 16 h until complete. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aqueous brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude substance was purified by chromatography (silica gel, 40% ethyl acetate in hexane) to give ethyl 3-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate as a colorless, viscous liquid (4.80 g, 15.1 mmol, 73.5% yield). m / z: 314.9, 317.0 (M+H) + .

[0874] Step 3. Ethyl 3-bromo-5-methyl-1-(tetramethyl-1,3,2-dioxane-2-yl)benzoate (7.34 g, 26.5 mmol, 1.2 equivalents) was added to a stirred solution of methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-pyrazole-4-carboxylate (7.00 g, 22.1 mmol, 1.0 equivalents) and tripotassium phosphate (9.36 g, 44.1 mmol, 2.0 equivalents) in 1,4-dioxane (112 mL) and water (28.0 mL), and the mixture was purged with nitrogen for 10 min at room temperature. Then, Pd(amphos)Cl2 adduct (0.781 g, 1.10 mmol, 0.05 equivalents) was added, and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 7.00 g of crude ethyl 5-(2-amino-5-(methoxycarbonyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate.

[0875] DBU (2.00 mL, 13.3 mmol, 12 equivalents) was added to a stirred solution of ethyl 5-(2-amino-5-(methoxycarbonyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (600 mg, 1.55 mmol, 1.0 equivalent) in 1,4-dioxane (9.60 mL) and water (2.40 mL) at room temperature under nitrogen atmosphere, and the reaction mixture was heated to 90 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, 5% MeOH in DCM) to give pure methyl 4-hydroxy-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (220 mg, 0.644 mmol, 41.6% yield). m / z: 377.1 (M+H) + (MW-THP group).

[0876] Step 4. A stirred solution of methyl 4-hydroxy-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (600 mg, 1.76 mmol, 1.0 equivalent) in dichloromethane (3.00 mL) was added. Trifluoromethanesulfonic anhydride (992 mg, 3.52 mmol, 2.0 equivalent) and DIPEA (921 μL, 5.27 mmol, 3.0 equivalent) were then added, and the reaction mixture was maintained at 30°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-pyran-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate.

[0877] DIPEA (332 μL, 1.90 mmol, 3.0 equivalent) was added to a stirred solution of crude methyl 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (300 mg, 0.634 mmol, 1.0 equivalent) in N,N-dimethylacetamide (2.00 mL). Then (4-methoxyphenyl)methylamine (130 mg, 0.950 mmol, 1.5 equivalent) was added, and the reaction mixture was heated at 90 °C for 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, 50% EtOAc:hexane) to give pure methyl 4-((4-methoxybenzyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (250 mg, 0.543 mmol, 86.0% yield). m / z: 377.1 (M+H) + (MW-THP group).

[0878] Step 5. A solution of methyl 4-((4-methoxybenzyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (2.80 g, 6.08 mmol, 1.0 equivalent) in trifluoroacetic acid (28.0 mL) was heated at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give crude methyl 4-amino-3-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (3.50 g, 13.7 mmol, 225% crude yield). m / z: 257.3 (M+H) + .

[0879] Step 6. 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 (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 rt 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 (150) (1.40 g, 5.78 mmol, 42.3% yield). m / z: 243.1 (M+H) + .

[0880] The following amines in Table 11 are prepared in a manner similar to that described for intermediate 150.

[0881] Table 11

[0882]

[0883] Intermediate 152: 2-amino-3-iodoquinoline-6-carboxylic acid

[0884]

[0885] Step 1. At 0 °C, LHMDS (423 mL, 423 mmol) was added to a stirred solution of diethyl(cyanomethyl)phosphonate (45.7 mL, 282 mmol) in tetrahydrofuran (1000 mL) and stirred for 30 min. N-iodosuccinimide (95 g, 423 mmol) was added to the reaction mixture and stirred at rt for 3 h. The reaction mixture was quenched with 3 M HCl solution and extracted with DCM. The combined organic layers were washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude diethyl(cyanoiodomethyl)phosphonate (90 g, 297 mmol, 105% yield) as a brownish-brown oil. m / z (ESI): 303.9 (M+H) + .

[0886] Step 2. At 0 °C, diethyl(cyanoiodomethyl)phosphonate (178 g, 586 mmol) in THF (500 mL) was slowly added to a stirred solution of sodium hydride (39.1 g, 977 mmol) in THF (500 mL). The reaction mixture was stirred at 0 °C for 30 min. Then, methyl 4-amino-3-carboxybenzoate (70 g, 391 mmol) in THF (500 mL) was slowly added at 0 °C, and the mixture was stirred at RT for 16 h. After the reaction was complete, ice water was added. The precipitated solid was filtered and washed with diethyl ether to give methyl 2-amino-3-iodoquinoline-6-carboxylate (90 g, 274 mmol, 70.2% yield) as a pale yellow solid.

[0887] Step 3. LiOH H2O (128 g, 3048 mmol) was added to a stirred solution of methyl 2-amino-3-iodoquinoline-6-carboxylic acid ester (250 g, 762 mmol) in water (1000 mL): tetrahydrofuran (1000 mL): methanol (1000 mL), and the reaction mixture was heated at 50 °C for 2 h. After the reaction was complete, the reaction mixture was concentrated and diluted with water until the lithium salt of the acid was completely dissolved, and the aqueous layer was acidified to pH 5.0 with 1.5 N HCl. The obtained solid was filtered, washed with water (1000 mL) and methanol (1000 mL), and dried under vacuum overnight to give 2-amino-3-iodoquinoline-6-carboxylic acid (152) (230 g, 732 mmol, 96% yield) as a grayish-white solid. m / z (ESI): 314.9 (M+H) + . 1 H NMR (400MHz, DMSO-d6): 12.84 (1H, s), 8.76 (1H, s), 8.31 (1H, d, J = 2.0 Hz), 7.99 (1H, dd, J = 8.7, 2.0 Hz), 7.49 (1H, d, J = 8.8 Hz), 6.87 (2H, s).

[0888] Example 200: (S)-4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0889]

[0890] A mixture of lithium 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (118) (0.050 g, 0.188 mmol), (S)-N-cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (32) (0.055 g, 0.225 mmol), TBTU (0.072 g, 0.225 mmol, Sigma-Aldrich), and TEA (0.079 mL, 0.564 mmol, Sigma-Aldrich) in N,N-dimethylacetamide (1 mL) was stirred at rt for 12 hours. The reaction mixture was purified directly on ISCO (using 0–100% EtOAc / EtOH (3:1) in heptane) to give (S)-4-amino-N-cyclopropyl-7-fluoro-1-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (200) (0.023 g, 0.047 mmol, 25.2% yield). m / z (ESI): 486.3 (M+H) + .1 ¹H NMR (400MHz, chloroform-d) δppm 8.15-8.37 (m, 1H) 7.98 (s, 1H) 7.50-7.65 (m, 1H) 7.34-7.47 (m, 1H) 7.25-7.28 (m, 1H) 7.10-7.19 (m, 1H) 6.11-6.39 (m, 1H) 5.44-5.80 (m, 2H) 4.58-5.01 (m, 2H) 4.46 (s, 3H) 2.49-2.85 (m, 1H) 0.28-0.61 (m, 2H) 0.06-0.27 (m, 2H). 19 F NMR (376MHz, DMSO-d6) δppm-67.16 (s, 3F), -117.06 (s, 1F).

[0891] The examples in Table 12 were prepared using the amide coupling reagents shown in the table in a manner similar to that described above for Example 200.

[0892] Table 12

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926] Examples 317 and 318: 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide

[0927]

[0928] Step 1. Add N-ethyl-N-isopropylpropyl-2-amine (92 mg, 0.124 mL, 0.709 mmol, Sigma-Aldrich) to a stirred mixture of 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (97) (82 mg, 0.355 mmol), N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (12) (77 mg, 0.355 mmol), and tripyrrolylphosphonium hexafluorophosphate bromide (331 mg, 0.709 mmol, Sigma-Aldrich) in DMA (2 mL). Stir the resulting mixture at rt for 1.5 h. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH (containing 0.5% ammonium hydroxide) / DCM (0 to 12%) on a 12-g ISCO gold column) to give 468 mg of impure 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide as an almost colorless film. m / z (ESI): 430.15 (M+H) + .

[0929] Step 2. The racemic compound was purified by preparative SFC (using a Chiralpak AS-H column with a mobile phase of 80% liquid CO2 and 20% MeOH containing TEA at a flow rate of 80 mL / min). The more potent (measured by IC50 in the HCT116 MTAP ineffective cell viability assay) enantiomer was designated as (S)-; the less potent (measured by IC50 in the HCT116 MTAP ineffective cell viability assay) enantiomer was designated as (R)-. The first elution peak was (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (317) (62 mg, 0.144 mmol, 40.7% yield), white solid. 1 ¹H NMR (methanol-d⁴, 400MHz) δ 7.83 (s, 1H), 7.6–7.7 (m, 3H), 7.28 (br d, 1H, J = 7.7 Hz), 7.12 (s, 1H), 5.45 (t, 2H, J = 3.2 Hz), 5.13 (t, 2H, J = 3.4 Hz), 4.8–4.9 (m, 1H), 4.7–4.8 (m, 2H), 2.76 (s, 3H). 19F NMR (methanol-d4, 376 MHz) δ -63.86 (br s, 1F). The second elution peak was (R)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (318) (57 mg, 0.133 mmol, 37.4% yield), white solid. 1 ¹H NMR (methanol-d⁴, 400MHz) δ 7.85 (s, 1H), 7.6–7.8 (m, 3H), 7.28 (d, 1H, J = 7.5 Hz), 7.12 (s, 1H), 5.45 (br d, 2H, J = 3.1 Hz), 5.13 (t, 2H, J = 3.4 Hz), 4.86 (br s, 1H), 4.6–4.8 (m, 2H), 2.77 (s, 3H). 19 F NMR (methanol-d4, 376MHz) δ -63.89 (br s, 1F).

[0930] The examples in Table 13 were prepared using the amide coupling reagents and purification conditions shown in the table, in a manner similar to those described above for Examples 317 and 318.

[0931] Table 13

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994] Example 442: (S)-4-amino-7-chloro-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide

[0995]

[0996] Step 1. Add 4M HCl in 1,4-dioxane (5.67 mL, 22.67 mmol) to a stirred suspension of 4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (103) (2.00 g, 7.56 mmol) in DCM (20.0 mL), and stir the resulting suspension at room temperature for 30 min. Concentrate the mixture under reduced pressure and then co-evaporate with toluene (2 x 10 mL). Resuspend the obtained crude material in dichloromethane (80.0 mL), cool to 0 °C, and treat with oxaloyl chloride (2 M in DCM, 15.11 mL, 30.2 mmol), followed by treatment with DMF (15 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-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl chloride hydrochloride (2.42 g, 7.56 mmol, quantitative yield) as a brownish-red solid. After quenching the aliquot with MeOH, the m / z (ESI) of the corresponding methyl ester was observed to be 279.1(M+H)+.

[0997] Step 2. A mixture of 4-amino-7-chloro-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl chloride hydrochloride (0.140 g, 0.438 mmol), (S)-N-cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (32) (0.071 g, 0.292 mmol), and diisopropylethylamine (0.204 mL, 1.168 mmol, Sigma-Aldrich) in THF (3 mL) was stirred at rt for 2 hours. The reaction was concentrated and the crude mixture was purified by column chromatography (using 0–20% MeOH in DCM) to give (S)-4-amino-7-chloro-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (442) (0.035 g, 0.071 mmol, 24.48% yield). m / z (ESI): 490.11 (M+H) + . 1H NMR (400MHz, DMSO-d6) δppm 7.52-7.73 (m, 3H) 7.30 (d, J = 7.73Hz, 1H) 7.21 (s, 1H) 6.87 (br s, 2H) 5.94-6.16 (m, 1H) 5.33 (br s,2H)5.01(t,J=3.24Hz,2H)4.81-4.95(m,1H)4.62-4.79(m,1H)2.68(br d,J=1.88Hz,1H)0.02-0.51(m,4H). 19 F NMR (376MHz, DMSO-d6) δppm-60.68 (s, 3F).

[0998] The examples in Table 14 were prepared in a manner similar to that described for example 442. Enantiomers were synthesized using chiral starting materials.

[0999] Table 14

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024] Examples 522 and 523: 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide

[1025]

[1026] The acidic chloride used in step 1 was synthesized using the same method as that used in the synthesis of 442 in step 1.

[1027] Step 1. Add 4-amino-1,3-dihydrofuran-3-amine (12) (70.2 mg, 0.323 mmol) to an ice-cooled solution of N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (12) in DCM (1.5 mL) and THF (1.5 mL) with stirring. Then add N-ethyl-N-isopropylpropyl-2-amine (88 mg, 0.119 mL, 0.681 mmol, Sigma-Aldrich). Stir the resulting mixture at 0 °C for 5 min and then at rt for 1 h. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH (containing 0.5% ammonium hydroxide) / DCM (0 to 16%) on a 24-g ISCO gold column) to give 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide as a white solid (92 mg, 0.214 mmol, 62.8% yield). m / z (ESI): 431.05 (M+H) + . 1¹H NMR (methanol-d⁴, 400MHz) δ 8.8–9.0 (m, 1H), 7.8–8.0 (m, 1H), 7.6–7.7 (m, 1H), 7.2–7.3 (m, 1H), 7.0–7.1 (m, 1H), 6.0–6.6 (m, 1H), 5.45 (br s, 2H), 5.15 (t, 2H, J = 3.4Hz), 4.75 (br s, 2H), 2.80 (br d, 3H, J = 10.2Hz).

[1028] Step 2. 4-Amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide was resolved via a preparative SFC (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) to produce (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide (42.6 m... g, 0.099 mmol, 29.1% yield)(522) and (R)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide (44.7 mg, 0.104 mmol, 30.5% yield)(523), as the second eluted enantiomer, each as a white solid, >99% ee. 1 H NMR(DMSO-d6,500MHz)δ8.8-9.0(m,1H),7.8-7.9(m,1H),7.5-7.8(m,1H),7.32(br d,1H,J=7.3Hz),7.2-7.3(m,1H),7.05(br d,2H,J=13.0Hz),5.9-6.5(m,1H),5.38(br s,2H),5.05(br s,2H),4.6-4.9(m,2H),2.6-2.8(m,3H).

[1029] The examples in Table 15 were prepared in a manner similar to that described for examples 522 and 523.

[1030] Table 15

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073] Examples 608 and 609: 4-amino-N-(7-bromoisosperan-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide

[1074]

[1075] Step 1. Add N-ethyl-N-isopropyl-2-amine (128 mg, 0.173 mL, 0.991 mmol, Sigma-Aldrich) to a stirred mixture of 4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (131) (189 mg, 0.496 mmol), 7-bromo-N-methylisosperazine-4-amine (6) (120 mg, 0.496 mmol) and tripyrrolylphosphonium hexafluorophosphate bromide (462 mg, 0.991 mmol, Sigma-Aldrich) in DMA (1.5 mL). Stir the resulting mixture at rt for 1.5 h. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to combi-flash column chromatography (eluting with MeOH (containing 0.5% ammonium hydroxide) / DCM (0 to 12%) on a 12-g ISCO gold column) to give 200 mg of impure N-(7-bromoisocretin-4-yl)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide as a nearly colorless film. It was used in the next step without further purification. m / z (ESI): 604.15 and 606.10 (M+H) + .

[1076] Step 2. Under rt, 1,1,1-trifluoroacetic acid (7650 mg, 5 mL, 67.1 mmol, Sigma-Aldrich) was added dropwise to a stirred solution / suspension of N-(7-bromoisocyanate-4-yl)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (150 mg, 0.248 mmol) in DCM (6 mL) in a 20 mL microwave reaction vessel. The resulting mixture was stirred under rt for 5 min, then the vessel was sealed and subjected to microwave reaction conditions (75 °C, 40 min). Volatiles were removed and the residue was dissolved in MeOH / TFA and subjected to preparative reversed-phase HPLC (Gemini). TM Prep C18 10 μm column; Phenomenex; gradient elution of 10% to 85% MeCN in water, wherein both solvents contain 0.1% TFA for 15 min in a 24-min process, to give 55 mg of 4-amino-N-(7-bromoisocyanate-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide as a white solid as a TFA salt after lyophilization. m / z (ESI): 454.00 and 456.10 (M+H) + . 1H NMR (methanol-d4, 400MHz) δ7.9-8.0 (m, 2H), 7.8-7.9 (m, 1H), 7.49 (br d, 1H, J = 8.6Hz), 7.2-7.4 (m, 2H), 5.77 (br s, 1H), 5.54 (br d,2H,J=2.9Hz),5.20(t,2H,J=3.6Hz),4.78(br d,1H,J=5.4Hz),4.5-4.7(m,1H),3.9-4.4(m,2H),2.7-3.0(m,3H).

[1077] Step 3. The 4-amino-N-(7-bromoisocyanate-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide from Step 2 is processed via a preparative SFC (using Chiral Technologies). AS column (250x21mm, 5mm), mobile phase of 55% liquid CO2 and 45% MeOH containing 0.2% TEA, at a flow rate of 60 mL / min) was used to resolve to produce (S)-4-amino-N-(7-bromoisocretin-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (608) (20 mg, 0.044 mmol, 17.74% yield) as the first eluted enantiomer and (R)-4-amino-N-(7-bromoisocretin-4-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (609) (22 mg, 0.048 mmol, 19.51% yield) as the second eluted enantiomer, each as a grayish-white solid, >99% ee. 1 ¹H NMR (methanol-d⁴, 400MHz) δ 7.6–7.8 (m, 3H), 7.47 (br d, 1H, J = 7.5Hz), 7.1–7.4 (m, 2H), 4.9–5.8 (m, 5H), 4.5–4.8 (m, 2H), 4.0–4.3 (m, 2H), 2.8–2.9 (m, 3H).

[1078] Examples 610 and 611: 4-amino-N-(6-cyclopropyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide

[1079]

[1080] Step 1. To a mixture of 4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (203) (0.100 g, 0.227 mmol), cyclopropylboronic acid (0.098 g, 1.136 mmol, Combibloc), and toluene (2 mL) purged with Ar, add tripotassium phosphate monohydrate (0.157 g, 0.681 mmol, Sigma-Aldrich) and water (0.222 mL) and stir at rt for 10 min. Then add tricyclohexylphosphine (0.013 g, 0.045 mmol, Strehm Chemicals) and palladium(II) acetate (5.10 mg, 0.023 mmol, Sigma-Aldrich). Stir the mixture overnight at 90 °C in a sealed vial. The mixture was filtered through diatomaceous earth and concentrated under vacuum. The crude substance was purified by silica gel column chromatography, eluting with 0-100% 3 / 1 EtOAc / EtOH in heptane. Pure 4-amino-N-(6-cyclopropyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (0.073 g, 0.182 mmol, 80% yield) was given as a white solid. m / z (ESI): 402 (M+H) + . 1 H NMR (400MHz, methanol-d4) δppm 7.57-7.81(m,3H),7.06-7.33(m,1H),6.73(br d,J=7.9Hz,1H),6.48-6.62(m,1H),5.45(br s,2H),5.13(t,J=3.3Hz,2H),4.46-4.72(m,3H),2.62-2.78(m,3H),1.84-1.94(m,1H),0.91-1.01(m,2H),0.57-0.74(m,2H).

[1081] Step 2. Dissolve 70 mg of 4-amino-N-(6-cyclopropyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide in 7 mL of DCM:MeOH and pass it through a preparative SFC (using Chiralpak). The purification process was performed using an AS column (250 x 21 mm, 5 μm) with a mobile phase of 75% liquid CO2 and 25% methanol containing 0.2% TEA at a flow rate of 90 mL / min to produce a peak of 28.2 mg for 1,(S)-4-amino-N-(6-cyclopropyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (610), with an ee of >99% (chemical purity >99%) and a peak of 28.9 mg for 2,(R)-4-amino-N-(6-cyclopropyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (611), with an ee of 98.06% (chemical purity >99%).

[1082] The examples in Table 16 were prepared using the indicated purification conditions in a manner similar to that described above for examples 610 and 611.

[1083] Table 16

[1084]

[1085] The examples in Table 16 were prepared via step 1 in a manner similar to that described above for examples 610 and 611. Chiral SFCs were not used because these compounds were either isolated as racemic mixtures (614) or enantiomerically pure starting materials were used (615-621).

[1086] Table 17

[1087]

[1088]

[1089] Intermediate 622: (S)-N-(6-(1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)-4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[1090]

[1091] A mixture of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (234) (0.030 g, 0.066 mmol), (1H-pyrazol-4-yl)boronic acid (0.015 g, 0.133 mmol, AABlocks), dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane adduct (9.71 mg, 0.013 mmol, Strehm Chemicals), potassium carbonate (0.027 g, 0.199 mmol, Sigma-Aldrich), 1,4-dioxane (1.5 mL), and water (0.167 mL) was purged with argon and then stirred overnight at 95 °C in a sealed vial. The crude product was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under vacuum. The crude product was dissolved in DMF and purified by HPLC (using an XBridge column (19 x 100 mm, 5 μm) with 0.1% NH₄OH and ACN in H₂O as the mobile phase) to obtain (S)-N-(6-(1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)-4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (622) (1.8 mg, 4.10 μmol, 6.18% yield). m / z (ESI): 440.2 (M+H) + . 1 H NMR(500MHz,DMSO-d6)δppm 8.31(s,1H),8.26(s,1H),7.84-8.17(m,2H),7.57-7.68(m,3H),7.30-7.44(m,1H),7.22(br d,J=7.7Hz,1H),7.09-7.17(m,3H),5.63-6.44(m,1H),4.68(br s,2H),4.42(s,3H),2.68(s,3H).

[1092] The examples in Table 18 were prepared using the indicated purification conditions in a manner similar to that described above for example 622.

[1093] Table 18

[1094]

[1095] The examples in Table 19 were prepared using chiral starting materials in a manner similar to that described above for example 622.

[1096] Table 19

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107] Intermediates 663 and 664: (S)-4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyano-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide and (R)-4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyano-4-yl)-1H-pyrazol[4,3-c]quinoline-8-carboxamide

[1108]

[1109] Step 1. Add 4-amino-N-(7-bromoisocyanate-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (287) (0.080 g, 0.172 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1-(trifluoromethyl)-1h-pyrazole (0.090 g, 0.090 mL, 0.343 mmol, Enamine) and tripotassium phosphate (0.109 g, 0.515 mmol, Sigma-Aldrich) in toluene (0.772 mL) / water (0.086 mL) to a resealable vial. The reaction mixture was purged with argon (gas) for 5 min, then tricyclohexylphosphine (0.019 g, 0.069 mmol, Strem Chemicals) followed by palladium(II) acetate (7.70 mg, 0.034 mmol, Sigma-Aldrich) was added to the reaction mixture, and the vial was sealed. The reaction mixture was stirred and heated at 90 °C for 16 h. The reaction mixture was then cooled to rt and diluted with EtOAc and brine. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was diluted with DMSO (0.8 mL) and directly adsorbed onto a C18 column. It was then purified by chromatography using a 0-40% MeCN gradient in water (0.1% TFA) to give 4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyanan-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.094 mmol, 55.0% yield) as a white solid. 1 H NMR (400MHz, methanol-d4) δppm 8.61(br s,1H),8.55(s,1H),8.50(s,1H),8.25(br s,1H),7.93(br d,J=8.4Hz,1H),7.87(br s,1H),7.66(br d,J=7.1Hz,1H),7.48-7.56(m,1H),7.45(br s,1H),5.87(br s,1H),4.87-5.10(m,2H),4.57(br s,3H),4.37(br d,J=11.7Hz,1H),4.09-4.28(m,1H),2.85-3.02(m,3H). m / z(ESI):522.1(M+H) + .

[1110] Step 2. The 4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyanan-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate from Step 1 was resolved via a preparative SFC (using an AS-H column (25 x 2 cm), with a mobile phase of 77% liquid CO2 and 23% MeOH containing 0.2% TEA, at a flow rate of 60 mL / min) to produce (S)-4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyanan-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate as the first elution peak. (R)-4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyano-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (663) (21 mg, 0.040 mmol, 42.9% yield), with >99% ee, and (R)-4-amino-N,1-dimethyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)isocyano-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (664) (20 mg, 0.038 mmol, 40.8% yield), with 97.9% ee, as the second elution peak.

[1111] Intermediates 665 and 666: (R)-4-amino-7-fluoro-N-methyl-N-(7-(4-(trifluoromethyl)phenyl)isocyanan-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide and (S)-4-amino-7-fluoro-N-methyl-N-(7-(4-(trifluoromethyl)phenyl)isocyanan-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide

[1112]

[1113] Step 1. Fill a resealable vial with 4-amino-N-(7-bromoisocyanate-4-yl)-7-fluoro-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (273) (0.110 g, 0.233 mmol), boric acid, β-[4-(trifluoromethyl)phenyl]- (0.049 g, 0.256 mmol, AA Blocks), and potassium carbonate (0.097 g, 0.699 mmol, Oakwood Chemical Company). Purge the reaction mixture with argon for 5 min. Then add (1,1'-bis(diphenylphosphino)ferrocene)palladium dichlorochloride (0.034 g, 0.047 mmol, Combilot) to the reaction mixture and seal the vial. Stir and heat the reaction mixture at 90 °C overnight, then concentrate under vacuum. The crude material was adsorbed onto a silica gel stopper and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) (eluted with a 0-25% EtOAc:EtOH (3:1) gradient in heptane) to provide 4-amino-7-fluoro-N-methyl-N-(7-(4-(trifluoromethyl)phenyl)isocyanan-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (0.075 g, 0.140 mmol, 59.9% yield) as an off-white solid.

[1114] Step 2. The 4-amino-7-fluoro-N-methyl-N-(7-(4-(trifluoromethyl)phenyl)isocyanan-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide from Step 1 is processed via preparative SFC (using Chiralpak). IC column (3x15cm, 5µm), mobile phase 70% liquid CO2 and 30% ethanol containing 0.1% DEA, at a flow rate of 80mL / min) was used to resolve peak 1,(R)-4-amino-7-fluoro-N-methyl-N-(7-(4-(trifluoromethyl)phenyl)isocyanan-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (665) (35mg, 0.065mmol, 46.7% yield), with ee>99% and peak 2,(S)-4-amino-7-fluoro-N-methyl-N-(7-(4-(trifluoromethyl)phenyl)isocyanan-4-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (666) (33mg, 0.061mmol, 44.0% yield), with ee>99%.

[1115] The examples in Table 20 were prepared using the indicated purification conditions or enantiomeric intermediates in a manner similar to that described above for Examples 665 and 666.

[1116] Table 20

[1117]

[1118]

[1119] Intermediate 671: (S)-4-amino-N-(6-methoxy-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[1120]

[1121] Fill a small vial with a red cap (equipped with a Teflon-coated magnetic stir bar) with tbubrettphos (0.051 g, 0.105 mmol, Sigma-Aldrich), sodium tert-butoxide (0.017 g, 0.176 mmol, Sigma-Aldrich), and (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (234) (0.053 g, 0.117 mmol), t-bubrettphos Pd G3 (0.090 g, 0.105 mmol, Sigma-Aldrich), 1,4-dioxane (1 mL), and methanol (0.131 g, 0.166 mL, 4.10 mmol, Sigma-Aldrich). Purge the mixture with argon, seal, and stir overnight at room temperature. The crude product was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography using 0-100% EtOAc / EtOH (3 / 1) in heptane. A crude product as an orange solid was obtained. The product was dissolved in DMF and purified by HPLC (using an XBridge column (19 x 100 mm, 5 μm) with 0.1% NH4OH and ACN in H2O as the mobile phase) to obtain pure (S)-4-amino-N-(6-methoxy-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (671) (13.1 mg, 0.032 mmol, 27.7% yield). m / z (ESI): 404 (M+H) + . 1H NMR(500MHz,DMSO-d6)δppm 8.29(s,1H),8.25(s,1H),7.61(s,2H),7.21-7.35(m,1H),7.12(s,2H),6.53(br d,J=8.2Hz,1H),6.48(d,J=1.6Hz,1H),5.75(s,1H),4.67(br s,2H),4.41(s,3H),3.73(s,3H),3.31(s,1H),2.63-2.66(m,2H).

[1122] Intermediates 672 and 673: (S)-4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate and (S)-4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[1123]

[1124] Fill a small vial with a red cap (equipped with a Teflon-coated magnetic stir bar) with t-bu-brettphos (8.57 mg, 0.018 mmol, Sigma-Aldrich), sodium tert-butoxide (6.37 mg, 0.066 mmol, Sigma-Aldrich), and (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (234) (0.020 g, 0.044 mmol, 128130-16-1), t-bu-brettphos Pd G3 (0.015 g, 0.018 mmol, Sigma-Aldrich), 1,4-dioxane (1 mL), and cyclopropanol (0.090 g, 0.098 mL, 1.548 mmol, Combilot). The mixture was purged with argon, sealed, and stirred overnight at room temperature. The crude product was diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under vacuum, and purified by silica gel rapid column chromatography using 0-100% EtOAc / EtOH (3 / 1) in heptane. Both products obtained contained impurities. The solids were dissolved in DMF and purified by reversed-phase preparative HPLC (using 10%-70% water in CH3CN (containing 0.1% TFA) as the mobile phase. The second elution peak was (S)-4-amino-N-(6-cyclopropoxy-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate (672) (9.9 mg, 0.018 mmol, 41.2% yield), which was obtained as a white solid. m / z (ESI): 430 (M+H) + . 1 ¹H NMR (400MHz, methanol-d⁴) δppm 8.48-8.53 (m, 2H), 7.79-7.93 (m, 2H), 7.17-7.37 (m, 1H), 6.57-6.70 (m, 2H), 5.53-6.40 (m, 1H), 4.66-4.77 (m, 2H), 4.53-4.59 (m, 3H), 3.76 (br s, 1H), 2.68-2.85 (m, 3H), 0.75-0.83 (m, 2H), 0.64-0.71 (m, 2H). The first elution peak was the byproduct (S)-4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate (673) (6.7 mg, 0.014 mmol, 31.1% yield). m / z (ESI): 374 (M+H) + . 1H NMR (400MHz, methanol-d4) δppm 8.53(d,J=1.5Hz,1H),8.49(s,1H),7.87-7.94(m,1H),7.84(br s,1H),7.45(br s,1H),7.29(t,J=7.6Hz,1H),7.00(br t,J=7.5Hz,1H),6.87(br d,J=7.3Hz,1H),6.35-6.52(m,1H),4.68(br d,J=6.5Hz,2H),4.55(s,3H),2.70-2.85(m,3H).

[1125] The examples in Table 21 were prepared in a manner similar to that described above for examples 671-673.

[1126] Table 21

[1127]

[1128] Intermediate 679: (S)-4-amino-N,1-dimethyl-N-(2-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[1129]

[1130] A solution of (S)-4-amino-N-(2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (418) (25 mg, 0.053 mmol), trimethylcycloboroxane (13.43 mg, 14.99 μL, 0.107 mmol, Sigma-Aldrich), Pd(PPh3)4 (6.80 mg, 5.88 μmol, Sigma-Aldrich), and cesium carbonate (33.1 mg, 0.102 mmol, Sigma-Aldrich) in 1,4-dioxane (708 μL) and water (79 μL) was purged with argon and stirred overnight at 95 °C. The solution was then filtered through a syringe filter and diluted with DCM. The organic matter was washed with NaHCO3 and extracted with DCM. The organic matter was dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an SCX column and washed with MeOH. The crude product was then eluted with NH3 in MeOH (2M) and concentrated. HPLC purification was performed on an XBridge column (19 x 100 mm, 5 μm) (using 0.1% NH4OH and ACN in H2O as the mobile phase) to give (S)-4-amino-N,1-dimethyl-N-(2-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (679) (6.698 mg, 0.017 mmol, 31.1% yield). m / z (ESI): 403.2 (M+H) + . 1 HNMR(500MHz,DMSO-d6)δppm 8.32(d,J=1.6Hz,1H),8.25(s,1H),7.71(br d,J=6.5Hz,1H),7.58-7.67(m,2H),7.22(br d,J=7.5Hz,1H),7.12(s,2H),5.63-5.84(m,1H),4.46-4.79(m,2H),4.39(s,3H),4.01-4.23(m,2H),2.76(s,3H),2.40-2.55(m,2H).

[1131] The examples in Table 22 were prepared using the indicated purification conditions in a manner similar to that described above for Example 679. Example 681 is a byproduct of the reaction used to prepare Example 680.

[1132] Table 22

[1133]

[1134]

[1135] Intermediates 685 and 686: methyl(S)-3-(4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide)-2,3-dihydrobenzofuran-6-carboxylate and (S)-4-amino-N-(6-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[1136]

[1137] Step 1. A test tube equipped with a stir bar was filled with (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (234) (0.1553 g, 0.343 mmol), dimethyl sulfoxide (1.3 mL), dppf (0.029 g, 0.052 mmol, Sigma-Aldrich), palladium diacetate (9.25 mg, 0.041 mmol, Sigma-Aldrich), and methanol (0.660 g, 0.833 mL, 20.60 mmol, Sigma-Aldrich). The mixture was purged with CO (30 psi) and stirred at 80 °C for 20 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel chromatography using 0-100% EtOAc / EtOH (3 / 1) in heptane. A grayish-white solid of methyl (S)-3-(4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide)-2,3-dihydrobenzofuran-6-carboxylate (75 mg, 0.174 mmol, 50.6% yield) was obtained. m / z (ESI): 432 (M+H) + . 1 H NMR (400MHz, chloroform-d) δppm 8.41 (d, J = 1.7Hz, 1H), 7.98 (s, 1H), 7.90 (br dd,J=11.0,8.0Hz,2H),7.81(d,J=8.6Hz,1H),7.71(dd,J=7.8,1.1Hz,1H),7.63(dd,J=8.6,1.9Hz,1H),7.53(s,1H ),5.16-5.28(m,2H),4.74-4.85(m,1H),4.60(dd,J=10.5,4.2Hz,1H),4.50(s,3H),3.92(s,3H),2.74-2.83(m,3H).

[1138] Step 2. Add LAH (2.0 M in THF, 0.028 mL, 0.056 mmol, Sigma-Aldrich) dropwise to methyl (S)-3-(4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide)-2,3-dihydrobenzofuran-6-carboxylate (0.012 g, 0.028 mmol) in THF (1.5 mL) in an ice bath. After 30 min, quench the reaction with sodium sulfate decahydrate and dilute with EtOAc. Filter the solid and concentrate the filtrate under vacuum. The crude product was purified by HPLC (using an XBridge column (19 x 100 mm, 5 μm) with 0.1% NH4OH and ACN in H2O as the mobile phase) to yield (S)-4-amino-N-(6-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (686) (0.001 g, 0.002 mmol, 8.91% yield). m / z (ESI): 404 (M+H) + . 1 ¹H NMR (400MHz, methanol-d⁴) δppm 8.41-8.47 (m, 1H), 8.24 (s, 1H), 7.67-7.79 (m, 2H), 7.28-7.47 (m, 1H), 6.99 (brd, J = 7.7Hz, 1H), 6.84-6.92 (m, 1H), 4.54-4.73 (m, 5H), 4.49 (s, 3H), 2.74-2.83 (m, 3H).

[1139] Intermediate 687: (S)-4-amino-N-(6-chloro-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate

[1140]

[1141] Add nickel(II) chloride (9.71 mg, 0.075 mmol, Sigma-Aldrich) to a mixture of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (234) (0.0113 g, 0.025 mmol) and N,N-dimethylformamide (0.5 mL) in a microwave-safe vial to a dry box. Seal the vial and heat in a microwave reactor at 170 °C for 5 min. Add more nickel(II) chloride (9.71 mg, 0.075 mmol, Sigma-Aldrich) and reset the reaction to 170 °C for 1 h. Filter the crude product and purify by reversed-phase preparative HPLC (using 10%–90% water in MeCN (containing 0.1% TFA)). (S)-4-amino-N-(6-chloro-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 2,2,2-trifluoroacetate (687) was obtained as a white solid (7.5 mg, 0.014 mmol, 57.5% yield). m / z (ESI): 408 (M+H) + . 1 H NMR (400MHz, methanol-d4) δppm 8.53 (s, 1H), 8.51 (s, 1H), 7.91-7.94 (m, 1H), 7.85 (br d, J = 8.5Hz, 1H), 7.35-7.50 (m, 1H), 6.97-7.05 (m, 1H), 6.93 (br s,1H),6.37-6.48(m,1H),4.93-4.95(m,1H),4.73-4.75(m,1H),4.56(s,3H),2.80(br s,3H). 19 F NMR (377MHz, methanol-d4) δppm -77.03 (m, 3F).

[1142] Intermediate 688: (S)-4-amino-N,1-dimethyl-N-(6-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[1143]

[1144] A mixture of 10% palladium on carbon (0.102 g, 0.095 mmol, Sigma-Aldrich), (S)-4-amino-N-(6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydrobenzofuran-3-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (618) (0.0435 g, 0.095 mmol), and ethanol (4 mL) was purged with N2, followed by H2. The mixture was stirred overnight in a sealed vial (35 psi H2 pressure). The reaction was reset to 35 psi and stirred for 4 h. Stirring was stopped and the reactants were allowed to stand at rt for 2 days. The catalyst was then filtered through diatomaceous earth, the solids were washed with EtOAc / EtOH (3 / 1), and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography using 0-30%-100% EtOAc / EtOH (3 / 1) in heptane. (S)-4-amino-N,1-dimethyl-N-(6-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (688) (20.8 mg, 0.045 mmol, 47.6% yield) was separated as a grayish-white solid. m / z (ESI): 458 (M+H) + . 1 H NMR (400MHz, chloroform-d) δppm 8.39(d,J=1.7Hz,1H),7.94-7.99(m,1H),7.79(d,J=8.6Hz,1H),7.62(dd,J=8.6,1.9Hz,1H),7.26-7.34(m,1H),6.85(dd,J=7.7,1.0Hz,1H ),6.75(s,1H),5.13-5.26(m,2H),4.63-4.80(m,1H),4.55(d,J=4.0Hz,1H),4.52(d,J=4.0Hz,1H),4.49(s,3H),4.08-4.11(m,1H),4.06(br d,J=2.9Hz,1H),3.48-3.56(m,2H),2.77-2.83(m,3H),2.71-2.76(m,1H),1.73-1.86(m,4H).

[1145] Example 689: N-(6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)-4-amino-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide

[1146]

[1147] Step 1. Add 0.5 mL of TFA to a mixture of tert-butyl 4-(3-(4-amino-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide)-2,3-dihydrobenzofuran-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (614) (0.070 g, 0.129 mmol) and DCM (2 mL). Stir the mixture at rt for 1 h. Concentrate the mixture under vacuum to give the TFA salt of the product as a grayish-white solid. m / z (ESI): 443 (M+H) + .

[1148] Acetic anhydride (8.31 mg, 7.68 μL, 0.081 mmol, Sigma-Aldrich) was added to a mixture of 4-amino-N-methyl-N-(6-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (3.00 mg, 6.78 μmol), DIPEA (70.1 mg, 95.0 μL, 0.542 mmol, Sigma-Aldrich), DCM (1 mL), and DMF (0.1 mL). The mixture was stirred at rt for 3 h, concentrated under vacuum, and used directly for the next step. m / z (ESI): 527 (M+H) + .

[1149] Step 2. The crude 4-acetamido-N-(6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide was diluted with THF (0.9 mL), MeOH (0.9 mL), and water (0.4 mL) and treated with lithium hydroxide hydrate (17.1 mg, 0.406 mmol, Sigma-Aldrich). The mixture was stirred overnight at rt. The mixture was diluted with Na2CO3 and EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography using EtOAc / EtOH (3 / 1) (0-100%) in heptane as the mobile phase to give N-(6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)-4-amino-N-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (689) as a white solid (1.9 mg, 3.92 μmol, 57.8% yield). m / z (ESI): 485 (M+H) + . 1H NMR (400MHz, methanol-d4) δppm7.63-7.75(m,3H),7.28-7.43(m,1H),7.08(br d,J=7.7Hz,1H),6.84-6.98(m,1H),6.05-6.18(m,1H),5.45(br s,2H),5.13(t,J=3.4Hz,2H),4.53-4.68(m,2H),4.16-4.24(m,2H),4.02-4.12(m,1H),3.69-3.82(m,2H),2.69-2.81(m,3H),2.61(br s,1H),2.49-2.57(m,1H),2.16(d,J=14.5Hz,3H).

[1150] HCT116 proliferation activity

[1151] To evaluate the selective antiproliferative activity of the compounds of this invention in cells lacking MTAP expression, an HCT-116 allogeneic cell line pair was used, one of which was engineered to knock out two MTAP alleles. Cell viability was then assessed in both the parental HCT-116 cell line and the MTAP-nulling cell line after 6 days of treatment with the compounds of this invention. The selective antiproliferative activity in the MTAP-nulling cell line demonstrates the ability of PRMT5 to synergistically inhibit MTAP and suppress the growth of cancer cells lacking MTAP.

[1152] HCT116 MTAP-ineffective and WT cells were seeded 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-point serially diluted compounds (using the highest concentration of 1 μM or 10 μM, 1:3 serial dilution steps) and a control with DMSO only. Cells were incubated for 6 days in the presence of the drug. Use according to the manufacturer's recommendations. The effect of luminescent cell viability assay (Promega) on cell viability was measured. An ultrasensitive luminescence module was used at EnVision. TM The analysis panel is read on a multi-marker reader. IC is calculated using GraphPad Prism v 5.01 with a symmetric sigmoid dose-response least-squares fit (with a fixed Hill slope of -1 and a top constraint of 100%) or using GeneData Screener with a 4-parameter logistic model to fit the dose-response curve. 50 value.

[1153] Alternatively, compounds can be analyzed using a 384-well plate format:

[1154] The compound (serially diluted 22 times, using the highest concentration of 10 μM or 50 μM, 1:2 serial dilution steps) and a control of DMSO alone were pre-spotted into 384-well plates. Then, HCT116 MTAP-ineffective and WT cells were seeded as above, and after 6 days, [the cells were then treated with...]. The effect of luminescent cell viability assay (Promega) on cell viability was measured. The analysis panel was read as above, and the IC50 was calculated using a 4-parameter logistic model fitted to the dose-response curve using GeneData Screener. 50 Value. Reported IC 50 This indicates the value of the curve after a 50% control.

[1155] Table 23. HCT116-MTAP ineffectiveness and WT cell line proliferation

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163] All publications and patent applications cited in this specification are incorporated herein by reference in their entirety, and for all purposes are as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference, and as if each reference were fully expounded in its entirety. Although the foregoing invention has been described in considerable detail by way of illustration and example for purposes of clarity, it will be readily apparent to those skilled in the art, based on the teachings of the invention, that certain changes and modifications may be made to the invention without departing from the spirit or scope of the appended claims.

Claims

1. A compound having Formula I I Its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing; Where R is a tricycle independently selected from formula IA: IA in Is it a single bond or a double bond? X 1 and X 2 In each case, the substituents are independently selected from N and optionally substituted C, wherein the substituents on C are independently selected from C. 1-3 Alkyl, Halogenated, Halogenated C 1-3 Alkyl or -CN; Where X 1 and X 2 It cannot be N at the same time; X 3 X 4 and X 5 In each case, the C, O, and N are independently selected from those that are optionally substituted, wherein the substituents on C and N are independently selected from C. 1-3 Alkyl and C 1-3 Alkyl-OH, wherein the alkyl group may optionally be halogenated; Where R 1 It is a double ring independently selected from formulas IB, IC, and ID, which is optionally controlled by R. 4 replace; IB IC ID Where X 6 In each case, the choices are independently selected from O and C; Where X 7 In each case, N and C are selected independently; Where R 2 In each case, the C that is optionally replaced is selected independently. 1-6 Alkyl or optionally substituted C 1-6 cycloalkyl, wherein the C 1-6 Alkyl or C 1-6 The substituents on the cycloalkyl group are selected from -CN and C. 1-6 cycloalkyl; Where R 3 Selected independently from C in each case 1-6 Alkyl, C 1-6 cycloalkyl, halogenated, C 1-6 Haloalkyl, -S(=O)2C 1-6 Alkyl group, -S(O)(NH)C 1-6 Alkyl, -S(O)(NC 1-3 Alkyl)C 1-6 Alkyl, -CN, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(=O)-OC 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, 3,6-dihydro-2H-pyranyl and pentafluorosulfalkyl; Where R 4 Selected independently from C in each case 1-6 Alkyl, halogenated and C 1-6 Halogenated alkyl groups.

2. The compound of claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is... 。 3. The compound of claim 2, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 It is C, which can be arbitrarily replaced by halogenation.

4. The compound of claim 2, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 It is N.

5. The compound of claim 2, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 3 C is the C that can be arbitrarily replaced.

6. The compound of claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is or .

7. The compound of claim 6, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 C is the C that can be arbitrarily replaced.

8. The compound of claim 7, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 It was replaced by halogenated products.

9. The compound of claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R is 。 10. The compound of claim 9, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 It is C, which can be arbitrarily replaced by halogenation.

11. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of claims 1, 7, or 9, wherein R 1 It's IB.

12. The compound of claim 11, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 R 4 replace.

13. The compound of claim 12, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 It is halogenated.

14. The compound of any one of claims 1, 7, or 9, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It's an IC.

15. The compound of claim 14, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 R 4 replace.

16. The compound of claim 15, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 It is halogenated.

17. The compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of claims 1, 7, or 9, wherein R 1 It's an ID.

18. The compound of claim 17, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 R 4 replace.

19. The compound of claim 18, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 It is halogenated.

20. The compound of claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 Selected independently from C in each case 1-6 Alkyl, halogenated and C 1-6 Halogenated alkyl groups.

21. The compound of claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 In each case, it is independently selected from -S(= O)2C 1-6 Alkyl groups and -CN.

22. The compound of any one of claims 1, 7, or 9, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 It is independently selected from methyl, ethyl and cyclopropyl.

23. A compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from: 4-Amino-7-chloro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N-((5S)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-7-chloro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-7-fluoro-N-methyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide, (3R)-4-amino-7-fluoro-N,3-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide, 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N,1-Dimethyl-N-((3S)-6-(pentafluoro-λ~6~-thioalkyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N,1-Dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c][1,7]naphthyl-8-carboxamide, 4-Amino-7-fluoro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[2,3-b]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-7-chloro-N,1-dimethyl-N-((5R)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N-((4S)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N-((5S)-2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N,1-Dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, (3R)-4-amino-N,3-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide, 4-Amino-N-methyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxamide, 4-Amino-7-fluoro-N,1-dimethyl-N-((5S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, 4-Amino-N-methyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxamide, 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide and 4-Amino-7-fluoro-N,1-dimethyl-N-((3S)-6-(trifluoromethyl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.

24. A pharmaceutical composition comprising a compound, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 or 23, and a pharmaceutically acceptable carrier.

25. Use of the compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of claims 1 or 23 in the preparation of a medicament for treating MTAP-ineffective cancers in a subject of need, wherein the MTAP-ineffective cancers are selected from ovarian cancer, lung cancer, HNSCC, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, pancreatic cancer, or bladder cancer.

26. Use of the compound, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of claims 1 or 23 in the preparation of a medicament for treating MTAP-ineffective cancers in a subject of need, wherein the MTAP-ineffective cancer is colon cancer.

Citation Information

Patent Citations

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