Compounds, compositions, and methods for treating cancer

Abstract

The present disclosure includes, inter alia, compounds, pharmaceutical compositions, and methods of making and using same that treat or reduce the severity of cancer. TIFF2024514339000953.tif30128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 175,974, filed April 16, 2021, and U.S. Provisional Patent Application No. 63 / 281,493, filed November 19, 2021, the contents of each of which are incorporated herein by reference. [Background technology]

[0002] background Cbl-b is an E3 ubiquitin-protein ligase that functions as a negative regulator of T cell activation. Modulation of Cbl-b has been shown to be a therapeutic target for diseases and disorders. There remains a need for compounds that inhibit Cbl-b. Summary of the Invention

[0003] overview In some embodiments, the present disclosure provides a compound of formula (A): TIFF2024514339000002.tif29128 or a pharmaceutically acceptable salt thereof.

[0004] Additionally, the present disclosure includes, inter alia, pharmaceutical compositions of the compounds of formula (A), methods of using said pharmaceutical compositions, and methods of making said pharmaceutical compositions. DETAILED DESCRIPTION OF THE INVENTION

[0005] Detailed Description In some embodiments, the present disclosure provides a compound of formula (A): TIFF2024514339000003.tif29128 or a pharmaceutically acceptable salt thereof, During the ceremony, Y is a group =C(H)-, =C(R a )-, or =N-; Z is =O or =S; E is an optionally substituted 5- to 6-membered heterocyclyl; B is an optionally substituted phenyl, an optionally substituted 8- to 10-membered bicyclyl, or an optionally substituted 5- to 6-membered heteroaryl; C is an optionally substituted 5- to 6-membered heterocyclyl; X is an optionally substituted C1-C3 alkylene chain, where one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, optionally substituted 3- to 6-membered ring carbocyclyl, and optionally substituted 3- to 6-membered ring heterosilyl, wherein X is optionally substituted with an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3- to 6-membered ring heteroaryl, 3- to 6-membered ring heterosilyl, and -(CH2)(3- to 6-membered ring carbocyclyl); Each R a LY, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, wherein R ais 1 to 5 R a1 may be substituted with; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, wherein A is selected from the group consisting of 1 to 5 R a1 may be substituted with; Each R a1 is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1, -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R c is hydrogen, optionally substituted C1-C6 aliphatic, OR 1 , -NH2, -NR 1 R 2 , optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 1 is an optionally substituted C1-C6 aliphatic, an optionally substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 2 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S; or R 1 and R 2 together with their intervening atoms form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; Each R 3 are independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0006] In some embodiments, the present disclosure provides a compound of formula (B): TIFF2024514339000004.tif35128 or a pharmaceutically acceptable salt thereof, During the ceremony, Y is a group =C(H)-, =C(R a )-, or =N-; Z is =O or =S; B is an optionally substituted phenyl, a substituted 5- to 6-membered heteroaryl, or an optionally substituted 8- to 10-membered bicyclyl; X is an optionally substituted C1-C3 alkylene chain, where one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterosilyl; Each R a LA, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R c is hydrogen, an optionally substituted C1-C6 aliphatic group, -OR 1 , -NH2, -NR 1 R 2, optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 1 is an optionally substituted C1-C6 aliphatic, an optionally substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 2 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S; or R 1 and R 2 together with their intervening atoms form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; Each R 3are independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, or 4.

[0007] In some embodiments, the present disclosure provides a compound of formula (I): TIFF2024514339000005.tif33128 or a pharmaceutically acceptable salt thereof, During the ceremony, X is an optionally substituted C1-C3 alkylene chain, where one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2024514339000006.tif28128, and each methylene unit may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, optionally substituted 5-membered heteroaryl, optionally substituted phenyl, optionally substituted C3-C4 carbosilyl, and optionally substituted C3-C4 heterocyclyl; Each R a LA, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1, -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, wherein R a is 1 to 5 R a1 may be substituted with; each Y is independently selected from the group consisting of -C=, -O-, -N=, and -S-; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, wherein A is selected from the group consisting of 1 to 5 R a1 may be substituted with; Each R a1 is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1, -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; B is an optionally substituted phenyl, a substituted 5- to 6-membered heteroaryl, or an optionally substituted 8- to 10-membered bicyclyl; Each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R cis hydrogen, an optionally substituted C1-C6 aliphatic, an optionally deuterated and substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 1 is an optionally substituted C1-C6 aliphatic, an optionally substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 2 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S; or R 1 and R 2 together with their intervening atoms form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; Each R 3are independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, or 4.

[0008] In some embodiments, the present disclosure provides a compound of formula (Ia) or (IIa): TIFF2024514339000007.tif34128 or a pharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C; and X, Y, Z, R a , R b , R c , n, and m are as defined above and described in the classes and subclasses herein.

[0009] In some embodiments, the present disclosure provides compounds of formula (Ia1) or (IIa1): TIFF2024514339000008.tif36128 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c , n, and m are as defined above and described in the classes and subclasses herein.

[0010] In some embodiments, the present disclosure provides a compound represented by formula (Ia2), (Ia3), or (Ia4): TIFF2024514339000009.tif77128 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c, n, and m are as defined above and described in the classes and subclasses herein.

[0011] In some embodiments, the present disclosure provides compounds of formula (Ia1) or (IIa1): TIFF2024514339000010.tif36128 or a pharmaceutically acceptable salt thereof, During the ceremony, X is an optionally substituted C1-C3 alkylene chain, where one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, May be replaced by TIFF2024514339000011.tif17128; Each R a LA, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; Each R c is hydrogen, an optionally substituted C1-C6 aliphatic group, an optionally substituted phenyl group, an optionally substituted 3- to 6-membered heterocyclyl group containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR3 , and -SO2R 3 are independently selected from the group consisting of: Each R 1 is an optionally substituted C1-C6 aliphatic, an optionally substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 are independently selected from the group consisting of: Each R 2 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S; or R 1 and R 2 together with their intervening atoms form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; Each R 3 are independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, or 4.

[0012] In some embodiments, the present disclosure provides a compound of formula (Ib) or (IIb): TIFF2024514339000012.tif34128 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0013] In some embodiments, the present disclosure provides compounds of formula (Ib1) or (IIb1): TIFF2024514339000013.tif41128 or a pharmaceutically acceptable salt thereof, wherein X, R a , R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0014] In some embodiments, the present disclosure provides a compound of formula (Ib2), (Ib3), or (Ib4): TIFF2024514339000014.tif87128 or a pharmaceutically acceptable salt thereof, wherein X, R a , R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0015] In some embodiments, the present disclosure provides compounds of formula (Ic) or (IIc): TIFF2024514339000015.tif41128 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0016] In some embodiments, the present disclosure provides compounds of formula (Ic1) or (IIc1): TIFF2024514339000016.tif41128 or a pharmaceutically acceptable salt thereof, wherein X, R a , R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0017] In some embodiments, the present disclosure provides compounds of formula (Id) or (IId): TIFF2024514339000017.tif35128 or a pharmaceutically acceptable salt thereof, wherein X, R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0018] In some embodiments, the present disclosure provides compounds of formula (Id1) or (IId1): TIFF2024514339000018.tif41128 or a pharmaceutically acceptable salt thereof, wherein X, R b , R c , and m are as defined above and described in the classes and subclasses herein.

[0019] X In some embodiments, X is an optionally substituted C1-C3 alkylene chain, where one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterosilyl, wherein X is optionally substituted with an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterosilyl, and -(CH2)(3- to 6-membered carbocyclyl). In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are selected from -N(H)-, -N(R 1)-, -O-, -S-, -SO-, -SO2-, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterosilyl. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are selected from the group consisting of -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2024514339000019.tif28128, and each methylene unit may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, optionally substituted 5-membered heteroaryl, optionally substituted phenyl, optionally substituted C3-C4 carbosilyl, and optionally substituted C3-C4 heterocyclyl. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are selected from -N(H)-, -N(R 1 )-, -O-, -S-, TIFF2024514339000020.tif17128. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are selected from the group consisting of -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2024514339000021.tif17128. In some embodiments, X is an optionally substituted C1-C2 alkylene. In some embodiments, X is TIFF2024514339000022.tif12128 or an optionally substituted C2 alkylene, wherein one methylene unit is TIFF2024514339000023.tif12128. In some embodiments, X is TIFF2024514339000024.tif123139TIFF2024514339000025.tif202142TIFF2024514339000026.tif48128.

[0020] In some embodiments, X is TIFF2024514339000027.tif31128.

[0021] R a In some embodiments, each R a LA, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 In some embodiments, R is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R is LA. In some embodiments, R is LA. a is halogen, -CN, -C(O)R 1 , -CO2H, -CONR 1 R 2, optionally substituted C1-C6 aliphatic, and optionally substituted C1-C6 heteroalkyl. a are halogens, -CN, -CO2H, -CHO, -CHF2, -CF3, -OMe, -S(O)2NHMe, TIFF2024514339000028.tif38128TIFF2024514339000029.tif221109TIFF2024514339000030.tif221109TIFF2024514339000031.tif219110TIFF2024514339000032.tif221110TIFF2024514339000033.tif201108.

[0022] In some embodiments, R a are halogens, -CN, -CO2H, TIFF2024514339000034.tif156128.

[0023] L In some embodiments, L is an optionally substituted C1-C3 alkylene chain. In some embodiments, L is -CH2- or -CH(CH3)-.

[0024] A In some embodiments, A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, A is optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, A is selected from optionally substituted piperidine, optionally substituted tetrahydropyridine, optionally substituted pyrrolidine, optionally substituted dihydropyrrole, optionally substituted aziridine, and optionally substituted morpholine.

[0025] C In some embodiments, C is an optionally substituted 5-membered heteroaryl. In some embodiments, C is an optionally substituted 5-membered heteroaryl containing 3 nitrogen atoms. In some embodiments, C is an optionally substituted triazolyl. In some embodiments, C is an optionally substituted 1, 2, or 4 trizaolyl. In some embodiments, C is an optionally substituted 1, 2, or 3 trizaolyl. In some embodiments, C is an optionally substituted 5-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, C is an optionally substituted pyrazolyl. In some embodiments, C is an optionally substituted isoxazolyl. In some embodiments, C is an optionally substituted thiazolyl. In some embodiments, C is an optionally substituted thiadizolyl. In some embodiments, C is an optionally substituted 1, 3, or 4 thiadizolyl. In some embodiments, C is an optionally substituted pyridinyl. In some embodiments, C is an optionally substituted pyrazinyl. In some embodiments, C is an optionally substituted pyrimidinyl. In some embodiments, C is an optionally substituted pyridazinyl.

[0026] R b In some embodiments, each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S.

[0027] R c In some embodiments, each R c is hydrogen, an optionally substituted C1-C6 aliphatic group, -OR 1 , -NH2, -NR 1 R 2 , optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 In some embodiments, each R c is hydrogen, an optionally substituted C1-C6 aliphatic group, an optionally substituted phenyl group, an optionally substituted 3- to 6-membered heterocyclyl group containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 In some embodiments, R c is an optionally substituted C1-C3 aliphatic. In some embodiments, R c is methyl.

[0028] R 1 In some embodiments, each R 1 is an optionally substituted C1-C6 aliphatic, an optionally substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 In some embodiments, each R 1 is an optionally substituted C1-C6 aliphatic. In some embodiments, each R 1 is methyl.

[0029] R 2 In some embodiments, each R 2 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S; Or, R 1 and R 2 together with the intervening atoms, form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S.

[0030] In some embodiments, each R 2 is an optionally substituted C1-C6 aliphatic. In some embodiments, each R2 is methyl.

[0031] R 3 In some embodiments, each R 3 are independently selected from the group consisting of optionally substituted C1-C6 aliphatic groups, optionally substituted 3- to 6-membered heterocyclyl groups containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl groups, and optionally substituted 5- to 6-membered heteroaryl groups containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S.

[0032] In some embodiments, the present disclosure includes a compound set forth in Table 1.

[0033] [Table 1] TIFF2024514339000036.tif212146TIFF2024514339000037.tif226146TIFF2024514339000038.tif205146TIFF2024514339000039.tif198146TIFF2024514339000040.tif195146TIFF2024514339000041.tif207146TIFF2024514339000042.tif222146TIFF2024514339000043.tif197146TIFF2024514339000044.tif202146TIFF2024514339000045.tif207146TIFF2024514339000046.tif223146TIFF2024514339000047.tif201146TIFF2024514339000048.tif201146TIFF2024514339000049.tif208146TIFF2024514339000050.tif208146TIFF2024514339000051.tif195146TIFF2024514339000052.tif222146TIFF2024514339000053.tif218146TIFF2024514339000054.tif195146TIFF2024514339000055.tif221146TIFF2024514339000056.tif202146TIFF2024514339000057.tif193146TIFF2024514339000058.tif224146TIFF2024514339000059.tif225146TIFF2024514339000060.tif195146TIFF2024514339000061.tif220146TIFF2024514339000062.tif225146TIFF2024514339000063.tif225146TIFF2024514339000064.tif222146TIFF2024514339000065.tif193146TIFF2024514339000066.tif205146TIFF2024514339000067.tif201146TIFF2024514339000068.tif198146TIFF2024514339000069.tif196146TIFF2024514339000070.tif192146TIFF2024514339000071.tif190146TIFF2024514339000072.tif190146TIFF2024514339000073.tif192146TIFF2024514339000074.tif192146TIFF2024514339000075.tif196146TIFF2024514339000076.tif192146TIFF2024514339000077.tif194146TIFF2024514339000078.tif194146TIFF2024514339000079.tif198146TIFF2024514339000080.tif195146TIFF2024514339000081.tif192146TIFF2024514339000082.tif188146TIFF2024514339000083.tif201146TIFF2024514339000084.tif194146TIFF2024514339000085.tif209146TIFF2024514339000086.tif193146TIFF2024514339000087.tif206146TIFF2024514339000088.tif200146TIFF2024514339000089.tif183146TIFF2024514339000090.tif199146TIFF2024514339000091.tif197146TIFF2024514339000092.tif197146TIFF2024514339000093.tif191146TIFF2024514339000094.tif190146TIFF2024514339000095.tif181146TIFF2024514339000096.tif198146TIFF2024514339000097.tif194146TIFF2024514339000098.tif199146TIFF2024514339000099.tif201146TIFF2024514339000100.tif199146TIFF2024514339000101.tif188146TIFF2024514339000102.tif199146TIFF2024514339000103.tif199146TIFF2024514339000104.tif182146TIFF2024514339000105.tif203146TIFF2024514339000106.tif212146TIFF2024514339000107.tif199146TIFF2024514339000108.tif192146TIFF2024514339000109.tif197146TIFF2024514339000110.tif192146TIFF2024514339000111.tif179146TIFF2024514339000112.tif197146TIFF2024514339000113.tif192146TIFF2024514339000114.tif192146TIFF2024514339000115.tif214146TIFF2024514339000116.tif225146TIFF2024514339000117.tif199146TIFF2024514339000118.tif195146TIFF2024514339000119.tif207146TIFF2024514339000120.tif194146TIFF2024514339000121.tif224146TIFF2024514339000122.tif207146TIFF2024514339000123.tif199146TIFF2024514339000124.tif198146TIFF2024514339000125.tif203146TIFF2024514339000126.tif208146TIFF2024514339000127.tif205146TIFF2024514339000128.tif204146TIFF2024514339000129.tif202146TIFF2024514339000130.tif200146TIFF2024514339000131.tif202146TIFF2024514339000132.tif197146TIFF2024514339000133.tif197146TIFF2024514339000134.tif221146TIFF2024514339000135.tif196146TIFF2024514339000136.tif197146TIFF2024514339000137 .tif204146TIFF2024514339000138.tif220146TIFF2024514339000139.tif196146TIFF2024514339000140 .tif212146TIFF2024514339000141.tif200146TIFF2024514339000142.tif206146TIFF202451433900014 3.tif195146TIFF2024514339000144.tif196146TIFF2024514339000145.tif205146TIFF202451433900014 6.tif204146TIFF2024514339000147.tif201146TIFF2024514339000148.tif198146TIFF20245143390001 49.tif220146TIFF2024514339000150.tif195146TIFF2024514339000151.tif221146TIFF20245143390001 52.tif196146TIFF2024514339000153.tif198146TIFF2024514339000154.tif224146TIFF2024514339000155.tif196146TIFF2024514339000156.tif213146TIFF2024514339000157.tif95146 or a pharmaceutically acceptable salt thereof.

[0034] Those skilled in the art will understand that the present disclosure includes compounds having the opposite stereochemistry to that depicted. Additionally, the present disclosure contemplates tautomers of the compounds depicted herein.

[0035] The present disclosure includes racemates of any of the compounds disclosed herein.

[0036] definition The terms "aliphatic" or "aliphatic group," as used herein, mean a straight-chain (i.e., unbranched) or branched, fully saturated or substituted or unsubstituted hydrocarbon chain containing one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0037] The term "haloaliphatic" refers to an aliphatic group substituted with one or more halogen atoms.

[0038] The term "alkyl" refers to a straight-chain or branched-chain alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0039] The term "haloalkyl" refers to a straight or branched chain alkyl group substituted with one or more halogen atoms.

[0040] The term "halogen" means F, Cl, Br, or I.

[0041] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring of the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0042] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, in which 6, 10, or 14 pi electrons are shared in a cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroa" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are optionally substituted independently.

[0043] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated, as defined above, and that has one or more, preferably 1 to 4, heteroatoms in addition to carbon atoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It can be NR (as in TV-substituted pyrrolidinyl). The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic group" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the group or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl portions are optionally substituted independently.

[0044] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0045] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from the specified group, the substituents may be the same or different at every position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their preparation, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0046] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0-4 R ° ;-(CH2) 0-4 OR ° ;-O(CH2) 0-4 R ° , -O-(CH2) 0-4 C(O)OR ° ;-(CH2) 0-4 CH(OR ° )2;-(CH2) 0-4 SR ° ;R ° May be substituted with -(CH2) 0-4 Ph;R° May be substituted with -(CH2) 0-4 O(CH2) 0-1 Ph;R ° May be substituted with -CH=CHPh;R ° May be substituted with -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R ° )2;-(CH2) 0-4 N(R ° )C(O)R ° ;-N(R ° )C(S)R ° ;-(CH2) 0-4 N(R ° )C(O)NR ° 2;-N(R ° )C(S)NR ° 2;-(CH2) 0-4 N(R ° )C(O)OR ° ;-N(R ° )N(R ° )C(O)R ° ;-N(R ° )N(R ° )C(O)NR ° 2;-N(R ° )N(R ° )C(O)OR ° ;-(CH2) 0-4 C(O)R ° ;-C(S)R ° ;-(CH2) 0-4 C(O)OR ° ;-(CH2) 0-4 C(O)SR ° ;-(CH2) 0-4 C(O)OSiR ° 3;-(CH2) 0-4 OC(O)R ° ;-OC(O)(CH2) 0-4 SR ° , SC(S)SR ° ;-(CH2) 0-4 SC(O)R ° ;-(CH2) 0-4 C(O)NR ° 2;-C(S)NR °2;-C(S)SR ° ;-SC(S)SR ° , -(CH2) 0-4 OC(O)NR ° 2;-C(O)N(OR ° )R ° ;-C(O)C(O)R ° ;-C(O)CH2C(O)R ° ;-C(NOR ° )R ° ;-(CH2) 0-4 SSR ° ;-(CH2) 0-4 S(O)2R ° ;-(CH2) 0-4 S(O)2OR ° ;-(CH2) 0-4 OS(O)2R ° ;-S(O)2NR ° 2;-(CH2) 0-4 S(O)R ° ;-N(R ° )S(O)NR ° 2;-N(R ° )S(O)2R ° ;-N(OR ° )R ° ;-C(NH)NR ° 2;-P(O)2R ° ;-P(O)R ° 2;-OP(O)R ° 2;-OP(O)(OR ° )2;SiR ° 3;-(C 1-4 Linear or branched alkylene)ON(R ° )2; or -(C 1-4 Straight or branched alkylene)C(O)ON(R ° )2, where each R ° are optionally substituted as defined below and independently represent hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and which may be substituted as defined below.

[0047] R ° (or two separate R ° Suitable monovalent substituents for the ring (wherein occurrences of - form, together with their intervening atoms) are independently halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if followed by "halo", is substituted with one or more halogens only, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1R is independently selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ° Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0048] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where R * Each independent occurrence of represents hydrogen, C which may be substituted as defined below. 1-6 The group is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2-3 O-, where R * Each independent occurrence of represents hydrogen, C which may be substituted as defined below. 1-6 It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] R * Suitable substituents for the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, optionally substituted C as defined below, 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definition, two independent R † together with their intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] R † Suitable substituents for the aliphatic group are independently halogen, -R ● ,-(Halo R● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0053] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N(C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0054] Combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds. The term "stable," as used herein, refers to compounds that have sufficient stability to permit their manufacture and maintain their integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0055] The recitation of a list of chemical groups within any definition of a variable herein includes the definition of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0056] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, biological specimen storage, and biological assays.

[0057] As used herein, a "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that, when administered as part of a therapeutic regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cell or tissue. For example, an effective amount of a compound provided in a formulation to treat a disease, disorder, and / or condition is an amount that ameliorates, alleviates, relieves, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of, one or more symptoms or characteristics of the disease, disorder, and / or condition.

[0058] As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely ameliorating, inhibiting, delaying the onset of, preventing, alleviating, and / or relieving a disorder or condition, or one or more symptoms of a disorder or condition as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals before symptoms develop (e.g., taking into account disease history and / or genetic or other susceptibility factors). Treatment can continue after symptoms have resolved, e.g., to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing recurrence or recurrence of a disease or disorder.

[0059] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0060] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the compounds disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine), sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium monohydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0061] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure, or an inhibitory active metabolite or residue thereof.

[0062] The expression "unit dosage form" used herein refers to a physically separate pharmaceutical unit suitable for treating a patient.However, it will be understood that the total daily use amount of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical diagnosis.The specific effective dose level for any specific patient or organism will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, administration route and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known in the medical field.

[0063] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total abundance of isotopes of the element present at a particular position in the compound.

[0064] Pharmaceutical Composition In some embodiments, the present disclosure provides a composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in the compositions contemplated herein is an amount effective to measurably treat a disease or disorder in a biological sample or a patient. In certain embodiments, the amount of compound in the compositions of the present disclosure is an amount effective to measurably treat a disease or disorder in a biological sample or a patient. In certain embodiments, the compositions contemplated by the present disclosure are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions contemplated by the present disclosure are formulated for oral administration to a patient.

[0065] In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some preferred embodiments, compositions are administered orally, intraperitoneally, or intravenously. In some embodiments, sterile injectable forms of compositions containing one or more compounds of Formula (I) may be aqueous or oily suspensions. In some embodiments, suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. In some embodiments, sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. In some embodiments, acceptable vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile, fixed oils conventionally used as solvents or suspending media.

[0066] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0067] Pharmaceutically acceptable compositions containing one or more compounds of formula (I) can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and cornstarch. Typically, lubricants such as magnesium stearate are also added. In some embodiments, useful diluents include lactose and dried cornstarch. In some embodiments, when aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0068] Alternatively, the pharmaceutically acceptable composition containing the compound of formula (I) may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0069] Pharmaceutically acceptable compositions containing compounds of Formula (I) may also be administered topically, particularly when the target of treatment includes areas or organs easily accessible by topical application, such as diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. In some embodiments, the pharmaceutically acceptable composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0070] Pharmaceutically acceptable compositions containing compounds of formula (I) may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0071] In some embodiments, the amount of a compound of the present disclosure that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions are formulated so that a patient receiving these compositions can receive a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor.

[0072] Methods of Use of the Disclosed Compounds In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with cell proliferation in a patient, the method comprising administering to the patient a composition according to the present disclosure.

[0073] The term "cell proliferation-associated disease or condition," as used herein, refers to any disease or other deleterious condition known to involve cell proliferation. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases known to involve cell proliferation. In some embodiments, the cell proliferation-associated disease or condition is hyperplasia or cancer. In some embodiments, the cell proliferation-associated disease or condition is cancer.

[0074] In some embodiments, administration of a compound of the present disclosure results in mitotic arrest.

[0075] In some embodiments, administration of a compound of the present disclosure results in mitotic arrest. In some embodiments, mitotic arrest is defined as a 10-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 20-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 30-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 40-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 50-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 60-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 70-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as an 80-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 90-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 100% reduction in mitosis.

[0076] In some embodiments, the compounds and compositions according to the disclosed methods can be administered using any dosage and any route of administration effective for treating or reducing the severity of cancer. The exact amount required may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, etc. The compounds of the present disclosure are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0077] In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is selected from the group consisting of lymphoma, leukemia, and myeloma. In some embodiments, the blood cancer is lymphoma. In some embodiments, the blood cancer is leukemia. In some embodiments, the blood cancer is myeloma.

[0078] In some embodiments, the cancer is a non-hematological cancer. In some embodiments, the non-hematological cancer is a sarcoma or carcinoma. In some embodiments, the non-hematological cancer is a sarcoma. In some embodiments, the non-hematological cancer is a carcinoma.

[0079] In some embodiments, the subject experiences one or more of increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, decreased T cell anergy, and decreased T cell tolerance after administration of a compound of the present disclosure. In some embodiments, administering a compound of the present disclosure to a patient in need thereof results in one or more of increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, decreased T cell anergy, and decreased T cell tolerance.

[0080] In some embodiments, the subject has increased NK cell activation, hi some embodiments, the increased NK cell activation comprises increased cytokine production.

[0081] In some embodiments, pharmaceutically acceptable compositions comprising compounds of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, compounds of the present disclosure may be administered orally or parenterally, one or more times daily, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, of subject body weight per day to achieve the desired therapeutic effect.

[0082] In some embodiments, one or more additional therapeutic agents may also be administered in combination with a compound of the present disclosure. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered as part of a multiple dose format. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered simultaneously, sequentially, or within an isocratic period. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered within 5 hours of each other. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered within 24 hours of each other. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered within one week of each other.

[0083] In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be formulated in a single dosage form. [Example]

[0084] Intermediate I-1: Synthesis of Intermediate 1 TIFF2024514339000158.tif60165 Synthesis of I-1a To a stirred mixture of triethyl phosphonoacetate (4.00 g, 17.842 mmol, 1.00 equiv) in THF (50.00 mL) was added t-BuOK (2.00 g, 17.842 mmol, 1.00 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min under an argon atmosphere. Next, 3-nitroacetophenone (0.97 g, 5.888 mmol, 0.33 equiv) was added, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The resulting mixture was diluted with water (150 mL) and extracted with EA (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give I-1a (1.2 g, 28.63%) as an orange oil.

[0085] Synthesis of I-1b To a stirred mixture of I-1a (1.20 g, 5.101 mmol, 1.00 equiv) in EtOH (20.00 mL) was added N2H4.HO (2.57 g, 51.012 mmol, 10.00 equiv) in one portion at room temperature. The resulting mixture was stirred at 80 °C under oxygen for 72 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (30 mL), washed with water (2 × 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (10:1) to give I-1b (1.00 g, 82.5%) as an orange oil.

[0086] Synthesis of I-1c To a stirred mixture of I-1b (500.00 mg, 2.240 mmol, 1.00 equiv) in DCM (10.00 mL) was added DMF-DMA (1.07 g, 8.959 mmol, 4.00 equiv) at room temperature. The resulting mixture was stirred at 40 °C under an argon atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was dissolved in EA (50 mL), washed with water (10 mL), and dried over anhydrous NaSO. After filtration, the combined organic layer was concentrated under reduced pressure. The residue was purified by trituration with CHCl / MeOH = 10 / 1 (200 mL). The resulting mixture was concentrated under reduced pressure to give I-1c (500 mg, 80.25%) as an orange oil.

[0087] Synthesis of I-1d To a stirred mixture of I-1c (500.00 mg, 1.796 mmol, 1.00 equiv) in HOAc (5.00 mL) was added CHNH (5.00 mL, 2 M in THF) at room temperature. The resulting mixture was stirred at 40 °C under an argon atmosphere for 2 h. The resulting mixture was diluted with EA (60 mL), washed with water (10 mL), and dried over anhydrous NaSO. After filtration, the combined organic layer was concentrated under reduced pressure. The residue was purified by trituration with CHCl / MeOH = 10 / 1 (200 mL). The resulting mixture was concentrated under reduced pressure to give I-1d (380 mg, 85.97%) as an orange oil.

[0088] Synthesis of I-1 To a stirred mixture of I-1d (380 mg, 2.030 mmol, 1.00 equiv) in EtOH (5.00 mL) was added NH4Cl (100.00 mg, 1.869 mmol, 0.92 equiv), HO (5.00 mL), and Fe (566.91 mg, 10.151 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with NaHCO3 (aq) at 0 °C. The resulting mixture was extracted with EA (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (150 mg) was purified using the following conditions: column, C18; mobile phase A: water (0.05% NH3 · Purification was performed by reverse-phase flash chromatography using HO, B:CHCN, gradient 3% B to 23% B in 20 min; UV 254 nm detection. This gave the product. These products and Si-thiol (20 mg) in THF (3 mL) were stirred at room temperature for 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dried by lyophilization to give I-1 (86.6 mg, 26.01%) as an orange oil. LC-MS: (ES, m / z): [M+H] + :216 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 1.19-1.21 (d, 3H), 2.86-2.88 (d, 2H), 2.99-3.04 (m, 1H), 3.31-3.38 (m, 3H), 4.95 (s, 1H), 6.36-6.42 (m, 3H), 6.88-6.93 (m, 1H), 8.27 (s, 1H).

[0089] Intermediate I-2: Synthesis of Intermediate 2 TIFF2024514339000159.tif81165 Synthesis of I-2a To 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (10.00 g, 41.663 mmol, 1.00 equiv.), Pd(DtBPF)Cl (1.00 g, 4.1663 mmol, 0.10 equiv.) in 500 mL of EtOH was added TEA (5.00 g, 83.326 mmol, 2.00 equiv.) in a pressure tank. The mixture was purged with nitrogen for 10 minutes, then pressurized to 30 atm with carbon monoxide at 100 °C and stirred overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (5 × 200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1) to give I-2a (7.1 g, 73.08%) as a brown liquid.

[0090] Synthesis of I-2b To a stirred solution of I-2a (3.50 g, 15.009 mmol, 1.00 equiv) and SeO (3.33 g, 30.018 mmol, 2.00 equiv) was added dioxane (400.00 mL) at room temperature under atmospheric pressure. The resulting mixture was stirred at 110 °C overnight. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (2 × 200 mL). The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give I-2b (3 g, 73.59%) as an off-white solid.

[0091] Synthesis of I-2c To a 250 mL three-necked round-bottom flask, I-2b (3.00 g, 0.012 mmol, 1.00 equiv), AcOH (6.40 mL), HSO (0.50 mL), and CH(OMe) (40.00 mL) were added at room temperature. The resulting mixture was stirred at 50 °C for an additional 30 min. The resulting mixture was stirred at room temperature overnight under atmospheric pressure. The reaction was quenched with water / NaHCO at room temperature. The aqueous layer was extracted with EtOAc (2 × 40 mL). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1), to afford 2.8 g (75.52%) of I-2c as an off-white solid.

[0092] Synthesis of I-2d To a 100 mL three-necked round-bottom flask, I-2c (2.80 g, 9.548 mmol, 1.00 equiv) and MeOH (30.00 mL) were added at room temperature. To the above mixture, NaBH (5.01 g, 18.096 mmol, 2 equiv) was added at 0 °C. The resulting mixture was stirred at 0 °C under atmospheric pressure for 2 h. The reaction was quenched with NH Cl (aq) at room temperature. The aqueous layer was extracted with EtOAc (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (6:1), to give I-2d (1.2 g, 40.02%) as an off-white solid.

[0093] Synthesis of I-2e To a 50 mL two-necked round-bottom flask, I-2d (1.10 g, 4.379 mmol, 1.00 equiv), MnO (5.71 g, 65.685 mmol, 15.00 equiv), and DCM (15.00 mL) were added at room temperature. The resulting mixture was stirred overnight at 40 °C under an atmospheric atmosphere. The reaction was quenched with water (15 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1), to give I-2e (500 mg, 41.24%) as an off-white solid.

[0094] Synthesis of I-2f To a 20 mL vial, I-2e (500.00 mg, 2.007 mmol, 1.00 equiv), (3S)-3-methylpiperidine (398.00 mg, 4.013 mmol, 2 equiv), TEA (406.08 mg, 4.014 mmol, 2.00 equiv), and DCE (6 mL) were added NaBH(OAc) (1275.78 mg, 6.021 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature under atmospheric pressure for 2 hours. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The residue was purified by preparative TLC (PE / EtOAc 5:1) to give I-2f (500 mg, 71.23%) as an off-white solid.

[0095] Synthesis of I-2 To a 20 mL vial, I-2f (500.00 mg, 1.504 mmol, 1.00 equiv), HO (5.50 mL), and HCl (0.50 mL) were added at room temperature. The resulting mixture was stirred at 80 °C overnight under atmospheric pressure. The reaction was quenched with NaHCO (aq) at room temperature. The aqueous layer was extracted with EtOAc (2 × 5 mL). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1), to give I-2 (300 mg, 55.72%) as a yellow oil.

[0096] Alternatively, I-2 can be generated as follows: TIFF2024514339000160.tif60165

[0097] Synthesis of I-2g To a solution of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (60 g, 249.976 mmol, 1 equiv.) in dioxane (350 mL) was added SeO2 (69.35 g, 624.940 mmol, 2.5 equiv.). The resulting mixture was stirred at 120 °C overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was diluted with water (300 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The residue was purified by silica gel column chromatography eluting with PE / EA (50:1) to give I-2g (49 g, 69.45%) as a yellow oil.

[0098] Synthesis of I-2h To a 250 mL round-bottom flask, I-2g (10 g, 40.48 mmol, 1.00 equiv) and CH(OMe) (100 mL) were added at room temperature. To the above mixture, HCOOH (3 mL) and HSO (1 mL) were added at room temperature. The resulting mixture was stirred at 50 °C overnight. The reaction was quenched by adding NaHCO (aq) (300 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give I-2h (8 g, 67.45%) as a yellow oil.

[0099] Synthesis of I-2i To a solution of I-2h (8 g, 26.660 mmol, 1 equiv.) in 100 mL of dioxane was added Pd(OAc)2 (0.60 g, 2.666 mmol, 0.1 equiv.) in a pressure tank. The mixture was purged with nitrogen and then pressurized to 10 atm with carbon monoxide / hydrogen (1:1) at 80 °C overnight. The reaction mixture was cooled to room temperature and diluted with water (600 mL). The aqueous layer was extracted with EtOAc (3 × 300 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give I-2i (5 g, 60.21%) as a brown oil.

[0100] Synthesis of I-2j To a 100 mL round-bottom flask, I-2i (1.9 g, 7.625 mmol, 1.00 equiv), (3S)-3-methylpiperidine hydrochloride (1.24 g, 9.150 mmol, 1.2 equiv), DCE (30 mL), and EtN (0.93 g, 9.150 mmol, 1.2 equiv) were added at room temperature. The mixture was stirred at room temperature for 10 minutes. To the above mixture, NaBH(OAc) (4.85 g, 22.875 mmol, 3 equiv) was added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl(aq) (100 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 40 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give I-2j (1.7 g, 61.04%) as a brown oil.

[0101] Synthesis of I-2 To a 50 mL round-bottom flask, I-2j (1.7 g, 5.115 mmol, 1.00 equiv) and 1 M HCl (20 mL) were added at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The residue was basified to pH 7 with NH4HCO3 (aq). The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give compound I-2 (1.5 g, 94.24%) as a colorless oil.

[0102] Alternatively, I-2g can be produced as follows. TIFF2024514339000161.tif29165

[0103] Synthesis of I-2k A mixture of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (25 g, 104.16 mmol, 1 equiv) in DMF (300 mL) and DMF-DMA (269.10 g, 2.26 mol, 300 mL) was stirred for 18 h at 140° C. The reaction mixture was concentrated in vacuo to afford I-2k (30 g, crude) as a brown oil, which was used immediately without further purification.

[0104] Synthesis of I-2g To a solution of I-2k (30 g, 101 mmol) in THF (150 mL) and water (150 mL) was added NaIO (65.2 g, 304 mmol). The mixture was stirred at 20 °C for 6 h. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (200 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (200 mL) and saturated aqueous brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by normal-phase SiO chromatography (0–20% EtOAc / petroleum ether) to afford I-2g (8 g, 30.9% yield) as a brown oil.

[0105] Intermediate I-3: Synthesis of Intermediate 3 TIFF2024514339000162.tif81165 Synthesis of I-3a To a stirred solution of KOH (23.68 g, 422.077 mmol, 1.2 equiv.) in HO (285.00 mL) and dioxane (1000.00 mL), [Rh(COD)Cl] (4.00 g, 8.112 mmol, 0.02 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture, ethyl 2-(oxetan-3-ylidene)acetate (50.00 g, 351.731 mmol, 1.00 equiv.) and 3-nitrophenylboronic acid (117.43 g, 703.462 mmol, 2 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 16 hours under a nitrogen atmosphere. The reaction was quenched by adding NH4Cl (aq.) (3 L) at room temperature. The aqueous layer was extracted with EtOAc (3×5 L). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give I-3a (41 g, 73.24%) as a yellow solid.

[0106] Synthesis of I-3b A mixture of I-3a (30.00 g, 113.094 mmol, 1.00 equiv) and hydrazine hydrate (98%) (45.29 g, 904.756 mmol, 8 equiv) in EtOH (150 mL) was stirred at 80 °C for 24 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (750 mL). The aqueous layer was extracted with CHCl / MeOH (10 / 1) (5 × 1 L). The resulting oil was dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 100 mL). The filtrate was concentrated under reduced pressure to give I-3b (26.0 g, crude) as a yellow oil.

[0107] Synthesis of I-3c To a stirred solution of I-3b (26.00 g, 103.486 mmol, 1.00 equiv) in tetrahydrofuran (260.00 mL) was added methyl isothiocyanate (15.13 g, 206.972 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was diluted with water (600 mL). The precipitated solid was collected by filtration and washed with water (3 × 50 mL) to give I-3c (35.0 g) as a yellow solid.

[0108] Synthesis of I-3d To a stirred solution of I-3c (35 g, 107.905 mmol, 1.00 equiv) was added NaOH (864 mL, 863.240 mmol, 8.00 equiv, 1 M) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (1 L). The mixture was acidified to pH 5 with HCl (1 M). The aqueous layer was extracted with CHCl / MeOH (10 / 1) (3 × 2 L). The resulting mixture was concentrated under reduced pressure to give I-3d (24 g) as a yellow solid.

[0109] Synthesis of I-3e To a stirred solution of I-3d (24.00 g, 78.344 mmol, 1.00 equiv) and NaNO (54.05 g, 783.443 mmol, 10.00 equiv) in HO (150.00 mL) and ethyl acetate (50.0 mL), HNO (500 mL, 783.443 mmol, 10.00 equiv, 1 M) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C overnight. The reaction was quenched by adding NaHCO (aq) (1 L) at room temperature. The aqueous layer was extracted with CHCl / MeOH (10 / 1) (3 × 2 L). The resulting mixture was concentrated under reduced pressure to give I-3e (19 g) as a yellow solid.

[0110] Synthesis of I-3 To a solution of I-3e (19.00 g) in 190 mL of MeOH was added Pd / C (30%, 5.7 g) in a 500 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature using a hydrogen balloon for 4 hours, filtered through a Celite pad, and concentrated under reduced pressure to give I-3 (16 g) as a yellow solid.

[0111] Example 1. Synthesis of Compound 1 TIFF2024514339000163.tif44165 Synthesis of 1a To a stirred solution of I-1 (300.00 mg, 1.387 mmol, 1.00 equiv) in MeOH (4.00 mL) was added 3-(trifluoromethyl)pyridine-2-carbaldehyde (242.88 mg, 1.387 mmol, 1.00 equiv) at room temperature under atmospheric pressure. The resulting mixture was stirred at room temperature overnight. To the above mixture, NaBH4 (104.95 mg, 2.774 mmol, 2.00 equiv) was added at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was quenched by adding NH4Cl(aq) (30 mL) at room temperature. The aqueous layer was extracted with EtOAc (15 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 30:1) to give 1a (200 mg, 38.41%) as a yellow solid.

[0112] Synthesis of 1 To a stirred mixture of 1a (180.00 mg, 0.479 mmol, 1.00 equiv.) and CDI (116.62 mg, 0.718 mmol, 1.50 equiv.) in CHCN (3.00 mL) was added DMAP (117.16 mg, 0.958 mmol, 2.00 equiv.) at room temperature under atmospheric pressure. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 20:1) to give compound 1 (80 mg) as a yellow solid. The crude product (80 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 41% B to 71% B in 8 min; Wavelength: 254; 220 nm; RT1 (min): 7.17) to give compound 1 (30.2 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 401. 1 H NMR: (300 MHz, DMSO-d6, ppm): δ 1.30-1.33 (d, 3H), 3.01-3.04 (m, 2H), 3.32-3.35 (m, 1H), 3.46 (s, 3H), 6.26-6.31 (m, 1H), 7.08-7.10 (m, 1H), 7.23-7.25 (m, 1H), 7.33 (s, 1H), 7.42-7.44 (m, 1H), 7.70-7.73 (m, 2H), 7.78-7.81 (d, 1H), 8.28 (s, 1H).

[0113] Example 2. Synthesis of Compound 2 TIFF2024514339000164.tif65165 Synthesis of 2 Compound 1 (340 mg) was separated by preparative chiral HPLC under the following conditions (Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2 M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 25% B to 25% B in 21.5 min; Wavelength: 254 / 220 nm; RT1 (min): 14.79; Sample solvent: EtOH; Injection volume: 0.4 mL; Run number: 18) to give compound 2 (92.4 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 402. 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 1.36-1.38 (d, 3H), 3.02-3.19 (m, 2H), 3.35-3.40 (m, 1H), 3.43 (s, 3H), 6.31-6.35 (m, 1H), 7.01-7.03 (m, 1H), 7.10 (s, 1H), 7.22-7.24 (m, 1H), 7.40-7.45 (m, 1H), 7.53-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.24 (s, 1H) 。

[0114] Example 3. Synthesis of Compound 3 TIFF2024514339000165.tif65165 Synthesis of 3 Compound 1 (340 mg) was purified by preparative chiral HPLC under the following conditions (Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2 M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 25% B to 25% B in 21.5 min; Wavelength: 254 / 220 nm; RT2 (min): 18.83; Sample solvent: EtOH; Injection volume: 0.4 mL; Run number: 18) to give compound 3 (92.0 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 402. 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.36-1.38 (d, 3H), 3.02-3.19 (m, 2H), 3.35-3.40 (m, 1H), 3.43 (s, 3H), 6.31-6.35 (m, 1H), 7.01-7.03 (m, 1H), 7.10 (s, 1H), 7.22-7.24 (m, 1H), 7.40-7.45 (m, 1H), 7.53-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.24 (s, 1H).

[0115] Example 4. Synthesis of Compound 4 TIFF2024514339000166.tif87165 Synthesis of 4a A solution of triethyl phosphonoacetate (10.00 g, 44.604 mmol, 1.00 equiv.) and t-BuOK (10.01 g, 0.089 mmol, 2 equiv.) in THF (100 mL) was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. 4-Bromo-2,3-dihydroinden-1-one (9.41 g, 0.045 mmol, 1 equiv.) in THF (20 mL) was added dropwise to the above mixture at 0° C. over 20 minutes. The resulting mixture was stirred at 0° C. for an additional 3 hours. The reaction was quenched at 0° C. by adding NH4Cl (aq.) (150 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give 4a (4.4 g, 34.03%) as a pale yellow oil.

[0116] Synthesis of 4b To a 250 mL three-necked round-bottom flask, 4a (4.40 g, 15.650 mmol, 1.00 equiv), EtOH (70.00 mL), and hydrazine hydrate (7.83 g, 156.500 mmol, 10.00 equiv) were added at room temperature. The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 72 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (100 mL), washed with water (20 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used immediately in the next step without further purification. This resulted in 4b (4.0 g, 83.57%) as a pale yellow oil.

[0117] Synthesis of 4c To a 250 mL three-necked round-bottom flask were added 4b (4.00 g, 14.862 mmol, 1.00 equiv), tetrahydrofuran (50.00 mL), and methyl isothiocyanate (2.17 g, 29.681 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with water (3 × 5 mL). This gave 4c (4.5 g, 88.47%) as an off-white solid.

[0118] 4D compositing To a 250 mL three-necked round-bottom flask were added 4c (4.50 g, 13.148 mmol, 1.00 equiv), HO (50.00 mL), and NaOH (0.53 g, 0.000 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched by adding NH4Cl (aq) (20 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with water (3 × 5 mL). This gave 4d (3 g, 63.33%) as an off-white solid.

[0119] Synthesis of 4e To a 500 mL three-necked round-bottom flask, 4d (2.50 g, 7.710 mmol, 1.00 equiv), ethyl acetate (50.00 mL), and NaNO (5.32 g, 77.100 mmol, 10.00 equiv) were added at 0 °C. To the above mixture, HNO (4.86 g, 77.127 mmol, 10.00 equiv) in HO (150.00 mL) was added dropwise over 0.5 h at 0 °C. The resulting mixture was stirred at 0 °C for 5 h under a nitrogen atmosphere. The reaction was quenched by adding ice / salt (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (30:1) to give 4e (1.6 g, 63.92%) as a pale yellow oil.

[0120] Synthesis of 4f To a 250 mL sealed tube, 4e (500.00 mg, 1.711 mmol, 1.00 equiv), NH3.HO (70.00 mL), CH3CN (70.00 mL), and Cu2O (48.97 mg, 0.342 mmol, 0.20 equiv) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give 4f (270 mg, 67.04%) as a pale yellow solid.

[0121] Synthesis of 4g To a 100 mL three-necked round-bottom flask, 4f (230.00 mg, 1.007 mmol, 1.00 equiv), MeOH (5.00 mL), and 3-(trifluoromethyl)pyridine-2-carbaldehyde (264.62 mg, 1.511 mmol, 1.50 equiv) were added at room temperature. The resulting mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. To the above mixture, NaBH (76.23 mg, 2.014 mmol, 2.00 equiv) was added portionwise over 10 min at 0 °C. The resulting mixture was stirred at 0 °C for an additional 2 h. The reaction was quenched at 0 °C by adding saturated NH Cl (aq) (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give 4g (130 mg, 30.98%) as a pale yellow solid.

[0122] Synthesis of 4 To an 8 mL sealed tube was added 4g (130.00 mg, 0.336 mmol, 1.00 equiv), DCM (2.00 mL), pyridine (159.26 mg, 2.016 mmol, 6.00 equiv), and triphosgene (39.83 mg, 0.134 mmol, 0.40 equiv) at 0 °C. The resulting mixture was stirred under a nitrogen atmosphere at 0 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give the crude product (120 mg). The crude product (120 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 50% B, 50% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.32) to give compound 4 (53.2 mg, 37.97%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 414 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.76-1.83 (m, 1H), 2.24-2.32 (m, 1H), 2.78-2.92 (m, 3H), 3.20-3.34 (m, 1H), 3.69 (s, 3H), 3.71-3.73 (m, 1H), 6.27-6.31 (m, 1H), 7.08-7.14 (m, 2H), δ7.30-7.35 (m, 3H), δ7.79-7.81 (d, 1H), δ8.34 (m, 1H).

[0123] Example 5. Synthesis of Compound 5 TIFF2024514339000167.tif76165 Synthesis of 5a A solution of borane-N,N-diethylaniline (1.99 g, 13.321 mmol, 1.10 equiv) and (R)-Me-CBS (12.00 mL, 12.0 mmol, 1.00 equiv, 1 M in toluene) in toluene (50.00 mL) was stirred at 30 °C for 20 min under a nitrogen atmosphere. 3-Nitroacetophenone (2.00 g, 12.110 mmol, 1.00 equiv) was then added at room temperature. The reaction was washed with water (20 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc 2:1) to give 5a (1.7 g, 80.62%) as a white solid.

[0124] Synthesis of 5b To a stirred mixture of 5a (1.50 g, 8.973 mmol, 1.00 equiv.), 4-methyl-1,2,4-triazole-3-thiol (1.24 g, 10.769 mmol, 1.20 equiv.), and PPh3 (4.71 g, 17.946 mmol, 2 equiv.) in THF (25.00 mL) was added dropwise DIAD (2.72 g, 13.460 mmol, 1.5 equiv.) at 0 °C under a nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (CH2Cl2 / MeOH 25:1) to give 5b (1.8 g, 70%) as a yellow solid.

[0125] Synthesis of 5c A mixture of 5b (1.80 g, 6.810 mmol, 1.00 equiv), Fe (1.14 g, 20.431 mmol, 3 equiv), and NH4Cl (2.19 g, 40.863 mmol, 6 equiv) in EtOH (20.00 mL) and HO (5.00 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through filter paper, and the filter cake was washed with EtOAc (3 × 5 mL). The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. This gave 5c (1.5 g, 87.42%) as a yellow solid.

[0126] 5d compositing A mixture of 5c (800.00 mg, 3.414 mmol, 1.00 equiv.), 3-(trifluoromethyl)pyridine-2-carbaldehyde (896.77 mg, 5.121 mmol, 1.50 equiv.), NaBH(OAc) (2170.79 mg, 10.242 mmol, 3 equiv.), and HOAc (1025.13 mg, 17.071 mmol, 5 equiv.) in DCE (7.00 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was washed with water (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1:1) to give 5d (540 mg, 37.79%) as a yellow solid.

[0127] Synthesis of 5 To a stirred mixture of 5d (350.00 mg, 0.890 mmol, 1.00 equiv) and pyridine (422.21 mg, 5.338 mmol, 6.00 equiv) in DCM (4.00 mL) was added triphosgene (92.40 mg, 0.311 mmol, 0.35 equiv) dropwise at 0 °C under a nitrogen atmosphere. The reaction was washed with water (10 mL) at room temperature. The residue was purified by preparative TLC (CHCl / MeOH = 15:1) to give compound 5 (53.1 mg, 13.79%) as an orange solid. LCMS: (ES, m / z): [M+H] + 420 1 H NMR: (400 MHz, DMSO-d6, δ ppm): δ 1.72-1.76 (d, 3H), 3.48 (s, 3H), 6.09-6.13 (d, 1H), 6.27-6.30 (m, 1H), 7.09-7.10 (d, 1H), 7.27-7.29 (d, 1H), 7.33 (s, 1H), 7.48-7.50 (m, 1H), 7.73-7.75 (d, 1H), 7.78-7.80 (d, 1H), 7.87 (s, 1H), 8.55 (s, 1H).

[0128] Example 6. Synthesis of Compound 6 TIFF2024514339000168.tif87165 Synthesis of 6a To a stirred mixture of (1R)-1-(3-nitrophenyl)ethanol (2.00 g, 11.964 mmol, 1.00 equiv.), 4-methyl-1,2,4-triazole-3-thiol (1.65 g, 14.329 mmol, 1.20 equiv.), and PPh3 (6.28 g, 23.929 mmol, 2 equiv.) in THF (25.00 mL) was added dropwise DIAD (3.63 g, 17.946 mmol, 1.5 equiv.) under a nitrogen atmosphere at 0 °C. The resulting mixture was diluted with brine (100 mL). The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 25:1) to give 6a (1.6 g, 49.59%) as a yellow solid.

[0129] Synthesis of 6b A mixture of 6a (1.60 g, 6.054 mmol, 1.00 equiv), Fe (1.01 g, 18.161 mmol, 3 equiv), and NH4Cl (1.94 g, 36.322 mmol, 6 equiv) in EtOH (20.00 mL) and HO (4.00 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 4 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6b (610 mg, 41.71%) as a yellow solid.

[0130] Synthesis of 6c A mixture of 6b (610.00 mg, 2.603 mmol, 1.00 equiv), 3-(trifluoromethyl)pyridine-2-carbaldehyde (683.79 mg, 3.905 mmol, 1.5 equiv), NaBH(OAc) (1655.22 mg, 7.810 mmol, 3 equiv), and HOAc (781.66 mg, 13.016 mmol, 5 equiv) in DCE (6.50 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with DCM (10 mL). The resulting mixture was washed with water (10 mL). The residue was purified by preparative TLC (CHCl / MeOH 25:1) to give 6c (375 mg, 35.52%) as a yellow solid.

[0131] Synthesis of 6 To a stirred mixture of 6c (280.00 mg, 0.712 mmol, 1.00 equiv) and pyridine (337.77 mg, 4.270 mmol, 6 equiv) in DCM (3.00 mL) was added triphosgene (73.92 mg, 0.249 mmol, 0.35 equiv) dropwise at 0 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 5 mL). The residue was purified by preparative TLC (CHCl / MeOH 15:1) to give compound 6 (151.8 mg, 50.24%) as an orange solid. LCMS: (ES, m / z): [M+H] + 420 1 H NMR: (400 MHz, DMSO-d6, δ ppm): δ 1.74-1.76 (d, 3H), 3.48 (s, 3H), 6.09-6.12 (m, 1H), 6.27-6.30 (m, 1H), 7.09-7.10 (d, 1H), 7.27-7.29 (d, 1H), 7.35 (s, 1H), 7.46-7.50 (m, 1H), 7.73-7.75 (d, 1H), 7.78-7.80 (d, 1H), 7.87 (s, 1H), 8.56 (s, 1H).

[0132] Example 7. Synthesis of Compound 7 TIFF2024514339000169.tif60165 Synthesis of 7 To a stirred solution of 10c (4.40 g, 9.123 mmol, 1.00 equiv) and pyridine (4.33 g, 54.741 mmol, 6.00 equiv) in DCM (250.00 mL) was added triphosgene (0.95 g, 3.193 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by adding NaHCO (aq) (100 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 200 mL). The resulting mixture was concentrated in vacuo. The residue was purified by trituration with methyl tert-butyl ether (50 mL). This gave compound 7 (4.2 g, 90.57%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 508 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.97 (s, 3H), 3.53 (s, 2H), 4.91-4.96 (m, 4H), 6.89-6.91 (d, 1H), 7.18 (s, 1H), 7.39-7.45 (m, 3H), 7.73-7.75 (m, 1H), 8.04 (s, 1H), 8.20 (s, 1H).

[0133] Example 8. Synthesis of Compound 8 TIFF2024514339000170.tif55165 Synthesis of 8 To a stirred solution of compound 7 (680.00 mg, 1.338 mmol, 1.00 equiv.) and tributyl(ethenyl)stannane (636.33 mg, 2.007 mmol, 1.50 equiv.) in dioxane (10.00 mL), Pd(PPh3)4 (155.00 mg, 0.1338 mmol, 0.1 equiv.) was added under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (30:1) to give compound 8 (400 mg, crude). The crude product (20 mg) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B, 45% B in 8 min; wavelength: 220 nm; RT1 (min): 7.92) to give compound 8 (7.4 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 456 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.98 (s, 3H), 3.54 (s, 2H), 4.92-4.97 (m, 4H), 5.25-5.27 (d, 1H), 5.80-5.85 (d, 1H), 6.66-6.73 (m, 1H), 6.88-6.90 (d, 1H), 7.39-7.43 (m, 4H), 7.75-7.77 (m, 1H), 7.91 (s, 1H), 8.21 (s, 1H).

[0134] Example 9. Synthesis of Compound 9 TIFF2024514339000171.tif50165 Synthesis of 9 An 8 mL sealed tube, purged with and maintained under an inert atmosphere of nitrogen, was charged with dioxane (2.00 mL), compound 7 (50.00 mg, 0.098 mmol, 1.00 equiv), XantPhos (22.77 mg, 0.039 mmol, 0.40 equiv), Pd(OAc) (4.42 mg, 0.020 mmol, 0.20 equiv), and CsCO (96.15 mg, 0.295 mmol, 3.00 equiv). The resulting solution was stirred at 100 °C overnight. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give the crude product. The crude product (20 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 45% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.35) to give compound 9 (2.5 mg, 5.91%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 430 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.97 (s, 3H), 3.53 (s, 2H), 4.91-4.96 (m, 4H), 6.27-6.30 (m, 1H), 6.88-6.90 (d, 1H), 7.09-7.11 (d, 1H), 7.38 (s, 1H), 7.40-7.42 (m, 2H), 7.74-7.79 (m, 2H), 8.20 (s, 1H).

[0135] Example 10. Synthesis of Compound 10 TIFF2024514339000172.tif97165 Synthesis of 10a To a stirred mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (25.00 g, 103.730 mmol, 1.00 equiv) in CH2I2 (75.00 mL) was added t-BuNO2 (12.84 g, 124.515 mmol, 1.20 equiv) dropwise. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added I2 (28.96 g, 114.102 mmol, 1.10 equiv) in portions. The resulting mixture was stirred at room temperature for an additional 6 h. The reaction was quenched by adding NaHCO3 (aq) (300 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1) to give 10a (17 g, 46.57%) as a pale yellow oil.

[0136] Synthesis of 10b To a stirred solution of 10a (17.00 g, 48.310 mmol, 1.00 equiv) in THF (300.00 mL) was added i-PrMgBr (18.32 mL, 53.141 mmol, 1.10 equiv) dropwise at −78° C. under an argon atmosphere. The resulting mixture was stirred at −78° C. for 30 min under an argon atmosphere. To the above mixture was added DMF (7.06 g, 96.588 mmol, 2.00 equiv) dropwise at −78° C. The resulting mixture was stirred at −78° C. for an additional 2 h. The reaction was quenched by adding NH4Cl(aq) (800 mL) at room temperature. The aqueous layer was extracted with EtOAc (2×400 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 10b (4.5 g, 36.67%) as a white solid.

[0137] Synthesis of 10c To a stirred solution of 10b (3.50 g, 13.779 mmol, 1.00 equiv) and I-3 (3.37 g, 13.795 mmol, 1.00 equiv) in DCE (50.00 mL) was added HOAc (1.65 g, 27.558 mmol, 2.00 equiv) and NaBH(OAc) (5.84 g, 27.558 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with CHCl (3 × 150 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (50:1) to give 10c (4.5 g, 67.71%) as a pale yellow solid.

[0138] Synthesis of compound 7 To a stirred solution of 10c (4.40 g, 9.123 mmol, 1.00 equiv) and pyridine (4.33 g, 54.741 mmol, 6.00 equiv) in DCM (250.00 mL) was added triphosgene (0.95 g, 3.193 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by adding NaHCO (aq) (100 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 200 mL). The resulting mixture was concentrated in vacuo. The residue was purified by trituration with methyl tert-butyl ether (50 mL). This gave compound 7 (4.2 g, 90.57%) as a yellow solid.

[0139] Synthesis of 10d To a solution of compound 7 (2.20 g, 4.328 mmol, 1.00 equiv.), TMEDA (0.50 g, 4.328 mmol, 1.00 equiv.) in dioxane (180.00 mL), butyldi-1-adamantylphosphine (0.31 g, 0.866 mmol, 0.20 equiv.), and Pd(OAc) (0.10 g, 0.433 mmol, 0.10 equiv.) were added in an autoclave. After flushing the autoclave with CO / H (1:1) three times, the mixture was pressurized to 10 atm with CO / H (1:1) at 90 °C and stirred overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (20:1) to give 10d (1.1 g, 55.56%) as a yellow solid, and eluted with CH2Cl2 / MeOH (5:1) to give compound 20 (600 mg) as a yellow solid.

[0140] Synthesis of 10 To a stirred mixture of 10d (300.00 mg, 0.656 mmol, 1.00 equiv.) and 5-azaspiro[2.4]heptane hydrochloride (175.27 mg, 1.312 mmol, 2.00 equiv.) in DCE (10.00 mL) was added EtN (132.73 mg, 1.312 mmol, 2.00 equiv.) and NaBH(OAc) (278.01 mg, 1.312 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 30 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 50% B, 50% B in 7 min; Wavelength: 220 nm; RT1 (min): 6.57) to give compound 10 (120.5 mg, 34.11%) as a yellow solid. LCMS: (ES, m / z): [M+H] + : 539 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 0.50-0.52 (m, 4H), 1.73-7.76 (t, 2H), 2.46 (s, 2H), 2.68-2.70 (t, 3H), 3.40 (s, 2H), 3.43 (2, 2H), 4.91-4.96 (m, 4H), 6.89-6.91 (d, 1H), 7.05 (s, 1H), 7.30 (s, 1H), 7.38-7.45 (m, 2H), 7.68 (s, 1H), 7.77-7.81 (d, 1H), 8.20 (s, 1H).

[0141] Example 11. Synthesis of Compound 11 TIFF2024514339000173.tif50165 Synthesis of 11 To a stirred solution / mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), 4-fluoro-4-methylpiperidine hydrochloride (67.17 mg, 0.438 mmol, 2.00 equiv.), and EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 50% B, 50% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.83) to give compound 11 (40.9 mg, 33.49%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 559 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.29-1.35 (d, 3H), 1.61-1.69 (m, 1H), 1.70-1.78 (m, 3H), 2.22-2.31 (m, 2H), 2.60-2.69 (m, 2H), 2.98 (s, 3H), 4.93-4.95 (m, 4H), 6.86-6.91 (d, 1H), 7.03 (s, 1H), 7.30 (s, 1H), 7.38-7.42 (m, 2H), 7.68 (s, 1H), 7.77-7.81 (d, 1H), 8.20 (s, 1H).

[0142] Alternatively, compound 11 can also be prepared as outlined below. TIFF2024514339000174.tif44165

[0143] To a stirred mixture of 10d (3 g, 6.559 mmol, 1 equiv.) and 4-fluoro-4-methylpiperidine hydrochloride (3.02 g, 19.677 mmol, 3 equiv.) in DCE (50 mL) was added TEA (2.65 g, 26.236 mmol, 4 equiv.). The resulting mixture was stirred at room temperature for 2 h. To the above mixture was added NaBH(OAc) (2.78 g, 13.118 mmol, 2 equiv.). The resulting mixture was further stirred at room temperature overnight. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CHCl (3 × 25 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol NH4HCO3), gradient from 5% to 85% in 40 min; detector, UV 254 nm, to give compound 11 (929.3 mg, 25.37%) as a yellow solid. LC-MS- 11: (ES, m / z): [M+H] + 559. H-NMR- 11: (400 MHz, DMSO-d6, ppm): δ 1.29-1.35 (d, 3H), δ 1.61-3 (m, 4H), δ 2.23-2.33 (m, 2H), δ 2.60-2.63 (m, 2H), δ 2.97 (s, 3H), δ 3.31 (s, 2H), δ 3.53 (s, 2H), δ 4.91-4.96 (m, 4H), δ 6.88-6.90 (d, 1H), δ 7.02 (s, 1H), δ 7.33 (s, 1H), δ 7.38-7.42 (m, 2H), δ 7.69 (s, 1H), δ 7.75-7.77 (m, 1H), δ 8.21 (s, 1H).

[0144] Example 12. Synthesis of Compound 12 TIFF2024514339000175.tif60165 Synthesis of 12 To a stirred mixture of 10d (100.00 mg, 1.00 equiv.), (2R)-2-methylmorpholine hydrochloride (60.17 mg, 0.437 mmol, 2.00 equiv.), and EtN (44.24 mg, 0.437 mmol, 2.00 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.437 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL) at room temperature. The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 50 mm, 5 μm, 13 nm; Mobile phase A: water (20 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 44% B, 44% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.83) to give compound 12 (30.8 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 543. 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.04-1.06 (d, 3H), 1.71-1.78(m, 1H), 2.02-2.10 (m, 1H), 2.67-2.71 (m, 1H), 2.72-2.76 (m, 1H), 2.98 (s, 3H), 3.28 (s, 3H), 3.35-3.54 (m, 4H), 3.73-3.78 (d, 1H), 4.92-4.97 (m, 4H), 6.86-6.91 (d, 1H), 7.03 (s, 1H), 7.33 (s, 1H), 7.38-7.42 (m, 2H), 7.70 (s, 1H), 7.77-7.81 (d, 1H), 8.21 (s, 1H).

[0145] Alternatively, compound 12 can also be prepared as follows. TIFF2024514339000176.tif50165

[0146] Synthesis of 1.12 To a stirred solution of 10d (2 g, 4.372 mmol, 1.00 equiv.) and (2R)-2-methylmorpholine (1.33 g, 13.116 mmol, 3 equiv.) in DCE (60 mL) was added NaBH(OAc) (1.85 g, 8.744 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 6 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CHCl / MeOH (2 × 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH in water, gradient from 10% to 65% in 30 min; detector, UV 254 nm. This gave 12 (1.1056 g, 46.60%) as a yellow solid. LC-MS- 12: (ES, m / z): [M+H] + 543. H-NMR- 12: (400 MHz, DMSO-d6, ppm): δ 1.04-1.06 (d, 3H), δ 1.71-1.78 (m, 1H), δ 2.05-2.08 (m, 1H), δ 2.67-2.72 (m, 1H), δ 2.72-2.75 (m, 1H), δ 2.97 (s, 3H), δ 3.28 (s, 2H), δ 3.45-3.54 (m, 4H), δ 3.73-3.76 (d, 1H), δ 4.91-4.96 (m, 4H), δ 6.88-6.91 (d, 1H), δ 7.02 (s, 1H), δ 7.33 (s, 1H), δ 7.40-7.42 (m, 2H), δ 7.68 (s, 1H), δ 7.77-7.81 (d, 1H), δ 8.21 (s, 1H).

[0147] Example 13. Synthesis of Compound 13 TIFF2024514339000177.tif60165 Synthesis of 13 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), 4-fluoropiperidine hydrochloride (61.04 mg, 0.437 mmol, 2.00 equiv.), and EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (20 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 50% B, 50% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.75) to give compound 13 (44.2 mg, 37.13%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 545 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 1.62-1.81 (m, 2H), 1.83-1.90 (m, 2H), 2.33-2.37 (m, 2H), 2.55-2.67 (m, 2H), 2.98 (s, 3H), 3.54 (s, 2H), 4.62-4.77 (m, 1H), 4.91-4.96 (m, 4H), 6.89-6.91 (d, 1H), 7.02 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 2H), 7.68 (s, 1H), 7.74-7.76 (d, 1H), 8.20 (s, 1H).

[0148] Example 14. Synthesis of Compound 14 TIFF2024514339000178.tif60165 Synthesis of 14 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), (3S)-3-fluoropyrrolidine hydrochloride (54.90 mg, 0.438 mmol, 2.00 equiv.), and EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (15 mL) at room temperature. The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B, 45% B in 7 min; Wavelength: 220 nm; RT1 (min): 6.32) to give compound 14 (50.8 mg, 43.80%) as a yellow solid. LCMS: (ES, m / z): [M+H]+ 531 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 1.84-1.95 (m, 1H), 2.10-2.20 (m, 1H), 2.33-2.37 (m, 1H), 2.60-2.72 (m, 1H), 2.77-2.87 (m, 2H), 2.97 (s, 3H), 3.43 (s, 2H), 3.54 (s, 2H), 4.91-4.96 (m, 4H), 5.13-5.30 (m, 1H), 6.88-6.90 (d, 1H), 7.03 (s, 1H), 7.32 (s, 1H), 7.38-7.42 (m, 2H), 7.71 (s, 1H), 7.74-7.77 (m, 1H), 8.20 (s, 1H).

[0149] Example 15. Synthesis of Compound 15 TIFF2024514339000179.tif44165 Synthesis of 15 A 20 mL sealed tube, purged with and maintained under an inert atmosphere of nitrogen, was charged with dioxane (10 mL), compound 7 (200.00 mg, 0.393 mmol, 1.00 equiv), 3-methyl-3,8-diazabicyclo[3.2.1]octane hydrochloride (320.01 mg, 1.967 mmol, 5.00 equiv), CsCO (641.00 mg, 1.967 mmol, 5 equiv), and Pd PEPPSI IPentCl (169.30 mg, 0.197 mmol, 0.50 equiv). The resulting solution was stirred at 90 °C overnight. The resulting mixture was filtered, and the filter cake was washed with CHCl (1 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give the crude product. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water, B: MeCN, gradient from 45% B to 60% B in 15 min; detector, UV 254 nm, to give compound 15 (33.7 mg, 15.19%) as a yellow solid. LCMS: (ES, m / z): [M+H] +554 1 H NMR: (400 MHz, DMSO-d6, δ ppm): δ 1.84-1.86 (m, 4H), 2.12 (s, 3H), 2.77-2.34 (m, 2H), 2.48-2.50 (m, 2H), 2.98 (s, 3H),3.53 (s, 2H), 4.09 (s, 2H), 4.90-4.96 (m, 4H), 6.86-6.88 (d, 1H), 6.93 (s, 1H), 7.14-7.16 (m, 1H), 7.28 (s, 1H), 7.37-7.41 (m, 2H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0150] Example 16. Synthesis of Compound 16 TIFF2024514339000180.tif55165 Synthesis of 16 Compound 4 (59.00 mg) was separated by preparative chiral SFC under the following conditions: column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.2% TEA), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 40% B to 40% B in 15 min; wavelength: 220 / 254 nm; RT1 (min): 10.54; RT2 (min): 12.60; first peak was product. This resulted in compound 16 (15.9 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 414 1 H NMR: (400 MHz, DMSO-d6 δ ppm) δ 1.76-1.81 (m, 1H), 2.25-2.30 (m, 1H), 2.78-2.92 (m, 3H), 3.20-3.34 (m, 1H), 3.69 (s, 3H), 3.71-3.73 (m, 1H), 6.27-6.31 (m, 1H), 7.07-7.08 (d, 1H), 7.09 (s, 1H), 7.30-7.32 (m, 3H), 7.79-7.81 (d, 1H), 8.38 (s, 1H).

[0151] Example 17. Synthesis of Compound 17 TIFF2024514339000181.tif55165 Synthesis of 17 Compound 4 (59.00 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.2% TEA), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 40% B to 40% B in 15 min; wavelength: 220 / 254 nm; RT (min): 12.60. This resulted in compound 17 (17.7 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 414 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 1.78-1.82 (m, 1H), 2.26-2.34 (m, 1H), 2.80-2.89 (m, 3H), 3.20-3.25 (m, 1H), 3.69 (s, 3H), 3.71-3.73 (m, 1H), 6.28-6.31(m, 1H), 7.08-7.10 (d, 1H), 7.14 (s, 1H), 7.29-7.35 (m, 3H), 7.79-7.81 (d, 1H), 8.39 (s, 1H).

[0152] Example 18. Synthesis of Compound 18 TIFF2024514339000182.tif50165 Synthesis of 18 An 8 mL sealed tube, purged with and maintained under an inert atmosphere of nitrogen, was charged with DMF (2.00 mL), compound 7 (50.00 mg, 0.098 mmol, 1.00 equiv.), Pd(PPh3)4 (11.37 mg, 0.010 mmol, 0.10 equiv.), and Zn(CN)2 (23.11 mg, 0.197 mmol, 2 equiv.). The resulting solution was stirred at 100 °C for 3 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 0% to 50% over 20 min; detector, UV 254 nm. This resulted in 17.9 mg (39.24%) of compound 18 as a yellow solid. LCMS: (ES, m / z): [M+H] + 455 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.98 (s, 3H), 3.53 (s, 2H), 4.89-4.96 (m, 4H), 6.91-6.93 (d, 1H), 7.30 (s, 1H), 7.42-7.43 (m, 2H), 7.52 (s, 1H), 7.71-7.74 (d, 1H), 8.20 (s, 1H), 8.71 (s, 1H).

[0153] Example 19. Synthesis of Compound 19 TIFF2024514339000183.tif44165 Synthesis of 19a To a stirred mixture of compound 7 (2000.00 mg, 3.935 mmol, 1.00 equiv.) and tributyl(1-ethoxyethenyl)stannane (2131.56 mg, 5.902 mmol, 1.5 equiv.) in dioxane (20.00 mL) was added Pd(PPh3)4 (454.68 mg, 0.393 mmol, 0.1 equiv.) at room temperature under an atmospheric atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h. The reaction was quenched by adding NH4Cl(aq) (60 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 40 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (20:1) to give 19a (1550 mg, 70.98%) as a yellow solid.

[0154] Synthesis of 19 To a stirred mixture of 6-(1-ethoxyethenyl)-2-(3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl)-8-(trifluoromethyl)imidazo[1,5-a]pyridin-3-one (19a) (1550.00 mg, 3.103 mmol, 1.00 equiv) in THF (10.00 mL) was added HCl (1.00 mL, 1 M) and HO (10.00 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with CHCl (3 × 30 mL). The resulting mixture was concentrated under reduced pressure to give the crude product (1.44 g) as a yellow solid. The crude product (20 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (20 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 45% B, 45% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.48) to give compound 19 (16.8 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 472 1H NMR: (400 MHz, DMSO, ppm): δ 2.57 (s, 3H), 3.00 (s, 3H), 3.55 (s, 2H), 4.93-4.98 (m, 4H), 6.93-6.95 (d, 1H), 7.31 (s, 1H), 7.42-7.46 (m, 2H), 7.51 (s, 1H), 7.76-7.77 (m, 1H), 8.22 (s, 1H), 8.58 (s, 1H).

[0155] Example 20. Synthesis of Compound 20 TIFF2024514339000184.tif44165 Synthesis of 20 To a solution of compound 7 (2.20 g, 4.328 mmol, 1.00 equiv.) and TMEDA (502.95 mg, 4.328 mmol, 1.00 equiv.) in dioxane (100.00 mL), butyldi-1-adamantylphosphine (0.31 g, 0.866 mmol, 0.20 equiv.) and Pd(OAc) (97.17 mg, 0.433 mmol, 0.10 equiv.) were added in an autoclave. After flushing the autoclave with CO / H (1:1) three times, the mixture was pressurized to 10 atm with CO / H (1:1) at 100 °C and stirred overnight. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (20:1) to give 10d (1.1 g, 55.56%) as a yellow solid, and eluted with CHCl / MeOH (5:1) to give compound 20 (600 mg) as a yellow solid. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 35% B, 35% B in 8 min; Wavelength: 220 nm; RT1 (min): 6.08) to give compound 20 (11.6 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 474 1H NMR: (400 MHz, DMSO-d6, ppm): δ 2.97 (s, 3H), 3.54 (s, 2H), 4.91-4.97 (m, 4H), 6.87-6.89 (d, 1H), 7.31 (s, 1H), 7.38-7.44 (m, 3H), 7.75-7.77 (d, 1H), 8.16 (s, 1H), 8.20 (s, 1H).

[0156] Example 21. Synthesis of Compound 21 TIFF2024514339000185.tif60165 Synthesis of 21 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), 5-azaspiro[2.3]hexane hydrochloride (52.29 mg, 0.438 mmol, 2.00 equiv.), and EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B, 45% B in 7 min; Wavelength: 220 nm; RT1 (min): 6.77) to give compound 21 (38.6 mg, 33.66%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 525 1H NMR: (400 MHz, DMSO-d6, ppm): δ 0.51 (s, 4H), 2.97 (s, 3H), 3.29 (s, 4H), 3.46 (s, 2H), 3.53 (s, 2H), 4.91-4.96 (m, 4H), 6.88-6.90 (d, 1H), 7.00 (s, 1H), 7.30 (s, 1H), 7.38-7.42 (m, 2H), 7.67 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0157] Example 22. Synthesis of Compound 22 TIFF2024514339000186.tif60165 Synthesis of 22 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), (3S)-3-fluoropiperidine hydrochloride (61.04 mg, 0.438 mmol, 2.00 equiv.), and EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL) at room temperature. The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 50% B, 50% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.65) to give compound 22 (42.9 mg, 36.03%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 545 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.44-1.67 (m, 2H), 1.72-1.82 (m, 2H), 2.28-2.39 (m, 1H), 2.42-2.50 (m, 2H), 2.71-2.75 (m, 1H), 2.98 (s, 3H), 3.54 (s, 2H), 4.58-4.72 (m, 1H), 4.91-4.96 (m, 4H), 6.89-6.91 (d, 1H), 7.01 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 2H), 7.69 (s, 1H), 7.74-7.75 (d, 1H), 8.20 (s, 1H).

[0158] Example 23. Synthesis of Compound 23 TIFF2024514339000187.tif60165 Synthesis of 23 To a stirred mixture of 10d (1.00 equiv.), 3-fluoroazetidine hydrochloride (2.00 equiv.), and EtN (2 equiv.) in DCE (2 mL) was added NaBH(OAc) (2 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL) at room temperature. The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 35% B, 35% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.13) to give compound 23 (26.5 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 517 1H NMR: (400 MHz, DMSO-d6, ppm): δ 2.97 (s, 3H), 3.13-3.17 (m, 1H), 3.19-3.23 (m, 1H), 3.44 (s, 2H), 3.50-3.60 (m, 4H), 4.91-4.97 (m, 4H), 5.11-5.30 (m, 1H), 6.88-6.91 (d, 1H), 6.98 (s, 1H), 7.30 (s, 1H), 7.38-7.42 (m, 2H), 7.70-7.76 (m, 2H), 8.20 (s, 1H).

[0159] Example 24. Synthesis of Compound 24 TIFF2024514339000188.tif60165 Synthesis of 24 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), (3R)-pyrrolidine-3-carbonitrile hydrochloride (57.97 mg, 0.437 mmol, 2 equiv.), and EtN (44.24 mg, 0.437 mmol, 2 equiv.) in DCE (2.00 mL) was added NaBH(OAc) (92.67 mg, 0.437 mmol, 2 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 35% B, 35% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.0) to give compound 24 (39.5 mg, 33.61%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 538 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.92-2.00 (m, 1H), 2.16-2.25(m, 1H), 2.50-2.51 (m, 1H), 2.67-2.75 (m, 2H), 2.78-2.82 (m, 1H), 2.98 (s, 3H), 3.25-3.30 (m, 2H), 3.45 (s, 2H), 3.54 (s, 2H), 4.91-4.97 (m, 4H), 6.89-6.91 (d, 1H), 7.03 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 2H), 7.72-7.77 (m, 2H), 8.20 (s, 1H).

[0160] Example 25. Synthesis of Compound 25 TIFF2024514339000189.tif55165 Synthesis of 25 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.) and 3-azabicyclo[3.1.0]hexane hydrochloride (52.29 mg, 2.00 equiv.) in DCE (2.00 mL), EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) and NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.) were added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B, 50% B in 7 min; wavelength: 220 nm; RT1 (min): 6.63) to give compound 25 (39.2 mg, 34.18%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 525 1H NMR: (400 MHz, DMSO-d6, ppm): δ 0.36-0.37 (m, 1H), 0.61-0.64 (m, 1H), 1.38-1.39 (m, 2H), 2.34-2.36 (m, 2H), 2.87-2.89 (m, 2H), 2.97 (s, 3H), 3.39 (s, 2H), 3.53 (s, 2H), 4.91-4.96 (m, 4H), 6.88-6.90 (d, 1H), 6.95 (s, 1H), 7.30 (s, 1H), 7.38-7.42 (m, 2H), 7.64 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0161] Example 26. Synthesis of Compound 26 TIFF2024514339000190.tif113165 Synthesis of 26a To a mixture of Zn (23.77 g, 0.363 mmol, 4.5 equiv.) and ethyl 2-bromo-2,2-difluoroacetate (0.2 g, 9.85 mmol) in THF (200 mL) was added DIBAL-H (0.46 g, 0.003 mmol, 0.04 equiv.) at 30 °C. The mixture was then stirred at 30 °C for 1 h. Next, tert-butyl N-(3-acetylphenyl)carbamate (19.00 g, 80.754 mmol, 1.00 equiv.) and ethyl 2-bromo-2,2-difluoroacetate (24.59 g, 0.121 mmol, 1.5 equiv.) in THF (200 mL) were added dropwise at 40 °C and stirred at 40 °C for 3 h. The mixture was filtered, and the filtrate was poured into saturated NH Cl (200 mL). The mixture was then extracted with EtOAc (3×200 mL). The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1) to give 26a (11.1 g, 36.34%) as a pale yellow oil.

[0162] Synthesis of 26b To a solution of 26a (11.00 g, 30.609 mmol, 1.00 equiv) in EtOH (150 mL) was added hydrazine hydrate (98%) (7.66 g, 153.046 mmol, 5 equiv). The mixture was then stirred at 25 °C for 16 h. The resulting mixture was diluted with water (200 mL). The aqueous layer was extracted with CHCl (4 × 100 mL). The resulting mixture was concentrated in vacuo. The crude product was used immediately in the next step without further purification. This resulted in 26b (10.1 g, 92.49%) as a pale yellow solid.

[0163] Synthesis of 26c To a solution of 26b (10.00 g, 28.956 mmol, 1.00 equiv) in THF (100 mL) was added methyl isothiocyanate (4.23 g, 0.058 mmol, 2 equiv). The mixture was then stirred at 70 °C for 2 h. The mixture was concentrated to give crude product 26c (12 g, 84.18%) as a yellow oil, which was used without purification.

[0164] Synthesis of 26d A solution of 26c (12 g, 28.677 mmol, 1.00 equiv) in NaOH (1.00 M, 100 mL) was stirred at 50° C. for 2 h. The mixture was acidified to pH 7 with HCl (1 M) and filtered, resulting in 26d (10 g, 79.25%) as an off-white solid.

[0165] Synthesis of 26e To a stirred solution of 26d (10.00 g, 24.973 mmol, 1.00 equiv) in DCM (100.00 mL) was added HO (8.49 g, 74.879 mmol, 3.00 equiv, 30%) in HOAc (3.00 g, 49.957 mmol, 2.00 equiv) at room temperature under atmospheric pressure. The resulting mixture was stirred at room temperature under atmospheric pressure for 3 h. The mixture was basified to pH 8 with saturated NaHCO (aq) and quenched with NaSO (aq). The aqueous layer was extracted with CHCl (2 × 100 mL). The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 26e (4.5 g, 46.96%) as an off-white solid.

[0166] Synthesis of 26f To a stirred solution of 26e (4.50 g, 12.215 mmol, 1.00 equiv) in DCM (100.00 mL) was added DAST (5.91 g, 0.037 mmol, 3.00 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with NaHCO3 (aq) at room temperature. The aqueous layer was extracted with CHCl2 (2 × 100 mL). The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give 26f (3.5 g, 72.72%) as an off-white solid.

[0167] Synthesis of 26g A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with HCl (g) in EtOAc (50.00 mL, 875.874 mmol, 92.69 equiv.). This was followed by the addition of 26g (3.50 g, 9.450 mmol, 1.00 equiv.) at room temperature. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. This resulted in the yield of 3 g (93.15%) of 26g as an off-white solid.

[0168] Synthesis of 26h A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with DCE (20.00 mL), 26g (1.50 g, 4.890 mmol, 1.00 equiv), TEA (0.49 g, 0.005 mmol, 1 equiv), 5-bromo-3-(trifluoromethyl)pyridine-2-carbaldehyde (1.24 g, 0.005 mmol, 1.00 equiv), and NaBH(OAc) (3.11 g, 0.015 mmol, 3 equiv). The resulting solution was stirred at room temperature overnight. The resulting mixture was diluted with DCM (100 mL) and washed with 50 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give 26h (1.2 g, 45.86%) as a pale yellow solid.

[0169] 26i synthesis To a stirred solution of 26h (1.20 g, 2.361 mmol, 1.00 equiv) and pyridine (1.12 g, 0.014 mmol, 6 equiv) in DCM (60.00 mL) was added triphosgene (0.25 g, 0.001 mmol, 0.35 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was washed with 30 mL of NaHCO (aq). The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give 26i (1.1 g, 82.39%) as a yellow solid.

[0170] Synthesis of 26j To a solution of 26i (1.00 g, 1.872 mmol, 1.00 equiv) in dioxane (30.00 mL) was added cataCXium (0.13 g, 0.363 mmol, 0.19 equiv), Pd(OAc) (0.04 g, 0.178 mmol, 0.10 equiv), and TMEDA (0.44 g, 3.744 mmol, 2.00 equiv) in a pressure tank. The mixture was purged with nitrogen for 3 minutes, then pressurized to 10 atm with CO / H (1:1) at 80 °C and stirred overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with CHCl (2 × 100 mL). The residue was purified by preparative TLC (CH2Cl2 / MeOH 20:1) to give 26j (500 mg, 50.29%) as a yellow solid.

[0171] Synthesis of 26 To a stirred solution of 26j (250.00 mg, 0.517 mmol, 1.00 equiv) and (3S)-3-fluoropyrrolidine hydrochloride (194.83 mg, 1.552 mmol, 3.00 equiv) in DCE (10.00 mL) was added EtN (157.01 mg, 1.552 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min. To the above mixture was added NaBH(OAc) (328.85 mg, 1.552 mmol, 3 equiv), and then the mixture was stirred at room temperature overnight. The resulting mixture was washed with 10 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give the crude product (top). The crude product (120 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 57% B, 57% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.23) to give compound 26 (59.3 mg, 20.42%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 557 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.83-1.95 (m, 1H), 1.99-2.17 (m, 3H), 2.19-2.24 (m, 1H), 2.41-2.49 (m, 1H), 2.67-2.71 (m, 1H), 2.75-2.84 (m, 2H), 3.31-3.52 (m, 5H), 5.16-5.29 (m, 1H), 7.05 (s, 1H), 7.36-7.38 (m, 2H), 7.56-7.60 (m, 1H), 7.73-7.75 (d, 1H), 7.89-7.92 (m, 2H), 8.64 (s, 1H).

[0172] Example 27. Synthesis of Compound 27 TIFF2024514339000191.tif60165 Synthesis of 27a To a stirred solution of 2-chloro-3-(trifluoromethyl)pyridine (1.00 g, 5.508 mmol, 1.00 equiv) in toluene (10.00 mL) was added tributyl(1-ethoxyethenyl)stannane (2.98 g, 8.263 mmol, 1.5 equiv) and Pd(PPh3)4 (0.64 g, 0.551 mmol, 0.1 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The residue was washed with water (15 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (40:1) to give 27a (1.1 g, 86.35%) as a white oil.

[0173] Synthesis of 27b To a stirred solution of 27a (1.08 g, 4.973 mmol, 1.00 equiv) in THF (2.00 mL) was added HCl (2.00 mL, 1 M) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was quenched with saturated Na2CO3 (aq) (20 mL). The resulting mixture was extracted with EtOAc (3 x 25 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo to give 27b (850 mg, 90.42%) as a yellow oil.

[0174] Synthesis of 27c To a stirred solution of 27b (800.00 mg, 4.230 mmol, 1.00 equiv) in MeOH (10.00 mL) was added NaBH (80.01 mg, 2.115 mmol, 0.5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with 40 mL of water. The resulting mixture was extracted with 3 × 40 mL of EtOAc. The residue was purified by preparative TLC (CH2Cl2 / MeOH 20:1) to give 27c (400 mg, 44.53%) as a yellow oil.

[0175] Synthesis of 27d To a stirred solution of 27c (500.00 mg, 2.616 mmol, 1.00 equiv) in DCM (6 mL) was added TsCl (997.35 mg, 5.232 mmol, 2.00 equiv) and TEA (794.05 mg, 7.848 mmol, 3.00 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The resulting mixture was washed with 2 × 5 mL of water. The organic layer was concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc 2:1) to give 27d (500 mg, 52.03%) as a yellow oil.

[0176] Synthesis of 27e To a stirred solution of 27d (500.00 mg, 1.448 mmol, 1.00 equiv) in DMF (6.00 mL) was added 3-[1-(4-methyl-1,2,4-triazol-3-yl)propan-2-yl]aniline (375.78 mg, 1.738 mmol, 1.20 equiv) and K2CO3 (600.30 mg, 4.344 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The resulting mixture was diluted with 20 mL of water. The resulting mixture was extracted with 3 × 20 mL of EtOAc. The residue was purified by preparative TLC (CHCl2 / MeOH 20:1) to give 27e (80 mg, 13.20%) as a yellow oil.

[0177] Synthesis of 27 To a stirred solution of 27e (80.00 mg, 0.205 mmol, 1.00 equiv) in DCM (2 mL) was added pyridine (98.72 mg, 1.230 mmol, 6.00 equiv) and BTC (16.38 mg, 0.072 mmol, 0.35 equiv) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 10 min under a nitrogen atmosphere. The resulting mixture was diluted with 15 mL of water and extracted with DCM (3 × 20 mL). The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase A: water (0.1% NH4HCO3), B: CH3CN, gradient from 45% B to 55% B in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give compound 27 (15.6 mg, 17.95%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 416 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.31-1.33 (d, 3H), 1.99 (s, 3H), 2.99-3.03 (m, 2H), 3.30-3.33 (m, 1H), 3.42 (s, 3H), 6.15-6.19 (m, 1H), 7.01-7.02 (d, 1H), 7.31-7.38 (m, 2H), 7.41-7.42 (d, 1H), 7.46-7.49 (m, 1H), 7.70-7.72 (d, 1H), 8.27 (s, 1H).

[0178] Example 28. Synthesis of Compound 28 TIFF2024514339000192.tif55165 Synthesis of 28 To a stirred solution of 26j (250.00 mg, 0.517 mmol, 1.00 equiv) and (3S)-3-fluoropyrrolidine hydrochloride (194.83 mg, 1.552 mmol, 3.00 equiv) in DCE (10.00 mL) was added EtN (157.01 mg, 1.552 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 minutes. To the above mixture was added NaBH(OAc) (328.85 mg, 1.552 mmol, 3 equiv), and then the mixture was stirred at room temperature overnight. The resulting mixture was washed with 10 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give the crude product (below). The crude product (100 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.55) to give compound 28 (27.2 mg, 9.33%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 557 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.83-1.95 (m, 1H), 1.99-2.17 (m, 3H), 2.19-2.24 (m, 1H), 2.41-2.49 (m, 1H), 2.67-2.91 (m, 3H), 3.31-3.36 (m, 1H), 3.36-3.42 (m, 1H), 3.52 (s, 3H), 5.17-5.31 (m, 1H), 7.06 (s, 1H), 7.37-7.39 (m, 2H), 7.56-7.60 (m, 1H), 7.73-7.75 (d, 1H), 7.89-7.92 (m, 2H), 8.64 (s, 1H).

[0179] Example 29. Synthesis of Compound 29 TIFF2024514339000193.tif60165 Synthesis of 29 To a stirred mixture of 10d (100.00 mg, 0.219 mmol, 1.00 equiv.) and (3S)-3-methylpiperidine hydrochloride (59.31 mg, 0.438 mmol, 2.00 equiv.) in DCE (2.00 mL) was added EtN (44.24 mg, 0.438 mmol, 2.00 equiv.) and NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 15 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.43) to give compound 29 (46.2 mg, 39.09%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 541 1H NMR: (400 MHz, DMSO-d6, ppm): δ 0.82-0.83 (d, 4H), 1.30-1.51 (m, 1H), 1.52-1.72 (m, 4H), 1.82-1.91 (m, 1H), 2.65-2.83 (m, 2H), 2.97 (s, 3H), 3.24 (s, 2H), 3.53 (s, 2H), 4.90-4.92 (d, 2H), 4.94-4.96 (d, 2H), 6.88-6.90 (d, 1H), 7.00 (s, 1H), 7.38 (s, 1H), 7.40-7.42 (m, 2H), 7.65 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0180] Alternatively, compound 20 can also be prepared as outlined below. TIFF2024514339000194.tif76165

[0181] Synthesis of 1.10b A mixture of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (100 g, 416.627 mmol, 1 equiv.) and SeO (92.47 g, 833.254 mmol, 2 equiv.) in AcOH (500 mL) was stirred at 120 °C overnight. The resulting mixture was diluted with water (1000 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane (100 mL). This gave 5-bromo-3-(trifluoromethyl)pyridine-2-carbaldehyde (62 g, 58.81%) as an off-white solid.

[0182] 2.10c Synthesis To a stirred solution of 10b (100 g, 395.26 mmol, 1.20 equiv) and I-3 (80 g, 329.38 mmol, 1.00 equiv) in DCE (1000.00 mL) was added NaBH(OAc)3 (139.65 g, 658.761 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (2500.00 mL). The aqueous layer was extracted with EtOAc (3 × 1000.00 mL). The organic layer was concentrated under reduced pressure. The residue was purified by trituration with MTBE (2 × 300.00 mL). This gave 10c (116 g, 61.01%) as a white solid.

[0183] Synthesis of 3.7 To a stirred solution of 10c (130 g, 269.539 mmol, 1 equiv) and pyridine (127.92 g, 1617.234 mmol, 6 equiv) in DCM (2600 mL) was added triphosgene (26.39 g, 94.594 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding NaHCO (aq) (1500 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (2 × 300 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with methyl tert-butyl ether (600 mL). This gave 7 (110 g, 80.29%) as a yellow solid. (ES, m / z): [M+H] + : 508

[0184] 4.10d Synthesis To a solution of 7 (110 g, 216.408 mmol, 1 equiv.), TMEDA (50.30 g, 432.816 mmol, 2 equiv.) in dioxane (4400 mL), bis(adamantan-1-yl)(butyl)phosphane (15.52 g, 43.282 mmol, 0.2 equiv.), and Pd(OAc) (4.86 g, 21.641 mmol, 0.1 equiv.) were added in an autoclave. After flushing the autoclave with CO / H (1:1) three times, the mixture was pressurized to 10 atm with CO / H (1:1) at 80 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (20:1) to give 10d (58 g, 58.59%) as a yellow solid. (ES, m / z): [M+H] + : 458

[0185] Synthesis of 5.29 To a stirred mixture of 10d (58 g, 126.800 mmol, 1.00 equiv) and (s)-3-methylpiperidine hydrochloride (34.40 g, 253.600 mmol, 2 equiv) in DCE (1600 mL) was added TEA (38.49 g, 380.400 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h. To the above mixture was added NaBH(OAc) (53.75 g, 253.600 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (1000 mL). The resulting mixture was extracted with CHCl / MEOH = 10 / 1 (2 × 1000 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 15% to 80% over 40 min; detector, UV 254 nm, to give 29 (30.9 g, 45.08%) as a yellow solid. LC-MS-29: (ES, m / z): [M+H] +541. H-NMR-29: (400 MHz, CD3OD, δ ppm): 0.75-0.95 (m, 4H), 1.43-1.49 (m, 1H), 1.49-1.66 (m, 4H), 1.86-1.91 (m, 1H), 2.67-2.76 (m, 2H), 2.96 (s, 3H), 3.31 (s, 2H), 3.53 (s, 2H), 4.90-4.95 (m, 1H), 6.88-9.90 (d, 1H), 7.00 (s, 1H), 7.29 (s, 1H), 7.37-7.40 (d, 1H), 7.64 (s, 1H), 7.74-7.76 (d, 1H), 8.19 (s, 1H).

[0186] Example 30. Synthesis of Compound 30 TIFF2024514339000195.tif55165 30 Synthesis To a stirred solution of compound 20 (180.00 mg, 0.380 mmol, 1.00 equiv.), methylamine (0.57 mL, 1.140 mmol, 3.00 equiv., 2 M in THF), and DIEA (147.42 mg, 1.141 mmol, 3.00 equiv.) in DMF (2.00 mL) was added HATU (289.14 mg, 0.760 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 40% B in 8 min, Wavelength: 220 nm; RT1 (min): 6.82) to give compound 30 (34.5 mg, 18.65%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 487 1H NMR: (400 MHz, DMSO-d6, ppm): δ 2.88 (s, 3H), 2.97 (s, 3H), 3.68 (s, 2H), 5.05-5.10 (m, 4H), 6.91-6.93 (d, 1H), 7.18 (s, 1H), 7.33 (s, 1H), 7.42 (s, 1H), 7.46-7.50 (m, 1H), 7.63-7.65 (d, 1H), 8.20 (s, 1H), 8.38 (s, 1H).

[0187] Example 31. Synthesis of Compound 31 TIFF2024514339000196.tif55165 Synthesis of 31 To a stirred solution of compound 20 (180.00 mg, 0.380 mmol, 1.00 equiv.), dimethylamine (0.57 mL, 1.140 mmol, 3.00 equiv., 2 M in THF), and DIEA (147.42 mg, 1.140 mmol, 3.00 equiv.) in DMF (2.00 mL) was added HATU (289.14 mg, 0.760 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 35% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.77) to give compound 31 (45 mg, 23.65%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 501 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.99 (s, 6H), 3.03 (s, 3H), 3.54 (s, 2H), 4.91-4.97 (m, 4H), 6.90-6.92 (d, 1H), 7.08 (s, 1H), 7.40-7.45 (m, 3H), 7.74-7.76 (m, 1H), 7.90 (s, 1H), 8.20 (s, 1H).

[0188] Example 32. Synthesis of Compound 32 TIFF2024514339000197.tif39165 Synthesis of 32a To a stirred mixture of 32a (400.00 mg, 0.848 mmol, 1.00 equiv) and 3-azabicyclo[3.1.0]hexane hydrochloride (152.20 mg, 1.273 mmol, 1.5 equiv) in DCE (5.00 mL) was added STAB (539.47 mg, 2.545 mmol, 3 equiv) and EtN (257.57 mg, 2.545 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight. The reaction was quenched by adding NH4Cl(aq) (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 32a (45 mg, 9.65%) as a yellow solid.

[0189] Synthesis of 32 32a (45 mg) was separated by preparative SFC under the following conditions (Column: Lux 5 μm Cellulose-4, 3 × 25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: MEOH (0.1% of 2 M NH-MEOH); Flow rate: 80 mL / min; Gradient: Isocratic 50% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 254 nm; RT (min): 13.78) to give compound 32 (4.3 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 539 1H NMR (400 MHz, DMSO, δ ppm): δ 0.31-0.37 (d, 1H), 0.59-0.66 (d, 1H), 1.20-1.27 (m, 3H), 1.31-1.37 (d, 1H), 1.38-1.42 (m, 1H), 2.20-2.31 (m, 1H), 2.32-2.43 (m, 1H), 2.61-2.71 (d, 1H), 2.97 (s, 3H), 3.00-3.04 (d, 1H), 3.25-3.30 (d, 1H), 3.50-3.55 (d, 2H), 4.87-5.05 (m, 4H), 6.80-6.95 (d, 1H), 6.97 (s, 1H), 7.31 (s, 1H), 7.38-7.51 (m, 2H), 7.63 (s, 1H), 7.70-7.80 (m, 1H), 8.20 (s, 1H).

[0190] Example 33. Synthesis of Compound 33 TIFF2024514339000198.tif39165 Synthesis of 33a To a stirred solution of 19a (200.00 mg, 0.424 mmol, 1.00 equiv.) and 4-fluoropiperidine hydrochloride (59.22 mg, 0.424 mmol, 1.00 equiv.) in DCE (2.00 mL) was added Ti(Oi-Pr) (241.15 mg, 0.848 mmol, 2.00 equiv.) and NaBHCN (31.99 mg, 0.509 mmol, 1.20 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was diluted with water (30 mL) at room temperature. The aqueous layer was extracted with EtOAc (2 × 10 mL). The residue was purified by preparative TLC (CHCl / MeOH = 20:1) to give 33a (40 mg, 16.88%) as a yellow solid.

[0191] Synthesis of 33 Compound 33a (40 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: MeOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 55% B to 55% B in 18 min; wavelength: 220 nm; RT2 (min): 16.44) to give compound 33 (4.4 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 559. 1 H NMR: (400 MHz, DMSO, δ ppm): δ 1.24-1.28 (m, 3H), 1.69-1.80 (m, 2H), 1.80-1.91 (m, 2H), 2.33-2.37 (m, 2H), 2.58-2.68 (m, 2H), 2.97 (s, 3H), 3.49-3.53 (m, 3H), 4.59-4.73 (m, 1H), 4.83-4.96 (m, 4H), 6.89-6.91 (m, 1H), 7.08 (s, 1H), 7.31-7.38 (m, 1H), 7.40-7.42 (m, 1H), 7.60-7.61 (m, 1H), 7.73-7.76 (m, 1H), 8.20 (s, 1H).

[0192] Example 34. Synthesis of Compound 34 TIFF2024514339000199.tif60165 Synthesis of 34 Compound 33a (40 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: MeOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 55% B to 55% B in 18 min; wavelength: 220 nm; RT1 (min): 14.61) to give compound 34 (5.2 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 559 1H NMR (400 MHz, DMSO, δ ppm): δ 1.22-1.28 (m, 3H), 1.69-1.80 (m, 2H), 1.81-1.87 (m, 2H), 2.34-2.36 (m, 2H), 2.57-2.68 (m, 2H), 2.87-2.88 (m, 1H), 2.97 (s, 2H), 3.48-3.53 (m, 3H), 4.60-4.72 (m, 1H), 4.82-4.96 (m, 4H), 6.89-6.91 (m, 1H),7.08-7.09 (m, 1H), 7.31-7.38 (m, 1H), 7.40-7.42 (m, 2H), 7.60-7.61 (m, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0193] Example 35. Synthesis of Compound 35 TIFF2024514339000200.tif39165 Synthesis of 35a To a stirred solution of 26j (250.00 mg, 0.517 mmol, 1.00 equiv) and 3,3-difluoropyrrolidine hydrochloride (222.75 mg, 1.552 mmol, 3.00 equiv) in DCE (10.00 mL) was added EtN (157.01 mg, 1.552 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min. To the above mixture was added NaBH(OAc) (328.85 mg, 1.552 mmol, 3 equiv), and then the mixture was stirred at room temperature overnight. The resulting mixture was washed with 10 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 35a (220 mg, 69.60%) as a yellow solid.

[0194] Synthesis of 35 The crude product (35a, 220 mg) was purified by preparative SFC under the following conditions (column: CHIRALPAK IF, 3 × 25 cm, 5 μm; mobile phase A: CO, mobile phase B: MeOH (0.5% of 2 M NH-MeOH)—HPLC; flow rate: 100 mL / min; gradient: isocratic 25% B; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 5.6; sample solvent: MeOH; injection volume: 1.8 mL; number of runs: 11) to give compound 35 (31.9 mg, 14.38%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 575 1 H NMR: (400 MHz, CD3OD-d4, ppm): δ 2.05-2.08 (m, 3H), 2.26-2.37 (m, 2H), 2.82-2.84 (m, 2H), 2.93-3.00 (m, 2H), 3.47 (s, 2H), 3.65 (s, 3H), 7.10 (s, 1H), 7.15 (s, 1H), 7.43-7.45 (d, 1H), 7.60-7.62 (m, 1H), 7.72 (s, 1H), 7.76-7.80 (m, 2H), 8.54 (s, 1H).

[0195] Example 36. Synthesis of Compound 36 TIFF2024514339000201.tif60165 Synthesis of 36 The crude product (35a, 220 mg) was purified by preparative SFC under the following conditions (column: CHIRALPAK IF, 3 × 25 cm, 5 μm; mobile phase A: CO, mobile phase B: MeOH (0.5% of 2 M NH)—HPLC; flow rate: 100 mL / min; gradient: isocratic 25% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT (min): 6.82) to give compound 36 (78.3 mg, 34.17%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 575 1H NMR: (400 MHz, CD3OD-d4, ppm): δ 1.99-2.08 (m, 3H), 2.26-2.37 (m, 2H), 2.81-2.84 (m, 2H), 2.93-3.00 (m, 2H), 3.48 (s, 2H), 3.65 (s, 3H), 7.10 (s, 1H), 7.14 (s, 1H), 7.42-7.47 (d, 1H), 7.57-7.61 (m, 1H), 7.72 (s, 1H), 7.76-7.82 (m, 2H), 8.53 (s, 1H).

[0196] Example 37. Synthesis of Compound 37 TIFF2024514339000202.tif50165 Synthesis of 37 Compound 32a (45 mg) was separated by preparative SFC under the following conditions: Column: Lux 5 μm Cellulose-4, 3 × 25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: MEOH (0.1% 2 M NH-MEOH); Flow rate: 80 mL / min; Gradient: Isocratic 50% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 254 nm; RT1 (min): 11.52) to give compound 37 (3.3 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 539 1H NMR: (400 MHz, DMSO, δ ppm): δ 0.26-0.40 (d, 1H), 0.57-0.66 (d, 1H), 1.22-1.27 (t, 3H), 1.31-1.37 (d, 1H), 1.38-1.45 (m, 1H), 2.19-2.31 (m, 1H), 2.35-2.44 (m, 1H), 2.61-2.71 (d, 1H), 2.95-2.98 (d, 2H), 3.00-3.07 (m, 1H), 3.25-3.30 (d, 1H), 3.41-3.50 (d, 1H), 3.51-3.61 (d, 2H), 4.87-5.05 (m, 4H), 6.88-6.90 (d, 1H), 6.97 (s, 1H), 7.30 (s, 1H), 7.38-7.42 (m, 2H), 7.62 (s, 1H), 7.73-7.76 (m, 1H), 8.20 (s, 1H).

[0197] Example 38. Synthesis of Compound 38 TIFF2024514339000203.tif55165 Synthesis of 38 To a stirred solution of compound 20 (180.00 mg, 0.380 mmol, 1.00 equiv.) and methylethaneolamine (57.12 mg, 0.760 mmol, 2.00 equiv.) in DMF (2.00 mL) was added DIEA (98.28 mg, 0.760 mmol, 2.00 equiv.) and DIEA (98.28 mg, 0.760 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 35% B, 35% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.50) to give compound 38 (34.3 mg, 17.00%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 531 1H NMR: (400 MHz, DMSO-d6, ppm): δ 2.86-3.01 (m, 6H), 3.44-3.49 (m, 2H), 3.54 (s, 2H), 3.58-3.62 (m, 2H), 4.89-4.97 (m, 4H), 6.89-6.91 (d, 1H), 7.09 (s, 1H), 7.39-7.45 (m, 3H), 7.74-7.76 (m, 1H), 8.09 (s, 1H), 8.21 (s, 1H).

[0198] Example 39. Synthesis of Compound 39 TIFF2024514339000204.tif102165 Synthesis of 39a To a stirred mixture of compound 19 (150.00 mg, 0.318 mmol, 1.00 equiv.) and (3S)-3-fluoropyrrolidine (42.53 mg, 0.477 mmol, 1.5 equiv.) in DCE (2.00 mL) was added NaBHCN (59.98 mg, 0.955 mmol, 3 equiv.) and titanium(IV) isopropoxide (90.43 mg, 0.318 mmol, 1 equiv.) dropwise at room temperature. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 4 hours. The reaction was quenched by adding NH Cl (aq.) (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give 39a (48 mg, 26.32%) as a yellow solid.

[0199] Synthesis of 39 39a (48 mg) was separated by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 40% B, 40% B in 7 min; wavelength: 254 nm; RT1 (min): 7.48) to give compound 39 (4.4 mg) as a yellow solid. LCMS: (ES, m / z): [M+H]+ 545 1 H NMR: (400 MHz, DMSO, ppm): δ 1.23-1.36 (d, 3H), 1.76-2.00 (m, 1H), 2.00-2.21 (m, 1H), 2.37-2.47 (d, 1H), 2.58-2.71 (m, 2H), 2.77-2.96 (m, 1H), 2.96-3.01 (s, 3H), 3.27-3.31 (t, 1H), 3.45-3.57 (s, 2H), 4.85-5.06 (m, 4H), 5.10-5.39 (d, 1H), 6.89-6.94 (d, 1H), 7.05 (s, 1H), 7.27-7.36 (d, 1H), 7.36-7.48 (m, 2H), 7.70 (s, 1H), 7.74-7.76 (d, 1H), 8.20(s, 1H).

[0200] Example 40. Synthesis of Compound 40 TIFF2024514339000205.tif50165 40 Synthesis Compound 39a (48 mg) was separated by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 40% B, 40% B in 7 min; wavelength: 254 nm; RT1 (min): 7.48) to give compound 40 (3.0 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 545 1H NMR: (400 MHz, DMSO, ppm): δ 1.27-1.36 (d, 3H), 1.78-2.01 (m, 1H), 2.00-2.22 (m, 1H), 2.22-2.34 (d, 1H), 2.58-2.80 (m, 2H), 2.80-2.95 (m, 1H), 2.95-3.01 (s, 3H), 3.23-3.31 (t, 1H), 3.53-3.57 (s, 2H), 4.85-5.00 (m, 4H), 5.05-5.32 (d, 1H), 6.82-6.92 (d, 1H), 7.06 (s, 1H), 7.32-7.36 (s, 1H), 7.40-7.42 (m, 2H), 7.70 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0201] Example 41. Synthesis of Compound 41 TIFF2024514339000206.tif44165 Synthesis of 41a To a stirred solution of compound 19 (60.00 mg, 0.552 mmol, 1.00 equiv.) and 4-fluoro-4-methylpiperidine hydrochloride (84.73 mg, 0.552 mmol, 1.00 equiv.) in DCE (3.00 mL) was added Ti(Oi-Pr) (156.75 mg, 0.552 mmol, 1.00 equiv.) and NaBHCN (41.59 mg, 0.662 mmol, 1.20 equiv.) at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was diluted with water (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 20 mL). The residue was purified by preparative TLC (CHCl / MeOH = 20:1) to give 41a (50 mg) as a yellow solid. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B, 55% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.55; Run number: 0) to give 41a (20 mg, 6.33%) as a yellow solid.

[0202] Synthesis of 41 Compound 41a (20 mg) was separated by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: MeOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 55% B to 55% B in 15 min; wavelength: 220 nm; RT2 (min): 13.73) to give compound 41 (6.9 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 573 1 H NMR (400 MHz, DMSO, δ ppm): δ 1.22-1.38 (m, 6H), 1.55-1.63 (m, 1H), 1.63-1.74 (m, 3H), 2.25-2.36 (m, 2H), 2.60-2.67 (m, 2H), 2.97 (s, 3H), 3.47-3.53 (m, 3H), 4.91-4.96 (m, 4H), 6.89-6.91 (m, 1H), 7.07-7.08 (m, 1H), 7.31-7.32 (m, 1H), 7.38-7.42 (m, 2H), 7.60-7.61 (m, 1H), 7.73-7.76 (m, 1H), 8.20 (s, 1H).

[0203] Example 42. Synthesis of Compound 42 TIFF2024514339000207.tif60165 Synthesis of 42 Compound 41a (20 mg) was separated by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: MeOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 55% B to 55% B in 15 min; wavelength: 220 nm; RT1 (min): 12.42) to give compound 42 (6.6 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 573 1 H NMR (400 MHz, DMSO, δ ppm): δ 1.24-1.33 (m, 6H), 1.59-1.62 (m, 1H), 1.71-1.74 (m, 3H), 2.29-2.33 (m, 2H), 2.61-2.67 (m, 2H), 2.97 (s, 3H), 3.47-3.53 (m, 3H), 4.91-4.96 (m, 4H), 6.89-6.91 (m, 1H), 7.08-7.08 (m, 1H), 7.31-7.32 (m, 1H), 7.38-7.42 (m, 2H), 7.61-7.62 (m, 1H), 7.73-7.76 (m, 1H), 8.20 (s, 1H).

[0204] Example 43. Synthesis of Compound 43 TIFF2024514339000208.tif97165 Synthesis of 43a To a stirred solution of cyclooctadiene rhodium chloride dimer (3.31 g, 6.713 mmol, 0.10 equiv) in DCM (150.00 mL) was added silver triflate (1.72 g, 6.694 mmol, 0.10 equiv) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. To the above mixture, ethyl diazoacetate (38.25 g, 0.335 mmol, 5 equiv) and (3-nitrophenyl)ethene (10.00 g, 67.047 mmol, 1.00 equiv) were added at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was washed with 1 × 100 mL of water. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give the crude product. The residue was purified by preparative TLC (PE / EtOAc 8:1) to give 43a (1.1 g, 6.63%) as a pale yellow oil.

[0205] Synthesis of 43b To a stirred solution of 43a (1.10 g, 4.676 mmol, 1.00 equiv) in EtOH (20.00 mL) was added hydrazine hydrate (98%) (3.51 g, 70.140 mmol, 15.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with CHCl / MeOH 10:1 (3 × 100 mL). The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 43b (600 mg, 52.20%) as a pale yellow oil.

[0206] Synthesis of 43c To a stirred solution of 43b (600.00 mg, 2.712 mmol, 1.00 equiv) in tetrahydrofuran (10.00 mL) was added methyl isothiocyanate (297.44 mg, 4.068 mmol, 1.50 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (50 mL). The precipitated solid was collected by filtration. This resulted in 43c (700 mg, 78.92%) as an off-white solid.

[0207] Synthesis of 43d To a stirred solution of NaOH (92.41 mg, 2.310 mmol, 1.00 equiv) in HO (23.00 mL) was added 43c (680.00 mg, 2.310 mmol, 1.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The precipitated solid was collected by filtration and washed with water (10 mL). This resulted in 43d (600 mg, 84.59%) as an off-white solid.

[0208] Synthesis of 43e To a stirred solution of 43d (600.00 mg, 2.171 mmol, 1.00 equiv) in HO (10.00 mL) was added NaNO (1498.22 mg, 21.715 mmol, 10.00 equiv) and HNO (10.00 mL, 1 M) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h. The mixture was basified to pH 7 with saturated NaHCO. The precipitated solid was collected by filtration and washed with water (10 mL). This resulted in 43e (400 mg, 68.63%) as an off-white solid.

[0209] Synthesis of 43f To a stirred solution of Fe (411.54 mg, 7.369 mmol, 5.00 equiv) and 43e (360.00 mg, 1.474 mmol, 1.00 equiv) in EtOH (10.00 mL) was added NH4Cl (788.39 mg, 14.739 mmol, 10 equiv) in HO (10.00 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with CHCl (3 × 100 mL). The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 43f (300 mg, 89.29%) as a pale yellow solid.

[0210] Synthesis of 43g To a stirred solution of 43f (280.00 mg, 1.307 mmol, 1.00 equiv) and 3-(trifluoromethyl)pyridine-2-carbaldehyde (228.83 mg, 1.307 mmol, 1.00 equiv) in DCE (10.00 mL) was added HOAc (156.95 mg, 2.614 mmol, 2 equiv) and STAB (830.86 mg, 3.920 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was washed with 20 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give 43g (400 mg, 75.42%) as a pale yellow solid.

[0211] Synthesis of 43 To a stirred solution of 43g (200.00 mg, 0.536 mmol, 1.00 equiv) and pyridine (254.22 mg, 3.214 mmol, 6 equiv) in DCM (10.00 mL) was added triphosgene (55.63 mg, 0.187 mmol, 0.35 equiv) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water, B: MeCN, gradient from 35% to 45% in 15 minutes; detector, UV 254 nm. This resulted in compound 43 (112.3 mg, 51.08%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 400 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 1.52-1.65 (m, 1H), 1.90-1.95 (m, 1H), 2.51-2.57 (m, 1H), 2.66-2.72 (m, 1H), 3.40 (s, 3H), 6.26-6.29 (m, 1H), 6.90-6.92 (d, 1H), 7.08-7.12 (m, 2H), 7.20-7.24 (m, 1H), 7.42-7.43 (m, 1H), 7.54-7.57 (d, 1H), 7.76-7.78 (d, 1H), 8.15 (s, 1H).

[0212] Example 44. Synthesis of Compound 44 TIFF2024514339000209.tif118165 Synthesis of 44a To a stirred solution of [Rh(COD)Cl] (700 mg, 0.011 mmol, 0.015 equiv) in dioxane (120 mL) was added KOH (79 mL, 118.182 mmol, 1.2 equiv, 1.5 M) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture were added ethyl 2-(oxetan-3-ylidene)acetate (14.00 g, 98.485 mmol, 1.00 equiv) and 3-bromophenylboronic acid (33.62 g, 167.424 mmol, 1.7 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl(aq) (500 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 500 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 44a (16 g) as a yellow oil.

[0213] Synthesis of 44b To a 100 mL three-necked round-bottom flask were added 44a (2.00 g, 6.685 mmol, 1.00 equiv), KHMDS (1 mol / L in THF) (10 mL, 10.028 mmol, 1.5 equiv), and THF (20.00 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h under a nitrogen atmosphere. To the above mixture was added 2-(benzenesulfonyl)-3-phenyloxaziridine (2.27 g, 8.691 mmol, 1.3 equiv). The resulting mixture was stirred at −65° C. for an additional 3 h. The resulting mixture was quenched with 60 mL of NH4Cl (aq). The aqueous layer was extracted with EtOAc (3 × 20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 44b (520 mg, 22.46%) as a yellow oil.

[0214] Synthesis of 44c To a 250 mL three-necked round-bottom flask were added 44b (4.00 g, 12.692 mmol, 1.00 equiv), NHNH.HO (6.35 g, 126.918 mmol, 10 equiv), and EtOH (40.00 mL, 688.541 mmol, 54.25 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The precipitated solid was collected by filtration and washed with water (3 × 10 mL) to give 44c (2.5 g, 58.87%) as an off-white solid.

[0215] Synthesis of 44d To a 250 mL three-necked round-bottom flask were added 44c (2.50 g, 8.302 mmol, 1.00 equiv), methyl isothiocyanate (1.21 g, 16.604 mmol, 2.00 equiv), and tetrahydrofuran (25.00 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with EtOAc (3 × 10 mL) to give 44d (2.4 g, 69.52%) as an off-white solid.

[0216] Synthesis of 44e To a 100 mL three-necked round-bottom flask were added 44d (2.00 g, 5.344 mmol, 1.00 equiv), NaOH (0.43 g, 10.688 mmol, 2 equiv), and HO (20.00 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The residue was neutralized to pH 7 with HCl (1 M). The aqueous layer was extracted with EtOAc (3 × 10 mL). The resulting mixture was concentrated in vacuo to give 44e (1.9 g, 91.82%) as an off-white solid.

[0217] Synthesis of 44f To a 100 mL three-necked round-bottom flask, 44e (1.90 g, 5.333 mmol, 1.00 equiv), NaNO (3.68 g, 53.335 mmol, 10 equiv), EtOAc (4.00 mL), and HO (20.00 mL) were added at room temperature. To the above, HNO (53.3 mL, 53.335 mmol, 10 equiv, 1 M) was added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The resulting mixture was concentrated in vacuo to give 44f (1.3 g, 69.17%) as an off-white solid.

[0218] 44g synthesis To a 100 mL three-necked round-bottom flask, 44f (1.90 g, 5.861 mmol, 1.00 equiv) and DCM (20.00 mL) were added at room temperature. To the above mixture, DAST (1889.45 mg, 11.722 mmol, 2 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched with NaHCO (20 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 20 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1), to give 44g (1 g, 52.31%) as a yellow solid.

[0219] 44h synthesis To a 50 mL round-bottom flask was added 44g (1.00 g, 3.066 mmol, 1.00 equiv.), CHCN (20.00 mL), NH.HO (20 mL), and CuO (43.87 mg, 0.307 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred at 100 °C overnight. The reaction was diluted with water (60 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 100 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 44h (680 mg, 84.56%) as a yellow solid.

[0220] 44i synthesis To a 25 mL three-necked round-bottom flask was added 44h (650.00 mg, 2.478 mmol, 1.00 equiv.), DCE (10.00 mL), 5-bromo-3-(trifluoromethyl)pyridine-2-carbaldehyde (1258.95 mg, 4.956 mmol, 2 equiv.), NaBH(OAc) (1050.46 mg, 4.956 mmol, 2 equiv.), and HOAc (446.46 mg, 7.435 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH 20:1) to afford 44i (980 mg, 79.04%) as a yellow solid.

[0221] Synthesis of 44j To a 25 mL three-necked round-bottom flask, 44i (980.00 mg, 1.959 mmol, 1.00 equiv), DCM (10.00 mL), and pyridine (309.89 mg, 3.918 mmol, 2.00 equiv) were added at room temperature. To the above mixture, triphosgene (232.50 mg, 0.784 mmol, 0.40 equiv) was added at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched with NaHCO (aq, 20 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 44j (900 mg, 87.30%) as a yellow solid.

[0222] 44k composite To a 50 mL pressure tank reactor was added 44j (300.00 mg, 0.570 mmol, 1.00 equiv), dioxane (20.00 mL), Pd(OAc) (12.80 mg, 0.057 mmol, 0.1 equiv), TMEDA (132.48 mg, 1.140 mmol, 2 equiv), and cataCXium (81.86 mg, 0.228 mmol, 0.4 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C under a 1:1 H:CO atmosphere at 20 atm. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 44k (150 mg, 55.35%) as a yellow solid.

[0223] Synthesis of 44l To an 8 mL vial, 44k (140.00 mg, 0.294 mmol, 1.00 equiv.), DCE (2.00 mL), 4-fluoropiperidine (60.75 mg, 0.589 mmol, 2 equiv.), and NaBH(OAc) (124.83 mg, 0.589 mmol, 2 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH 15:1) to give 44l (90 mg, 54.33%) as a yellow solid.

[0224] Synthesis of 44 44l (90 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 40% B to 50% B in 17 min; wavelength: 220 / 254 nm; RT1 (min): 11.29) to give compound 44 (15.5 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 563 1H NMR: (300 MHz, DMSO-d6, ppm): δ 1.72 (s, 2H), 1.96 (s, 2H), 2.33-2.36 (m, 2H), 2.55 (s, 2H), 3.28 (s, 5H), 4.60-4.85 (m, 1H), 4.86-4.87 (d, 1H), 5.18-5.22 (m, 2H), 5.34-5.36 (d, 1H), 6.22-6.34 (s, 1H), 7.03 (s, 1H), 7.13-7.15 (d, 1H), 7.34 (s, 1H), 7.42-7.46 (m, 1H), 7.56 (s, 1H), 7.69 (s, 1H), 7.78-7.80 (m, 1H), 8.38 (s, 1H).

[0225] Example 45. Synthesis of Compound 45 TIFF2024514339000210.tif60165 Synthesis of 45 44l (90 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 40% B to 50% B in 17 min; wavelength: 220 / 254 nm; RT1 (min): 11.29) to give compound 45 (14.5 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 563 1H NMR: (400 MHz, DMSO-d6, ppm): δ 1.72 (s, 2H), 1.96 (s, 2H), 2.33-2.36 (m, 2H), 2.55 (s, 2H), 3.28 (s, 5H), 4.60-4.85 (m, 1H), 4.86-4.87 (d, 1H), 5.18-5.22 (m, 2H), 5.34-5.36 (d, 1H), 6.22-6.34 (s, 1H), 7.03 (s, 1H), 7.13-7.15 (d, 1H), 7.34 (s, 1H), 7.42-7.46 (m, 1H), 7.56 (s, 1H), 7.69 (s, 1H), 7.78-7.80 (m, 1H), 8.38 (s, 1H).

[0226] Example 46. Synthesis of Compound 46 TIFF2024514339000211.tif71165 Synthesis of 46a To a stirred solution of I-1c (3.60 g, 12.935 mmol, 1.00 equiv) in HOAc (50.00 mL) was added 1-(2,4-dimethoxyphenyl)methanamine (21.63 g, 129.360 mmol, 10.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 46a (1.2 g, 21.35%) as a yellow oil.

[0227] Synthesis of 46b To a stirred solution of 46a (1.20 g, 3.138 mmol, 1.00 equiv) in EtOH (50.00 mL) was added NH4Cl (1.68 g, 31.379 mmol, 10 equiv) in HO (50.00 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with CHCl / MeOH = 10:1 (3 × 100 mL). The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 46b (1.1 g, 90.51%) as a pale yellow oil.

[0228] Synthesis of 46c To a stirred solution of 46b (1.10 g, 3.121 mmol, 1.00 equiv.) and 3-(trifluoromethyl)pyridine-2-carbaldehyde (0.55 g, 0.003 mmol, 1 equiv.) in DCE (50.00 mL) was added HOAc (0.37 g, 0.006 mmol, 2 equiv.) and STAB (1.98 g, 0.009 mmol, 3 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 h. The resulting mixture was washed with water (50 mL). The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 46c (1.4 g, 78.92%) as a yellow oil.

[0229] Synthesis of 46d To a stirred solution of 46c (1.50 g, 2.932 mmol, 1.00 equiv) and pyridine (1.39 g, 17.594 mmol, 6 equiv) in DCM (60.00 mL) was added triphosgene (0.30 g, 1.026 mmol, 0.35 equiv) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was washed with NaHCO (aq) (100 mL). The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 46d (1.2 g, 75.86%) as a yellow solid.

[0230] Synthesis of 46e To a stirred solution of 46d (1.20 g, 2.232 mmol, 1.00 equiv) in DCM (10.00 mL) was added TFA (10.00 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 20:1) to give 46e (300 mg, 32.96%) as a yellow solid.

[0231] Synthesis of 46 The crude product (46e, 300 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 15% B to 15% B in 12.5 min; wavelength: 254 nm; RT1 (min): 9.43) to give compound 46 (90.6 mg, 29.90%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 388 1 H NMR: (400 MHz, CD3OD-d4, ppm): δ 1.27-1.39 (d, 3H), 3.03-3.15 (m, 2H), 3.37-3.42 (m, 1H), 6.34-6.38 (m, 1H), 7.04-7.05 (d, 1H), 7.11 (s, 1H), 7.18-7.29 (m, 1H), 7.41-7.45 (m, 1H), 7.54-7.56 (m, 1H), 7.56-7.60 (m, 1H), 7.77-7.79 (m, 1H), 7.79-8.40 (m, 1H).

[0232] Example 47. Synthesis of Compound 47 TIFF2024514339000212.tif65165 Synthesis of 47 Compound 46e (300 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: MtBE (0.5% 2 M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 15% B to 15% B in 12.5 min; wavelength: 220 / 254 nm; RT2 (min): 10.8) to give compound 47 (95.0 mg, 31.35%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 388 1 H NMR: (400 MHz, CD3OD-d4, ppm): δ 1.30-1.43 (d, 3H), 3.03-3.15 (m, 2H), 3.37-3.42 (m, 1H), 6.34-6.38 (m, 1H), 7.03-7.05 (d, 1H), 7.11 (s, 1H), 7.18-7.25 (m, 1H), 7.41-7.45 (m, 1H), 7.53-7.55 (m, 1H), 7.55-7.59 (m, 1H), 7.76-7.78 (m, 1H), 7.88-8.40 (m, 1H).

[0233] Example 48. Synthesis of Compound 48 TIFF2024514339000213.tif81165 Synthesis of 48a To a stirred solution of I-3a (5.00 g, 18.867 mmol, 1.00 equiv) in MeOH (100.00 mL) was added NaOH (29.85 mL, 29.850 mmol, 1.50 equiv, 1 M). The resulting mixture was stirred at room temperature overnight. MeOH was removed under vacuum. The mixture was acidified to pH 4 with HCl (1 M). The precipitated solid was collected by filtration and washed with water (10 mL). The resulting solid was dried in an oven under reduced pressure. This resulted in 48a (4 g, 89.45%) as a white solid.

[0234] Synthesis of 48b To a stirred mixture of 48a (4.00 g, 16.863 mmol, 1.00 equiv) and NH4Cl (2.71 g, 50.589 mmol, 3.00 equiv) in DMF (100.00 mL) was added DIEA (8.72 g, 67.470 mmol, 4.00 equiv) and HATU (9.62 g, 25.295 mmol, 1.50 equiv). The resulting mixture was stirred overnight at room temperature under an argon atmosphere. The resulting mixture was diluted with water (300 mL). The aqueous layer was extracted with EtOAc (3 × 150 mL). The resulting mixture was concentrated in vacuo. The residue was purified by trituration with water (15 mL). The resulting solid was dried in an oven under reduced pressure. This gave 48b (3.2 g, 80.33%) as a light brown solid.

[0235] Synthesis of 48c A solution of 48b (3.50 g, 1 equiv.) in DMF-DMA (16.00 mL) was stirred at 80 °C overnight. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 48c (3.4 g, 78.78%) as a gray solid.

[0236] Synthesis of 48d To a stirred solution of 48c (3.20 g, 10.985 mmol, 1.00 equiv) in HOAc (16.00 mL) was added hydrazine hydrate (14.00 mL, 98%) dropwise at room temperature. The resulting mixture was stirred at 60 °C overnight. The resulting mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 48d (2.9 g, 101.44%) as a gray solid.

[0237] Synthesis of 48e To a stirred solution of 48d (2.90 g, 11.143 mmol, 1.00 equiv) in DMF (30.00 mL) was added NaH (2.23 g, 55.715 mmol, 5.00 equiv, 60%) in portions at 0° C. under an argon atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under an argon atmosphere. To the above mixture was added bromodifluoromethane (87.53 g, 66.858 mmol, 6.00 equiv, 10% in DMF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (400 mL). The aqueous layer was extracted with EtOAc (3×150 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol NH3HO), gradient from 0% to 80% in 35 min; detector, UV 254 nm, to give 48e (0.8 g, 23.14%) as a white solid.

[0238] Synthesis of 48f To a solution of 48e (780.00 mg, 2.514 mmol, 1.00 equiv) in MeOH (30.00 mL) was added Pd / C (70.00 mg) in a 100 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give 48f (710 mg, 92.70%) as a light brown solid.

[0239] 48g synthesis To a stirred solution of 48f (300.00 mg, 1.070 mmol, 1.00 equiv) and 5-bromo-3-(trifluoromethyl)pyridine-2-carbaldehyde (271.88 mg, 1.070 mmol, 1.00 equiv) in DCE (10.00 mL) was added HOAc (64.28 mg, 1.070 mmol, 1 equiv) and NaBH(OAc) (680.56 mg, 3.211 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was washed with 10 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 15:1) to give 48g (370 mg, 63.48%) as a pale yellow solid.

[0240] 48h synthesis To a stirred solution of 48g (350.00 mg, 0.677 mmol, 1.00 equiv) and pyridine (321.11 mg, 4.060 mmol, 6 equiv) in DCM (10.00 mL) was added triphosgene (70.27 mg, 0.237 mmol, 0.35 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was washed with 10 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to afford 48h (300 mg, 79.02%) as a yellow solid.

[0241] 48i Composition To a solution of 48h (280.00 mg, 0.514 mmol, 1.00 equiv) in dioxane (8.00 mL) was added cataCXium (36.89 mg, 0.103 mmol, 0.20 equiv), Pd(OAc) (11.55 mg, 0.051 mmol, 0.1 equiv), and TMEDA (119.56 mg, 1.029 mmol, 2 equiv) in a pressure tank. The mixture was purged with nitrogen for 3 min and then pressurized to 10 atm with CO:H at 90 °C overnight. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (2 × 50 mL). The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 48i (160 mg, 57.36%) as a yellow solid.

[0242] Synthesis of 48 To a stirred solution of 48i (150.00 mg, 0.304 mmol, 1.00 equiv) and (3S)-3-methylpiperidine hydrochloride (123.71 mg, 0.912 mmol, 3.00 equiv) in DCE (6.00 mL) was added EtN (92.29 mg, 0.912 mmol, 3 equiv) and NaBH(OAc) (193.30 mg, 0.912 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with CHCl (20 mL). The resulting mixture was washed with 20 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give compound 48 (60.0 mg, 33.89%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 577 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 0.82-0.86 (d, 3H), 1.41-1.50 (m, 1H), 1.50-1.66 (m, 4H), 1.91-1.94 (m, 2H), 2.74-2.84 (m, 2H), 3.27 (s, 2H), 3.75 (s, 2H), 4.95 (s, 4H), 7.01-7.02 (m, 1H), 7.06-7.08 (m, 1H), 7.31 (s, 1H), 7.38-7.55 (m, 3H), 7.70-7.72 (m, 1H), 7.73-7.75 (d, 1H), 8.82 (s, 1H).

[0243] Example 49. Synthesis of Compound 49 TIFF2024514339000214.tif55165 Synthesis of 49 To a stirred solution / mixture of 10d (100 mg, 0.21 mmol, 1.0 equiv) and 4-methoxypiperidine (25 mg, 0.21 mmol, 1.0 equiv) in DCE (1 mL) was added NaBH(OAc) (923 mg, 0.43 mmol, 2.0 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with NH4Cl(aq) (20 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 42% B, 42% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.38) to give compound 49 (18.8 mg, 15%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 557 1 H NMR: (400 MHz, DMSO-d6, δ ppm): δ 1.42-1.44 (m, 2H), 1.81-1.83 (m, 2H), 2.11-2.16 (m, 2H), 2.61-2.67 (m, 2H), 2.97 (s, 3H), 3.18-3.22 (m, 4H), 3.28-3.30 (m, 2H), 3.53 (s, 2H), 4.91-4.96 (m, 4H), 6.88-6.90 (d, 1H), 7.01 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 2H), 7.66 (s, 1H), 7.74-7.76 (d, 1H), 8.20 (s, 1H).

[0244] Example 50. Synthesis of Compound 50 TIFF2024514339000215.tif60165 50 Synthesis To an 8 mL sealed tube, 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), DCE (1.00 mL), and 2-methoxyethanamine (16.42 mg, 0.219 mmol, 1 equiv.), NaBH(OAc) (92.67 mg, 0.437 mmol, 2 equiv.), and HOAc (26.26 mg, 0.437 mmol, 2 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated NH Cl (aq.) (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 30 mL). The resulting mixture was concentrated in vacuo. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 45% B, 45% B in 8 min; Wavelength: 254 nm; RT1 (min): 7.23) to give compound 50 (30.9 mg, 27.04%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 517 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.62-2.64 (d, 2H), 3.22 (s, 3H), 3.33-3.38 (m, 3H), 3.40-3.43 (m, 2H), 3.52-3.53 (d, 4H), 4.91-4.96 (m, 4H), 6.87-6.89 (d, 1H), 7.12 (s, 1H), 7.30 (s, 1H), 7.38-7.41 (m, 2H), 7.42 (s, 1H), 7.68-7.77 (d, 1H), 8.20 (s, 1H).

[0245] Alternatively, compound 50 can also be prepared as outlined below. TIFF2024514339000216.tif118165

[0246] Synthesis of 1.59-1 To a solution of methylpropanediol (59 g, 554.803 mmol, 1 equiv.) and TsCl (264.42 g, 1387.007 mmol, 2.5 equiv.) in DCM (590 mL) was added TEA (168.43 g, 1664.409 mmol, 3 equiv.) dropwise at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction was quenched with water (800 mL) at room temperature. The aqueous layer was extracted with DCM (2 × 800 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (80:1) to give 59-1 (190 g, 79.38%) as a yellow oil.

[0247] Synthesis of 2.59-2 To a stirred solution of methyl 2-(3-nitrophenyl)acetate (59 g, 256.182 mmol, 1.00 equiv) and CsCO (392.30 g, 1204.055 mmol, 5 equiv) in DMF (590 mL) was added 59-1 (190 g, 476.800 mmol, 1.86 equiv) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. The reaction was quenched with NHCl (aq) at room temperature. The aqueous layer was extracted with EtOAc (3 × 600 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (80:1) to give 59-2 (18 g, 26.99%) as a yellow oil.

[0248] Synthesis of 3.59-3 A solution of 59-2 (51 g, 204.601 mmol, 1 equiv) and hydrazine hydrate (65.56 g, 2046.010 mmol, 10 equiv) in EtOH (510 mL) was stirred at 80 °C overnight. The reaction was quenched by adding NH4Cl (aq) (800 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). This resulted in 59-3 (46 g, 81.18%) as an off-white solid.

[0249] Synthesis of 4.59-4 A solution of 59-3 (46 g, 184.539 mmol, 1 equiv.) and methyl isothiocyanate (26.98 g, 369.078 mmol, 2 equiv.) in THF (460 mL) was stirred at room temperature for 5 h. The reaction was quenched with water (400 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). This resulted in 59-4 (45 g, 68.08%) as a yellow solid.

[0250] Synthesis of 5.59-5 To a stirred solution of 59-4 (45 g, 139.587 mmol, 1 equiv) in HO (459 mL) was added NaOH (55.83 g, 1395.870 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at room temperature for 5 h. The mixture was acidified to pH 5 with HCl (aq). The precipitated solid was collected by filtration and washed with water (3 × 200 mL). This resulted in 59-5 (42 g, 88.97%) as a yellow solid.

[0251] Synthesis of 6.59-6 To a stirred solution of 59-5 (42 g, 137.990 mmol, 1 equiv) and NaNO (95.21 g, 1379.900 mmol, 10 equiv) in HO (420 mL) was added HNO (1380 mL, 1379.90 mmol, 10 equiv, 1 M) dropwise at room temperature. The resulting mixture was stirred at room temperature for 5 h. The mixture was neutralized with saturated NaHCO (aq) (590 mL). The aqueous layer was extracted with EtOAc (3 × 400 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (80:1) to give 59-6 (30 g, 71.85%) as a yellow solid.

[0252] Synthesis of 7.59-7 To a solution of 59-6 (30 g, 110.169 mmol, 1 equiv) in MeOH (590 mL) was added Pd / C (10%, 3.0 g) under a nitrogen atmosphere. The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give 59-7 (22 g, 74.17%) as a yellow solid.

[0253] Synthesis of 8.59L To a stirred solution of 59-7 (10 g, 41.267 mmol, 1 equiv.) and I-2 (14.18 g, 49.520 mmol, 1.2 equiv.) in DCE (100 mL) was added STAB (17.49 g, 82.534 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated Na2CO3 (aq.) (159 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 159 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (70:1) to give 59l (16.7 g, 71.05%) as a yellow solid.

[0254] 9.59k synthesis To a stirred solution of 591 (16.5 g, 32.187 mmol, 1 equiv.) and pyridine (15.28 g, 193.122 mmol, 6 equiv.) in DCM (200 mL) was added triphosgene (3.53 g, 11.909 mmol, 0.37 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated NaHCO (aq.) (159 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 159 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 30% to 59% in 30 min; detector, UV at 254 nm. This resulted in 59k (12 g, 65.76%) as a yellow solid.

[0255] 10.50 Synthesis 59k (11.5 g) was purified by preparative SFC under the following conditions: Column: CHIRALPAK AD-H, 5 × 25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: ETOH (0.1% 2 M NH-MEOH); Flow rate: 200 mL / min; Gradient: Isocratic 40% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.55; RT2 (min): 4.71; second peak is product) to give 50 (2.0630 g, 19.11%) as a yellow solid. LC-MS-50 (ES, m / z): [M+H] + 539. H-NMR-59: (400 MHz, DMSO-d6, δ ppm): 0.79-0.84 (d, 3H), 0.86-0.92 (m, 1H), 1.01-1.18 (d, 3H), 1.41-1.52 (m, 1H), 1.53-1.65 (m, 4H), 1.91-2.03 (m, 1H), 2.25-2.40 (m, 3H), 2.69-2.77 (m, 2H), 3.07-3.10 (m, 2H), 3.25 (s, 3H), 3.34-3.42 (m, 2H), 7.02 (s, 1H), 7.08-7.10 (d, 1H), 7.35 (s, 1H), 7.44-7.48 (m, 1H), 7.61-7.63 (d, 1H), 7.67-7.71 (m, 2H), 8.37 (s,1H).

[0256] Example 51. Synthesis of Compound 51 TIFF2024514339000217.tif60165 Synthesis of 51 To an 8 mL sealed tube was added 10d (100.00 mg, 0.219 mmol, 1.00 equiv.), (2-methoxyethyl)(methyl)amine (19.49 mg, 0.000 mmol, 1.00 equiv.), NaBH(OAc) (92.67 mg, 0.438 mmol, 2.00 equiv.), HOAc (26.26 mg, 0.438 mmol, 2.00 equiv.), and DCE (1.50 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated NH4Cl(aq) (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 30 mL). The resulting mixture was concentrated in vacuo. The crude product (80 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 50% B, 50% B in 8 min; Wavelength: 220 / 254 nm; RT1 (min): 7.23) to give compound 51 (34.9 mg, 29.85%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 531 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 2.30 (s, 2H), 2.50-2.57 (m, 2H), 2.93-2.97 (m, 3H), 3.32 (s, 3H), 3.40-3.46 (m, 2H), 3.53 (s, 2H), 3.60 (s, 2H), 4.88-4.96 (m, 4H), 6.87-6.89 (d, 1H), 7.01 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 2H), 7.68-7.77 (m, 1H), 8.20 (s, 1H).

[0257] Example 52. Synthesis of Compound 52 TIFF2024514339000218.tif87165 Synthesis of 52a To a stirred solution of 1-(4-fluoro-3-nitrophenyl)ethanone (30.00 g, 163.811 mmol, 1.00 equiv) in HCl (78.00 mL, 1 M), SnCl (93.19 g, 491.457 mmol, 3.00 equiv), HO (300.00 mL) were added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 15 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 25 minutes under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched with ice at room temperature. The mixture was acidified to pH 12 with NaOH. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 52a (20 g, 73.34%) as a yellow solid.

[0258] Synthesis of 52b To a stirred solution of 52a (5.00 g, 32.646 mmol, 1.00 equiv) and TEA (9.91 g, 97.939 mmol, 3 equiv) in THF (100.00 mL) was added DMAP (0.40 g, 3.265 mmol, 0.1 equiv) and BocO (14.25 g, 65.293 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 200 mL of brine. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (30:1) to give 52b (6 g, 65.31%) as a white solid.

[0259] Synthesis of 52c To a stirred solution of triethyl phosphonoacetate (7.97 g, 0.036 mmol, 3 equiv) in THF (50.00 mL) was added potassium tert-butoxide (3.99 g, 0.036 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. To the above mixture was added 52b (3.00 g, 11.845 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl(aq) (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (2 x 100 mL). The residue was purified by silica gel column chromatography eluting with PE / EtOAc (15:1) to give 52c (3 g, 70.49%) as an off-white solid.

[0260] Synthesis of 52d To a solution of 52c (3.00 g, 9.277 mmol, 1.00 equiv) in EtOH (100.00 mL) was added Pd / C (0.3 g) in a 500 mL round-bottom flask. The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. The crude product was used immediately in the next step without further purification. This resulted in 52d (2.8 g, 83.48%) as a pale yellow oil.

[0261] Synthesis of 52e To a stirred solution of 52d (2.80 g, 8.605 mmol, 1.00 equiv) in EtOH (80.00 mL) was added hydrazine hydrate (98%) (4.31 g, 86.050 mmol, 10.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 days. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with DCM / MeOH = 10:1 (3 × 100 mL). The residue was purified by preparative TLC (CHCl / MeOH 25:1) to give 52e (1.5 g, 51.51%) as an off-white solid.

[0262] Synthesis of 52f To a stirred solution of 52e (1.00 g, 3.212 mmol, 1.00 equiv) in DCM (10.00 mL) was added DMF-DMA (1.91 g, 16.059 mmol, 5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give 52f (800 mg, 61.18%) as an off-white solid.

[0263] Synthesis of 52g To a stirred solution of 52f (750.00 mg, 2.047 mmol, 1.00 equiv) in HOAc (3.00 mL) was added CHNH in THF (5.00 mL, 1 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with CHCl (3 × 50 mL). The residue was purified by preparative TLC (CHCl / MeOH 12:1) to give 52g (350 mg, 30.68%) as an off-white solid.

[0264] Synthesis of 52h A solution of 52g (350.00 mg, 0.628 mmol, 1.00 equiv, 60%) in HCl in 1,4-dioxane (5.00 mL) was stirred overnight. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL). The residue was basified to pH 8 with NH in MeOH. The residue was purified by preparative TLC (CH2Cl2 / MeOH 15:1) to afford 52h (200 mg, 108.75%) as an off-white solid.

[0265] 52i synthesis To a stirred solution of 52h (180.00 mg, 0.768 mmol, 1.00 equiv) and 3-(trifluoromethyl)pyridine-2-carbaldehyde (134.54 mg, 0.768 mmol, 1.00 equiv) in DCE (10.00 mL) was added HOAc (46.14 mg, 0.768 mmol, 1 equiv) and STAB (488.51 mg, 2.305 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with DCM (50 mL). The resulting mixture was washed with 50 mL of water. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 52i (200 mg, 60.22%) as a pale yellow oil.

[0266] Synthesis of 52 To a stirred solution of 52i (180.00 mg, 0.458 mmol, 1.00 equiv) and pyridine (217.16 mg, 2.745 mmol, 6 equiv) in DCM (20.00 mL) was added triphosgene (47.52 mg, 0.160 mmol, 0.35 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give the crude product. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water, B: MeCN, gradient from 30% B to 40% B in 15 min; detector, UV 254 nm. This resulted in compound 52 (18.9 mg, 9.63%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 420 1H NMR: (400 MHz, CD3OD-d4, ppm): δ 1.42-1.43 (d, 3H), 3.06-3.18 (m, 2H), 3.35-3.47 (m, 1H), 3.53 (s, 3H), 6.35-6.38 (m, 1H), 7.00 (s, 1H), 7.04-7.06 (d, 1H), 7.25-7.30 (m, 1H), 7.34-7.38 (m, 1H), 7.48-7.51 (d, 1H), 7.75-7.77 (d, 1H), 8.30 (s, 1H).

[0267] Example 53. Synthesis of Compound 53 TIFF2024514339000219.tif50165 Synthesis of 53 To a stirred solution of 10d (40 mg, 0.08 mmol, 1.0 equiv) and piperidin-4-ol (9 mg, 0.08 mmol, 1.0 equiv) in DCE (0.8 mL) was added NaBH(OAc) (37 mg, 0.17 mmol, 2.0 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with MeOH (3 mL). The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Column: Xselect CSH OBD column, 30 × 150 mm, 5 μm, n; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 15% B, 15% B in 7 min; Wavelength: 220 nm; RT1 (min): 7.62) to give Compound 53 (14.5 mg, 28%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 543 1H NMR: (400 MHz, CD3OD, δ ppm): δ 1.65-7.74 (m, 2H), 1.87-1.98 (m, 2H), 2.75-2.83 (m, 2H), 2.97 (s, 3H), 3.10-3.15 (m, 2H), 3.68 (s, 2H), 3.77-3.83 (m, 3H), 5.09 (s, 4H), 6.92-6.94 (d, 1H), 7.14-7.17 (d, 2H), 7.31 (s, 1H), 7.46-7.50 (m, 1H), 7.63-7.65 (m, 1H), 7.85 (s, 1H), 8.21-8.28 (m, 1H), 8.40 (s, 1H).

[0268] Example 54. Synthesis of Compound 54 TIFF2024514339000220.tif55165 Synthesis of 54a To a stirred mixture of 44j (700.00 mg, 1.330 mmol, 1.00 equiv) and tributyl(1-ethoxyethenyl)stannane (720.54 mg, 1.995 mmol, 1.5 equiv) in dioxane (7.00 mL) was added Pd(PPh3)4 (153.70 mg, 0.133 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with CHCl2 (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl2 / MeOH 12:1) to give 54a (510 mg, 67.43%) as a yellow solid.

[0269] Synthesis of 54b To a stirred mixture of 54a (500.00 mg, 0.966 mmol, 1.00 equiv) in THF (5.00 mL) was added HCl (5.00 mL, 1 M) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with CHCl (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 54b (440 mg, 84.67%) as a yellow solid.

[0270] Synthesis of 54c To a stirred mixture of 54b (400.00 mg, 0.817 mmol, 1.00 equiv) and 5-azaspiro[2.4]heptane (119.11 mg, 1.226 mmol, 1.5 equiv) in DCE (4.00 mL) was added NaBHCN (154.08 mg, 2.452 mmol, 3 equiv), TEA (248.10 mg, 2.452 mmol, 3 equiv), and titanium(IV) isopropoxide (232.28 mg, 0.817 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was diluted with water (15 mL) at room temperature. The aqueous layer was extracted with DCM (2 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give 54c (180 mg, 37.83%) as a yellow solid.

[0271] Synthesis of 54d 54c (180 mg) was separated by preparative chiral HPLC under the following conditions (Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2 M NH3-MeOH), Mobile phase B: EtOH:DCM = 1:1; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 9 min; Wavelength: 220 / 254 nm; RT1 (min): 5.66) to give 54d (65 mg) as a yellow solid.

[0272] Synthesis of 54 54d (65 mg) was separated by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2M NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 40% B to 40% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 10.09) to give compound 54 (22.8 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 571 1 H NMR (400 MHz, DMSO, δ ppm): δ 0.40-0.58 (d, 4H), 1.02-1.32 (d, 3H), 1.74 (s, 2H), 2.35-2.41 (d, 1H), 2.52-2.63 (d, 2H), 2.67-2.80 (d, 1H), 3.14-3.33 (m, 4H), 4.80-4.94 (d, 1H), 5.16-5.25 (t, 2H), 5.25-5.40 (d, 1H), 6.16-6.40 (d, 1H), 7.09 (s, 1H), 7.13-7.15 (d, 1H), 7.34 (s, 1H), 7.42-7.44 (m, 1H), 7.55 (s, 1H), 7.68 (s, 1H), 7.79-7.83 (d, 1H), 8.38 (s, 1H).

[0273] Example 55. Synthesis of Compound 55 TIFF2024514339000221.tif39165 Synthesis of 55a Compound 54c (180 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 30% B to 30% B in 9 min; wavelength: 220 nm; RT2 (min): 7.34) to give 55a (65 mg) as a yellow solid.

[0274] Synthesis of 55 The crude product (55a, 65 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2M NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 40% B to 40% B in 20 min; wavelength: 220 nm; RT1 (min): 12.01) to give compound 55 (19.3 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 571 1 H NMR: (400 MHz, DMSO, δ ppm): δ 0.45-0.58 (d, 4H), 1.20-1.30 (d, 3H), 1.74 (s, 2H), 2.35-2.41 (d, 1H), 2.52-2.63 (d, 2H), 2.68-2.80 (d, 1H), 3.12-3.25 (d, 1H), 3.28 (s, 3H), 4.76-4.94 (d, 1H), 5.13-5.28 (t, 2H), 5.28-5.40 (d, 1H), 6.22-6.33 (d, 1H), 7.09 (s, 1H), 7.13-7.15 (d, 1H), 7.34 (s, 1H), 7.41-7.45 (m, 1H), 7.55 (s, 1H), 7.68 (s, 1H), 7.77-7.79 (d, 1H), 8.38 (s, 1H).

[0275] Example 56. Synthesis of Compound 56 TIFF2024514339000222.tif50165 Synthesis of 56 Compound 55a was separated by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2M NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 40% B to 40% B in 20 min; wavelength: 220 / 254 nm; RT2 (min): 15.44; first peak is product) to give compound 56 (20.6 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 571.3 1 H NMR (400 MHz, DMSO, δ ppm): δ 0.40-0.58 (d, 4H), 1.20-1.31 (d, 3H), 1.74 (s, 2H), 2.31-2.40 (d, 1H), 2.52-2.60 (d, 2H), 2.68-2.81 (d, 1H), 3.15-3.25 (d, 1H), 3.25-3.30 (d, 3H), 4.86 (s, 1H), 5.10-5.29 (t, 2H), 5.29-5.42 (d, 1H), 6.22-6.34 (d, 1H), 7.08(s, 1H), 7.13-7.15 (d, 1H), 7.33 (s, 1H), 7.41-7.46 (t, 1H), 7.55 (s, 1H), 7.68 (s, 1H), 7.77-7.79 (d, 1H), 8.37 (s, 1H).

[0276] Example 57. Synthesis of Compound 57 TIFF2024514339000223.tif50165 Synthesis of 57 Compound 54d (65 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2 M NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 40% B to 40% B in 16 min; wavelength: 220 / 254 nm; RT2 (min): 12.95) to give compound 57 (20.0 mg) as a yellow solid. LCMS: (ES, m / z): [M+H] + 571.3 1H NMR (400 MHz, DMSO, δ ppm): δ 0.40-0.58 (d, 4H), 1.02-1.32 (d, 3H), 1.74 (s, 2H), 2.35-2.41 (d, 1H), 2.52-2.63 (d, 2H), 2.67-2.80 (d, 1H), 3.14-3.30 (d, 4H), 4.86 (s, 1H), 5.16-5.25 (t, 2H), 5.25-5.40 (d, 1H), 6.16-6.40 (d, 1H), 7.00-7.11 (d, 1H), 7.11-7.19 (d, 1H), 7.33 (s, 1H), 7.39-7.48 (t, 1H), 7.56 (s, 1H), 7.68 (s, 1H), 7.72-7.83 (d, 1H), 8.38 (s, 1H).

[0277] Example 58. Synthesis of Compound 58 TIFF2024514339000224.tif55165 Synthesis of 58 To a stirred mixture of compound 7 (100.00 mg, 0.197 mmol, 1.00 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (65.84 mg, 0.296 mmol, 1.50 equiv.), KPO (83.52 mg, 0.394 mmol, 2.00 equiv.) in dioxane (2.00 mL) and HO (0.50 mL), Pd(dppf)Cl (14.40 mg, 0.020 mmol, 0.10 equiv.) was added under an argon atmosphere. The resulting mixture was stirred at 80 °C for 2 h under an argon atmosphere. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with CHCl / MeOH (50:1). The crude product was dissolved in CHCl (10 mL). SiliaMetS thiol (200 mg) was added to the above mixture. The resulting mixture was stirred overnight. The resulting mixture was filtered, and the filter cake was washed with CHCl (5 mL). The filtrate was concentrated under reduced pressure. The crude product was recrystallized from MeOH to give 2-(3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]phenyl)-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8-(trifluoromethyl)imidazo[1,5-a]pyridin-3-one (Compound 58, 57 mg, 55.23%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 525 1H NMR: (400 MHz, DMSO-d6, ppm): δ 2.24-3.01 (s, 3H), 2.39-2.44 (m, 2H), 2.54-2.56 (m, 2H), 2.92 (s, 3H), 2.97-3.02 (m, 2H), 3.54 (s, 2H), 4.89-4.96 (m, 4H), 6.32 (s, 1H), 6.88-6.90 (d, 1H), 7.36-7.43 (m, 4H), 7.55 (s, 1H), 7.75-7.77 (d, 1H), 8.21 (s, 1H).

[0278] Example 59. Synthesis of Compound 59 TIFF2024514339000225.tif124165 Synthesis of 59a To a stirred solution of methylpropanediol (5 g, 55.480 mmol, 1 equiv.) and EtN (5.61 g, 55.480 mmol, 1 equiv.) in DCM (50 mL) was added TsCl (21.15 g, 110.960 mmol, 2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (500 mL) at room temperature. The aqueous layer was extracted with CHCl (2 × 150 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA = 50:1 to give 59a (15 g, 63.10%) as a brown solid.

[0279] Synthesis of 59b To a stirred mixture of methyl 2-(3-nitrophenyl)acetate (5 g, 25.618 mmol, 1 equiv.) in DMF (50 mL) was added CsCO (41.74 g, 128.090 mmol, 5.0 equiv.) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. To the above mixture was added 59a (15.31 g, 38.427 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 days. The reaction was quenched by adding 200 mL of NHCl (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (2 × 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA = 100:1 to give 59b (1 g, 14.09%) as a white solid.

[0280] Synthesis of 59c To a stirred solution of 59b (1 g, 4.012 mmol, 1 equiv) in EtOH (10 mL) was added NHNHHO (2.01 g, 40.120 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was quenched by adding HO (100 mL) at room temperature. The aqueous layer was extracted with CHCl:MeOH = 10:1 (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 15:1) to give 59c (900 mg, 87.30%) as a white solid.

[0281] Synthesis of 59d To a stirred mixture of 59c (880 mg, 3.530 mmol, 1 equiv.) in tetrahydrofuran (9 mL) was added methyl isothiocyanate (516.20 mg, 7.060 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water (10 mL). The resulting solid was dried under vacuum to give 59d (900 mg, 73.54%) as a yellow solid.

[0282] Synthesis of 59e To a stirred solution of 59d (900 mg, 2.792 mmol, 1 equiv) was added NaOH (558.31 mg, 13.960 mmol, 5 equiv) in 7 mL of HO at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 5 with HCl (aq) (1 M). The aqueous layer was extracted with CHCl:MeOH = 10:1 (3 × 5 mL). The residue was purified by preparative TLC (CHCl / MeOH = 15:1) to give 59e (700 mg, 79.08%) as a white solid.

[0283] Synthesis of 59f To a stirred solution of 59e (700 mg, 2.300 mmol, 1 equiv) and NaNO (1586.78 mg, 23.000 mmol, 10 equiv) in HO (7 mL) was added HNO (23 mL, 1 M, 23.000 mmol, 10 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding NaHCO (20 mL) at 0 °C. The aqueous layer was extracted with CHCl:MeOH = 10:1 (2 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH = 15:1 to give 59f (600 mg, 91.97%) as a white solid.

[0284] Synthesis of 59g To a solution of 59f (600 mg, 2.203 mmol, 1 equiv) in 20 mL of MeOH was added Pd / C (10%, 60 mg) in a 100 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature overnight using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give 59g (500 mg, 88.03%) as a yellow solid.

[0285] Synthesis of 59h To a stirred solution of 59g (480 mg, 1.981 mmol, 1.00 equiv) and I-2g (754.70 mg, 2.972 mmol, 1.5 equiv) in DCE (5 mL) was added HOAc (118.95 mg, 1.981 mmol, 1 equiv) and NaBH(OAc) (1259.44 mg, 5.943 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding 10 mL of HO at room temperature. The aqueous layer was extracted with CHCl (2 × 10 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH = 20:1) to give 59h (500 mg, 50.45%) as a yellow solid.

[0286] 59i synthesis To a stirred solution of 59h (480 mg, 1.763 mmol, 1 equiv) and pyridine (836.58 mg, 10.578 mmol, 6 equiv) in DCM (5 mL) was added triphosgene (261.54 mg, 0.881 mmol, 0.5 equiv) in one portion at 0 °C. The reaction was quenched by adding 30 mL of NaHCO (aq) at room temperature. The aqueous layer was extracted with CHCl (2 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 15:1) to give 59i (400 mg, 84.28%) as a yellow solid.

[0287] Synthesis of 59j To a stirred solution of 59i (14 g, 27.650 mmol, 1 equiv.) and TMEDA (6.43 g, 55.300 mmol, 2 equiv.) in dioxane (500 mL), butyldi-1-adamantylphosphine (1.985 g, 5.530 mmol, 0.2 equiv.) and Pd(OAc) (0.62 g, 2.765 mmol, 0.1 equiv.) were added at room temperature under a nitrogen atmosphere. The mixture was purged with nitrogen and then pressurized to 10 atm with CO and H (1:1) at 80 °C overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH = 20:1 to give 59j (8 g, 60.35%) as an orange solid.

[0288] 59k synthesis To a stirred mixture of 59j (800 mg, 1.757 mmol, 1.00 equiv) and (3S)-3-methylpiperidine hydrochloride (476.51 mg, 3.514 mmol, 2 equiv) in DCE (8 mL) was added EtN (533.25 mg, 5.271 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added NaBH(OAc) (1116.84 mg, 5.271 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (50 mL) at room temperature. The aqueous layer was extracted with CHCl (2 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 15:1) to give the crude product. The crude product (500 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 73% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.68) to give 59k (400 mg, 41.43%) as a yellow solid.

[0289] Synthesis of 59 59k (400 mg) was purified by chiral separation under the following conditions: column: CHIRALPAK AD-H, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 15% B to 15% B in 20 min; wavelength: 220 / 254 nm; RT1 (min): 9.69; RT2 (min): 13.84; first peak is product) to give compound 59 (216.6 mg, 42.40%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 539. H-NMR: (400 MHz, DMSO-d6, ppm, δ): 0.78-0.95 (d, 4H), 1.05-1.16 (d, 3H), 1.37-1.53 ​​(m, 1H), 1.53-1.70 (m, 4H), 1.89 (s, 1H), 2.54-2.56 (s, 3H), 2.72-2.80 (m, 2H), 2.90 (s, 2H), 3.21 (s, 3H), 3.24 (s, 2H), 7.00 (s, 1H), 7.24-7.26 (d, 1H),7.37 (s, 1H), 7.47-7.52 (m, 1H), 7.63-7.65 (m, 2H), 7.84 (s, 1H), 8.29 (s, 1H).

[0290] Alternatively, compound 59 can also be prepared as outlined below. TIFF2024514339000226.tif50165

[0291] Synthesis of 1.59 50-9 (11.5 g) was purified by preparative SFC under the following conditions: (Column: CHIRALPAK AD-H, 5 × 25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: ETOH (0.1% 2 M NH-MEOH); Flow rate: 200 mL / min; Gradient: Isocratic 40% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.55; RT2 (min): 4.71; First peak is product) to give 59 (5.7744 g, 53.79%) as a yellow solid. LC-MS-: (ES, m / z): [M+H] + 539 H-NMR: (400 MHz, DMSO-d6, δ ppm): 0.79-0.92 (m, 4H), 0.98-1.15 (d, 3H), 1.35-1.52 (m, 1H), 1.55-1.71 (m, 4H), 1.81-1.93 (m, 1H), 2.50-2.61 (m, 3H), 2.69-2.77 (m, 2H), 2.81-2.93 (m, 2H), 3.15-3.22 (m, 4H), 6.99 (s, 1H), 7.23-7.25 (d, 1H), 7.35 (s, 1H), 7.47-7.51 (m, 1H), 7.64-7.66 (m, 2H), 7.85 (s, 1H), 8.29 (s, 1H).

[0292] Example 60. Synthesis of Compound 60 TIFF2024514339000227.tif34165 60 Synthesis 59k (400 mg) was purified by chiral separation under the following conditions: column: CHIRALPAK AD-H, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 15% B to 15% B in 20 min; wavelength: 220 / 254 nm; RT1 (min): 9.69; RT2 (min): 13.84; second peak is product) to give compound 60 (97.3 mg, 19.05%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 539. H-NMR: (400 MHz, DMSO-d6, ppm, δ): 0.75-0.98 (d, 4H), 1.05-1.28 (d, 3H), 1.35-1.45 (m, 1H), 1.45-1.66 (m, 4H), 1.89 (s, 1H), 2.25-2.34 (m, 2H), 2.34-2.41 (m, 1H), 2.75 (s, 2H), 3.10-3.14 (m, 2H), 3.25 (s, 5H), 6.98-7.02 (m, 1H), 7.08-7.10 (m, 1H),7.36 (s, 1H), 7.45-7.49 (m, 1H), 7.60-7.67 (m, 2H), 7.70 (s, 1H), 8.36 (s, 1H).

[0293] Example 61. Synthesis of Compound 61 TIFF2024514339000228.tif81165 Synthesis of 61a To a stirred solution of methyl 5-bromo-3-chloropyridine-2-carboxylate (30.00 g, 119.770 mmol, 1.00 equiv.) and methylboronic acid (21.51 g, 359.310 mmol, 3 equiv.) in dioxane (350.00 mL), KPO (50.85 g, 239.540 mmol, 2 equiv.) and Pd(dppf)Cl (8.76 g, 11.977 mmol, 0.1 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 600 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 61a (14 g, 56.68%) as an off-white oil.

[0294] Synthesis of 61b To a stirred solution of 61a (3.00 g, 16.163 mmol, 1.00 equiv) and NBS (4.32 g, 24.272 mmol, 1.50 equiv) in CHCl3 (30.00 mL) was added AIBN (7.96 g, 48.489 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 80 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (30:1) to give 61b (1.5 g, 21.05%) as an off-white oil.

[0295] Synthesis of 61c To a stirred solution of 61b (1.50 g, 5.671 mmol, 1.00 equiv) and (3S)-3-fluoropyrrolidine hydrochloride (1.42 g, 11.342 mmol, 2 equiv) in ACN (15.00 mL) was added KCO (1.57 g, 11.342 mmol, 2 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 61c (800 mg, 50.18%) as an off-white solid.

[0296] Synthesis of 61d To a stirred solution of 61c (800.00 mg, 2.934 mmol, 1.00 equiv) in MeOH (10.00 mL) was added NaBH4 (221.98 mg, 5.867 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched with NH4Cl (aq) at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give 61d (500 mg, 65.48%) as a white oil.

[0297] Synthesis of 61e To a stirred solution of 61d (500.00 mg, 2.043 mmol, 1.00 equiv) in DCM (7.00 mL) was added MnO2 (1776.47 mg, 20.434 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 40 °C overnight. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 2:1) to give 61e (400 mg, 75.82%) as a white oil.

[0298] Synthesis of 61f To a stirred solution of 61e (400.00 mg, 1.648 mmol, 1.00 equiv) in DCE (6.00 mL) was added I-3 (402.67 mg, 1.648 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture were added NaBH(OAc) (1048.00 mg, 4.945 mmol, 3 equiv) and HOAc (9.9 mg, 0.165 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with NH4Cl (aq) at room temperature. The aqueous layer was extracted with DCM (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 15:1) to give 61f (500 mg, 62.48%) as a white solid.

[0299] Synthesis of 61 To a stirred solution of 61f (35.00 mg, 0.074 mmol, 1.00 equiv) and pyridine (35.27 mg, 0.446 mmol, 6 equiv) in DCM (1.00 mL) was added triphosgene (7.72 mg, 0.026 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with NaHCO (aq) (10.00 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 8 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water (0.5% NHHCO), B: CHCN, gradient from 30% B to 50% B in 30 min; detector, UV 254 nm. This resulted in 61 (2.3 mg, 6.10%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 497 H-NMR: (400 MHz, CDCl3, ppm, δ): 2.40-2.48 (m, 2H), 2.95 (s, 3H), 3.26-3.39 (m, 2H), 3.62 (s, 2H), 3.72-3.78 (m, 2H), 4.06 (s, 2H), 5.07-5.09 (d, 2H), 5.13-5.14 (d, 2H), 5.36-5.49 (d, 1H), 6.79 (s, 1H), 6.88-6.91 (d, 2H), 7.16 (s, 1H), 7.42-7.48 (m, 2H), 7.65 (s, 1H), 8.12 (s, 1H).

[0300] Example 62. Synthesis of Compound 62 TIFF2024514339000229.tif34165 Synthesis of 62 To a stirred mixture of 10d (200 mg, 0.437 mmol, 1 equiv.) and azetidin-3-ol hydrochloride (143.70 mg, 1.311 mmol, 3 equiv.) in DCE (2 mL) was added EtN (44.24 mg, 0.437 mmol, 1 equiv.) and NaBH(OAc) (185.34 mg, 0.874 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated NH4Cl(aq.) (10 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 9:1) to give 62 (150 mg, crude). The crude product (150 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 m; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.23) to give Compound 62 (23.1 mg, 10.27%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 515 H-NMR: (400 MHz, DMSO, δ ppm): 2.67-2.96 (m, 2H), 2.96-3.00 (d, 3H), 3.33-3.35 (d, 2H), 3.46-3.53 (m, 4H), 4.18-4.23 (m, 1H), 4.88-4.96 (m, 4H), 5.32-5.34 (d, 1H), 6.87-6.89 (d, 1H), 6.96 (s, 1H), 7.31 (s, 1H), 7.38-7.41 (m, 2H), 7.64 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0301] Example 63. Synthesis of Compound 63 TIFF2024514339000230.tif34165 Synthesis of 63 To a stirred mixture of 10d (200 mg, 0.437 mmol, 1 equiv.) and 3-methoxyazetidine hydrochloride (162.10 mg, 1.311 mmol, 3 equiv.) in DCE (2 mL), EtN (176.96 mg, 1.748 mmol, 4 equiv.) and NaBH(OAc) (185.34 mg, 0.874 mmol, 2 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched with water (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give the crude product (150 mg). The crude product (150 mg) was purified by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.23. This resulted in compound 63 (63.6 mg, 27.52%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 529 H-NMR: (400 MHz, DMSO, ppm): δ2.86-2.89 (m, 2H), 2.96 (s, 3H), 3.00 (s, 3H), 3.15 (m, 2H), 3.33-3.38 (d, 2H), 3.45-3.53 (m, 2H), 3.95-3.99 (m, 1H), 4.90-4.96 (m, 4H), 6.87-6.89 (d, 1H), 6.97 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 2H), 7.67 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0302] Example 64. Synthesis of Compound 64 TIFF2024514339000231.tif76165 Synthesis of 64a To a 100 mL round-bottom flask was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (2 g) and TFA (5 mL) in DCM (15 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This resulted in 64a (1 g, 73.94%) as a colorless oil.

[0303] Synthesis of 64b A solution of 64a (1.00 g, 4.782 mmol, 1.00 equiv) and formaldehyde solution (1.16 g, 14.346 mmol, 3.00 equiv, 37%) in MeOH (10.00 mL) was stirred overnight at room temperature under a nitrogen atmosphere. To the above mixture was added NaBH (0.36 g, 9.516 mmol, 1.99 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. The reaction was quenched with NH Cl (aq) (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. This resulted in 64b (500 mg, 46.86%) as a colorless oil.

[0304] Synthesis of 64 To a stirred mixture of 64b (200.00 mg, 0.393 mmol, 1.00 equiv.) and 7 (131.69 mg, 0.590 mmol, 1.50 equiv.) in dioxane (1.60 mL) and HO (0.4 mL), Pd(dppf)Cl (57.58 mg, 0.079 mmol, 0.20 equiv.) and KPO (167.04 mg, 0.787 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The product was dissolved in DCM (10 mL), and isolute Si-thiol (100 mg) was added. The mixture was stirred for 30 min. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 43% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 8.22) to give compound 64 (36.7 mg, 17.78%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 525 H-NMR: (400 MHz, DMSO, δ ppm): δ2.29 (s, 2H), 2.34 (s, 3H), 2.44-2.49 (m, 2H), 2.97 (s, 3H), 3.15 (s, 2H), 3.57 (s, 2H), 4.91-4.96 (m, 4H), 6.35 (s, 1H), 6.88-6.90 (d, 1H), 7.33-7.36 (d, 1H), 7.39-7.41 (d, 1H), 7.42-7.43 (m, 2H), 7.51 (s, 1H), 7.75-7.77 (d, 1H), 8.21 (s, 1H).

[0305] Example 65. Synthesis of Compound 65 TIFF2024514339000232.tif76165 Synthesis of 65a To a stirred mixture of 7 (200.00 mg, 0.393 mmol, 1.00 equiv.), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (174.22 mg, 0.590 mmol, 1.50 equiv.), and KPO (167.04 mg, 0.786 mmol, 2.00 equiv.) in dioxane (4.00 mL) and HO (1.00 mL), Pd(dppf)Cl (28.79 mg, 0.039 mmol, 0.10 equiv.) was added under an argon atmosphere. The resulting mixture was stirred overnight at 80 °C under an argon atmosphere. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with DCM (2 × 15 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CHCl / MeOH (40:1). The product was dissolved in CHCl (20 mL). SiliaMetS thiol (250 mg) was added to the above mixture. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with CHCl (5 mL). The filtrate was concentrated under reduced pressure. This resulted in 65a (220 mg, 93.72%) as a yellow solid.

[0306] Synthesis of 65 To a stirred solution of 65a (200.00 mg, 0.335 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (0.40 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH 8:1) to afford 65 (150 mg, 90.12%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 497 H-NMR: (400 MHz, CD3OD, ppm): δ 2.95 (s, 3H), δ3.68 (s, 2H), δ3.94-3.95 (d, 2H), δ4.05-4.06 (d, 2H), δ5.08 (s, 4H), δ6.40(s, 1H), δ6.91-6.93 (d, 1H), δ7.17(s, 1H), δ7.31(s, 1H), δ7.35(s, 1H), δ7.46-7.49 (m, 1H), δ7.54 (s, 1H), δ7.63-7.65 (m, 1H), δ8.21 (s, 1H).

[0307] Example 66. Synthesis of Compound 66 TIFF2024514339000233.tif76165 Synthesis of 66a To a 20 mL round-bottom flask was added 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (1.00 g, 4.166 mmol, 1.00 equiv.), dioxane (8.00 mL), HO (2.00 mL), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (1.23 g, 4.167 mmol, 1.00 equiv.), Pd(dppf)Cl (0.30 g, 0.417 mmol, 0.1 equiv.), and KPO (1.77 g, 8.333 mmol, 2 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 5 hours. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc 5:1) to give 66a (1.1 g, 77.20%) as a white solid.

[0308] Synthesis of 66b To a stirred solution of 66a (1.00 g, 3.046 mmol, 1.00 equiv) in MeOH (30.00 mL) was added Pd / C (200.00 mg, 10%) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere at room temperature for 4 h, filtered through a Celite pad, and concentrated under reduced pressure to give 66b (1 g, 99.39%) as a white oil.

[0309] Synthesis of 66c To a stirred solution of 66b (1 g, 3.027 mmol, 1 equiv.) in dioxane (10 mL) was added SeO (1.01 g, 9.081 mmol, 3 equiv.). The resulting mixture was stirred at 110 °C overnight. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 66c (860 mg, 82.51%) as a yellow solid.

[0310] Synthesis of 66d To a stirred solution of 66c (350 mg, 1.016 mmol, 1 equiv.) and I-3 (248.32 mg, 1.016 mmol, 1 equiv.) in DCE (10 mL) was added HOAc (122.08 mg, 2.032 mmol, 2 equiv.) and NaBH(OAc) (430.86 mg, 2.032 mmol, 2 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (20 mL). The resulting mixture was extracted with CHCl (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 66d (300 mg, 51.54%) as a pale yellow solid.

[0311] Synthesis of 66 To a stirred solution of 66d (300.00 mg, 0.524 mmol, 1.00 equiv) and pyridine (248.64 mg, 3.144 mmol, 6.00 equiv) in DCM (5.00 mL) was added triphosgene (54.41 mg, 0.183 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched by adding NaHCO (aq) (10 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (3 × 20 mL). The resulting mixture was concentrated in vacuo. The crude product was recrystallized from CHCl / methyl tert-butyl ether (1:5) to give compound 66 (200 mg, 63.77%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 599 H-NMR: (400 MHz, DMSO-d6, ppm): δ1.42 (s, 9H), δ 1.89-2.01 (m, 1H), δ2.02-2.08 (m, 1H), δ2.97 (s, 3H), δ3.14-3.16 (m, 1H), δ3.20-3.29 (m, 2H), δ3.42-3.46 (m, 1H), δ3.53(s, 2H), δ3.60-3.65 (m, 1H), δ4.91-4.96 (m, 4H), δ6.89-6.91 (d, 1H), δ7.18-7.19 (d, 1H), δ7.32 (s, 1H), δ7.38-7.42 (m, 2H), δ7.61 (s, 1H), δ7.74-7.77 (m, 1H), δ8.20 (s, 1H).

[0312] Example 67. Synthesis of Compound 67 TIFF2024514339000234.tif44165 Synthesis of 67a To a 100 mL round-bottom flask was added 10d (400 mg, 0.874 mmol, 1.00 equiv), DCE (5.00 mL), 4,4-difluoro-3-methylpiperidine hydrochloride (149.45 mg, 0.874 mmol, 1 equiv), and NaBH(OAc) (556.02 mg, 2.622 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with CHCl / MeOH (10:1) to give 67a (100 mg, 19.83%) as a yellow solid.

[0313] Synthesis of 67 67a (100 mg) was purified by chiral separation under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2 M NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 50% B to 50% B in 18 min; wavelength: 220 / 254 nm; RT1 (min): 14.18; RT2 (min): 16.17, first peak is product) to give compound 67 (34.3 mg, 34.30%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 577 H-NMR: 1H NMR (300 MHz, DMSO-d6, ppm, δ) 0.92-0.94 (d, 3H), 1.99-2.15 (m, 4H), 2.21 -2.32(m, 1H), 2.62-2.81(m, 2H), 2.97 (s, 3H), 3.32-3.35 (d, 2H), 3.53 (s, 2H), 4.91 - 4.96 (m, 4H), 6.89-6.91 (d, 1H), 7.03 (s, 1H), 7.32 (s, 1H), 7.38-7.42 (m, 2H), 7.71 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0314] Example 68. Synthesis of Compound 68 TIFF2024514339000235.tif44165 Synthesis of 68 68a (100 mg) was purified by chiral separation under the following conditions: column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2 M NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 50% B to 50% B in 18 min; wavelength: 220 / 254 nm; RT1 (min): 14.18; RT2 (min): 16.17, the second peak is the product), to give compound 68 (34.2 mg, 34.20%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 577 H-NMR: 1H NMR (300 MHz, DMSO-d6) δ 0.92-0.94 (d, 3H), 1.99-2.15 (m, 4H), 2.21 -2.32(m, 1H), 2.62-2.81(m, 2H), 2.97 (s, 3H), 3.32-3.35 (d, 2H), 3.53 (s, 2H), 4.91 - 4.96 (m, 4H), 6.89-6.91 (d, 1H), 7.03 (s, 1H), 7.32 (s, 1H), 7.38-7.42 (m, 2H), 7.71 (s, 1H), 7.74-7.76 (m, 1H), 8.20 (s, 1H).

[0315] Example 69. Synthesis of Compound 69 TIFF2024514339000236.tif50165 Synthesis of 69 To a stirred solution of 10d (200.00 mg, 0.437 mmol, 1.00 equiv) and ethanolamine (40.06 mg, 0.656 mmol, 1.50 equiv) in DCE (3 mL) was added STAB (278.01 mg, 1.311 mmol, 3.00 equiv) and AcOH (26.26 mg, 0.437 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated NH4Cl(aq) (10 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The crude product (101 mg) was purified by preparative HPLC under the following conditions (Column: Xselect CSH F-Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 47% B in 7 min; Wavelength: 220 nm; RT1 (min): 5.81) to give Compound 69 (43.6 mg, 18.73%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + :503 H-NMR: (400 MHz, DMSO-d6, ppm): δ 2.61-2.64 (m, 2H), δ 2.90-2.91 (m, 3H), δ 3.30-3.32 (d, 2H), δ 3.47-3.57 (m, 4H), δ 4.91-4.96 (m, 4H), δ 6.88-6.90 (d, 1H), δ 7.14 (s, 1H), δ 7.38-7.40 (d, 1H), δ 7.41-7.42 (d, 2H), δ 7.42 (s, 1H), δ 7.43-7.44 (d, 1H), δ 8.20-8.21 (d, 2H).

[0316] Example 70. Synthesis of Compound 70 TIFF2024514339000237.tif50165 70 Synthesis To a stirred solution of 10d (200.00 mg, 0.437 mmol, 1.00 equiv) and methylethaneolamine (49.26 mg, 0.656 mmol, 1.50 equiv) in DCE (3 mL) was added STAB (278.01 mg, 1.311 mmol, 3.00 equiv) and AcOH (26.26 mg, 0.437 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated NH4Cl(aq) (5 mL) at room temperature. The resulting mixture was extracted with CHCl (2 × 10 mL). The resulting mixture was concentrated under reduced pressure. The crude product (110 mg) was purified under the following conditions: column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 28% B in 10 min; wavelength: 220 nm; RT1 (min): 10.25) to give 70 (42.3 mg, 18.62%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + :517 H-NMR: (400 MHz, DMSO-d6, ppm): δ 2.19 (m, 3H), δ 2.45-2.51 (m, 2H), δ 2.97 (s, 3H), δ 3.33 (s, 2H), δ 3.49-3.53 (m, 4H), δ 4.43-4.46 (m, 1H), δ 4.91-4.96 (m, 4H), δ 6.88-6.90 (d, 1H), δ 7.05 (s, 1H), δ 7.30 (s, 1H), δ 7.38-7.42 (m, 2H), δ 7.74 (s, 1H), δ 7.76-7.77 (d, 1H), δ 8.20 (s, 1H).

[0317] Example 71. Synthesis of Compound 71 TIFF2024514339000238.tif65165 Synthesis of 71a To a stirred solution of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (3 g, 12.499 mmol, 1 equiv.) and (tributylstannyl)methanol (6.02 g, 18.748 mmol, 1.5 equiv.) in toluene (30 mL, 281.967 mmol, 22.56 equiv.) was added Pd(PPh3)4 (0.29 g, 0.250 mmol, 0.02 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA = 30:1 to give 71a (1.3 g, 48.97%) as a colorless oil.

[0318] Synthesis of 71b To a stirred mixture of 71a (380 mg, 1.988 mmol, 1 equiv) in DMF (5 mL) was added NaH (159.01 mg, 3.976 mmol, 2 equiv, 60%) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. To the above mixture was added 2-bromoethyl methyl ether (414.46 mg, 2.982 mmol, 1.5 equiv) at 0 °C. The above mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with NH Cl (aq) (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 100:1) to give 71b (300 mg, 54.49%) as a colorless oil.

[0319] Synthesis of 71b To a stirred mixture of 71b (290 mg, 1.164 mmol, 1 equiv.) in dioxane (4 mL) was added SeO (516.44 mg, 4.656 mmol, 4 equiv.) at room temperature. The resulting mixture was stirred at 110 °C for 4 h. The resulting mixture was diluted with water (30 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 100:1) to give 71c (180 mg, 52.31%) as a colorless oil.

[0320] Synthesis of 71c To a stirred mixture of 71c (170 mg, 0.646 mmol, 1 equiv.) and I-3 (173.56 mg, 0.711 mmol, 1.1 equiv.) in DCE (2 mL) was added HOAc (38.79 mg, 0.646 mmol, 1 equiv.) and NaBH(OAc) (410.65 mg, 1.938 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 30:1) to give 71d (200 mg, 59.22%) as a yellow solid.

[0321] Synthesis of 71 To a stirred solution of 71d (190 mg, 0.387 mmol, 1.00 equiv) and pyridine (607.52 mg, 2.322 mmol, 6 equiv) in DCM (2 mL) was added triphosgene (45.88 mg, 0.155 mmol, 0.4 equiv) at room temperature. The resulting mixture was stirred at 0 °C for 5 min. The reaction was quenched by adding NaHCO (aq) (20 mL) at room temperature. The aqueous layer was extracted with CHCl (3 × 10 mL). The residue was purified by preparative TLC (CHCl / MeOH = 15:1) to give 71 (200 mg) as a yellow solid. The crude product (200 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.23) to give Compound 71 (30.7 mg, 15.35%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 518. H-NMR: (400 MHz, DMSO-d6, ppm) δ 2.97 (s, 3H), 3.26 (s, 3H), 3.32-3.47 (m, 2H), 3.47-3.49 (m, 2H), 3.53-3.58 (m, 2H), 4.32 (s, 2H), 4.91-4.96 (m, 4H), 6.88-6.90 (d, 2H), 7.03 (s, 1H), 7.33-7.42 (m, 3H), 7.75-7.80 (m, 2H), 8.20 (s, 1H).

[0322] Example 72. Synthesis of Compound 72 TIFF2024514339000239.tif60165 Synthesis of 72 To a stirred solution of 65 (130.00 mg, 0.262 mmol, 1.00 equiv) and HCHO (63.75 mg, 0.786 mmol, 3 equiv, 37%) in MeOH (4.00 mL) was added HOAc (15.72 mg, 0.262 mmol, 1 equiv) and NaBHCN (110.99 mg, 0.524 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding water (20 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD column, 30 × 150 mm, 5 μm, n; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 22% B in 7 min; Wavelength: 220 nm; RT1 (min): 6.62) to give Compound 72 (49.7 mg, 37.18%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 511 H-NMR: (400 MHz, DMSO-d6, ppm): δ 2.33 (s, 3H), δ2.97 (s, 3H), δ3.51-3.56 (m, 4H), δ3.71 (s, 2H), δ4.88-4.96 (m, 4H), δ6.45(s, 1H), δ6.88-6.90 (d, 1H), δ7.39-7.43 (m, 5H), δ7.74-7.76 (m, 1H), δ8.21 (s, 1H).

[0323] Example 73. Synthesis of Compound 73 TIFF2024514339000240.tif108165 Synthesis of 73a To a stirred solution of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]carbamate (1 g, 3.094 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 9 with saturated NaHCO (aq.). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. This resulted in 73a (600 mg, crude) as a pale yellow solid.

[0324] Synthesis of 73b To a stirred solution of 73a (600 mg, 2.689 mmol, 1 equiv.) and formaldehyde solution (872.91 mg, 10.756 mmol, 4 equiv., 37%) in MeOH (10 mL) was added NaBHCN (506.97 mg, 8.067 mmol, 3 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (50 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (4 × 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (30:1) to give 73b (310 mg, 45.89%) as a pale yellow solid.

[0325] Synthesis of 73 To a stirred mixture of compound 7 (100 mg, 0.197 mmol, 1 equiv.) and 73b (98.83 mg, 0.394 mmol, 2 equiv.) in dioxane (4 mL) and HO (1 mL) was added KPO (83.52 mg, 0.394 mmol, 2 equiv.) and Pd(dppf)Cl (14.40 mg, 0.020 mmol, 0.1 equiv.). The resulting mixture was stirred overnight at 80 °C under an argon atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 40% B to 62% B in 8 min; Wavelength: 220 nm; RT1 (min): 7.23) to give Compound 73 (20.2 mg, 18.58%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 497 H-NMR: (400 MHz, DMSO, ppm): δ 1.45-1.46 (m, 1H), δ1.99-2.02 (m, 1H), δ2.10-2.15 (m, 1H), δ2.22 (s, 6H), δ2.31-2.36 (m, 3H), δ2.45-2.49 (m, 1H), δ2.97 (s, 3H), δ3.54 (s, 2H), δ4.88-4.96 (m, 4H), δ6.28(s, 1H), δ6.89-6.90 (d, 1H), δ7.33-7.42(m, 4H), δ7.54 (s, 1H), δ7.75-7.77 (m, 1H), δ8.22 (s, 1H).

[0326] Example 74. Synthesis of Compound 74 TIFF2024514339000241.tif60165 Synthesis of 74 To a stirred solution of 66 (200 mg, 0.334 mmol, 1 equiv.) in DCM (2 mL) was added TFA (0.4 mL). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give compound 74 (140 mg, 84.06%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 599 H-NMR: (400 MHz, DMSO-d6, ppm): δ1.66-1.71 (m, 1H), δ 2.18-2.12 (m, 1H), δ2.73-2.77 (m, 1H), δ2.89-2.93 (m, 1H), δ2.98 (s, 3H), δ3.14-3.20 (m, 3H), δ3.53(s, 2H), δ4.93-4.97 (m, 4H), δ6.90-6.91 (d, 1H), δ7.13 (s, 1H), δ7.32 (s, 1H), δ7.39-7.43 (m, 2H), δ7.61 (s, 1H), δ7.75-7.77 (m, 1H), δ 8.21 (s, 1H).

[0327] Example 75. Synthesis of Compound 75 TIFF2024514339000242.tif55165 Synthesis of 75 To a stirred solution of 10d (20.00 mg, 0.044 mmol, 1.00 equiv) and NaBH(OAc) (27.80 mg, 0.131 mmol, 3.00 equiv) in DCE (1.00 mL) was added AcOH (2.63 mg, 0.044 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give compound 75 (2.6 mg, 12.81%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 460 H-NMR: (400 MHz, CD3OD, δ ppm): 2.96 (s, 3H), 3.66 (s, 2H), 4.44 (s, 2H), 5.06 (s, 4H), 6.88-6.90 (m, 1H), 7.07-7.12 (m, 2H), 7.32-7.33 (m, 1H), 7.47-7.49 (m, 1H), 7.62-7.65 (d, 1H), 7.72 (s, 1H), 8.21 (s, 1H).

[0328] Example 76. Synthesis of Compound 76 TIFF2024514339000243.tif113165 Synthesis of 76a To a 20 mL sealed tube was added 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (1.00 g, 4.166 mmol, 1.00 equiv.), dioxane (8.00 mL), HO (2.00 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.29 g, 4.172 mmol, 1.00 equiv.), Pd(dppf)Cl (0.30 g, 0.417 mmol, 0.10 equiv.), and KPO (1.77 g, 8.333 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 6 hours. The reaction was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 3:1) to give 76a (1 g, 70.11%) as a white solid.

[0329] Synthesis of 76b To a solution of 76a (810 mg, 2.366 mmol, 1 equiv) in MeOH (20 mL) was added Pd / C (10%, 20 mg) in a 100 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature using a hydrogen balloon for 4 h, filtered through a Celite pad, and concentrated under reduced pressure to give 76b (820 mg) as a colorless oil.

[0330] Synthesis of 76c To a stirred solution of 76b (820 mg, 2.381 mmol, 1 equiv.) in dioxane (20 mL) was added SeO (792.62 mg, 7.143 mmol, 3 equiv.). The resulting mixture was stirred at 110 °C overnight. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 76c (760 mg, 89.07%) as a yellow oil.

[0331] Synthesis of 76d To a stirred mixture of 76c (350 mg, 0.977 mmol, 1 equiv.) and I-3 (238.60 mg, 0.977 mmol, 1 equiv.) in DCE (10 mL) was added HOAc (58.65 mg, 0.977 mmol, 1 equiv.) and NaBH(OAc) (413.99 mg, 1.954 mmol, 2 equiv.). The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CHCl / MeOH (2 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 15:1) to give 76d (360 mg, 62.83%) as an off-white solid.

[0332] Synthesis of 76e To a stirred solution of 76d (360 mg, 0.614 mmol, 1 equiv) and pyridine (291.23 mg, 3.684 mmol, 6 equiv) in DCM (10 mL) was added triphosgene (72.84 mg, 0.246 mmol, 0.4 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding NaHCO (aq) (10 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 76e (220 mg, 58.52%) as a yellow solid.

[0333] Synthesis of 76f To a stirred solution of 76e (320 mg, 0.522 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give 76f (170 mg, 63.50%) as a yellow solid.

[0334] Synthesis of 76 To a stirred solution of 76f (150 mg, 0.293 mmol, 1 equiv.) and formaldehyde solution (71.25 mg, 0.879 mmol, 3 equiv., 37%) in MeOH (5 mL) was added HOAc (17.57 mg, 0.293 mmol, 1 equiv.) and NaBHCN (36.78 mg, 0.586 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding NaHCO (aq.) (20 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give compound 76 (107 mg, 69.43%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 527 H-NMR: (400 MHz, DMSO-d6, ppm): δ 1.62-1.66 (m, 2H), δ1.68-1.79 (m, 2H), δ1.92-1.98 (m, 2H), δ2.21 (s, 3H), δ2.34-2.40 (m, 1H), δ2.83-2.89 (m, 2H), δ3.02 (s, 3H), δ3.59 (s, 2H), δ4.91-4.96(m, 4H), δ6.89-6.91(d, 1H), δ7.10 (s, 1H), δ7.29 (s, 1H), δ7.38-7.42 (m, 2H), δ7.47(s, 1H), δ7.74-7.76(d, 1H), δ8.20 (s, 1H).

[0335] Example 77. Synthesis of Compound 77 TIFF2024514339000244.tif50165 Synthesis of 77 To a stirred solution of 74 (130 mg, 0.261 mmol, 1 equiv.) and HCHO (63.49 mg, 0.783 mmol, 3 equiv., 37%) in MeOH (2 mL) was added HOAc (15.66 mg, 0.261 mmol, 1 equiv.) and NaBHCN (32.78 mg, 0.522 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding water (15 mL). The resulting mixture was extracted with CHCl / MeOH 10:1 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 77 (48.2 mg, 36.06%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 513 H-NMR: (400 MHz, DMSO-d6, ppm): δ 1.65-1.72 (m, 1H), δ2.14-2.19 (m, 1H), δ2.20 (s, 3H), δ2.31-2.45 (m, 2H), δ2.63-2.67 (m, 1H), δ2.72-2.76 (m, 1H), δ2.97(s, 3H), δ3.23-3.29 (m, 1H), δ3.54 (s, 3H), δ4.91-4.96 (m, 4H), δ6.88-6.91 (d, 1H), δ7.12 (s, 1H), δ7.31 (s, 1H), δ7.38-7.42 (m, 2H), δ7.74-7.77 (d, 1H), δ8.20 (s, 1H).

[0336] Example 78. Synthesis of Compound 78 TIFF2024514339000245.tif76165 Synthesis of 78a To a stirred mixture of 1-2h (500.00 mg, 1.666 mmol, 1.00 equiv.) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine (446.13 mg, 2.000 mmol, 1.20 equiv.) in dioxane (4.00 mL) and HO (1.00 mL), KPO (707.38 mg, 3.333 mmol, 2.00 equiv.) and Pd(dppf)Cl (243.84 mg, 0.333 mmol, 0.20 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction was quenched with water (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (3×50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 78a (400 mg, 75.89%) as a tan oil.

[0337] Synthesis of 78b To a solution of 78a (400.00 mg, 1.265 mmol, 1.00 equiv) in MeOH (5.00 mL) was added Pd / C (79.40 mg, 0.746 mmol, 0.59 equiv) in a pressure tank. The mixture was hydrogenated under a hydrogen atmosphere at room temperature overnight using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give 78b (300 mg, 74.53%) as a colorless oil.

[0338] Synthesis of 78c To a 50 mL three-necked round-bottom flask, 78b (300.00 mg, 0.942 mmol, 1.00 equiv), HO (6.00 mL), and HCl (0.50 mL) were added at room temperature. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched by adding NaHCO (aq) (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 78c (200 mg, 77.95%) as a colorless oil.

[0339] Synthesis of 78d To a stirred mixture of 78c (180.00 mg, 0.661 mmol, 1.00 equiv) and I-3 (193.81 mg, 0.793 mmol, 1.20 equiv) in DCE (2.00 mL) was added HOAc (39.70 mg, 0.661 mmol, 1.00 equiv) and NaBH(OAc) (280.23 mg, 1.322 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl(aq) (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 5:1) to give 78d (150 mg, 45.33%) as a colorless oil.

[0340] Synthesis of 78 To a stirred mixture of 78d (200.00 mg, 0.400 mmol, 1.00 equiv) and pyridine (191.99 mg, 2.397 mmol, 6.00 equiv) in DCM (8.00 mL) was added triphosgene (15.26 mg, 0.140 mmol, 0.35 equiv) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction was quenched with NaHCO (aq) (100 mL) at room temperature. The precipitated solid was collected by filtration and washed with DCM (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 5:1) to give compound 78 (52.3 mg, 24.86%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 527 H-NMR: (400 MHz, DMSO, δ ppm): 1.32-1.40 (m, 1H), 1.50-1.59 (m, 1H), 1.66-1.70 (m, 1H), 1.76-1.79 (m, 1H), 1.97-2.00 (d, 2H), 2.20 (s, 3H), 2.63-2.68 (m, 2H), 2.77-2.80 (d, 1H), 2.97-3.01 (d, 3H), 3.53 (s, 2H), 4.87-4.96 (m, 4H), 6.88-6.90 (d, 1H), 7.11 (s, 1H), 7.28-7.38 (d, 1H), 7.40-7.42 (t, 2H), 7.58 (s, 1H), 7.73-7.76 (m, 1H), 8.19-8.22 (d, 1H).

[0341] Example 79. Synthesis of Compound 79 TIFF2024514339000246.tif108165 Synthesis of 79a To a stirred solution of methyl 2-(3-nitrophenyl)acetate (3.5 g, 17.933 mmol, 1 equiv) in DMF (70 mL) was added CsCO (11.69 g, 35.866 mmol, 2 equiv) under atmospheric pressure at 0 °C. The resulting mixture was stirred at 0 °C for 2 h under atmospheric pressure. To the above mixture was added 1,1-bis(bromomethyl)cyclopropane (12.26 g, 53.799 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (2 × 200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1) to give 79a (560 mg, 11.00%) as a colorless oil.

[0342] Synthesis of 79b To a stirred solution of 79a (560 mg, 2.143 mmol, 1 equiv) in EtOH (6 mL, 103.281 mmol, 48.19 equiv) was added hydrazine hydrate (98%) (1071.5 mg, 21.43 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was quenched with water (40.00 mL) at room temperature. The aqueous layer was extracted with (CHCl / MeOH 10:1) (2 × 80 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (20:1) to give 79b (480 mg, 81.43%) as a colorless oil.

[0343] Synthesis of 79c To a stirred solution of 79b (480 mg, 1.837 mmol, 1 equiv) in tetrahydrofuran (6 mL) was added methyl isothiocyanate (265.93 mg, 3.637 mmol, 1.98 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water (2 × 2 mL). This resulted in 79c (510 mg, 80.53%) as a white solid.

[0344] Synthesis of 79d To a stirred mixture of NaOH (122.00 mg, 3.050 mmol, 2 equiv) in HO (6 mL) was added 79c (510 mg, 1.525 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (aq). The resulting mixture was filtered, and the filter cake was washed with water (3 × 1 mL). The filtrate was concentrated under reduced pressure. This resulted in 79d (480 mg, 94.50%) as a white solid.

[0345] Synthesis of 79e To a stirred solution of 79d (250 mg, 0.790 mmol, 1.00 equiv) and NaNO (545.19 mg, 7.900 mmol, 10 equiv) in ethyl acetate (13 mL) and HO (3 mL) was added HNO (497.92 mg, 7.900 mmol, 10 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 7 with saturated NaHCO (aq). The aqueous layer was extracted with CHCl (3 × 7 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE / EA 2:1) to give 79e (180 mg, 74.51%) as a white solid.

[0346] Synthesis of 79f To a stirred solution of 79e (150 mg, 0.528 mmol, 1 equiv) in MeOH (4 mL) was added Pd / C (45 mg, 10%) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 5 h. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH 12:1) to give 79f (110 mg, 73.78%) as a white solid.

[0347] 79g synthesis To a stirred solution of 79f (80 mg, 0.315 mmol, 1 equiv.) and I-2 (90.05 mg, 0.315 mmol, 1 equiv.) in DCE (2 mL) was added NaBH(OAc) (199.99 mg, 0.945 mmol, 3 equiv.) and HOAc (37.78 mg, 0.630 mmol, 2 equiv.) at room temperature. The reaction was quenched with NH4Cl (aq.) at room temperature. The resulting mixture was stirred at 0 °C for 2 h. The aqueous layer was extracted with EtOAc (3 × 5 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 79g (69 mg, 36.80%) as a white solid.

[0348] Synthesis of 79 To a stirred solution of 79g (60.00 mg, 0.114 mmol, 1.00 equiv) and pyridine (54.28 mg, 0.686 mmol, 6 equiv) in DCM (1.50 mL) was added triphosgene (30.54 mg, 0.103 mmol, 0.90 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with NaHCO (aq) (3.00 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 8 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water (0.5% NHHCO), B: CHCN, gradient from 30% B to 50% B in 30 min; detector, UV 254 nm. This resulted in compound 79 (14.8 mg, 23.22%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 551 H-NMR: (400 MHz, DMSO-d6, ppm, δ): 0.42-0.47 (m, 2H), 0.53-0.62(m, 2H), 1.44-1.50 (m, 1H), 1.58-1.67 (m, 4H), 1.86-1.92 (m, 1H), 2.68-2.79 (d, 4H), 3.18-3.33 (t, 7H), 7.01 (s, 1H), 7.18-7.20 (d, 1H), 7.36 (s, 1H), 7.49-7.53 (m, 1H), 7.63-7.67 (d, 2H), 7.84 (s, 1H), 8.40 (s, 1H).

[0349] Example 80. Synthesis of Compound 80 TIFF2024514339000247.tif77165 Synthesis of 80a To a stirred solution of 61b (950.00 mg, 3.592 mmol, 1.00 equiv.) and 5-azaspiro[2.4]heptane hydrochloride (955.34 mg, 7.183 mmol, 2 equiv.) in acetonitrile (10.00 mL) was added EtN (725.48 mg, 7.183 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 80a (700 mg, 65.95%) as an off-white solid.

[0350] Synthesis of 80b To a stirred solution of 80a (700.00 mg, 2.493 mmol, 1.00 equiv) in MeOH (8.00 mL) was added NaBH (188.66 mg, 4.987 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature under atmospheric pressure for 5 h. The reaction was quenched with NH Cl (aq) at room temperature. The aqueous layer was extracted with EtOAc (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to afford 80b (310 mg, 47.72%) as a white oil.

[0351] Synthesis of 80c To a stirred solution of 80b (290.00 mg, 1.147 mmol, 1.00 equiv) in DCM (3.00 mL) was added MnO (997.53 mg, 11.474 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 40 °C overnight. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 2:1) to give 80c (310 mg, 96.98%) as a white oil.

[0352] 80d synthesis To a stirred solution of 80c (300.00 mg, 1.197 mmol, 1.00 equiv) in DCE (3.00 mL) was added I-3 (292.30 mg, 1.197 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture were added NaBH(OAc) (760.77 mg, 3.590 mmol, 3.00 equiv) and HOAc (7.19 mg, 0.120 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with NH4Cl (aq) at room temperature. The aqueous layer was extracted with DCM (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 80d (140 mg, 14.66%) as an off-white oil.

[0353] 80 Synthesis To a stirred solution of 80d (140.00 mg, 0.292 mmol, 1.00 equiv) and pyridine (138.71 mg, 1.754 mmol, 6 equiv) in DCM (2.00 mL) was added triphosgene (30.35 mg, 0.102 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with NaHCO (aq) (3.00 mL) at room temperature. The aqueous layer was extracted with DCM (3 × 8 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water (0.5% NHHCO), B: CHCN, gradient from 30% B to 50% B in 30 min; detector, UV 254 nm. This resulted in compound 80 (4.8 mg, 3.20%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 505 H-NMR: (400 MHz, DMSO-d6, ppm): δ 0.60 (s, 1H), δ1.84-1.91 (m, 1H), δ2.05-2.06 (m, 1H), δ3.06 (s, 3H), δ3.23 (s, 2H), δ3.32-3.33 (m, 1H), δ0.68-0.74 (m, 3H), δ3.60 (s, 3H), δ4.16-4.26 (m, 2H), δ4.93 (s, 4H), δ6.88 (s, 1H), δ6.97-6.99 (d, 1H), δ7.41-7.78 (m, 4H), δ7.93 (s, 1H), δ8.47 (s, 1H).

[0354] Example 81. Synthesis of Compound 81 TIFF2024514339000248.tif124165 Synthesis of 81a To a 250 mL three-necked round-bottom flask, methyl 2-(3-nitrophenyl)acetate (5 g, 25.618 mmol, 1 equiv.) and DMF (50 mL) were added at room temperature. To the above mixture, CsCO (25.04 g, 76.854 mmol, 3 equiv.) was added at 0 °C. The mixture was stirred at 0 °C for 3 h. To the above mixture, 3-bromo-2-methylprop-1-ene (6.92 g, 51.236 mmol, 2 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (150 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (50:1), to give 81a (3.4 g, 53.24%) as a white solid.

[0355] Synthesis of 81b A solution of 81a (3.4 g, 13.640 mmol, 1 equiv.) and hydrazine hydrate (10.93 g, 218.240 mmol, 16 equiv.) in MeOH (17 mL) was stirred at 80° C. for 2 h under a nitrogen atmosphere. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with MeCN (2×30 mL). This resulted in 81b (3 g, 88.23%) as a white solid.

[0356] Synthesis of 81c To a stirred solution of 81b (3 g, 12.035 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was added methyl isothiocyanate (1.76 g, 24.070 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with MeCN (2×20 mL). This resulted in 81c (2.98 g, 76.81%) as a white solid.

[0357] Synthesis of 81d To a 100 mL round-bottom flask, HO (40 mL) and NaOH (1 g, 25.002 mmol, 2.69 equiv.) were added at room temperature. To the above mixture, 81c (3 g, 9.306 mmol, 1 equiv.) was added at room temperature. The resulting mixture was stirred overnight at room temperature. The residue was acidified to pH 5 with 1 mol / L HCl (aq.). The resulting mixture was filtered, and the filter cake was washed with water (3 × 20 mL). The resulting solid was dried under vacuum. This gave 81d (2.5 g, 80.32%) as a yellow solid.

[0358] Synthesis of 81e To a 100 mL round-bottom flask, HO (25 mL), NaNO (2.83 g, 41.070 mmol, 5 equiv.), and 81d (2.5 g, 8.214 mmol, 1 equiv.) were added at room temperature. To the above mixture, HNO (25 mL, 1 mol / L) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 h. The reaction was quenched with NaHCO (aq.) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 40 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (100:1), to give 81e (2 g, 80.48%) as a yellow oil.

[0359] Synthesis of 81f To a 100 mL three-necked round-bottom flask were added 81e (2 g, 7.345 mmol, 1 equiv), Fe (2.05 g, 36.725 mmol, 5 equiv), NH4Cl (1.96 g, 36.725 mmol, 5 equiv), EtOH (30 mL), and HO (10 mL) at room temperature. The resulting mixture was stirred at 95 °C overnight. The resulting mixture was filtered, and the filter cake was washed with DCM / MeOH (20:1) (3 × 20 mL). The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH 15:1) to give 81f (800 mg, 42.70%) as a white solid.

[0360] Synthesis of 81g To a 50 mL round-bottom flask, 81f (400 mg, 1.651 mmol, 1 equiv), I-2 (519.84 mg, 1.816 mmol, 1.1 equiv), and DCE (10 mL) were added at room temperature. To the above mixture, STAB (699.69 mg, 3.302 mmol, 2 equiv) was added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl(aq) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH 15:1) to give 81g (300 mg, 33.33%) as a tan solid.

[0361] Synthesis of 81h To a 50 mL round-bottom flask, 81g (280 mg, 0.546 mmol, 1 equiv), DCM (10 mL), and pyridine (345.64 mg, 4.368 mmol, 8 equiv) were added at room temperature. To the above mixture, triphosgene (113.46 mg, 0.382 mmol, 0.7 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The reaction was quenched with NaHCO3 (aq) (40 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH 15:1) to afford 81h (150 mg, 47.42%) as a yellow solid.

[0362] Synthesis of 81 81h (150 mg, 0.278 mmol, 1 equiv.) was purified by chiral separation under the following conditions: column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 50% B to 50% B in 11 min; wavelength: 220 / 254 nm; RT1 (min): 6.93; RT2 (min): 9.14; first peak is product) to give compound 81 (26.2 mg, 17.34%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 539 H-NMR: 1H NMR (400 MHz, DMSO-d6, ppm, δ): 0.78-0.95 (m, 4H), 1.44-1.49 (m, 1H), 1.58-1.67 (m, 4H), 1.71 (s, 3H), 1.87-1.89 (m, 1H), 2.76-2.81 (m, 3H), 2.95-3.00 (m, 1H), 3.25 (s, 1H), 3.49 (s, 3H), 4.53-4.69 (t, 1H), 4.61-4.69 (d, 2H), 7.01 (s, 1H), 7.25-7.27 (d, 1H), 7.31 (s, 1H), 7.42-7.46 (t, 1H), 7.66-7.71 (m, 2H), 7.78 (s, 1H), 8.34 (s, 1H).

[0363] Example 82. Synthesis of Compound 82 TIFF2024514339000249.tif60165 Synthesis of 82 Compound 82h (150 mg, 0.278 mmol, 1 equiv.) was purified by chiral separation under the following conditions: column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 50% B to 50% B in 11 min; wavelength: 220 / 254 nm; RT1 (min): 6.93; RT2 (min): 9.14; the second peak is the product), to give compound 82 (36.1 mg, 23.99%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 539 H-NMR: 1H NMR (400 MHz, DMSO-d6, ppm, δ): 0.78-0.95 (m, 4H), 1.44-1.49 (m, 1H), 1.58-1.67 (m, 4H), 1.71 (s, 3H), 1.87-1.89 (m, 1H), 2.76-2.81 (m, 3H), 2.95-3.00 (m, 1H), 3.25 (s, 1H), 3.49 (s, 3H), 4.53-4.69 (t, 1H), 4.61-4.69 (d, 2H), 7.01 (s, 1H), 7.25-7.27 (d, 1H), 7.31 (s, 1H), 7.42-7.46 (t, 1H), 7.66-7.71 (m, 2H), 7.78 (s, 1H), 8.34 (s, 1H).

[0364] Example 83. Synthesis of Compound 83 TIFF2024514339000250.tif50165 Synthesis of 83a To a stirred solution of I-3 (300 mg, 1.228 mmol, 1 equiv.) and 3-methylpyridine-2-carbaldehyde (178.51 mg, 1.474 mmol, 1.2 equiv.) in DCE, HOAc (73.74 mg, 1.228 mmol, 1 equiv.) and NaBH(OAc) (520.53 mg, 2.456 mmol, 2 equiv.) were added. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL). The resulting mixture was extracted with CHCl (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to give 83a (160 mg, 37.29%) as a white solid.

[0365] Synthesis of 83 To a stirred solution of 83a (150.00 mg, 0.429 mmol, 1.00 equiv) in DCM (10.00 mL) was added triphosgene (44.58 mg, 0.150 mmol, 0.35 equiv) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was washed with 10 mL of NaHCO (aq). The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH-HPLC; Flow rate: 60 mL / min; Gradient: 40% B to 50% B in 7 min; Wavelength: 220 nm; RT1 (min): 6.28) to give compound 83 (42.5 mg, 25.58%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 376 H-NMR: (400 MHz, CD3OD, ppm): δ 2.22 (s, 3H), δ2.95 (s, 3H), δ3.73 (s, 2H), δ5.11 (s, 4H), δ6.24-6.27 (m, 1H), δ6.39-6.41 (d, 1H), δ6.87-6.88(d, 1H), δ7.01 (s, 1H), δ7.31-7.48 (m, 2H), δ7.67-7.69 (m, 1H), δ8.22 (s, 1H).

[0366] Example 84. Synthesis of Compound 84 TIFF2024514339000251.tif34165 Synthesis of 84a To a stirred solution of I-3 (200 mg, 0.819 mmol, 1 equiv) in MeOH (10 mL) was added 2-formylpyridine (87.69 mg, 0.819 mmol, 1 equiv). The resulting mixture was stirred at room temperature overnight. To the above mixture was added NaBH (30.97 mg, 0.819 mmol, 1 equiv). The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by adding NH Cl (aq) (40 mL). The resulting mixture was extracted with EtOAc (2 × 40 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 20:1) to afford 84a (200 mg, 72.84%) as a white solid.

[0367] Synthesis of 84 To a stirred solution of 84a (220.00 mg, 0.656 mmol, 1.00 equiv) in DCM (10.00 mL) was added triphosgene (64.23 mg, 0.216 mmol, 0.33 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched by adding NaHCO (aq) (15 mL). The aqueous layer was extracted with CHCl / MeOH = 10 / 1 (2 × 30 mL). The resulting mixture was concentrated in vacuo. The crude product (300 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 20% B in 16 min; Wavelength: 220 nm; RT1 (min): 15.20) to give Compound 84 (45.3 mg, 19.11%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 376 H-NMR: (400 MHz, CD3OD, ppm): δ2.95 (s, 3H), δ3.67 (s, 2H), δ5.11 (s, 4H), δ6.25-6.27 (m, 1H), δ6.56-6.58 (d, 1H), δ6.87-6.89(d, 1H), δ7.01 (s, 1H), δ7.03-7.05 (d, 1H), δ7.29 (s, 1H), δ7.41-7.44 (m, 1H), δ7.54-7.56 (d, 1H), δ7.63-7.65 (d, 1H), δ8.22 (s, 1H).

[0368] Example 85. Synthesis of Compound 85 TIFF2024514339000252.tif124165 Synthesis of 85a A mixture of methyl 2-(3-nitrophenyl)acetate (48.1 g, 246.447 mmol, 1 equiv.) and CsCO (401.49 g, 1232.235 mmol, 5 equiv.) in DMF (500 mL) was stirred at 0 °C for 3 h under a nitrogen atmosphere. To the above mixture, bromocyclobutane (99.81 g, 739.341 mmol, 3 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with NHCl (aq.) (3 L) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (150:1) to give 85a (49 g, 73.38%) as an off-white solid.

[0369] Synthesis of 85b To a stirred solution of 85a (49 g, 196.577 mmol, 1 equiv.) in EtOH (500 mL) was added hydrazine hydrate (98%) (251.04 g, 4914.425 mmol, 25 equiv., 98%) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was diluted by adding water (500 mL) at room temperature. The aqueous layer was extracted with CHCl / MeOH (10:1) (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (100:1) to give 85b (43 g, 79.86%) as a yellow oil.

[0370] Synthesis of 85c To a stirred solution of 85b (45 g, 180.527 mmol, 1 equiv.) in THF (450 mL) was added methyl isothiocyanate (33.00 g, 451.317 mmol, 2.5 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (280 mL). The resulting mixture was filtered, and the filter cake was washed with water (3 × 50 mL). The resulting solid was dried under vacuum. This gave 85c (55 g, 86.00%) as a white solid.

[0371] Synthesis of 85d To a stirred solution of NaOH (66 g, 1650.120 mmol, 9.67 equiv) in HO (1.65 L) was added 85c (55 g, 170.606 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 with HCl (1 M). The resulting mixture was filtered, and the filter cake was washed with water (3 × 50 mL). The resulting solid was dried under vacuum. This gave 85d (50 g, 86.66%) as an off-white solid.

[0372] Synthesis of 85e To a stirred mixture of 85d (50 g, 164.274 mmol, 1 equiv) in EtOAc (190 mL) and HO (760 mL) was added NaNO (113.3 g, 1642.74 mmol, 10 equiv) at room temperature. To the above mixture was added HNO (1642 mL, 1642.74 mmol, 10.00 equiv, 1 M) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 7 with saturated NaHCO (aq). The aqueous layer was extracted with CHCl / MeOH (10:1) (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (50:1) to give 85e (40 g, 85.84%) as a yellow solid.

[0373] Synthesis of 85f To a solution of 85e (40 g, 146.892 mmol, 1 equiv.) in 1.2 L of MeOH was added Pd / C (20%, 8 g) in a 2 L round-bottom flask. The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give 85f (35 g, 94.39%) as an off-white solid.

[0374] 85g synthesis To a stirred solution of 85f (31.45 g, 123.800 mmol, 1.2 equiv.) and I-2g (31.45 g, 123.800 mmol, 1.2 equiv.) in DCE (300 mL) was added NaBH(OAc) (43.73 g, 206.334 mmol, 2 equiv.) and HOAc (6.20 g, 103.167 mmol, 1 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched by adding water (500 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MTBE (2 × 50 mL). This resulted in 85g (34 g, 65.18%) as a white solid.

[0375] Synthesis of 85h To a stirred solution of 85g (34 g, 70.784 mmol, 1 equiv.) and pyridine (33.59 g, 424.704 mmol, 6 equiv.) in DCM (400 mL) was added triphosgene (7.35 g, 24.774 mmol, 0.35 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. The reaction was quenched by adding water (500 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 500 mL) and dried over anhydrous CaCl. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MTBE (2 × 100 mL). 85g (33 g, 87.47%) is a yellow solid.

[0376] 85i Composition To a solution of 85h (33 g, 65.175 mmol, 1 equiv.) and TMEDA (15.15 g, 130.350 mmol, 2 equiv.) in dioxane (1000 mL), bis(adamantan-1-yl)(butyl)phosphane (4.67 g, 13.035 mmol, 0.2 equiv.) and Pd(OAc) (1.46 g, 6.518 mmol, 0.1 equiv.) were added in an autoclave. After flushing the autoclave with CO / H (1:1) three times, the mixture was pressurized to 10 atm with CO / H (1:1) and reacted at 80 °C overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1) to CH2Cl2 / MeOH (5:1) to give 85i (20 g, 67.38%) as a yellow solid.

[0377] Synthesis of 85j To a stirred mixture of 85i (10 g, 21.957 mmol, 1 equiv.) and (3S)-3-methylpiperidine hydrochloride (8.93 g, 65.871 mmol, 3 equiv.) in DCE (150 mL) was added EtN (8.89 g, 87.828 mmol, 4 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. To the above mixture was added NaBH(OAc) (6.98 g, 32.936 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (200 mL) at room temperature. The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (2 × 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mol / L NH4HCO3), gradient from 15% to 60% in 40 min; detector, UV 254 nm, to give 85j (6.5 g, 54.96%) as a yellow solid.

[0378] Synthesis of 85 85j (6.5 g) was purified by preparative chiral SFC under the following conditions: Column: CHIRAL ART Cellulose-SB, 5 × 25 cm, 10 μm; Mobile phase A: CO, Mobile phase B: MEOH (0.1% 2 M NH-MeOH); Flow rate: 200 mL / min; Gradient: Isocratic 30% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT (min): 6.26; Sample solvent: MEOH (0.1% 2 M NH-MEOH); Injection volume: 1 mL; Run number: 30. This resulted in compound 85 (3.0062 g) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 540 H-NMR: (400 MHz, DMSO-d6, ppm): δ0.84-0.91 (m, 4H), δ1.38-1.95 (m, 12H), δ2.08-2.10 (m, 1H), δ2.68-2.77 (m, 2H), δ3.19-3.25 (m, 3H), δ3.43 (s, 3H), δ4.25-4.28 (d, 1H), δ7.01 (s, 1H), δ7.19-7.21 (d 1H), δ7.32 (s, 1H), δ7.43-7.46 (t, 1H), δ7.66-7.75 (m, 3H), δ8.34 (s, 1H).

[0379] Example 86. Synthesis of Compound 86 TIFF2024514339000253.tif60165 Synthesis of 86 85j (85.00 mg, 0.158 mmol, 1.00 equiv) was purified by preparative chiral HPLC under the following conditions (Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2 M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 8.5 min; Wavelength: 220 / 254 nm; RT1 (min): 5.19) to give compound 86 (24.1 mg, 27.90%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 539 H-NMR: (400 MHz, CDCl3, ppm): δ0.81-0.83 (d, 4H), δ1.66-1.78(m, 11H), δ2.04-2.11 (m, 1H), δ2.65-3.69 (m, 1H), δ2.72-3.73 (m, 1H), δ3.22-3.35 (m, 3H), δ3.42 (s, 3H), δ4.24-4.28 (d, 1H), δ7.00 (s, 1H), δ7.19-7.22 (d, 1H), δ7.33 (s, 1H), δ7.44-7.47 (m, 1H), δ7.70-7.72 (m, 3H), δ8.32 (s, 1H).

[0380] Example 87. Synthesis of Compound 87 TIFF2024514339000254.tif113165 Synthesis of 87a To a 20 mL sealed tube was added 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (1.00 g, 4.166 mmol, 1.00 equiv.), dioxane (8.00 mL), HO (2.00 mL), tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]carbamate (1.35 g, 4.176 mmol, 1.00 equiv.), Pd(dppf)Cl (0.30 g, 0.417 mmol, 0.1 equiv.), and KPO (1.77 g, 8.333 mmol, 2 equiv.) under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 6 hours. The resulting mixture was diluted with water (30 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc 3:1) to give 87a (1.1 g, 71.12%) as a colorless oil.

[0381] Synthesis of 87b To a 50 mL round-bottom flask was added 87a (1.10 g, 3.087 mmol, 1 equiv.), MeOH (30.00 mL), and Pd / C (200.00 mg) under a nitrogen atmosphere. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give 87b (920 mg, 79.84%) as a colorless oil.

[0382] Synthesis of 87c To a stirred solution of 87b (910 mg, 2.539 mmol, 1 equiv.) in dioxane (20 mL) was added SeO2 (845.19 mg, 7.617 mmol, 3 equiv.). The resulting mixture was stirred at 110 °C overnight. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 87c (710 mg, 75.09%) as a yellow oil.

[0383] Synthesis of 87d To a stirred mixture of 87c (370 mg, 0.994 mmol, 1 equiv.) and I-3 (242.73 mg, 0.994 mmol, 1 equiv.) in DCE (15 mL) was added HOAc (59.67 mg, 0.994 mmol, 1 equiv.) and NaBH(OAc) (421.16 mg, 1.988 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL). The resulting mixture was extracted with CHCl / MeOH 10:1 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 87d (320 mg, 53.62%) as a pale yellow solid.

[0384] Synthesis of 87e To a stirred solution of 87d (320 mg, 0.533 mmol, 1 equiv) and pyridine (252.83 mg, 3.198 mmol, 6 equiv) in DCM (10 mL) was added triphosgene (63.23 mg, 0.213 mmol, 0.4 equiv). The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by adding NaHCO (aq) (15 mL). The resulting mixture was extracted with CHCl / MeOH (10 / 1) (4 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give 87e (240 mg, 71.89%) as a yellow solid.

[0385] Synthesis of 87f To a stirred solution of 87e (240 mg, 0.383 mmol, 1 equiv) in DCM (3 mL) was added TFA (0.6 mL). The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 8:1) to give 87f (180 mg, 89.26%) as a yellow solid.

[0386] Synthesis of 87 To a stirred solution of 87f (180 mg, 0.342 mmol, 1 equiv) and formaldehyde solution (83.22 mg, 1.026 mmol, 3 equiv, 37%) in MeOH (3 mL) was added HOAc (20.5 mg, 0.342 mmol, 1 equiv) and NaBHCN (42.96 mg, 0.684 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding NaHCO (aq) (15 mL). The resulting mixture was extracted with CHCl / MeOH = 10 / 1 (4 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 8:1) to give compound 87 (49.1 mg, 25.90%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 556 H-NMR: (400 MHz, DMSO-d6, ppm): δ 1.48-1.58 (m, 4H), δ 1.66-1.75 (m, 2H), δ1.93-1.96 (m, 4H), δ2.19-2.33 (m, 6H), δ2.97 (s, 1H), δ3.54 (s, 2H), δ4.91-4.96 (m, 4H), δ6.89-6.91(d, 1H), δ7.04 (s, 1H), δ7.39-7.45 (m, 3H), δ7.75-7.77 (d, 1H), δ8.21 (s, 1H).

[0387] Example 88. Synthesis of Compound 88 TIFF2024514339000255.tif92165 Synthesis of 88a To a stirred mixture of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (1 g, 4.166 mmol, 1 equiv.) and Pd(dba) (0.38 g, 0.417 mmol, 0.1 equiv.) in MeOH (5 mL) was added dioxane (10 mL) and KOH (0.70 g, 12.498 mmol, 3 equiv.) at room temperature under a nitrogen atmosphere. t-Brettphos (0.40 g, 0.833 mmol, 0.2 equiv.) was added in one portion to the above mixture at room temperature. The final reaction mixture was irradiated with microwave radiation at 80 °C for 40 minutes. The reaction was quenched with NHCl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH=40:1 to give 88a (300 mg, 37.67%) as a colorless oil.

[0388] Synthesis of 88b A mixture of 88a (280 mg, 1.465 mmol, 1 equiv.) and SeO2 (487.60 mg, 4.395 mmol, 3 equiv.) in 1,4-dioxane was stirred at 110 °C overnight under a nitrogen atmosphere. The resulting mixture was washed with 3 × 20 mL of water. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl2 / MeOH = 40:1) to give 88b (60 mg, 19.97%) as a yellow oil.

[0389] Synthesis of 88c To a stirred mixture of 88b (580 mg, 2.827 mmol, 1 equiv.) and I-3 (1036.09 mg, 4.240 mmol, 1.5 equiv.) in DCE, HOAc (169.79 mg, 2.827 mmol, 1 equiv.) and NaBH(OAc) (1797.72 mg, 8.481 mmol, 3 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with CHCl (2 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 20:1) to give 88c (700 mg, 51.41%) as a yellow solid.

[0390] Synthesis of 88 To a stirred solution of 88c (90 mg, 0.208 mmol, 1 equiv) and pyridine (98.55 mg, 1.248 mmol, 6 equiv) in DCM (4 mL) was added triphosgene (21.56 mg, 0.073 mmol, 0.35 equiv) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. The resulting mixture was washed with 3 × 10 mL of water. The resulting mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH = 10:1) to give compound 88 (42.1 mg, 42.01%) as a yellow solid. LCMS: (ES, m / z): [M+H] + 460. H-NMR: (400 MHz, DMSO-d6, ppm, δ): 2.82-3.01 (s, 3H), 3.53 (s, 2H), 3.77 (s, 3H), 4.91-5.02 (m, 4H), 6.88 (s, 1H), 6.94 (s, 1H), 7.24 (s, 1H), 7.33-7.40 (m, 2H), 7.69-7.77 (m, 1H), 8.20 (s, 1H).

[0391] Example 89. Synthesis of Compound 89 TIFF2024514339000256.tif50165 Synthesis of 89 To an 8 mL sealed tube, 7 (150 mg, 0.295 mmol, 1.00 equiv.), THF (2 mL), TEA (89.58 mg, 0.885 mmol, 3 equiv.), 1-(prop-2-yn-1-yl)pyrrolidine (48.33 mg, 0.443 mmol, 1.5 equiv.), CuI (11.24 mg, 0.059 mmol, 0.2 equiv.), and Pd(PPh3)4 (34.10 mg, 0.029 mmol, 0.1 equiv.) were added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 40 °C for 12 h. The reaction was quenched by adding water (10 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH 10:1) to give the crude product (55 mg). The crude product was purified by reverse-phase flash chromatography under the following conditions (column: Xselect CSH C18 OBD column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 44% B to 54% B in 7 min; wavelength: 254) to give compound 89 (57.6 mg, 35.43%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + 537 H-NMR: 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.76 (m, 4H), δ2.58 (s, 4H), δ2.97 (s, 3H), δ3.37 (s, 2H), δ3.47-3.67 (m, 2H), δ4.84-4.96 (m, 4H), δ6.88-6.90 (d, 1H), δ6.84 (s, 1H), δ7.38-7.43 (m, 3H), δ7.73-7.75 (t, 1H), δ7.89 (s, 1H), δ8.14 (s, 1H), δ8.17-8.22 (t, 1H).

[0392] Example 90. Synthesis of Compound 90 TIFF2024514339000257.tif71165 Synthesis of 90a To a stirred solution of 71a (1 g, 5.231 mmol, 1 equiv) in DMF (10 mL) was added NaH (0.25 g, 10.462 mmol, 2 equiv) in two portions at 0 °C. The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. To the above mixture was added (2-bromoethoxy)(tert-butyl)dimethylsilane (1.88 g, 7.846 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched by adding saturated NH4Cl(aq) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 40 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 3:1) to give 90a (220 mg, 12.03%) as a colorless oil.

[0393] Synthesis of 90b To a stirred solution of 90a (300 mg, 0.858 mmol, 1 equiv) in dioxane (3 mL) was added SeO2 (190.51 mg, 1.716 mmol, 2 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 4 h. The resulti...

Claims

1. Formula (A): A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Y is based on the base = C(H)-, = C(R ａ ) - or = N - selected; Z is either =O or =S; E is a substituted 5-6 membered heterocyclyl ring; B is an optionally substituted phenyl, an optionally substituted 8-10 membered bisicryl, or an optionally substituted 5-6 membered heteroaryl; C is a substituted or otherwise substituted 5- to 6-membered ring heterocyclyl; X may be replaced by C. １ ~C ３ It is an alkylene chain, where one or more methylene units are -N(H)-, -N(R) １ )-, -O-, -S-, -SO-, -SO ２ - may be replaced by a substituted 3- to 6-membered carbocyclyl ring, and a substituted 3- to 6-membered heterosilyl ring, where X is a halogen, C １ ~C ３ Aliphatic, phenyl, 3-6 membered heteroaryl rings, 3-6 membered heterosilyl rings, and -(CH ２ ) may be substituted with a group selected from the group consisting of (3-6 membered carbocyclyl rings); Each R ａ is L-Y, halogen, -CN, -OH, -OR １ , -NH ２ , -NR １ R ２ , -SH, -SR １ , -SF ５ , -CO ２ H, -CO ２ R １ , -C(O)R １ , -CONH ２ , -CONR １ R ２ , -SO ２ NH ２ , -SO ２ NR １ R ２ , -SO ２ OH, -SO ２ OR １ , -S(O)R １ , -S(O) ２ R １ , -S(O)(NH)R １ , -S(O)(NR １ )R １ , optionally substituted C １ ~C ６ aliphatic, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing from 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of, where R ａ may be optionally substituted with 1 to 5 R ａ１ ; L may be substituted for C. １ ~C ３ It is an alkylene chain; A may be replaced by C. ３ ~C ７ Carbosilyl, optionally substituted C １ ~C ６ Selected from the group consisting of heterocyclyl rings containing 1 to 4 heteroatoms selected from the group consisting of heteroalkyl, N, O, and S, which may be substituted, phenyl, and heteroaryl rings containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, where A is 1 to 5 R ａ１ It is also fine if it is replaced with; Each R ａ１ These are halogen, -CN, -OH, -OR １ , -NH ２ , -NR １ R ２ -SH, -SR １ , -SF ５ , -CO ２ H, -CO ２ R １ , -CONH ２ , -CONR １ R ２ , -SO ２ NH ２ , -SO ２ NR １ R ２ , -SO ２ OH, -SO ２ OR １ , -S(O)R １ , -S(O) ２ R １ , -S(O)(NH)R １ , -S(O)(NR １ ) R １ C may be substituted. １ ~C ６ Aliphatic C, may be substituted. １ ~C ６ A substituted or substituted 3-6 membered ring heterocyclyl containing 1-4 heteroatoms selected from the group consisting of heteroalkyl, N, O, and S; a substituted or substituted 5-6 membered ring heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S; Each R ｂ is halogen, -CN, -OH, -OR １ , -NH ２ , -NR １ R ２ , -SH, -SR １ , -SF ５ , -CO ２ H, -CO ２ R １ , -CONH ２ , -CONR １ R ２ , -SO ２ NH ２ , -SO ２ NR １ R ２ , -SO ２ OH, -SO ２ OR １ , -S(O)R １ , -S(O) ２ R １ , -S(O)(NH)R １ , -S(O)(NR １ )R １ , optionally substituted C １ ~C ６ aliphatic, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, and is independently selected from the group consisting of; Each R ｃ C may be hydrogen or substituted. １ ~C ６ aliphatic, OR １ , -NH ２ , -NR １ R ２ , a substituted 3-6 membered ring heterocyclyl containing 1-4 heteroatoms selected from the group consisting of phenyl, N, O, and S, a substituted 5-6 membered ring heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, -C(O)R ３ , -CO ２ R ３ , -C(O)NHR ３ , and -SO ２ R ３ Independently selected from the group consisting of; Each R １ C may be substituted. １ ~C ６ A substituted 3-6 membered ring heterocyclyl containing 1-4 heteroatoms selected from the group consisting of aliphatic, optionally substituted phenyl, N, O, and S, an optionally substituted 5-6 membered ring heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, and -C(O)R ３ , -CO ２ R ３ , -C(O)NHR ３ , and -SO ２ R ３ Independently selected from the group consisting of; Each R ２ C may be hydrogen or substituted. １ ~C ６ A substituted or substituted 3-6 membered ring heterocyclyl containing 1-4 heteroatoms selected from the group consisting of aliphatic, N, O, and S; or R １ and R ２ Together with these intervening atoms, they form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or a substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; Each R ３ C may be substituted. １ ~C ６ A substituted or alternatively substituted 3-6 membered ring heterocyclyl containing 1-4 heteroatoms selected from the group consisting of aliphatic, N, O, and S; or a substituted or alternatively substituted 5-6 membered ring heteroaryl containing 1-4 heteroatoms selected from the group consisting of substituted or alternatively substituted phenyl, N, O, and S; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. The aforementioned compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein C is selected from the group consisting of optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted thiadizolyl, optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, and optionally substituted pyridazinyl.

3. Formula (B): The compound according to any one of claims 1 to 2, which is a compound or a pharmaceutically acceptable salt thereof.

4. Equation (I): The compound according to any one of claims 1 to 2, which is a compound or a pharmaceutically acceptable salt thereof.

5. Equation (Ia) or (IIa): A compound of or a pharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C, according to any one of claims 1 to 4.

6. Equation (Ia1) or (IIa1): The compound according to any one of claims 1 to 5, which is a compound or a pharmaceutically acceptable salt thereof.

7. Equations (Ia2), (Ia3), or (Ia4): The compound according to any one of claims 1 to 5, which is a compound of or a pharmaceutically acceptable salt thereof.

8. Equation (Ib) or (IIb): A compound of or a pharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C, according to any one of claims 1 to 5.

9. Formula (Ic) or (IIc): The compound according to any one of claims 1 to 5, which is a compound of or a pharmaceutically acceptable salt thereof.

10. R ｃ However, C may be substituted. １ ~C ３ The compound according to any one of claims 1 to 9, wherein the compound is aliphatic.

11. Each R ｃ However, methyl, -CD ３ ,-CHF ２ A compound according to claim 10, independently selected from the group consisting of the following.

12. R ｃ The compound according to claim 11, wherein the compound is methyl.

13. C may be substituted for X. １ ~C ２ The compound according to any one of claims 1 to 12, wherein it is an alkylene.

14. X, Or C may be replaced ２ It is an alkylene, and here, one methylene unit, The compound according to any one of claims 1 to 12, which is replaced by [the compound].

15. X, A compound according to any one of claims 1 to 12, selected from the group consisting of the following.

16. R ａ The compound according to any one of claims 1 to 15, wherein L-A.

17. L is -CH ２ - or -CH(CH ３ The compound according to claim 16, wherein the compound is as follows:

18. The compound according to any one of claims 16 to 17, wherein A is a substituted or otherwise substituted 3-6 membered ring heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S.

19. R ａ However, halogen, -CN, -C(O)R １ , -CO ２ H, -CONR １ R ２ C may be substituted. １ ~C ６ Aliphatic and optionally substituted C １ ~C ６ A compound according to any one of claims 1 to 16, wherein the compound is a heteroalkyl compound.

20. Each R ａ However, halogen, -CN, -CO ２ H, -CHO, -CHF ２ , -CF ３ , -OMe, -S(O) ２ NHMe, A compound according to any one of claims 1 to 16, independently selected from the group consisting of the following.

21. Compounds selected from the following group, or pharmaceutically acceptable salts thereof: 。

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable adjuvant or carrier.

23. A method for treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22 to a subject in need.

24. The method according to claim 23, wherein the disease or condition related to cell proliferation is hyperplasia or cancer.

25. The method according to claim 24, wherein the cancer is a blood cancer.

26. The method according to claim 25, wherein the blood cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

27. The method according to claim 26, wherein the cancer is a non-hematological cancer.

28. The method according to claim 27, wherein the non-hematological cancer is a sarcoma or carcinoma.

29. The method according to any one of claims 23 to 28, wherein the subject, after administration of the compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 16, exhibits one or more of the following: increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, decreased T cell anergy, and decreased T cell tolerability.

30. The method according to claim 29, wherein increased T cell activation includes increased cytokine production.

31. The method according to claims 23 to 28, wherein the subject has an increase in NK cell activation.

32. The method according to claim 31, wherein the increase in NK cell activation includes an increase in cytokine production.

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