BENZOYPARAZINE Pyrazine and Their Uses

Abstract

The present invention relates to a compound of formula I, [Chemical Formula 1] JPEG2025516570000730.jpg32128 Formula I, or a pharmaceutically acceptable salt thereof, and a formulation containing the same are characterized. A method for treating BAF complex-related disorders such as cancer is also disclosed.

Description

[Technical Field]

[0001] The present invention relates to compounds useful for modulating the BRG1- or BRM-associated factor (BAF) complex. In particular, the present invention relates to compounds useful for treating disorders associated with BAF complex function.

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human Switch / Sucrose Non-Fermentable (SWI / SNF) chromatin remodeling complex, also known as the BAF complex, contains two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is required for cancer cell proliferation. BRM, also known as the likely global transcriptional activator SNF2L2 and / or the ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell proliferation in cells characterized by loss-of-function mutations in BRG1. Deactivation of BRGs and / or BRMs leads to downstream effects in cells, including cell cycle arrest and tumor suppression. Summary of the Invention

[0003] The present invention features compounds useful for modulating the BAF complex. In some embodiments, the compounds are useful for treating disorders associated with alterations in the BAF complex, such as disorders associated with alterations in one or both of the BRG1 and BRM proteins. The compounds of the present invention can be used alone or in combination with other pharmaceutically active agents to treat such disorders.

[0004] In one aspect, the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, m is 0, 1, 2, or 3; k is 0, 1, or 2; Each R 1 are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano; each X is independently halo or optionally substituted C1-C6 heteroalkyl; L is a linker, B is characterized as a degrading moiety, a compound of formula I or a pharmaceutically acceptable salt thereof.

[0005] In another aspect, the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, m is 0, 1, 2, or 3; k is 0, 1, or 2; Each R 1 are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C3-C8 cycloalkyl; each X is independently halo; L is a linker, B is characterized as a degrading moiety, a compound of formula I or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the compound has the structure of formula IA. [ka]

[0007] In some embodiments, the compound has the structure of formula IB. [ka]

[0008] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0009] In some embodiments, R 1 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 1 is alkoxy. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is halo. In some embodiments, R 1 is F or Cl. In some embodiments, R 1 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is difluoromethoxy. In some embodiments, R 1 is difluoromethyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is a methine. In some embodiments, R 1 is an optionally substituted C-C cycloalkyl. In some embodiments, R 1 is cyclopropane. In some embodiments, R 1is cyclopropoxy. In some embodiments, R 1 is an optionally substituted C2-C9 heterocyclyl. In some embodiments, R 1 is optionally substituted amino. In some embodiments, R 1 is cyano.

[0010] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, X is optionally substituted C1-C6 heteroalkyl. In some embodiments, X is methoxy. In some embodiments, X is halo. In some embodiments, X is F.

[0011] In some embodiments, m is 0.

[0012] In some embodiments, m is 1.

[0013] In some embodiments, R 1 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is halo. In some embodiments, R 1 is F or Cl.

[0014] In some embodiments, k is 1.

[0015] In some embodiments, k is 0.

[0016] In one aspect, the present invention provides a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, k is 0, 1, or 2; each X is independently halo; L is a linker, B is characterized as a degrading moiety, a compound of formula IV or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the decomposition moiety B has the structure of formula A-1: [ka] During the ceremony, Y 1 teeth, [ka] and R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A6 is H or optionally substituted C1-C6 alkyl, and R A7 is H or optionally substituted C1-C6 alkyl, or R A6 and R A7 each combines together with the carbon atom to which it is attached to form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl, or R A6 and R A7 each combines with the carbon atom to which it is attached to form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl; R A8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A1 , R A2 , R A3 , and R A4 Each of the following may be independently H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted —O—C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino, or R A1 and R A2 , R A2 and R A3 , and / or R A3 and R A4 combine with the carbon atoms to which they are attached, [ka] Forming [ka] optionally substituted C6 to C 10 Aryl, optionally substituted C-C 10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is 2 and optionally substituted with R A1 , R A2 , R A3 , and R A4 One of them is A 2 is, or [ka] But, A 2 is replaced by A 2 is the bond between the degradation moiety and the linker.

[0018] In some embodiments, R A5 is H or methyl. In some embodiments, R A5 is H.

[0019] In some embodiments, R A1 , R A2 , R A3 , and R A4 each independently represents H or A 2 is.

[0020] In some embodiments, R A1 is A 2 and R A2 , R A3 , and R A4 Each of is H.

[0021] In some embodiments, R A2 is A 2 and R A1 , R A3 , and R A4 Each of is H.

[0022] In some embodiments, R A3 is A 2 and R A1 , R A2 , and R A4 Each of is H.

[0023] In some embodiments, R A4 is A 2 and R A1 , R A2 , and R A3 Each of is H.

[0024] In some embodiments, Y 1 teeth, [ka] is.

[0025] In some embodiments, R A6 is H. In some embodiments, R A7 is H.

[0026] In some embodiments, Y 1 teeth, [ka] is.

[0027] In some embodiments, R A8 is H or optionally substituted C1-C6 alkyl. In some embodiments, R A8 is H or methyl. In some embodiments, R A8 is methyl.

[0028] In some embodiments, the degrading moiety comprises a structure of formula A2. [ka]

[0029] In some embodiments, the degradation moiety is [ka] is.

[0030] In some embodiments, the degrading moiety comprises a structure of formula A4. [ka]

[0031] In some embodiments, the degradation moiety is [ka] is.

[0032] In some embodiments, the degrading moiety has the structure of formula A5. [ka]

[0033] In some embodiments, the degrading moiety has the structure of formula A6. [ka]

[0034] In some embodiments, the degrading moiety has the structure of formula A8. [ka]

[0035] In some embodiments, the degrading moiety has the structure of formula A10. [ka]

[0036] In some embodiments, the degradation moiety is [ka] Includes the structure of

[0037] In some embodiments, the degradation moiety is [ka] Includes the structure of

[0038] In some embodiments, the degrading moiety has the structure of Formula C [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 is independently, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B7 and R B8each independently represents H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 is aryl, R B9 is H or optionally substituted C1-C6 alkyl, A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 and or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the degrading moiety has the structure of Formula C [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 is independently, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; R B7 and R B8 each independently represents H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 is aryl, R B9 is H or optionally substituted C1-C6 alkyl, R B10 is H or F, A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 and or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the degrading moiety has the structure of formula C3. [ka]

[0041] In some embodiments, the degrading moiety has the structure of formula C4. [ka]

[0042] In some embodiments, the degrading moiety has the structure of formula C1. [ka]

[0043] In some embodiments, the degradation moiety is [ka] is.

[0044] In some embodiments, the degradation moiety is [ka] is.

[0045] In some embodiments, the degradation moiety is [ka] is.

[0046] In some embodiments, the degradation moiety is [ka] is.

[0047] In some embodiments, the degradation moiety is [ka] is.

[0048] In some embodiments, the degradation moiety is [ka] is.

[0049] In some embodiments, the degrading moiety has the structure of formula C2. [ka]

[0050] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0051] In some embodiments, R B9 is attached to the (S)-steric center.

[0052] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B8 is H. In some embodiments, R B2 is H.

[0053] In some embodiments, the degradation moiety is [ka] is.

[0054] In some embodiments, the degradation moiety has a structure of formula Ca2. [ka]

[0055] In some embodiments, the decomposition moiety has a structure of formula Cb2. [ka]

[0056] In some embodiments, the decomposition moiety has the structure of formula Cc2. [ka]

[0057] In some embodiments, the decomposition moiety has a structure of formula Cd2. [ka]

[0058] In some embodiments, the decomposition moiety has a structure of formula Ce2. [ka]

[0059] In some embodiments, the decomposition moiety has a structure of formula Cf2. [ka]

[0060] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0061] In some embodiments, R B9 is attached to the (S)-steric center.

[0062] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B3 is an optionally substituted C3-C 10 In some embodiments, R B3 is cyclopropane. In some embodiments, R B3 is cyclobutane. In some embodiments, R B3 is fluoro-2-methylpropane. In some embodiments, R B8 is H. In some embodiments, R B2 is H.

[0063] In some embodiments, the degradation moiety is [ka] is.

[0064] In some embodiments, the degradation moiety is [ka] is.

[0065] In some embodiments, the degradation moiety is [ka] is.

[0066] In some embodiments, the degradation moiety is [ka] is.

[0067] In some embodiments, the degradation moiety is [ka] is.

[0068] In some embodiments, the degradation moiety is [ka] is.

[0069] In some embodiments, the degradation moiety is [ka] is.

[0070] In some embodiments, the degradation moiety is [ka] is.

[0071] In some embodiments, the degradation moiety is [ka] is.

[0072] In some embodiments, the decomposition moiety has the structure of formula C5 [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 is independently, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B7 and R B8each independently represents H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 is aryl, R B9 is H or optionally substituted C1-C6 alkyl, R B11 is H, alcohol, boronic acid, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, and A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 That is, or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, R B11 is boric acid.

[0074] In some embodiments, the degrading moiety has the structure of formula C6. [ka]

[0075] In some embodiments, the degrading moiety has the structure of formula C1. [ka]

[0076] In some embodiments, the degrading moiety has the structure of formula C8. [ka]

[0077] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0078] In some embodiments, R B9 is attached to the (S)-steric center.

[0079] In some embodiments, v2 is 0. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B8 is H. In some embodiments, R B2 is H.

[0080] In some embodiments, the degradation moiety is [ka] is.

[0081] In some embodiments, the degradation moiety has the structure of Formula D [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 is independently, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B9 is H or optionally substituted C1-C6 alkyl, A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 That is, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the degrading moiety has the structure of formula D3. [ka]

[0083] In some embodiments, the degrading moiety has the structure of formula D1. [ka]

[0084] In some embodiments, the degradation moiety is [ka] is.

[0085] In some embodiments, the degradation moiety is [ka] is.

[0086] In some embodiments, the degradation moiety is [ka] is.

[0087] In some embodiments, the degrading moiety has the structure of formula D2. [ka]

[0088] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0089] In some embodiments, R B9 is attached to the (S)-stereocenter. In some embodiments, R B9 is H.

[0090] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B6 is H. In some embodiments, R B6 is halogen. In some embodiments, R B6 is fluorine. In some embodiments, R B6 is bromine. In some embodiments, R B6 is chlorine. In some embodiments, R B6 is cyano. In some embodiments, R B6 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R B6 is an optionally substituted C-C alkynyl. In some embodiments, R B6 is methoxy. In some embodiments, RB6 is 3-methoxy-1-propanoxy.

[0091] In some embodiments, the degradation moiety is [ka] is.

[0092] In some embodiments, the degradation moiety is [ka] is.

[0093] In some embodiments, the degradation moiety is [ka] is.

[0094] In some embodiments, the degradation moiety is [ka] is.

[0095] In some embodiments, the degradation moiety is [ka] is.

[0096] In some embodiments, the degradation moiety is [ka] is.

[0097] In some embodiments, the degradation moiety is [ka] is.

[0098] In some embodiments, the degradation moiety is [ka] is.

[0099] In some embodiments, the degradation moiety is [ka] is.

[0100] In some embodiments, the degradation moiety is [ka] is.

[0101] In some embodiments, the degradation moiety is [ka] is.

[0102] In some embodiments, the degradation moiety is [ka] is.

[0103] In some embodiments, the degradation moiety is [ka] is.

[0104] In some embodiments, the degradation moiety is [ka] is.

[0105] In some embodiments, the degradation moiety is [ka] is.

[0106] In some embodiments, the degradation moiety is [ka] is.

[0107] In some embodiments, the degradation moiety is [ka] is.

[0108] In some embodiments, the degradation moiety is [ka] is.

[0109] In some embodiments, the degradation moiety is [ka] is.

[0110] In some embodiments, the degradation moiety is [ka] is.

[0111] In some embodiments, the degradation moiety is [ka] is.

[0112] In some embodiments, the degradation moiety is [ka] is.

[0113] In some embodiments, the degradation moiety is [ka] is.

[0114] In some embodiments, the degradation moiety is [ka] is.

[0115] In some embodiments, the degradation moiety is [ka] is.

[0116] In some embodiments, the degradation moiety has a structure of formula Da [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; Each of X1 and X2 is independently C, N, or O. v2 is 0, 1, 2, 3, or 4; Each R B6 is independently, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B9 is H or optionally substituted C1-C6 alkyl, A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 That is, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the degradation moiety has the structure of formula Da3. [ka]

[0118] In some embodiments, the degradation moiety has the structure of formula Da1. [ka]

[0119] In some embodiments, the degradation moiety has the structure of formula Da2. [ka]

[0120] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0121] In some embodiments, R B9 is attached to the (S)-steric center.

[0122] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 is H. In some embodiments, X1 is C. In some embodiments, X2 is N.

[0123] In some embodiments, the degradation moiety is [ka] is.

[0124] In some embodiments, the degrading moiety has the structure of Formula E [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B9is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclyl or optionally substituted C-C 10 is heterocyclyl, B 10 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 heterocyclyl, optionally substituted amino, or cyano; and A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 That is, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the degrading moiety has the structure of formula E3. [ka]

[0126] In some embodiments, the degrading moiety has the structure of formula E1. [ka]

[0127] In some embodiments, the degradation moiety is [ka] is.

[0128] In some embodiments, the degradation moiety is [ka] is.

[0129] In some embodiments, the degrading moiety has the structure of formula E2. [ka]

[0130] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0131] In some embodiments, R B9 is attached to the (S)-steric center.

[0132] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 is H. In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl. In some embodiments, R B9 is H. In some embodiments, R B9 is an optionally substituted C-C alkynyl. In some embodiments, R B10 is absent. In some embodiments, R B9 is [1.1.1]pentane. In some embodiments, R B9 is cyclopropane. In some embodiments, R B9 is cyclobutane. In some embodiments, R B9 is cyclopentane. In some embodiments, RB10 is H. In some embodiments, R B10 is cyano. In some embodiments, R B10 is an optionally substituted C3-C 10 In some embodiments, R B10 is an optionally substituted C1-C6 alkyl. In some embodiments, R B10 is methyl.

[0133] In some embodiments, the degradation moiety is [ka] is.

[0134] In some embodiments, the degradation moiety is [ka] is.

[0135] In some embodiments, the degradation moiety is [ka] is.

[0136] In some embodiments, the degradation moiety is [ka] is.

[0137] In some embodiments, the degradation moiety is [ka] is.

[0138] In some embodiments, the degradation moiety is [ka] is.

[0139] In some embodiments, the degradation moiety is [ka] is.

[0140] In some embodiments, the degradation moiety is [ka] is.

[0141] In some embodiments, the degradation moiety is [ka] is.

[0142] In some embodiments, the degradation moiety has the structure of formula F [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] and R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; A 2 is the bond between the degradation moiety and the linker, R B1 or R B3 Only one of the 2 That is, or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the decomposition moiety has the structure of formula F3. [ka]

[0144] In some embodiments, the degrading moiety has the structure of formula F1. [ka]

[0145] In some embodiments, the degradation moiety is [ka] is.

[0146] In some embodiments, the degradation moiety is [ka] is.

[0147] In some embodiments, the degradation moiety is [ka] is.

[0148] In some embodiments, the decomposition moiety has the structure of formula F2. [ka]

[0149] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0150] In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 is H.

[0151] In some embodiments, the degradation moiety is [ka] is.

[0152] In some embodiments, the linker has the structure of Formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h-(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 , Formula II or a pharmaceutically acceptable salt thereof; During the ceremony, A 1 is the bond between the linker and ring system A, A 2 is the bond between the degradation moiety and the linker, B 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted C1-C4 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C-C 10 Aryl C 1~4 Alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 carbocyclyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C 6~12 Aryl, O, S, S(O)2, or NR N and Each R N are independently H, optionally substituted C 1~4 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkynyl, optionally substituted C 2~10 Heterocyclyl, optionally substituted C 2~6 Heteroaryl or optionally substituted C 1~7 is heteroalkyl, C 1 and C 2 each is independently carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; each of f, g, h, i, j, and k is independently 0 or 1; D is an optionally substituted C 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkynyl, optionally substituted C 2~10 Heterocyclyl, optionally substituted C 2~6 Heteroaryl, optionally substituted C 6~12 Aryl, optionally substituted C-C 10 Polyethylene glycol, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Carbocyclyl or optionally substituted C 1~10 or D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is.

[0153] In some embodiments, B 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, an optionally substituted C2-C 10 Heterocyclyl, optionally substituted C 2~6 Heteroaryl, O, or NR N and D is optionally substituted C 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkynyl, optionally substituted C 2~10Heterocyclyl, optionally substituted C 6~12 Aryl, optionally substituted C-C 10 Polyethylene glycol or optionally substituted C 1~10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 It is a chemical bond that bonds to

[0154] In some embodiments, B 1 ,B 2 ,B 3 and B 4 are independently selected from optionally substituted C1-C2 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C 2~6 Heteroaryl, optionally substituted C-C 10 Cycloalkyl, optionally substituted C-C 10 Carbocyclyl, O, or NR N is.

[0155] In some embodiments, B 1 and B 4 each of which independently [ka] [ka] is.

[0156] In some embodiments, B 1 teeth, [ka] [ka] is.

[0157] In some embodiments, B 4 teeth, [ka] [ka] is.

[0158] In some embodiments, C 1 teeth, [ka] is.

[0159] In some embodiments, B 2 is an optionally substituted C1-C4 alkyl.

[0160] In some embodiments, D is an optionally substituted C1-C 10 It is alkyl.

[0161] In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0162] In some embodiments, D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is.

[0163] In some embodiments, the linker is D. In some embodiments, D is optionally substituted C 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkynyl, optionally substituted C 2~10 Heterocyclyl, optionally substituted C 2~6 Heteroaryl, optionally substituted C 6~12 Aryl, optionally substituted C-C 10 Polyethylene glycol or optionally substituted C 1~10 In some embodiments, D is an optionally substituted C-C heteroalkyl. 10 cycloalkyl, where f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, where f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, where f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10carbocyclyl, where f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, where f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is [ka] [ka] is.

[0164] In some embodiments, the linker is [ka] [ka] It has the following structure.

[0165] In some embodiments, the linker has the structure of Formula III: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 , Formula III During the ceremony, A 1 is the bond between the linker and ring system A, A 2 is the bond between the degradation moiety and the linker, B 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted ethynyl, an optionally substituted C-C 10 Aryl, optionally substituted C-C 10 Cycloalkyl, optionally substituted C-C 10 Carbocyclyl, optionally substituted C-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O)2, or NR N and Each R N are independently H, optionally substituted C 1~4 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkynyl, optionally substituted C 2~10 Heterocyclyl, optionally substituted C 6~12 aryl, or optionally substituted C 1~7 is heteroalkyl, C 1 and C 2 each is independently carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; Each of f, g, h, i, j, and k is independently 0 or 1.

[0166] In some embodiments, the linker has the structure -(L 1 ) n where n is 1, 2, or 3, and each L 1 are independently O, NR N , ethynyl, optionally substituted C-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 Aryl or optionally substituted C-C 10 It is cycloalkyl.

[0167] In some embodiments, at least one L1 is an optionally substituted C2 to C 10 In some embodiments, an optionally substituted 2-C heterocyclyl is 10 The heterocyclyl is a 4-, 5-, or 6-membered monocyclic heterocyclyl. In some embodiments, the 4-, 5-, or 6-membered monocyclic heterocyclyl is: [ka] is.

[0168] In some embodiments, optionally substituted C-C 10 The heterocyclyl is a spirocyclic heterocyclyl. In some embodiments, the heterocyclyl is: [ka] is.

[0169] In some embodiments, optionally substituted C-C 10 The heterocyclyl is a bridged heterocyclyl. In some embodiments, the bridged heterocyclyl is: [ka] is.

[0170] In some embodiments, optionally substituted C-C 10 The heterocyclyl is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic heterocyclyl is: [ka] is.

[0171] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is -(L 1 ) q-(optionally substituted C2-C9 heteroaryl)-(L 1 ) q wherein each q is independently 0 or 1. In some embodiments, the optionally substituted C2-C9 heteroaryl is a 6-membered monocyclic heteroaryl. In some embodiments, the 6-membered monocyclic heteroaryl is [ka] is.

[0172] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is [ka] is.

[0173] In some embodiments, at least one L 1 is an optionally substituted C-C 10 In some embodiments, optionally substituted C-C aryl. 10 The aryl is a 6-membered monocyclic aryl. In some embodiments, the 6-membered monocyclic aryl is an optionally substituted phenyl.

[0174] In some embodiments, at least one L 1 is an optionally substituted C3-C 10 In some embodiments, an optionally substituted C-C cycloalkyl is 10 The carbocyclyl is a monocyclic cycloalkyl. In some embodiments, the 6-membered monocyclic cycloalkyl is: [ka] is.

[0175] In some embodiments, optionally substituted C3-C 10The cycloalkyl is a bridged cycloalkyl. In some embodiments, the bridged cycloalkyl is: [ka] is.

[0176] In some embodiments, at least one L 1 is ethynyl.

[0177] In some embodiments, L 1 and only one of L is O. In some embodiments, 1 Only one of them is NR N In some embodiments, R N is an optionally substituted C1-C4 alkyl. In some embodiments, R N is H.

[0178] In some embodiments, the linker is of the following structure: A 1 -(B 1 ) f -(B 2 ) h -(B 3 ) i -(B 4 ) k -A 2 , where B 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted ethynyl, an optionally substituted C-C 10 Aryl, optionally substituted C-C 10 Cycloalkyl, optionally substituted C-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N is.

[0179] In some embodiments, at least one of f, h, i, and k is 1.

[0180] In some embodiments, B 1 , B 2 , B 3 , and B 4 each independently represents O, ethynyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C-C 10 Cycloalkyl or optionally substituted C-C 10 In some embodiments, B is aryl. 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted C2-C9 heteroaryl or an optionally substituted C2-C 10 In some embodiments, B is heterocyclyl. 1 and B 4 each of which independently [ka] [ka] is.

[0181] In some embodiments, B 1 teeth, [ka] [ka] is.

[0182] In some embodiments, B 4 teeth, [ka] [ka] is.

[0183] In some embodiments, B 2 is NR N In some embodiments, B 2 is NH. In some embodiments, B 2 is an optionally substituted C2-C9 heteroaryl. In some embodiments, B 2 teeth, [ka] is.

[0184] In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0185] In some embodiments, the linker is [ka] [ka] [ka] It has the following structure.

[0186] In some embodiments, the shortest chain of atoms connecting the two valences of the linker is 2 to 10 atoms in length, hi some embodiments, the shortest chain of atoms connecting the two valences of the linker is 6 atoms in length.

[0187] In some embodiments, the linker is any one of compounds 1-291 in Table 1 (e.g., BRG1 IC 50and BRM IC 50 In some embodiments, the linker has the structure of any one of compounds 1-291 in Table 1 (e.g., BRM IC 50 In some embodiments, the linker has the structure of any one of compounds 1-291 in Table 1 (e.g., BRM IC 50 is ++ or higher (e.g., +++ or ++++ (e.g., ++++)), and BRG1 IC 50 and BRM IC 50 and the ratio of 1 to 1 is at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30).

[0188] In one aspect, the invention features a compound selected from the group consisting of 1-291 in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a BRG1 IC 50 and BRM IC 50 In some embodiments, the compound is any one of compounds 1-291 in Table 1, or a pharmaceutically acceptable salt thereof, having a BRM IC ratio of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30), as seen in Table 21. 50 In some embodiments, the compound is any one of compounds 1-291 in Table 1, or a pharmaceutically acceptable salt thereof, having a BRM IC of ++ or higher (e.g., +++ or ++++ (e.g., ++++)). 50 is ++ or higher (e.g., +++ or ++++ (e.g., ++++)), and BRG1 IC 50 and BRM IC 50 or a pharmaceutically acceptable salt thereof.

[0189]

Table 1-1

[0190]

Table 1-2

[0191]

Table 1-3

[0192]

Table 1-4

[0193]

Table 1-5

[0194]

Table 1-6

[0195]

Table 1-7

[0196]

Table 1-8

[0197]

Table 1-9

[0198]

Table 1-10

[0199]

Table 1-11

[0200]

Table 1-12

[0201]

Table 1-13

[0202]

Table 1-14

[0203]

Table 1-15

[0204]

Table 1-16

[0205]

Table 1-17

[0206]

Table 1-18

[0207]

Table 1-19

[0208]

Table 1-20

[0209]

Table 1-21

[0210]

Table 1-22

[0211]

Table 1-23

[0212]

Table 1-24

[0213]

Table 1-25

[0214]

Table 1-26

[0215]

Table 1-27

[0216]

Table 1-28

[0217]

Table 1-29

[0218]

Table 1-30

[0219]

Table 1-31

[0220]

Table 1-32

[0221]

Table 1-33

[0222]

Table 1-34

[0223]

Table 1-35

[0224]

Table 1-36

[0225]

Table 1-37

[0226]

Table 1-38

[0227]

Table 1-39

[0228]

Table 1-40

[0229]

Table 1-41

[0230]

Table 1-42

[0231]

Table 1-43

[0232]

Table 1-44

[0233]

Table 1-45

[0234]

Table 1-46

[0235]

Table 1-47

[0236]

Table 1-48

[0237]

Table 1-49

[0238]

Table 1-50

[0239]

Table 1-51

[0240]

Table 1-52

[0241]

Table 1-53

[0242]

Table 1-54

[0243]

Table 1-55

[0244]

Table 1-56

[0245]

Table 1-57

[0246]

Table 1-58

[0247]

Table 1-59

[0248]

Table 1-60

[0249]

Table 1-61

[0250]

Table 1-62

[0251]

Table 1-63

[0252]

Table 1-64

[0253]

Table 1-65

[0254]

Table 1-66

[0255]

Table 1-67

[0256]

Table 1-68

[0257]

Table 1-69

[0258]

Table 1-70

[0259]

Table 1-71

[0260] [Table 1-72]

[0261] [Table 1-73]

[0262] [Table 1-74]

[0263] [Table 1-75]

[0264] [Table 1-76]

[0265] [Table 1-77]

[0266] [Table 1-78]

[0267] [Table 1-79]

[0268] In some embodiments, the compound has a BRG1 IC of at least 5 50 BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 7. 50 BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 10. 50 BRM IC 50In some embodiments, the compound has a BRG1 IC of at least 15. 50 BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 20. 50 BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 25. 50 BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 30. 50 BRM IC 50 has a ratio to

[0269] In one aspect, the invention features a pharmaceutical composition including any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0270] In another aspect, the invention features a method for decreasing the activity of a BAF complex in a cell, the method comprising contacting the cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0271] In some embodiments, the cell is a cancer cell.

[0272] In another aspect, the invention features a method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0273] In some embodiments, the BAF complex-associated disorder is cancer or a viral infection.

[0274] In a further aspect, the invention features a method of inhibiting BRM, the method including contacting a cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0275] In some embodiments, the cell is a cancer cell.

[0276] In another aspect, the invention features a method for inhibiting BRG1, the method comprising contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0277] In some embodiments, the cell is a cancer cell.

[0278] In a further aspect, the invention features a method for inhibiting BRM and BRG1, the method comprising contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0279] In some embodiments, the cell is a cancer cell.

[0280] In another aspect, the invention features a method of treating a disorder associated with a loss-of-function mutation in BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0281] In some embodiments, the disorder associated with a BRG1 loss-of-function mutation is cancer. In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, for example, a BRG1 loss-of-function cancer (e.g., the cancer is determined to contain cancer cells with BRG1 loss-of-function).

[0282] In another aspect, the invention features a method of inducing apoptosis in a cell, the method including contacting the cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0283] In some embodiments, the cell is a cancer cell.

[0284] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0285] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0286] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0287] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0288] In some embodiments of any of the foregoing methods, the cancer is a drug-resistant cancer or has undergone prior therapy (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolomide, irinotecan, CAR-T therapy, Herceptin®, Perjeta®, tamoxifen, Xeloda®, docetaxel, platinum agents such as carboplatin, paclitaxel, ribozyme, ribozyme inhibitors ... have not responded to taxanes such as taxel and docetaxel, ALK inhibitors, MET inhibitors, Alimta®, Abraxane®, Adriamycin®, gemcitabine, Avastin®, Halaven®, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, Gemzar®, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabine, or PDL1 inhibitors.

[0289] In some embodiments of any of the aforementioned methods, the cancer has, or has been determined to have, a BRG1 mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is homozygous. In some embodiments of any of the aforementioned methods, the cancer does not have, or has been determined to not have, an Epidermal Growth Factor Receptor (EGFR) mutation. In some embodiments of any of the aforementioned methods, the cancer does not have, or has been determined to not have, an Anaplastic Lymphoma Kinase (ALK) driver mutation. In some embodiments of any of the aforementioned methods, the cancer has, or has been determined to have, a KRAS mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is in the ATPase catalytic domain of the protein. In some embodiments of any of the aforementioned methods, the BRG1 mutation is a deletion at the C-terminus of BRG1.

[0290] In another aspect, the disclosure provides a method of treating a BAF-associated disorder (e.g., cancer or viral infection) in a subject in need thereof, the method comprising contacting a cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is a viral infection, such as a retrovirus from the Retroviridae family, including lentiviruses (e.g., human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T-cell leukemia virus I (HTLV-I)), human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae (e.g., hepatitis B virus (HBV)), Flaviviridae (e.g., hepatitis C virus (HCV)), Adenoviridae (e.g., human adenovirus), Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K), or a viral infection, such as a virulent virus (e.g., virulent virus (VHK)). * In some embodiments, the disorder is an infection with a virus of the family Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1)), Parvoviridae (e.g., parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., measles virus), or Togaviridae (e.g., rubella virus). In some embodiments, the disorder is coffin schisis, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0291] In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is a viral infection, such as a retrovirus from the Retroviridae family, including lentiviruses (e.g., human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T-cell leukemia virus I (HTLV-I)), human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae (e.g., hepatitis B virus (HBV)), Flaviviridae (e.g., hepatitis C virus (HCV)), Adenoviridae (e.g., human adenovirus), Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K), or a viral infection, such as a virulent virus (e.g., virulent virus (VHK)). * , CMV, varicella-zoster virus), Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1)), Parvoviridae (e.g., parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., measles virus), or Togaviridae (e.g., rubella virus).

[0292] In some embodiments of any of the foregoing aspects, the compound is a BRM-selective compound. In some embodiments, the BRM-selective compound inhibits the level and / or activity of BRM to a degree that is at least 10 times greater than the compound inhibits the level and / or activity of BRG1, and / or the compound binds to BRM to a degree that is at least 10 times greater than the compound binds to BRG1. For example, in some embodiments, the BRM-selective compound has an IC 50 or IP 50At least 10-fold lower IC 50 or IP 50 In some embodiments of any of the foregoing aspects, the compound is a BRM / BRG1 dual inhibitor compound. In some embodiments, the BRM / BRG1 dual inhibitor compound has similar activity against both BRM and BRG1 (e.g., activity of the compound against BRM and BRG1 within 10-fold (e.g., less than 5-fold, less than 2-fold)). In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRM. In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRG1. For example, in some embodiments, the BRM / BRG1 dual inhibitor compound has an IC 50 or IP 50 However, IC against BRG1 50 or IP 50 It is within 10 times of

[0293] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the preceding compounds or a pharmaceutical composition thereof.

[0294] In another aspect, the invention features a method of reducing melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer tumor growth in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the preceding compounds or a pharmaceutical composition thereof.

[0295] In another aspect, the invention features a method of inhibiting metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, the method comprising administering an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0296] In another aspect, the invention features a method of inhibiting metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, the method comprising administering an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0297] In another aspect, the invention features a method for reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer cells, the method comprising contacting the cells with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0298] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cells are in the subject.

[0299] In some embodiments of any of the above aspects, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0300] In some embodiments, an effective amount of a compound reduces BRG1 levels and / or activity by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of a compound that reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0301] In some embodiments of any of the above aspects, an effective amount of compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of compound reduces the level and / or activity of a BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of compound reduces the level and / or activity of a BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0302] In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of a compound that reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0303] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein, and / or the cells or subject have been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein, and / or the cells or subject have been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein, and / or the cells or subject have been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematological cancer, such as multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the cancer is breast cancer (e.g., ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer). In some embodiments, the cancer is bone cancer (e.g., Ewing's sarcoma). In some embodiments, the cancer is renal cell carcinoma (e.g., Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). Metastatic cancers may include cells that exhibit migratory cell migration and / or invasion, and / or may include cells that exhibit endothelial recruitment and / or angiogenesis. In other embodiments, the migratory cancer is a cell migration cancer. In yet other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. A metastatic cancer may be a cancer that spreads via seeding the surfaces of the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, a metastatic cancer may be a cancer that spreads via the lymphatic system or hematogenously.In some embodiments, the effective amount of the agent that reduces the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colonization of the liver by cancer.

[0304] In some embodiments, the cancer harbors a mutation in GNAQ. In some embodiments, the cancer harbors a mutation in GNA11. In some embodiments, the cancer harbors a mutation in PLCB4. In some embodiments, the cancer harbors a mutation in CYSLTR2. In some embodiments, the cancer harbors a mutation in BAP1. In some embodiments, the cancer harbors a mutation in SF3B1. In some embodiments, the cancer harbors a mutation in EIF1AX. In some embodiments, the cancer harbors a TFE3 translocation. In some embodiments, the cancer harbors a TFEB translocation. In some embodiments, the cancer harbors a MITF translocation. In some embodiments, the cancer harbors an EZH2 mutation. In some embodiments, the cancer harbors a SUZ12 mutation. In some embodiments, the cancer harbors an EED mutation.

[0305] In some embodiments, the method further comprises administering to the subject or contacting the cells with an anti-cancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation. In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, e.g., antimetabolite, antimitotic, antitumor antibiotic, asparagine-specific enzyme, bisphosphonate, anti-neoplastic agent, alkylating agent, DNA repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulator, Janus-related kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor.

[0306] In some embodiments, the compounds of the present invention are used in combination with another anti-cancer therapy used to treat uveal melanoma, such as surgery, a MEK inhibitor, and / or a PKC inhibitor. For example, in some embodiments, the method further comprises performing surgery before, after, or simultaneously with the administration of the compound of the present invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or simultaneously with the administration of the compound of the present invention.

[0307] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other, and each in an amount that is together effective to treat the subject.

[0308] In some embodiments, the subject or cancer has and / or has been identified as having a loss-of-function mutation in BRG1.

[0309] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to a chemotherapeutic or cytotoxic agent (e.g., by a genetic marker) or has been determined to be likely to be resistant to a chemotherapeutic or cytotoxic agent (e.g., a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent)). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic agents. In some embodiments, the cancer is resistant to or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or trametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0310] In some embodiments, the cancer is resistant to or has not responded to previously administered therapeutic agents used to treat uveal melanoma, such as MEK inhibitors or PKC inhibitors. For example, in some embodiments, the cancer is resistant to or has not responded to mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or tametinib) and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0311] In one aspect, the present invention provides the use of any of the aforementioned compounds (e.g., BRM / BRG1 dual inhibitor compounds or BRM-selective compounds), pharmaceutically acceptable salts thereof, or aforementioned pharmaceutical compositions in the manufacture of a medicament. In some embodiments, the use is as described for the methods described herein.

[0312] chemical terms The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0313] For any of the following chemical definitions, the number following an atomic symbol indicates the total number of atoms of that element present in a particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituents described herein, may be present, as needed, to satisfy the valence of an atom. For example, an unsubstituted C alkyl group has the formula —CHCH. When used with groups defined herein, references to the number of carbon atoms include divalent carbons in acetal and ketal groups, but do not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. References to the number of oxygen, nitrogen, or sulfur atoms in heteroaryl groups include only those atoms that form part of the heterocyclic ring.

[0314] The term "acyl," as used herein, represents an H or alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0315] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0316] Alkylene is a divalent alkyl group. As used herein, the term "alkenyl," alone or in combination with other groups, refers to a straight- or branched-chain hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0317] As used herein, the term "alkynyl," alone or in combination with other groups, refers to a straight- or branched-chain hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0318] As used herein, the term “amino” refers to —N(R N1 )2, and each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these enumerated R N1 Each of the groups may be optionally substituted, or two R N1 combine to form an alkylene or heteroalkylene, and each R N2 are independently H, alkyl, or aryl. The amino groups of the present invention can be unsubstituted amino (i.e., —NH) or substituted amino (i.e., —N(R N1 )2).

[0319] As used herein, the term "aryl" refers to an aromatic mono- or polycarbocyclic group of 6 to 12 carbon atoms having at least one aromatic ring. If polycyclic, the aryl group contains two or three rings. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0320] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups include those having 7 to 30 carbons (e.g., C1-C6 alkyl, C6-C6 alkyl), such as benzyl and phenethyl. 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl or C1-C 20 Alkyl C6-C 10 In some embodiments, alkyl and aryl each contain 7 to 16 or 7 to 20 carbons, regardless of valence, as defined herein for each group.

[0321] As used herein, the term "azido" refers to an -N3 group.

[0322] As used herein, the term "bridged polycycloalkyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges. Bridged polycycloalkyl groups can be unsubstituted or substituted as defined herein for cycloalkyl.

[0323] As used herein, the term "cyano" refers to a -CN group.

[0324] As used herein, the term "carbocyclyl" refers to a non-aromatic C-C carbocyclyl in which the ring is formed by carbon atoms. 12 It refers to a monocyclic, bicyclic, or tricyclic structure. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl groups.

[0325] As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monovalent monoradical, diradical, or tricycloradical having 3 to 10, preferably 3 to 6, carbon atoms. Cycloalkyl groups may be fully saturated or may contain one or more double or triple bonds, provided that the ring is not aromatic. This term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. As used herein, the term "cycloalkoxy" refers to cycloalkyl-O groups (e.g., cyclopropoxy and cyclobutoxy).

[0326] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0327] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group is further substituted with 1, 2, 3, or 4 substituents, as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy," which, as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkylene is a divalent heteroalkyl group.

[0328] As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced with nitrogen, oxygen, or sulfur. In some embodiments, heteroalkenyl groups are further substituted with 1, 2, 3, or 4 substituents, regardless of valence, as described herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy," which, as used herein, refers to alkenyl-O-. Heteroalkenylene is a divalent heteroalkenyl group.

[0329] As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced with nitrogen, oxygen, or sulfur. In some embodiments, heteroalkynyl groups are further substituted with 1, 2, 3, or 4 substituents, regardless of valence, as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy," which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0330] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic group of 5 to 12 atoms having at least one aromatic ring and containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0331] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups include groups with 7 to 30 carbons (e.g., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 alkyl C2-C9 heteroaryl, or C1-C 20 In some embodiments, the alkyl and heteroaryl each contain 7 to 16 or 7 to 20 carbons, such as alkyl C2-C9 heteroaryl. In some embodiments, the alkyl and heteroaryl are each further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group, regardless of valence.

[0332] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or tricyclic group having 3 to 12 atoms with at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and the ring is not aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0333] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Unsubstituted heterocyclylalkyl groups include groups of 7 to 30 carbons (e.g., C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 alkyl C2-C9 heterocyclyl, or C1-C 20 alkyl (e.g., C2-C9 heterocyclyl, containing 7 to 16 or 7 to 20 carbons). In some embodiments, the alkyl and heterocyclyl are each further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0334] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0335] As used herein, the term "hydroxyl" refers to an --OH group.

[0336] As used herein, the term "N-protecting group" refers to a group intended to protect an amino group against undesired reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).N-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries, such as protected or unprotected D,L, or D,L-amino acids. for example, alanine, leucine, and phenylalanine, with sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl, and carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl , 2,4-20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl aryl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups such as trimethylsilyl.Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0337] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0338] The term "oxo," as used herein, represents a divalent oxygen atom (e.g., the structure of oxo can be depicted as =0). For example, a carbonyl group is a carbon (e.g., an alkyl carbon, alkenyl carbon, alkynyl carbon, heteroalkyl carbon, heteroalkenyl carbon, heteroalkynyl carbon, carbocyclyl carbon, etc.) substituted with an oxo. Alternatively, sulfur can be substituted with one or two oxo groups (e.g., -SO- or -SO2- in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group).

[0339] As used herein, the term "thiol" refers to a -SH group.

[0340] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. If substituted, there will be 1, 2, 3, 4, or 5 substituents present, regardless of valence, unless otherwise specified. The 1 to 5 substituents are each independently selected from the group consisting of acyl, alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, thiol, and oxo. Each of the substituents is unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, thiol, and oxo. Each of the substituents is unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, the substituents are themselves unsubstituted.

[0341] The compounds of the present invention may have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). Thus, certain disclosed compounds may exist in various diastereomeric forms. Diastereomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of diastereomers whose mirror images are not superimposable because they contain asymmetrically substituted carbon atoms that function as chiral centers. An enantiomer refers to one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are most commonly diastereomers that are not related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating enantiomers of the compounds described herein from a racemic mixture can be readily determined by one of ordinary skill in the art. A "racemate" or "racemic mixture" refers to a compound containing two enantiomers; such mixtures do not exhibit optical activity; i.e., they do not rotate the plane of polarized light. A "geometric isomer" refers to an isomer that differs in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond can be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S" * "," "R*"," "E," "Z," "cis," and "trans" indicate configuration relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are diastereomers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation is high enough to allow isolation of the conformers. The compounds of the invention can be prepared as individual isomers by isomer-specific synthesis or resolved from an isomeric mixture. Traditional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either the starting materials or the final product using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure relative to the other diastereomer. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Percent optical purity is the weight of the enantiomer, or the ratio of the weight of the enantiomer to the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers.When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to the other diastereomer. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. Percent purity by mole fraction is the ratio of moles of enantiomer or moles of enantiomer to moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of moles of a diastereomer, or moles of a diastereomer to moles of its isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass any enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, a mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other diastereomer, some diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or mixtures of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms.

[0342] The compounds of the present disclosure also include all isotopes of atoms present in the intermediate or final compounds. "Isotopes" refer to atoms having the same atomic number but different mass numbers resulting from different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0343] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may afford certain therapeutic benefits (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. In some embodiments, one or more hydrogen atoms are 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 replaced by C-enriched carbon. 15O. 13 N, 11 C, and 18 Positron-emitting isotopes, such as F, are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparation of isotopically labeled compounds is well known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the present invention described herein, substituting a non-isotopically labeled reagent for an isotopically labeled reagent. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in this disclosure. Other suitable methods and materials known in the art can also be used. These materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0344] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," and (iii) the terms "comprising" and "including" may be understood to encompass the listed elements or steps, whether presented alone or together with one or more additional elements or steps.

[0345] As used herein, the terms "about" and "approximately" refer to values ​​within 10% above or below the stated value. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0346] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial infusion), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal infusion), transdermal, vaginal, and intravitreal.

[0347] As used herein, the term "BAF complex" refers to the BRG1 or HRBM-associated factor complex in human cells.

[0348] As used herein, the term "BAF complex-related disorder" refers to a disorder caused by or affected by the level of activity of the BAF complex.

[0349] As used herein, the term "BRG1 loss of function mutation" refers to a mutation in BRG1 that results in a protein with reduced activity (e.g., at least a 1% reduction in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss of function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0350] As used herein, the term "BRG1 loss of function disorder" refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., at least a 1% reduction in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).

[0351] The term "cancer" refers to conditions caused by the proliferation of malignant cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0352] As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dosage and periodicity of administration of each agent so that the effects of the separate agents on the subject overlap. In some embodiments, delivery of two or more agents may be simultaneous or concurrent, or the agents may be co-formulated. In some embodiments, two or more agents are not co-formulated but are administered in a sequential manner as part of a prescribed regimen. In some embodiments, the administration of two or more agents or combined treatments is such that the reduction in symptoms or other parameters associated with the disorder is greater than that observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments may be partially additive, fully additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can occur by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection, while a second therapeutic agent of the combination may be administered orally.

[0353] "Determining the level" of protein or RNA means detecting the protein or RNA, either directly or indirectly, by methods well known in the art. "Directly determining" means performing a process to obtain a physical entity or value (e.g., performing an assay or test on a sample, or "analyzing a sample" as that term is defined herein). "Indirectly determining" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Methods for measuring protein levels generally include, but are not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemistry, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC) mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on properties of the protein, including, but not limited to, enzymatic activity or interaction with other protein partners. Methods for measuring RNA levels are well known in the art and include, but are not limited to, quantitative Polymerase Chain Reaction (qPCR) and Northern blot analysis.

[0354] "Decreasing the activity of a BAF complex" means decreasing the level of activity associated with the BAF complex or an associated downstream effect. A non-limiting example of decreasing the activity of a BAF (B cell activating factor) complex is activation of Sox2. The activity level of a BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al., Cell 2013:153-85(71), which is incorporated herein by reference.

[0355] As used herein, the term "degrader" refers to a small molecule compound that contains a degrading moiety, and the compound interacts with a protein (e.g., BRG1 and / or BRM) in a manner that results in degradation of the protein (e.g., binding of the compound results in at least a 5% reduction in the levels of the protein, e.g., in a cell or subject).

[0356] As used herein, the term "degradation moiety" refers to a moiety that, upon binding, results in degradation of a protein (e.g., BRG1 and / or BRM). In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes the protein (e.g., BRG1 and / or BRM).

[0357] "Modulating the activity of a BAF complex" means altering the level of activity associated with a BAF complex (e.g., GBAF) or an associated downstream effect. The activity level of a BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al., Cell 153:71-85 (2013), which is incorporated herein by reference.

[0358] "Reducing the activity of BRG1 and / or BRM" means reducing the level of activity or downstream effects associated with BRG1 and / or BRM. A non-limiting example of inhibiting the activity of BRG1 and / or BRM is reducing the level of the BAF complex in a cell. The activity level of BRG1 and / or BRM can be measured using any method known in the art. In some embodiments, the agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrader.

[0359] "Reducing the level of BRG1 and / or BRM" means decreasing the level of BRG1 and / or BRM in a cell or a subject. The level of BRG1 and / or BRM can be measured using any method known in the art.

[0360] "Level" refers to the level of a protein or mRNA encoding a protein, as compared to a reference material. A reference material can be any useful reference material, as defined herein. A "decreased level" or "increased level" of a protein refers to a decrease or increase in protein level compared to a reference material (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more decrease or increase), as compared to a reference material, such as about 10%, about 15%, about 20%, about 30%, about 40%, about 500%, or more decrease or increase). "A decrease or increase of more than 0%, about 50%, about 75%, about 100%, or about 200%, a decrease or increase of less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less, or an increase of about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more. Protein levels may be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of total protein or mRNA in the sample.

[0361] As used herein, the term "inhibiting BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition can be determined using methods well known in the art, such as a BRM ATPase assay, a Nano DSF assay, or a BRM luciferase cellular assay.

[0362] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein that is formulated with a pharmaceutically acceptable excipient and is suitable for administration to a mammal, e.g., a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. A pharmaceutical composition may be formulated, for example, in a unit dosage form for oral administration (e.g., a tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a particulate-free sterile solution and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0363] As used herein, "pharmaceutically acceptable excipient" refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound) that has the properties of being substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration.

[0364] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound, e.g., any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein may include salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0365] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as methods for preparing suitable salts, are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0366] "Reference" refers to any useful reference material used to compare protein or RNA levels. A reference can be any sample, standard, standard curve, or level used for comparison purposes. A reference can be a normal reference sample or reference standard or level. A "reference sample" can be, for example, a control, e.g., a predetermined negative control value such as a "normal control," or a previous sample taken from the same subject; a sample from a normal healthy subject such as normal cells or normal tissue; a sample (e.g., cells or tissue) from a subject without a disease; a sample from a subject diagnosed with a disease but not yet treated with a compound of the invention; a sample from a subject treated with a compound of the invention; or a sample of a known normal concentration of purified protein or RNA (e.g., any described herein). A "reference standard or level" refers to a value or numerical value derived from a reference sample. A "normal control value" is a predetermined value indicative of a non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("no higher than X"), or a low threshold ("no lower than X"). Subjects with measurements within the normal control value for a particular biomarker are typically referred to as being "within normal limits" for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject who does not have a disease or disorder (e.g., cancer), a subject who is being treated with a compound of the invention. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, stage of disease, and overall health. A standard curve of levels of purified protein or RNA, such as any described herein, within the normal reference range can also be used as a reference.

[0367] As used herein, the term "subject" refers to any living organism to which a composition according to the invention can be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal seeking or in need of treatment, requesting treatment, undergoing treatment, or may be undergoing treatment in the future, or being treated by a trained professional for a particular disease or condition.

[0368] As used herein, the terms "treat," "treated," or "treating" refer to therapeutic treatment or any procedure aimed at slowing (reducing) an undesirable physiological condition, disorder, or disease, or achieving a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the severity of a condition, disorder, or disease, a stable (i.e., not worsening) state of a condition, disorder, or disease, a delay in the onset or slowing of progression of a condition, disorder, or disease, an improvement or remission (partial or total) of a condition, disorder, or disease state, an improvement in at least one measurable physical parameter, not necessarily discernible by the patient, or an enhancement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to expected survival without treatment. The compounds of the invention may also be used to "prophylactically treat" or "prevent" disorders, for example, in subjects at increased risk of developing the disorder.

[0369] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0370] The present disclosure features compounds useful for inhibiting BRG1 and optionally BRM. These compounds may be used to modulate the activity of the BAF complex, for example, for the treatment of BAF-associated disorders (e.g., loss-of-function disorders of BRG1), such as cancer. Exemplary compounds described herein include compounds having a structure according to Formula I, or a pharmaceutically acceptable salt thereof.

[0371] In one aspect, the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, m is 0, 1, 2, or 3; k is 0, 1, or 2; Each R 1 are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano; each X is independently halo or optionally substituted C1-C6 heteroalkyl; L is a linker, B is a degrading moiety, characterized in that the compound of formula IV, or a pharmaceutically acceptable salt thereof, is

[0372] In some embodiments, the compound has the structure of any one of compounds 1-47 in Table 1, or a pharmaceutically acceptable salt thereof.

[0373] Other embodiments, and exemplary methods for synthesis of the production of these compounds, are described herein.

[0374] Pharmaceutical use The compounds described herein are useful in the methods of the invention and, without being bound by theory, are believed to exert their ability to modulate the level, status, and / or activity of the BAF complex, i.e., by inhibiting the activity of BRG1 and / or BRM proteins within the mammalian BAF complex. BAF complex-associated disorders include, but are not limited to, disorders associated with loss-of-function mutations in BRG1.

[0375] One aspect of the invention relates to a method of treating a disorder associated with a loss-of-function mutation in BRG1, such as cancer (e.g., non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) a reduction in tumor size; (b) a reduction in tumor growth rate; (c) an increase in tumor cell death; (d) a reduction in tumor progression; (e) a reduction in the number of metastases; (f) a reduction in the rate of metastasis; (g) a reduction in tumor recurrence; (h) an increase in the subject's survival; or (i) an increase in the subject's progression-free survival.

[0376] Treating cancer can result in a reduction in tumor size or volume. For example, after treatment, tumor size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) relative to its size before treatment. Tumor size may be measured by any reproducible means of measurement. For example, tumor size may be measured as the diameter of the tumor.

[0377] Treating cancer can also result in a reduction in tumor number. For example, after treatment, tumor number is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the number before treatment. The number of tumors can be measured by any reproducible means of measurement; for example, the number of tumors can be measured by counting tumors visible to the naked eye or at a particular magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0378] Treating cancer can result in a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the number before treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a particular magnification (e.g., 2x, 10x, or 50x).

[0379] Treating cancer may result in an increase in the average survival time of a population of subjects treated according to the present invention compared to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in average survival time of a population may be measured by any reproducible means. The increase in average survival time of a population may be measured, for example, by calculating the average length of survival for a population after initiation of treatment with a compound of the present invention. The increase in average survival time of a population may also be measured, for example, by calculating the average length of survival for a population after completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0380] Treating cancer may also result in a reduction in mortality in a population of treated subjects compared to an untreated population. For example, mortality is reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in mortality in a population of treated subjects may be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time for the population after initiation of treatment with a pharmaceutically acceptable salt of the present invention. The reduction in mortality in a population may also be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0381] Exemplary cancers that may be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colon cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumors, adrenocortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0382] Combination preparations and their uses The compounds of the invention can be combined with one or more therapeutic agents. In particular, the therapeutic agents can be those that treat or prophylactically treat any of the cancers described herein.

[0383] Combination therapy The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as other drugs for treating cancer or related conditions, or in combination with other types of therapy for treating cancer. In combination therapy, the dosage of one or more therapeutic compounds may be reduced from the standard dosage when administered alone. For example, dosages may be empirically determined from drug combinations and permutations or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the combined compounds should provide a therapeutic effect.

[0384] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metadopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; kallistatin; and CC-1065 (including its derivatives adozelesin, carzelesin, and bilephrine derivatives). Xeresin synthetic analogs), cryptophycins (especially cryptophycin 1 and cryptophycin 8), dolastatins, duocarmycins (including synthetic analogs KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictin, spongistatin, nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembucil, fenesterine, prednimustine, trofosfamide, uracil mustard, and nitrosoureas,Antibiotics such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine, antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gammaol and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)) and dynemicins, including dynemicin A, bisphosphonates such as clodronate and esperamicin, and neocarzinostatin chromophore and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, kakuchi cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin and deoxydoxorubicin), elastase, Pirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, and antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate, purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,Floxuridine, androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, antiadrenal drugs such as aminoglutethimide, mitotane, trilostane, folic acid supplements such as floric acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfomitin hine), elliptinium acetate, epothilones, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansinoids such as maytansine and ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamt, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazine, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziconazole, 2,2',2''-trichlorotriethylamine, trichothecenes (particularly T-2 toxin, verulaculin A, roridin A, and anguidin), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, and taxoids such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane®, a Cremophor-free albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® doxetaxel (Rhone-Poulenc Rorer, Antony, France);Chlorambucil, Gemzar® gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, Navelbine® vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan (e.g., CPT-11), and the topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO), retinoids, such as retinoic acid, capecitabine, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail administered in combination with a first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are well known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

[0385] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (Avastin®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. These include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab), Synagis (palivizumab), Remicade (infliximab), Herceptin (trastuzumab), Mylotarg (gemtuzumab ozogamicin), Cambus (alemtuzumab), Zevalin (ibritumomab tiuxetan), Humira (adalimumab), Xolair (omalizumab), Bexar (tositumomab-I-131), Raptiva (efalizumab), Erbitux (cetuximab), Avastin (bevacizumab), Tysabri (natalizumab), and Actemra (tocilizumab). Antibody-drug conjugates (antibody-drug conjugates) include: Vectibix (panitumumab), Lucentis (ranibizumab), Soliris (eculizumab), Cimzia (certolizumab pegol), Simponi (golimumab), Ilaris (canakinumab), Stelara (ustekinumab), Arzera (ofatumumab), Prolia (denosumab), Numax (motavizumab), ABThrax (raxibacumab), Benlysta (belimumab), Yervoy (ipilimumab), Adcetris (brentuximab vedotin), Perjeta (pertuzumab), Kadcyla (Ado-trastuzumab emtansine), and Gazyva (obinutuzumab).

[0386] The second agent may be a therapeutic agent that is a non-drug treatment, for example, the second therapeutic agent is radiation therapy, cryotherapy, thermotherapy, and / or surgical removal of tumor tissue.

[0387] The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, a humanized antibody or a fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of the checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®, pembrolizumab / Keytruda®, pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.

[0388] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in any order. The first therapeutic agent can be administered immediately before, immediately after, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days before or after the second therapeutic agent.

[0389] Pharmaceutical Composition The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biologically compatible form suitable for administration in vivo. Thus, in one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

[0390] The compounds of the present invention may be used in the form of free base, salt, solvate, and prodrug. All forms are within the scope of the present invention. According to the method of the present invention, as will be understood by those skilled in the art, the described compounds, or their salts, solvates, or prodrugs, can be administered to patients in various forms depending on the selected administration route. The compounds of the present invention may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, via patch, pump, or transdermal administration, and the pharmaceutical composition will be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may also be by continuous infusion over a selected period of time.

[0391] The compounds of the present invention can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with dietary food. For oral therapeutic administration, the compounds of the present invention can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without alcohol, and in oils. These preparations may contain preservatives to prevent the growth of microorganisms under ordinary conditions of storage and use. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th ed.) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and sufficiently fluid for easy administration via syringe. Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually provided in single or multiple doses in sterile form in a sealed container, which can be in the form of a cartridge or refill for use with a nebulizer device. Alternatively, the sealed container may be a single-dispensing device, such as a single-dose nasal inhaler or aerosol dispenser fitted with a metering valve, intended to be discarded after use.When the dosage form comprises an aerosol dispenser, it contains a propellant, which may be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage form may also take the form of a pump-type sprayer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. The compounds described herein may be administered intratumorally, for example, by intratumoral injection. Intratumoral injection is a direct injection into the tumor vasculature and is particularly intended for individual, solid, accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein may be advantageously contacted with the tumor by injection or multiple injections, for example, spaced approximately 1 cm apart. In the case of surgical intervention, the present invention can be used preoperatively, such as to subject an inoperable tumor to resection. Continuous administration can also be applied where appropriate, for example, by implanting a catheter into the tumor or tumor vasculature.

[0392] The compounds of the invention, as described herein, can be administered to animals, e.g., humans, alone or in combination with pharmaceutically acceptable carriers, the ratios being determined by the solubility and chemical properties of the compounds, the chosen route of administration, and standard pharmaceutical practice.

[0393] Dosage The dosage of the compounds of the present invention and / or compositions containing the compounds of the present invention can vary depending on many factors, including the pharmacodynamic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and severity of the symptoms, the frequency of treatment, and the type of concurrent treatment, if any, as well as the clearance rate of the compound in the treated animal. Those skilled in the art will be able to determine appropriate dosages based on the above factors. The compounds of the present invention may be initially administered at a suitable dosage, which may be adjusted as necessary depending on the clinical response. Generally, satisfactory results can be obtained when the compounds of the present invention are administered to humans at a daily dose of, for example, 0.05 mg to 3000 mg (measured as solid form). Dose ranges include, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0394] Alternatively, the patient's body weight can be used to calculate the dosage. For example, the dose of a compound or pharmaceutical composition thereof administered to a patient may be in the range of 0.1 to 100 mg / kg (e.g., 0.25 to 25 mg / kg). In exemplary, non-limiting embodiments, the dose may be in the range of 0.5 to 5.0 mg / kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg) or 5.0 to 20 mg / kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg). [Example]

[0395] The following abbreviations are used throughout the examples below:

[0396] [Table 2-1]

[0397] [Table 2-2]

[0398] Example 1. Preparation of Compounds Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2) . [ka]

[0399] Step 1: Preparation of 2-(3-bromoisoxazol-5-yl)acetic acid [ka]

[0400] To a stirred solution of 2-(3-bromo-1,2-oxazol-5-yl)ethan-1-ol (30 g, 156 mmol) in acetone (389 mL) was added Jones reagent (2 M in acetone, 156 mL, 312 mmol) dropwise at 0 °C. The resulting solution was stirred at 25 °C overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 86.5%) as a brown solid. LCMS (ESI) m / z: [M+H] + =206.08 and 208.08.

[0401] Step 2: Preparation of methyl 2-(3-bromoisoxazol-5-yl)acetate . [ka]

[0402] A solution of 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 135 mmol) and concentrated H2SO4 (3 mL, 72 mmol) in methanol (250 mL) was stirred at 70 °C for 2 h, and the resulting solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc / petroleum ether) to give methyl 2-(3-bromoisoxazol-5-yl)acetate (23.4 g, 79%) as a white solid. LCMS (ESI) m / z: [M+H] + =219.90 and 221.86.

[0403] Step 3: Preparation of methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate. [ka]

[0404] Methyl 2-(3-bromoisoxazol-5-yl)acetate (23.4 g, 106 mmol) and KO in THF (210 mL) t To a stirred solution of Bu (17.8 g, 159 mmol), 2-iodopropane (13.8 mL, 137 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h and then quenched with water / ice. The resulting solution was extracted several times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc / petroleum ether) to give methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (16.7 g, 60%) as a clear oil.

[0405] Step 4: Preparation of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid. [ka]

[0406] To a solution of methyl 2-(3-bromo-1,2-oxazol-5-yl)-3-methylbutanoate (16.7 g, 63.7 mmol) in methanol (130 mL) was added potassium hydroxide (35.7 g, 637 mmol). The mixture was stirred at 100 °C for 4 hours. The mixture was concentrated in vacuo and then diluted with water. The resulting solution was washed with EtOAc, and the pH of the aqueous layer was adjusted to pH 5 with 1 N HCl. This mixture was extracted several times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The residue was purified by silica gel flash chromatography (EtOAc / petroleum ether) to give 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (8.8 g, 70%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =200.15.

[0407] Step 5: Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid. [ka]

[0408] A solution of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (8.8 g, 44.1 mmol) in HOAc (80 mL) and HBr (80 mL) was stirred for 16 h at 60° C. The resulting mixture was concentrated under reduced pressure to give crude 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (8.16 g, quantitative).

[0409] Step 6: Preparation of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate. [ka]

[0410] To a solution of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (8.16 g, 44.0 mmol) in methanol (30 mL) was slowly added SOCl (14.2 mL, 197 mmol). The mixture was stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (MeOH / DCM) to give methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (7.79 g, 89%) as a clear oil. LCMS (ESI) m / z: [M+H] + =200.15.

[0411] Step 7: Preparation of methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate. [ka]

[0412] To a solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (7.79 g, 39.1 mmol) in DMF (90 mL) was added 2-bromo-1,1-diethoxyethane (8.77 mL, 58.6 mmol) and potassium carbonate (10.8 g, 78.2 mmol). The reaction was stirred at 70 °C overnight. The reaction mixture was cooled and then added to the mixture. The resulting mixture was extracted several times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel flash chromatography (EtOAc:heptane) to give methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate (7.8 g, 63%) as a colorless oil. LCMS (ESI) m / z: [M-CHO] + =270.30.

[0413] Step 8: Preparation of 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid. [ka]

[0414] To a solution of methyl 2-[3-(2,2-diethoxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate (7.8 g, 24.7 mmol) in methanol (50 mL) and water (25 mL) was added lithium hydroxide monohydrate (4.14 g, 98.8 mmol). The reaction was stirred at 40 °C for 2 h. The pH was adjusted to 4-5 with 1 N HCl. The mixture was extracted several times with ethyl acetate, and the combined organic layers were dried over MgSO. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (DCM:MeOH) to give 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid (6.1 g, 89%) as a colorless oil. LCMS (ESI) m / z: [MH] - =300.21.

[0415] Step 9: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylic acid. [ka]

[0416] To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0 °C, HATU (8.98 g, 23.5 mmol) was added, followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (MeOH:DCM) to give tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylic acid (8.33 g, 98%). LCMS (ESI) m / z: [M+H] + =432.38.

[0417] Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride. [ka]

[0418] To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.33 g, 19.3 mmol) at 0° C. was added HCl in 1,4-dioxane (4 N, 50 mL, 200 mmol) to give a viscous yellow gum. 15 mL of MeOH was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was washed with diethyl ether to give (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride, which was used in the next step without further purification.

[0419] Step 11: Preparation of (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1). [ka]

[0420] To a solution of 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoic acid (5.75 g, 19.0 mmol) in DMF (30 mL) was added HATU (8.6 g, 22.7 mmol). After stirring at 20 °C for 0.5 h, a solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine 2-carboxamide hydrochloride (6.97 g, 19.0 mmol) and triethylamine (7.92 mL, 56.9 mmol) in DMF (20 mL) was added to the mixture, and the resulting mixture was stirred at 20 °C. The reaction mixture was quenched by adding water and extracted several times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (DCM:MeOH) to give (2S,4R)-1-[2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (10 g, 16.2 mmol) as a white solid. The mixture of diastereomers was separated by chiral SFC chromatography to give (2S,4R)-1-((S)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide and (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. (2S,4R)-1-((S)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, Peak 1: (2.2 g, 19%). LCMS (ESI) m / z [M+H]+ =615.4. (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1), Peak 2: (2.5 g, 21%). LCMS (ESI) m / z [M+H] + =615.4.

[0421] Step 12: Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2). [ka]

[0422] To a stirred solution of H2SO4 (1N, 6.00 mL) and THF (6.00 mL), (2S,4R)-1-[(2R)-2-[3-(2-ethoxy-2-methoxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (I-1, 300 mg, 0.499 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 50 °C for 8 h. The resulting mixture was diluted with water and neutralized to approximately pH 7 with saturated aqueous NaHCO3. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed twice with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2, 256 mg, 97.3%) as a white solid. LCMS (ESI) m / z: [M+H] + =541.

[0423] (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-3) and Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4). [ka]

[0424] Step 1: Preparation of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate. [ka]

[0425] To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (100.00 mg, 0.502 mmol, 1.00 equiv) in MeCN (0.50 mL) was added perfluorobutanesulfonyl fluoride (303.29 mg, 1.004 mmol, 2.00 equiv) and K2CO3 (208.13 mg, 1.506 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 3 h and then carefully quenched with water at 0 °C. The resulting mixture was extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (50 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 / EA (2 / 1) to give methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate (217 mg) as a white solid. LCMS (ESI) m / z: [M+H] + =482.

[0426] Step 2: Preparation of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylic acid. [ka]

[0427] To a stirred solution of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate (217.00 mg, 0.451 mmol, 1.00 equiv) in DMF (3.00 mL) was added tert-butylpiperazine-1-carboxylic acid (83.98 mg, 0.451 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 130 °C for 1 h. The mixture was allowed to cool to room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, gradient 0 to 100% FA in 30 min. This gave tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate (54 mg, 32.59%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =368.

[0428] Step 3: Preparation of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid. [ka]

[0429] To a stirred solution of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate (54.00 mg, 0.147 mmol, 1.00 equiv) in MeOH (0.80 mL) was added THF (0.80 mL) and HO (0.80 mL) at room temperature, followed by LiOH .HO (18.50 mg, 0.441 mmol, 3.00 equiv) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 6 with HCl (1 M, aq) and then extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. This gave 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid (52 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =354.

[0430] Step 4: Preparation of tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylic acid. [ka]

[0431] To a stirred solution of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid (52.00 mg, 0.119 mmol, 1.00 equiv) in DMF (2.00 mL) was added HATU (135.56 mg, 0.357 mmol, 3.00 equiv) and DIEA (76.80 mg, 0.595 mmol, 5.00 equiv) at room temperature. To the above mixture was added (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (70.90 mg, 0.214 mmol, 1.80 equiv) at room temperature. The resulting mixture was stirred for 1 hour. The mixture was directly purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0-100% in 30 min. This afforded tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate (73 mg, 92.12%) as a white solid. LCMS (ESI) m / z: [M+H] + =667.

[0432] Step 5: Preparation of tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate. [ka]

[0433] tert-Butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylic acid (73 mg) was purified by SFC under the following conditions: column, CHIRAL ART Amylose-C NEO, 3 *A 25 cm, 5 mm mobile phase, MeOH, was prepared, which provided:

[0434] tert-Butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (37 mg, 2nd peak). LCMS (ESI) m / z: [M+H] + =667.

[0435] tert-Butyl 4-(5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (34 mg, first peak). LCMS (ESI) m / z: [M+H] + =667.

[0436] Step 6: Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-3) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4). [ka]

[0437] tert-Butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (37.00 mg, 0.055 mmol, 1.00 equiv) was dissolved in DCM (1.50 mL) and HCl in 1,4-dioxane (1.50 mL, 26.276 mmol, 473.57 equiv) was added at 0° C. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. This afforded I-3 (45 mg, crude) as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0438] I-4 was prepared according to the same protocol as I-3 and obtained as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0439] The following intermediates in Table 2 were prepared in a manner similar to that described in the preparation of intermediate I-3, starting with methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate and the appropriate amine.

[0440] [Table 3]

[0441] Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. [ka]

[0442] Step 1: (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine. [ka]

[0443] 2-Chloropyrimidine-5-carbaldehyde (5 g, 35.078 mmol, 1 equiv.) and NHOH in EtOH (250 mL) . To a stirred solution of HCl (4.93 g, 70.945 mmol, 2.02 equiv) was added NaOAc (14.48 g, 176.512 mmol, 5.03 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with brine (500 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine (4.6 g, crude) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H]+ =158.

[0444] Step 2: Preparation of (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride. [ka]

[0445] A solution of (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine (4.6 g, 29.195 mmol, 1 equiv.) and NCS (4.4 g, 32.951 mmol, 1.13 equiv.) in DMF (150 mL) was stirred for 2 h at room temperature. The mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with water (3 × 300 mL), brine (1 × 300 mL), and the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride (4.8 g, crude product) as a yellow solid. LCMS (ESI) m / z: [M+H] + =192.

[0446] Step 3: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate. [ka]

[0447] A solution of (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride (4.8 g, 25.00 mmol, 1 equiv) in EtOAc (80 mL) was treated with NaHCO (3 g, 35.712 mmol, 1.43 equiv) under a dry nitrogen atmosphere for 30 min at 0 °C, followed by the addition of methyl but-3-ynoate (2.02 g, 20.591 mmol, 0.82 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (1 × 400 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 PE / EA (3:1) to give methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (2.5 g, 38.64%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =254.

[0448] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid. [ka]

[0449] A solution of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (3 g, 11.828 mmol, 1 equiv.) and NaOMe (1.92 g, 35.484 mmol, 3.00 equiv.) in MeOH (50 mL) was stirred at room temperature under a dry nitrogen atmosphere for 1 h. The mixture was acidified to pH 6 with HCl (aq.). The residue was dissolved in EtOAc (300 mL). The resulting mixture was washed with water (2 × 300 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.5 g, crude product) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =236.

[0450] Step 5: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate. [ka]

[0451] A solution of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.4 g, 10.204 mmol, 1 equiv.) and (trimethylsilyl)diazomethane (2.33 g, 20.408 mmol, 2 equiv.) in DCM (20 mL) and MeOH (5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (1.2 g, 45.77%) as a white solid. LCMS (ESI) m / z: [M+H] + =250.

[0452] Step 6: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. [ka]

[0453] A solution of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (2.5 g, 10.031 mmol, 1 equiv) in THF (20 mL) was treated with t-BuOK (1.2 g, 10.694 mmol, 1.07 equiv) under a dry nitrogen atmosphere at 0 °C for 30 min, followed by the dropwise addition of 2-iodopropane (1.5 g, 8.824 mmol, 0.88 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The mixture was acidified to pH 6 with HCl (aq). The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 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 PE / EA (3:1) to give methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (310 mg, 10.08%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =292.

[0454] Step 7: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. [ka]

[0455] A solution of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (200 mg, 0.687 mmol, 1 equiv.) and POCl3 (1.9 mL, 20.61 mmol, 30 equiv.) in DMF (1.5 mL) was stirred at 60 °C under a dry nitrogen atmosphere for 3 h. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (160 mg, crude product) as a brown oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =296.

[0456] Preparation of 2-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(2-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)acetic acid (I-8). [ka]

[0457] To a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(2-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (30.00 mg, 0.055 mmol, 1.00 equiv) and 2-methyl-2-butene (0.78 mg, 0.011 mmol, 0.20 equiv) in tert-butanol (2 mL) was added dropwise a solution of NaClO (50.19 mg, 0.550 mmol, 10.00 equiv) and NaHPO (78.77 mg, 0.550 mmol, 10.00 equiv) in water (2.00 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then warmed to room temperature and stirred for 1.5 h. The reaction was quenched by adding a mixture of saturated NaSO solution and brine, and CHCl 3( The resulting mixture was extracted with 20 mL of HCl (3×20 mL). The combined organic extracts were dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (PE / EtOAc = 1:1 to 1:3). This afforded intermediate I-8 (15.80 mg, 49.93%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =557.

[0458] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]-5-methylthieno[2,3-c]pyridazin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 1). Preparation of 2-[6-(azetidin-3-yl)cinnolin-3-yl]phenol (intermediate I-9). [ka]

[0459] Step 1: Preparation of tert-butyl 3-[3-(2-methoxy-2-oxoethyl)-4-nitrophenyl]azetidine-1-carboxylate (Intermediate 3). [ka]

[0460] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (10.33 g, 36.488 mmol, 2.00 equiv) in DMF (10.00 mL) at 0 °C, I (2.32 g, 9.122 mmol, 0.50 equiv) and Zn (3.58 g, 54.732 mmol, 3.00 equiv) were added (= Solution A). The resulting mixture was stirred under a nitrogen atmosphere at 0 °C for 1 h. To a stirred solution of methyl 2-(5-bromo-2-nitrophenyl)acetate (5.00 g, 18.244 mmol, 1.00 equiv.) in DMF (10.00 mL), Pd(dba)-CHCl (1.89 g, 1.824 mmol, 0.10 equiv.), t-BuXPhos (0.77 g, 1.824 mmol, 0.10 equiv.), and CuI (0.35 g, 1.824 mmol, 0.10 equiv.) were added at room temperature (=solution B). Solution B was added to solution A at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and then 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 (2:1) to give Intermediate 3 (4.1 g, 64.14%) as a brown oil. LCMS (ESI) m / z: [M+H] + =351.

[0461] Step 2: Preparation of methyl 2-[5-(azetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 4). [ka]

[0462] To a stirred solution of Intermediate 3 (4.10 g, 11.416 mmol, 1.00 equiv) in DCM (32.00 mL) was added TFA (8.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This afforded Intermediate 4 (3.0 g, crude) as a brown oil. LCMS (ESI) m / z: [M+H] + =251.

[0463] Step 3: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 5). [ka]

[0464] To a stirred solution of intermediate 4 (3.00 g, 11.988 mmol, 1.00 equiv) in DCM (30.00 mL) was added AcO (3.67 g, 35.964 mmol, 3.00 equiv) and EtN (3.64 g, 35.964 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give intermediate 5 (4.5 g, >100%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =293.

[0465] Step 4: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-2-aminophenyl]acetate (Intermediate 6). [ka]

[0466] To a stirred solution of intermediate 5 (4.50 g, 15.396 mmol, 1.00 equiv) in MeOH (30.00 mL) was added NH4Cl (8.24 g, 153.960 mmol, 10.00 equiv) and Zn (10.07 g, 153.960 mmol, 10.00 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. To the residue was added water (100 mL), and the product was extracted with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 6 (2.1 g, 52.00%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =263.

[0467] Step 5: Preparation of 5-(1-acetylazetidin-3-yl)-1-amino-3H-indol-2-one (Intermediate 7). [ka]

[0468] To a stirred solution of intermediate 6 (2.10 g, 8.006 mmol, 1.00 equiv) in DCM (34.00 mL) was added NOBF (1.87 g, 16.012 mmol, 2.00 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. To the above mixture was added SnCl 2H O (18.23 g, 80.060 mmol, 10.00 equiv) and concentrated HCl. HCl (68.00 mL) was added at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 / 220 nm. This gave intermediate 7 (1.6 g, 81.48%) as a brown oil. LCMS(ESI)m / z:[M+H] + =246.

[0469] Step 6: Preparation of 1-[3-(3-hydroxycinnolin-6-yl)azetidin-1-yl]ethanone (Intermediate 8). [ka]

[0470] To a stirred solution of intermediate 7 (1.60 g, 5.708 mmol, 1.00 equiv) in DCM (10.00 mL) at 0 °C was added Pb(OAc) (3.80 g, 8.562 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with MeOH at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water, gradient 0% to 100% in 30 min, detector, UV 254 / 220 nm. This afforded intermediate 8 (880 mg, 63.38%) as a green oil. LCMS (ESI) m / z: [M+H] + =244.

[0471] Step 7: Preparation of 6-(1-acetylazetidin-3-yl)cinnolin-3-yl trifluoromethanesulfonate (Intermediate 9). [ka]

[0472] To a stirred solution of intermediate 8 (880.00 mg, 3.617 mmol, 1.00 equiv) in DCM (20.00 mL) was added TfO (10.21 g, 36.170 mmol, 10.00 equiv) and pyridine (2.86 g, 36.170 mmol, 10.00 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified directly by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% in 30 min, detector, UV 254 / 220 nm. This afforded intermediate 9 (415 mg, 30.57%) as a brown oil. LCMS (ESI) m / z: [M+H] + =376.

[0473] Step 8: Preparation of 1-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (Intermediate 11). [ka]

[0474] To a stirred solution of Intermediate 9 (415.00 mg, 1.106 mmol, 1.00 equiv) and 2-hydroxyphenylboronic acid (458.16 mg, 3.320 mmol, 3.00 equiv) in 1,4-dioxane (8.00 mL) and HO (2.00 mL) was added XPhos Pd G (187.13 mg, 0.221 mmol, 0.20 equiv) and CsCO (1.082 g, 3.320 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water; gradient: 0% to 100% in 30 min; detector: UV 254 / 220 nm. This afforded Intermediate 11 (254 mg, 71.95%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =320.

[0475] Step 9: Preparation of 2-[6-(azetidin-3-yl)cinnolin-3-yl]phenol (I-9). [ka]

[0476] To a stirred solution of intermediate 11 (254.00 mg, 0.794 mmol, 1.00 equiv) in MeOH (5.00 mL) and HO (5.00 mL) was added KOH (133.39 mg, 2.382 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 70 °C for 1 h. After the mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm. This afforded I-9 (134 mg, 60.91%) as a white solid. LCMS (ESI) m / z: [M+H] + =278.

[0477] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 1). [ka]

[0478] To a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (29.24 mg, 0.054 mmol, 1.00 equiv.) in DMSO (1.00 mL) was added IO-9 (15.00 mg, 0.054 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. To the above mixture, NaBH(OAc)3 (34.39 mg, 0.162 mmol, 3.00 equiv.) and AcOH (catalytic) were added at room temperature. The resulting mixture was stirred at 60°C for 1 hour. The mixture was allowed to cool to room temperature. The reaction was quenched with water at 0° C. and then purified by Chiral-Prep-HPLC using the following conditions: column, Xselect CSH F-phenyl OBD column, 19 * 250 mm, 5 μm, mobile phase: water (0.05% FA) and MeOH (43% MeOH, max. 67% in 7 min), detector: UV 254 / 220 nm. This gave compound 1 (6.8 mg, 15.50%) as a white solid. 1H NMR (400 MHz, DMSO-d) δ 12.16-11.87(m, 1H), 8.98(d, J=2.1Hz, 1H), 8.87(d, J=8.2Hz, 1H), 8.4 7-8.39(m, 2H), 8.30-8.15(m, 1H, FA), 8.14-8.06(m, 1H), 8.04-7.94(m, 2H), 7.47-7.41(m, 2H), 7.41-7.31(m, 3H), 7.09-7.00(m, 2H), 6.10(s, 1 H), 5.25-4.97(m, 1H), 4.97-4.85(m, 1H), 4.37(t, J=7.9Hz, 1H), 4.31-4 .23(m, 1H), 4.18(t, J=5.4Hz, 2H), 3.97-3.86(m, 1H), 3.79(t, J=7.3Hz , 2H), 3.73-3.62(m, 2H), 3.59-3.42(m, 3H), 2.86(t, J=5.4Hz, 2H), 2.45 (d, J=6.6Hz, 3H), 2.30-2.13(m, 1H), 2.08-1.98(m, 1H), 1.82-1.72(m, 1H), 1.37(d, J=7.0Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.81(d, J=6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + =802.40.

[0479] The compounds in Table 3 were prepared using procedures similar to those used above for the preparation of Compound 1, using the appropriate amine and aldehyde (or ketone).

[0480] [Table 4]

[0481] (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 4) and (2 Preparation of (S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6]-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1),3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 5). [ka]

[0482] Step 1: Preparation of methyl 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 3). [ka]

[0483] To a stirred solution of I- (50.00 mg, 0.180 mmol, 1.00 equiv) in DMSO (2.00 mL) at room temperature, methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (53.32 mg, 0.180 mmol, 1.00 equiv) and DIEA (69.91 mg, 0.540 mmol, 3.00 equiv) were added. The resulting mixture was stirred at 100 °C for 6 h. The mixture was cooled to room temperature and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% in 30 min, detector, UV 254 / 220 nm. This afforded intermediate 3 (20 mg, 20.67%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =537.

[0484] Step 2: Preparation of 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 4). [ka]

[0485] To a stirred solution of intermediate 3 (20.00 mg, 0.037 mmol, 1.00 equiv) in MeOH (1.00 mL) and HO (1.00 mL) was added LiOH·HO (4.69 mg, 0.111 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 6 h. The mixture was acidified to pH 3 with aqueous HCl (1 M). The resulting mixture was concentrated under reduced pressure. This afforded intermediate 4 (20 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =523.

[0486] Step 3: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 6). [ka]

[0487] To a stirred solution of Intermediate 4 (20.00 mg, 0.038 mmol, 1.00 equiv.) in DMF (1.00 mL), PyBOP (59.28 mg, 0.114 mmol, 3 equiv.) and DIEA (24.51 mg, 0.190 mmol, 5 equiv.) were added at room temperature. To the above mixture, (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (12.62 mg, 0.038 mmol, 1 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in H2O, gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm. This gave intermediate 6 (5 mg, 15.62%) as an off-white oil. LCMS (ESI) m / z: [M+H] + =836.

[0488] Step 4: (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 4) and Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6]-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1),3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 5). [ka]

[0489] Intermediate 6 (5.00 mg) was purified by Chiral-Prep-HPLC under the following conditions: column, CHIRALPAK ID, 2 * 25 cm, 5 mm, mobile phase: MtBE (10 mM NH3-MeOH) and MeOH (hold 50% MeOH for 29 min), detector: UV 254 / 220 nm. This gave the following results:

[0490] Compound 4 (1.0 mg, 20.00%) as a white solid. 1H NMR(400MHz, メタノール-d4)δ 8.89-8.77(m, 4H), 8.48(d, J=8.9Hz, 1H), 8.12-8.02(m, 3H), 7.48-7.34(m, 5H), 7.07-7.0 1(m, 2H), 6.80(s, 1H), 5.08-5.00(m, 1H), 4.74(d, J=8.6Hz, 2H), 4.63-4.49(m, 1H), 4.49- 4.26 (m, 3H), 3.92-3.85 (m, 1H), 3.71-3.59 (m, 3H), 2.47 (d, J=7.8Hz, 3H), 2.23-2.14 (m, 1 H), 2.09-1.87 (m, 2H), 1.53 (d, J=7.0Hz, 3H), 1.10 (d, J=6.6Hz, 3H), 0.93 (d, J=6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + =836.40.

[0491] White solid としてのCompound 5 (0.6 mg, 12.00%). 1 H NMR(400MHz, メタノール-d4)δ 8.89-8.82(m, 2H), 8.82-8.75(m, 2H), 8.48(d, J=8.9Hz, 1H), 8.13-8.02(m, 3H), 7.41-7.32(m, 5 H), 7.07-7.00(m, 2H), 6.78(s, 1H), 5.04-4.96(m, 1H), 4.78-4.70(m, 2H), 4.59(d, J=8.0Hz, 1H) ,4.47-4.28(m,3H),4.00-3.86(m,1H),3.79-3.68(m,1H),3.63(s,2H),2.44(s,3H),2.29-2.11 (m, 1H), 2.06-1.86 (m, 2H), 1.49 (d, J=7.0Hz, 3H), 1.10 (d, J=6.7Hz, 3H), 0.95 (d, J=6.7Hz, 3H). LCMS(ESI)m / z:[M+H] + =836.50.

[0492] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}-2-oxoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 6).

change

[0493] ({5-[(2R)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazol-3-yl}oxy)acetic acid (30.11 mg, 0.054 mmol, 1.00 equiv.) was dissolved in DMF (1.00 mL) with stirring, and PyBOP (84.44 mg, 0.162 mmol, 3.00 equiv.) and DIEA (34.95 mg, 0.270 mmol, 5.00 equiv.) were added at room temperature. To the above mixture, I-9 (15.00 mg, 0.054 mmol, 1.00 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 * Chiral Prep-HPLC with 150 mm, 5 μm, mobile phase: water (10 mmol / L NH4HCO3) and CH3CN (from 42% CH3CN up to 55% in 7 min), detector: UV 254 / 220 nm, which gave compound 6 (15.5 mg, 33.86%) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 11.93-11.69(m, 1H), 8.98(s, 1H), 8.88(s, 1H), 8.50(d, J=8.8Hz, 1H), 8.43(d, J=7.7Hz, 1H), 8.15-8.07(m, 2H), 8.02-7.97(m, 1H), 7.47-7.41(m, 2H), 7.41-7.33(m, 3H), 7.10-7.01(m, 2H), 6.19(d, J=1.6Hz, 1H), 5.11(d, J=3.7Hz, 1H), 4.97-4.86(m, 1H), 4.80(s, 2) H), 4.77-4.65(m, 1H), 4.48-4.34(m, 3H), 4.32-4.18(m, 2H), 4.15-4.05(m, 1H), 3.74-3.65(m, 2H), 3.51-3.42(m, 1H), 2.47-2.43(m , 3H), 2.31-2.15(m, 1H), 2.07-1.96(m, 1H), 1.83-1.69(m, 1H), 1.37(d, J=6.9Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.80(d, J=6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + =816.70.

[0494] The compounds in Table 4 were prepared using procedures similar to those used above for the preparation of compound 6, using the appropriate amine and carboxylic acid.

[0495] [Table 5]

[0496] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 8). Preparation of 2-[7-(azetidin-3-yl)cinnolin-3-yl]phenol (I-10). [ka]

[0497] Step 1: Preparation of tert-butyl 3-[4-(2-methoxy-2-oxoethyl)-3-nitrophenyl]azetidine-1-carboxylate (Intermediate 2). [ka]

[0498] A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (12.40 g, 43.784 mmol, 1.2 equiv.) and I2 (4.63 g, 18.244 mmol, 0.5 equiv.) in DMF (100 mL) was cooled to 0 °C. Zn (7.16 g, 109.461 mmol, 3 equiv.) was added portionwise at this temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. Next, CuI (1.39 g, 7.297 mmol, 0.2 equiv.), Pd(dba) (4.20 g, 7.297 mmol, 0.2 equiv.), XPhos (3.478 g, 7.297 mmol, 0.2 equiv.), and methyl 2-(4-bromo-2-nitrophenyl)acetate (10 g, 36.487 mmol, 1 equiv.) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc (3 × 200 mL). The filtrate was washed with water (3 × 300 mL). The organic layer was 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 / EA (3:1) to give Intermediate 2 (5 g, 35.20%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =351.

[0499] Step 2: Preparation of methyl 2-[4-(azetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 3). [ka]

[0500] To a stirred mixture of intermediate 2 (5 g, 14.271 mmol, 1 equiv.) in DCM (15 mL) was added TFA (5 mL) dropwise. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This gave intermediate 3 (5.5 g, 95.22%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =251.

[0501] Step 3: Preparation of methyl 2-[4-(1-acetylazetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 4). [ka]

[0502] To a stirred mixture of intermediate 3 (5 g, 13.726 mmol, 1.00 equiv.) and EtN (6.94 g, 68.630 mmol, 5 equiv.) in DCM (20 mL) was added AcO (2.10 g, 20.589 mmol, 1.5 equiv.) dropwise. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (14:1) to give intermediate 4 (3.5 g, 78.52%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =293.

[0503] Step 4: Preparation of methyl 2-[4-(1-acetylazetidin-3-yl)-2-aminophenyl]acetate (Intermediate 5). [ka]

[0504] A mixture of intermediate 4 (3.5 g, 11.974 mmol, 1 equiv) and NH4Cl (12.81 g, 239.480 mmol, 20 equiv) in MeOH (50 mL) was cooled to 0 °C, followed by the portionwise addition of Zn (7.83 g, 119.740 mmol, 10 equiv). The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 5 (2 g, 57.31%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =263.

[0505] Step 5: Preparation of 6-(1-acetylazetidin-3-yl)-1-amino-3H-indol-2-one (Intermediate 6). [ka]

[0506] A mixture of intermediate 5 (2 g, 7.625 mmol, 1 equiv.) in DCM (40 mL) was cooled to 0 °C. Then, NOBF (1.34 g, 11.438 mmol, 1.5 equiv.) was added in one portion. The resulting mixture was stirred at 0 °C for 1 h. To the above mixture, SnCl (11.69 g, 61.000 mmol, 8 equiv.) in HCl (60 mL) was added dropwise at 0 °C. The resulting mixture was then stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This afforded intermediate 6 (600 mg, 28.87%) as a green solid. LCMS (ESI) m / z: [M+H] + =246.

[0507] Step 6: Preparation of 1-[3-(3-hydroxycinnolin-7-yl)azetidin-1-yl]ethanone (Intermediate 7). [ka]

[0508] A mixture of intermediate 6 (600 mg, 2.446 mmol, 1 equiv.) in DCM (10 mL) was cooled to 0 °C. Pb(OAc) (1301.55 mg, 2.935 mmol, 1.2 equiv.) was then added portionwise. The resulting mixture was stirred at 0 °C for 1 h and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water, gradient 0% to 100% in 30 min, detector, UV 254 nm. This gave intermediate 7 (400 mg, 60.50%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =244.

[0509] Step 7: Preparation of 7-(1-acetylazetidin-3-yl)cinnolin-3-yl trifluoromethanesulfonate (Intermediate 8). [ka]

[0510] To a stirred mixture of intermediate 7 (400 mg, 1.644 mmol, 1 equiv) and DMAP (40.18 mg, 0.329 mmol, 0.2 equiv) in DCM (10 mL) was added TEA (499.17 mg, 4.932 mmol, 3 equiv). The mixture was cooled to 0 °C. To the above mixture, TfO (695.86 mg, 2.466 mmol, 1.5 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The resulting mixture was diluted with water (50 mL) and extracted with CHCl (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This afforded intermediate 8 (400 mg, 58.33%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =376.

[0511] Step 8: Preparation of 1-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}ethanone (Intermediate 9). [ka]

[0512] To a solution of intermediate 3 (310 mg, 0.826 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (341.77 mg, 2.478 mmol, 3 equiv.) in dioxane (5 mL) and HO (1 mL) was added CsCO (807.34 mg, 2.478 mmol, 3 equiv.) and XPhos Pd G (139.83 mg, 0.165 mmol, 0.2 equiv.). After stirring at 80 °C under a nitrogen atmosphere for 1 h, the resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This gave intermediate 9 (100 mg, 34.12%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =320.

[0513] Step 9: Preparation of 2-[7-(azetidin-3-yl)cinnolin-3-yl]phenol (I-10). [ka]

[0514] To a stirred mixture of intermediate 9 (100 mg, 0.313 mmol, 1 equiv.) in MeOH (3 mL) and HO (3 mL), KOH (175.68 mg, 3.130 mmol, 10 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 70 °C for 2 h and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% in 30 min, detector, UV 254 nm. This afforded I-10 (92 mg, 95.35%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =278.

[0515] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 8). [ka]

[0516] I-10 (16 mg, 0.058 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (31.19 mg, 0.058 mmol, 1 equiv.) were dissolved in DCM (1 mL) and MeOH (1 mL), and AcOH (3.46 mg, 0.058 mmol, 1 equiv.) and NaBHCN (10.88 mg, 0.174 mmol, 3 equiv.) were added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions: Kinetex EVO C18 Column, 21.2 *150 mm, 5 mm, Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: CH3CN, Flow rate: 25 mL / min, Gradient: 35% B to 62% B in 7 min, then 62% B, Detector: UV 254 / 220 nm. This gave compound 8 (18.1 mg, 38.77%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6)δ 12.03(d, J=6.3Hz, 1H), 8.96(d, J=22.1Hz, 2H), 8.48-8.32(m, 2H), 8.13(d, J=8.5Hz, 2H), 7.99(d, J=8.7Hz, 1H), 7.50-7.30(m, 5H), 7 .13-6.99(m, 2H), 6.03(d, J=50.8Hz, 1H), 5.11(d, J=3.7Hz, 1H), 4.92(t, J=7.1Hz, 1H), 4.38(t, J=7.8Hz, 1H), 4.29(s, 1H), 4.19(t, J =5.4Hz, 2H), 3.98(t, J=7.1Hz, 1H), 3.83(d, J=7.2Hz, 2H), 3.75-3.62(m, 2H), 3.46(d, J=11.2Hz, 3H), 2.89(s, 2H), 2.46(d, J=2.7Hz, 3H), 2.24(s, 1H), 2.04(t, J=10.3Hz, 1H), 1.86-1.69(m, 1H), 1.42(dd, J=22.1, 7.0Hz, 3H), 0.96(d, J=6.5Hz, 3H), 0.89-0.73(m, 3H). LCMS(ESI)m / z:[M+H] + =802.30.

[0517] The compounds in Table 5 were prepared using procedures similar to those used above for the preparation of compound 8, using the appropriate amine and aldehyde (or ketone).

[0518] [Table 6]

[0519] (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 11) and (2 Preparation of (S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7]-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1),3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 12). [ka]

[0520] Step 1: Preparation of methyl 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 2). [ka]

[0521] To a stirred solution of I-10 (80 mg, 0.288 mmol, 1 equiv.) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (106.63 mg, 0.288 mmol, 1 equiv.) in DMSO (3.00 mL) was added DIEA (111.85 mg, 0.864 mmol, 3 equiv.). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature and then purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase A: water (0.1% FA), mobile phase B: CH3CN, flow rate: 35 mL / min, gradient: 0% B to 100% B in 40 min, detector, UV 254 / 220 nm. This gave Intermediate 2 (110 mg, 67.51%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =537.

[0522] Step 2: Preparation of 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 3). [ka]

[0523] A solution of LiOH (49.10 mg, 2.050 mmol, 10 equiv.) in THF (3.00 mL) and HO (0.60 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere. To the above mixture was added Intermediate 2 (110 mg, 0.205 mmol, 1 equiv.). The resulting mixture was then stirred overnight at room temperature and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase A: water (0.1% FA), mobile phase B: CH3CN, flow rate: 35 mL / min, gradient: 0% B to 100% B in 40 min, UV 254 / 220 nm. This afforded Intermediate 3 (98 mg, 86.91%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =523.

[0524] Step 3: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4). [ka]

[0525] Intermediate 3 (98 mg, 0.188 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (62.16 mg, 0.188 mmol, 1 equiv.) were dissolved in DMF (3.00 mL), and PyBOP (195.19 mg, 0.376 mmol, 2 equiv.) and DIEA (72.72 mg, 0.564 mmol, 3 equiv.) were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase A: water (0.1% FA), mobile phase B: CH3CN, flow rate: 35 mL / min, gradient: 0% B to 100% B in 40 min, detector, UV 254 / 220 nm. This gave intermediate 4 (90 mg, 54.54%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =836.

[0526] Step 4: (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 11) and Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7]-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1),3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 12). [ka]

[0527] Intermediate 4 (90 mg) was purified by Chiral-Prep-HPLC with the following conditions: column, CHIRALPAK ID, 2 * 25 cm, 5 μm, Mobile phase A: MtBE (10 mM NH3-MeOH), Mobile phase B: MeOH, Flow rate: 20 mL / min, Gradient: 10% B to 50% B in 65 min, Detector: UV 254 / 220 nm. The following results were obtained:

[0528] Compound 11 (30.1 mg, 34.64%) was obtained as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6)δ 11.96(s, 1H), 8.97(d, J=16.6Hz, 2H), 8.87(d, J=2.0Hz, 2H), 8.45(d, J=11.1Hz, 2H), 8.21-8.11(m, 2H), 8.05(dd, J=8.6, 1.7Hz, 1H), 7.45(d, J=8.2Hz, 2H), 7.41-7.33(m, 3H), 7.11-7.01(m, 2H), 6.90(d, J=33.8Hz, 1H), 5.12(d, J=3.6Hz, 1H), 4.94(t, J=7.3Hz, 1H), 4. 76-4.63(m, 2H), 4.46-4.21(m, 5H), 3.87(d, J=9.7Hz, 1H), 3.82-3.70(m, 1H), 3.51(t, J=5.3Hz, 1H), 2.46(d, J=4.2Hz, 3H), 2.34(d, J =10.2Hz, 1H), 2.05(t, J=10.5Hz, 1H), 1.87-1.69(m, 1H), 1.45(dd, J=31.1, 7.0Hz, 3H), 1.02(d, J=6.4Hz, 3H), 0.86(t, J=6.2Hz, 3H). LCMS(ESI)m / z:[M+H] + =836.35.

[0529] Compound 12 (21.0 mg, 24.32%) was obtained as a pale yellow solid. 1H NMR (300MHz, DMSO-d6)δ 11.97(s, 1H), 9.04-8.91(m, 2H), 8.85(d, J=14.4Hz, 2H), 8.48(s, 1H), 8.28(d, J=7.9Hz, 1H), 8.19(d, J=8.6Hz, 1H), 8.14( d, J=7.7Hz, 1H), 8.07(d, J=6.9Hz, 1H), 7.48(d, J=7.2Hz, 1H), 7.42-7.22(m, 4H), 7.11-7.01(m, 2H), 6.96(s, 1H), 5.15(d, J =3.6Hz, 1H), 4.93-4.84(m, 1H), 4.68(t, J=8.3Hz, 2H), 4.49-4.25(m, 5H), 3.96(d, J=8.9Hz, 1H), 3.63(s, 1H), 3.51(s, 1H), 2.41(s, 3H), 2.27(s, 1H), 2.08(s, 1H), 1.49(d, J=7.0Hz, 1H), 1.38-1.20(m, 3H), 1.02(d, J=6.5Hz, 3H), 0.91-0.81(m, 3H). LCMS(ESI)m / z:[M+H] + =836.30.

[0530] The compounds in Table 6 were prepared using procedures similar to those used above to prepare compound 11, using the appropriate amine and heteroaryl halide.

[0531] [Table 7-1]

[0532] [Table 7-2]

[0533] [Table 7-3]

[0534] [Table 7-4]

[0535] [Table 7-5]

[0536] [Table 7-6]

[0537] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 13) and ( Preparation of 2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 14). [ka]

[0538] Step 1: Preparation of methyl 2-(2-amino-5-bromophenyl)acetate (Intermediate 2) [ka]

[0539] To a mixture of methyl 2-(5-bromo-2-nitrophenyl)acetate (10.00 g, 36.663 mmol, 1.00 equiv.) and NH4Cl (38.80 g, 733.26 mmol, 20.00 equiv.) in MeOH (150 mL) was added Zn (47.60 g, 733.26 mmol, 20.00 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This gave Intermediate 2 (8.00 g, 89.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =244.

[0540] Step 2: Preparation of 1-amino-5-bromoindolin-2-one (Intermediate 3). [ka]

[0541] To a mixture of intermediate 2 (8.00 g, 32.921 mmol, 1.00 equiv) in DCM (80 mL) was added NOBF (5.72 g, 49.381 mmol, 1.50 equiv) at 0 °C. The mixture was stirred for 1 h, and then a solution of SnCl·2H O (44.4 g, 197.526 mmol, 6.00 equiv) in HCl (50 mL) was added at 0 °C. The resulting mixture was then stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, ACN in water, gradient 0% to 30% in 10 min, detector, UV 254 nm. This gave intermediate 3 (3.71 g, 50.0%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =227.

[0542] Step 3: Preparation of 6-bromosinnoline-3-ol (Intermediate 4). [ka]

[0543] To a mixture of intermediate 3 (2.00 g, 8.849 mmol, 1.00 equiv.) in DCM (30 mL) at 0 °C was added Pb(OAc) (5.88 g, 13.273 mmol, 1.50 equiv.). The mixture was stirred for 20 min and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, ACN in water, gradient 0% to 30% in 10 min, detector, UV 254 nm. This gave intermediate 4 (1.50 g, 75.7%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =225.

[0544] Step 4: Preparation of tert-butyl 4-(3-hydroxycinnolin-6-yl)piperazine-1-carboxylate (Intermediate 5). [ka]

[0545] To a mixture of intermediate 4 (800.0 mg, 3.571 mmol, 1.00 equiv.), tert-butylpiperazine-1-carboxylic acid (2.65 g, 14.284 mmol, 4.00 equiv.), Xantphos (412.6 mg, 0.714 mmol, 0.20 equiv.), and t-BuONa (1.028 g, 10.713 mmol, 3.00 equiv.) in dioxane (20 mL), Pd(dba) (654 mg, 0.714 mmol, 0.20 equiv.) was added under a nitrogen atmosphere. The mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, ACN in water, gradient 10% to 50% in 10 min, detector, UV 254 nm. This gave Intermediate 5 (205.0 mg, 17.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =331.

[0546] Step 5: Preparation of tert-butyl 4-(3-(((trifluoromethyl)sulfonyl)oxy)cinnolin-6-yl)piperazine-1-carboxylate (Intermediate 6). [ka]

[0547] To a mixture of intermediate 5 (205.0 mg, 0.621 mmol, 1.00 equiv) and pyridine (496.8 mg, 6.210 mmol, 10.00 equiv) in DCM (5 mL) at 0 °C was added TfO (350.2 mg, 1.242 mmol, 2.00 equiv). The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 6 (210.0 mg, crude). LCMS (ESI) m / z: [M+H] + =463.

[0548] Step 6: Preparation of tert-butyl 4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazine-1-carboxylate (Intermediate 7) [ka]

[0549] To a mixture of intermediate 6 (210.0 mg, 0.453 mmol, 1.00 equiv.), (2-hydroxyphenyl)boronic acid (125.0 mg, 0.906 mmol, 2.00 equiv.), and Cs2Co3 (441.6 mg, 1.359 mmol, 3.00 equiv.) in dioxane (5 mL) and water (1 mL) was added XPhos Pd G3 (76.6 mg, 0.090 mmol, 0.20 equiv.). The mixture was stirred at 80 °C for 1 h and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, ACN in water, 10% to 50% gradient in 10 min, detector, UV 254 nm. This afforded intermediate 7 (110.0 mg, 59.7%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =407.

[0550] Step 7: Preparation of 2-(6-(piperazin-1-yl)cinnolin-3-yl)phenol (I-11) [ka]

[0551] To a mixture of Intermediate 7 (110.0 mg, 0.270 mmol, 1.00 equiv) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give Intermediate 8 (160.0 mg, crude). LCMS (ESI) m / z: [M+H] + =307.

[0552] Step 8: Preparation of methyl 2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 9). [ka]

[0553] To a stirred mixture of I-11 (160.0 mg, 0.521 mmol, 1.00 equiv.) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (153.6 mg, 0.521 mmol, 1 equiv.) in DMSO (3 mL), DIEA (336.0 mg, 2.605 mmol, 5.00 equiv.) was added dropwise. The resulting mixture was stirred at 100° C. for 1 h. The mixture was cooled to room temperature, and the product was precipitated by the addition of water. The precipitated solid was collected by filtration and washed with water (3×10 mL). This afforded intermediate 9 (130.0 mg, 44.1%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =566.

[0554] Step 9: Preparation of 2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 10). [ka]

[0555] To a stirred mixture of intermediate 9 (130.0 mg, 0.229 mmol, 1.00 equiv) in MeOH (2 mL) and HO (1 mL) was added LiOH.HO (93.8 mg, 2.290 mmol, 10 equiv). After stirring at 60 °C for 2 h, the mixture was cooled to room temperature. The mixture was acidified to pH 6 with 4 M HCl (aq). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). This gave intermediate 10 (150.0 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =552.

[0556] Step 10: Preparation of (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 11). [ka]

[0557] Intermediate 10 (150 mg, 0.264 mmol, 1.00 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (87.58 mg, 0.264 mmol, 1 equiv.) were dissolved in DMF (4 mL), and DIEA (102.4 mg, 0.792 mmol, 3.00 equiv.) and PyBOP (274.5 mg, 0.528 mmol, 2.00 equiv.) were added. The resulting mixture was stirred at room temperature for 2 h. The mixture was then directly purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L FA), gradient from 0% to 100% FA in 30 min; detector, UV 254 nm. This gave Intermediate 11 (130.0 mg, 57.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =865.

[0558] Step 11: (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 13) and preparation of (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 14). [ka]

[0559] Intermediate 11 (130 mg) was separated by chiral HPLC using the following conditions: Column: CHIRALPAK IA, 2 * 25 cm, 20 μm, Mobile phase A: MtBE (10 mM NH3-MeOH), Mobile phase B: MeOH, Flow rate: 20 mL / min, Gradient: 10% B to 50% B in 30 min, Detector: UV 254 / 220 nm. The following results were obtained.

[0560] Compound 13 (53.6 mg, 40.82%) was obtained as a yellow solid. 1H NMR(400MHz, DMSO-d6)δ 13.05(s, 1H), 9.00-8.96(m, 1H), 8.91-8.86(m, 2H), 8.61(s, 1H), 8.41(d, J=7.6Hz, 1H), 8.26(d, J=9.6Hz, 1H), 8.05(dd, J=8.3, 1.7Hz, 1H), 7.90(dd , J=9.7, 2.5Hz, 1H), 7.48-7.41(m, 2H), 7.41-7.31(m, 3H), 7.16(d, J=2.6H z, 1H), 7.05-6.97(m, 2H), 6.95(s, 1H), 5.10(d, J=3.7Hz, 1H), 4.97-4.89(m , 1H), 4.39 (t, J=7.9Hz, 1H), 4.31 (s, 1H), 4.05 (t, J=5.4Hz, 4H), 3.86 (d, J =9.7Hz, 1H), 3.76 (dd, J=10.8, 4.3Hz, 1H), 3.68 (t, J=5.4Hz, 4H), 3.51 (d, J=10.6Hz, 1H), 2.47-2.43(m, 3H), 2.38-2.28(m, 1H), 2.08-1.99(m, 1H), 1 .84-1.76 (m, 1H), 1.52-1.36 (m, 3H), 1.05-0.99 (m, 3H), 0.89-0.81 (m, 3H). LCMS(ESI)m / z:[M+H] + =865.30.

[0561] Compound 14 (28.4 mg, 21.8%) was obtained as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.00 - 8.96 (m, 1H), 8.91 - 8.86 (m, 2H), 8.61 (s, 1H), 8.29 - 8.21 (m, 2H), 8.05 (dd, J = 8.3, 1.7 Hz, 1H), 7.90 (dd, J = 9.7, 2.5 Hz, 1H), 7.52 - 7.41 (m, 1H), 7.39 - 7.26 (m, 4H), 7.16 (d, J = 2.6 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.95 (s, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.97 - 4.89 (m, 1H), 4.39 (t, J = 7.9 Hz, 1H), 4.33 - 4.24 (m, 1H), 4.05 (t, J = 5.4 Hz, 4H), 3.86 (d, J = 9.7 Hz, 1H), 3.68 (t, J = 5.4 Hz, 4H), 3.64 - 3.60 (m, 1H), 3.29 - 3.27 (m, 1H), 2.47 - 2.43 (m, 3H), 2.38 - 2.28 (m, 1H), 2.08 - 1.99 (m, 1H), 1.84 - 1.76 (m, 1H), 1.52 - 1.36 (m, 3H), 1.05 - 0.99 (m, 3H), 0.89 - 0.81 (m, 3H). LCMS (ESI) m / z: [M+H] + = 865.30。

[0562] Preparation of 7-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-12).

Chem.

[0563] Step 1: Preparation of dimethyl 2-(4-chloro-2-nitrophenyl)malonate intermediate 2.

Chem.

[0564] 4-Chloro-1-fluoro-2-nitrobenzene (11 g, 63 mmol), dimethyl malonate (12.5 g, 95 mmol), CsCO (41.1 g, 126 mmol), and DMF (63 mL) were stirred at room temperature for 6 hours. The reaction mixture was partitioned between 1 M aqueous HCl and EtOAc. The organic layer was washed with brine, dried over NaSO, and concentrated to give Intermediate 2 (18 g, 99%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0565] Step 2: Preparation of 2-(4-chloro-2-nitrophenyl)acetic acid (Intermediate 3). [ka]

[0566] Intermediate 2 was combined with AcOH (30 mL) and concentrated. The reaction mixture was quenched with saturated HCl (30 mL) and heated at 95° C. for 16 hours. The mixture was diluted with HO, causing a precipitate to form. The solid was collected by vacuum filtration, washed with HO, hexane / ether (1:1), and dried to give Intermediate 3 as a white solid (11.2 g, 83%).

[0567] Step 3: Preparation of methyl 2-(4-chloro-2-nitrophenyl)acetate (Intermediate 4). [ka]

[0568] Intermediate 3 (11.2 g, 52 mmol) was suspended in CHCl (250 mL). Oxalyl chloride (7 mL, 79 mmol) was added to the mixture, followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room temperature for 1 hour and then added dropwise to MeOH at 0° C. The solvent was removed in vacuo to give Intermediate 4 (12 g, 98%) as a white solid. The crude product was used directly in the next step without further purification.

[0569] Step 4: Preparation of methyl 2-(2-amino-4-chlorophenyl)acetate (Intermediate 5). [ka]

[0570] Intermediate 4 (12 g, 51 mmol) was suspended in a mixture of MeOH (200 mL) and NH4Cl (55 g, 1.03 mol) at 0 °C. Zinc powder (16.8 g, 257 mmol) was added in one portion. The mixture was stirred at room temperature for 2 h and then filtered through Celite. The filtrate was concentrated and then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give Intermediate 5 (9.5 g, 94%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =200.

[0571] Step 5: Preparation of 1-amino-6-chloroindolin-2-one (Intermediate 6). [ka]

[0572] Intermediate 5 (9.5 g, 48 mmol) was dissolved in 0 o The mixture was suspended in CH2Cl2 (150 mL) at 0 °C. Nitrosonium tetrafluoroborate (8.4 g, 72 mmol) was added to the mixture in one portion. The mixture was stirred at 0 °C for 1 hour. o The mixture was stirred at 0° C. for 1 hour. The mixture was added directly to a vigorously stirred mixture of concentrated SnCl dihydrate (43.8 g, 194 mmol). HCl (200 mL) was added at 0° C. The mixture was allowed to warm slowly to room temperature while stirring. After 24 hours, the mixture was filtered. The solid was washed with H2O and ether and then dried to give Intermediate 6 as a yellow solid (6.6 g, 76%). LCMS (ESI) m / z: [M+H] + =183.

[0573] Step 6: Preparation of 7-chlorocinnolin-3-ol (Intermediate 7). [ka]

[0574] Intermediate 6 (6.6 g, 37 mmol) was suspended in toluene (500 mL) at 0° C. tert-Butyl hypochlorite (4 g, 37 mmol) was added to the mixture in one portion. The mixture was stirred at 0° C. for 20 minutes. The solid was collected by vacuum filtration, washed with HO, hexane / ether (1:1), and dried to give Intermediate 7 (3 g, 45%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =181.

[0575] Step 7: Preparation of 7-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 8). [ka]

[0576] To intermediate 7 (3 g, 16.7 mmol) in CH2Cl2 (20 mL) at 0 °C was added triethylamine (4.7 mL, 33 mmol), 4-(dimethylamino)pyridine (0.2 g, 0.16 mmol), and N-phenylbis(trifluoromethanesulfonimide) (9.0 g, 25 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with PE / EtOAc to give intermediate 8 (4.2 g, 82%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =313.

[0577] Step 8: Preparation of 7-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-12). [ka]

[0578] A mixture of intermediate 8 (4.2 g, 13.4 mmol), Pd(dppf)Cl (1 g, 1.3 mmol), KPO (5.6 g, 26.8 mmol), and (2-(methoxymethoxy)phenyl)boronic acid (3 g, 16 mmol) in dioxane (20 mL) / HO (2 mL) was stirred at 40 °C for 1 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-12 (2.8 g, 70%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =301.

[0579] Preparation of 6-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-13). [ka]

[0580] Step 1: Preparation of dimethyl 2-(5-chloro-2-nitrophenyl)malonate (Intermediate 2). [ka]

[0581] 4-Chloro-2-fluoro-1-nitrobenzene (16.5 g, 94.5 mmol), dimethyl malonate (18.8 g, 143 mmol), CsCO (61.6 g, 189 mmol), and DMF (100 mL) were stirred at room temperature for 6 hours. The reaction mixture was partitioned between 1 M aqueous HCl and EtOAc. The organic layer was washed with brine, dried over NaSO, and concentrated to give Intermediate 2 (28 g, 99%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0582] Step 2: Preparation of 2-(5-chloro-2-nitrophenyl)acetic acid (Intermediate 3). [ka]

[0583] Intermediate 2 was combined with AcOH (30 mL) and concentrated. HCl (30 mL) was added and heated at 95° C. for 16 hours. The mixture was cooled to 0° C. and then diluted with H2O, forming a precipitate. The solid was collected by vacuum filtration and diluted with H2O, hexane / ether. 1:1 and dried to give Intermediate 3 (17 g, 83%) as a white solid.

[0584] Step 3: Preparation of methyl 2-(5-chloro-2-nitrophenyl)acetate (Intermediate 4). [ka]

[0585] Intermediate 3 (17 g, 78 mmol) was suspended in CHCl (300 mL). Oxalyl chloride (10.5 mL, 119 mmol) was added to the mixture, followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room temperature for 1 hour and then added dropwise to MeOH at 0° C. The solvent was removed in vacuo to give Intermediate 4 (18 g, 98%) as a white solid. The crude product was used directly in the next step without further purification.

[0586] Step 4: Preparation of methyl 2-(2-amino-5-chlorophenyl)acetate intermediate 5. [ka]

[0587] Intermediate 4 (18 g, 77 mmol) was suspended in a mixture of MeOH (300 mL) and NH4Cl (83 g, 1.53 mol) at 0 °C. Zinc powder (25 g, 386 mmol) was added in one portion. The mixture was stirred at room temperature for 1 h and then filtered through Celite. The filtrate was concentrated and then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give Intermediate 5 (14.3 g, 94%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =200.

[0588] Step 5: Preparation of 1-amino-5-chloroindolin-2-one (Intermediate 6). [ka]

[0589] Intermediate 5 (14.3 g, 72 mmol) was dissolved in 0 o The resulting mixture was suspended in CH2Cl2 (200 mL) at 0 °C. Nitrosonium tetrafluoroborate (12.6 g, 108 mmol) was added in one portion to the mixture. The mixture was stirred at 0 °C for 1 h. The mixture was added directly to a vigorously stirred mixture of concentrated SnCl2 dihydrate (66 g, 291 mmol). HCl (300 mL) was added at 0 °C. The mixture was allowed to warm slowly to room temperature while stirring. After 24 h, the mixture was filtered. The solid was washed with H2O and ether and then dried to give Intermediate 6 (10 g, 76%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =183.

[0590] Step 6: Preparation of 6-chlorocinnolin-3-ol (Intermediate 7). [ka]

[0591] Intermediate 6 (10 g, 56 mmol) was suspended in toluene (500 mL) at 0° C. tert-Butyl hypochlorite (6 g, 56 mmol) was added to the mixture in one portion. The mixture was stirred at 0° C. for 20 minutes. The solid was collected by vacuum filtration, washed with HO, hexane / ether (1:1), and dried to give Intermediate 7 (4.5 g, 45%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =181.

[0592] Step 7: Preparation of 6-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 8). [ka]

[0593] To intermediate 7 (4.5 g, 25 mmol) in CH2Cl2 (40 mL) at 0 °C was added triethylamine (7 mL, 50 mmol), 4-(dimethylamino)pyridine (0.3 g, 0.25 mmol), and N-phenylbis(trifluoromethanesulfonimide) (13.5 g, 37.5 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with PE / EtOAc to give intermediate 8 (6.3 g, 82%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =313.

[0594] Step 8: Preparation of 6-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-13). [ka]

[0595] A mixture of intermediate 8 (6.3 g, 20.1 mmol), Pd(dppf)Cl (1.5 g, 1.95 mmol), KPO (8.4 g, 40.2 mmol), and (2-(methoxymethoxy)phenyl)boronic acid (4.5 g, 24 mmol) in dioxane (40 mL) / HO (6 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-13 (4.1 g, 69%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =301.

[0596] Preparation of 2-(7-bromo-6-chlorocinnolin-3-yl)phenol, methyl ether (I-14) [ka]

[0597] Step 1: Preparation of 1,3-dimethyl 2-(4-bromo-5-chloro-2-nitrophenyl)propanedioate (Intermediate 2). [ka]

[0598] A solution of 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (100 g, 393.020 mmol, 1 equiv.) and dimethyl malonate (57.12 g, 432.322 mmol, 1.1 equiv.) in DMF (500 mL) was stirred at room temperature for 12 hours. The resulting mixture was diluted with water (300 mL). The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (1×1000 mL). The combined organic layers were washed with brine (3×1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This gave Intermediate 2 (140 g, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =366.

[0599] Step 2: Preparation of 4-bromo-5-chloro-2-nitrophenyl)acetic acid (Intermediate 3) [ka]

[0600] A solution of intermediate 2 (70 g, 190.970 mmol, 1 equiv.) in AcOH (500 mL) and concentrated hydrochloric acid (500 mL) was stirred at 100° C. for 12 hours. The mixture was cooled to 0° C. The precipitated solid was collected by filtration and washed with water (3×300 mL). The resulting mixture was concentrated under reduced pressure. This gave intermediate 3 (50 g, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =294.

[0601] Step 3: Preparation of methyl 2-(4-bromo-5-chloro-2-nitrophenyl)acetate (Intermediate 4) [ka]

[0602] A solution of intermediate 3 (50 g, 169.785 mmol, 1 equiv) and H2SO4 (4 mL) in MeOH (400 mL) was stirred at 60 °C for 12 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (400 mL). The mixture was neutralized to pH 6 with saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc (1 x 1000 mL). The combined organic layers were washed with water (3 x 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification. This gave intermediate 4 (46 g, crude) as a yellow solid. LCMS (ESI) m / z [M+H] + =308.

[0603] Step 4: Preparation of methyl 2-(4-bromo-5-chloro-2-nitrophenyl)acetate (Intermediate 5) [ka]

[0604] A solution of intermediate 4 (50 g, 169.785 mmol, 1 equiv) and H2SO4 (4 mL) in MeOH (400 mL) was stirred at 60 °C for 12 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (400 mL). The mixture was neutralized to pH 6 with saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc (1 x 1000 mL). The combined organic layers were washed with water (3 x 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 5 (46 g, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =278.

[0605] Step 5: Preparation of 1-amino-6-bromo-5-chloro-3H-indol-2-one (Intermediate 6) [ka]

[0606] A solution of intermediate 5 (16 g, 57.444 mmol, 1 equiv.) and NOBF (10.07 g, 86.166 mmol, 1.5 equiv.) in DCM (300 mL) was stirred at 0 °C for 2 h. To the above mixture, SnCl (88.06 g, 459.552 mmol, 8.0 equiv.) in HCl (300 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for another 24 h. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The resulting mixture was concentrated under reduced pressure. This gave intermediate 6 (10.4 g, crude) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =261.

[0607] Step 6: Preparation of 7-bromo-6-chlorocinnolin-3-ol (Intermediate 7) [ka]

[0608] To a stirred solution of intermediate 6 (10.4 g, 39.771 mmol, 1 equiv.) in toluene (100 mL) was added tert-butyl hypochlorite (4.32 g, 39.771 mmol, 1.0 equiv.) dropwise at room temperature. The resulting mixture was stirred for 25 minutes at room temperature. The resulting mixture was filtered, and the filter cake was washed with PE (3×50 mL). The filtrate was concentrated under reduced pressure. This afforded intermediate 7 (9.5 g, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =259.

[0609] Step 7: Preparation of 7-bromo-6-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 8). [ka]

[0610] A solution of intermediate 7 (9.5 g, 36.610 mmol, 1 equiv.) and DMAP (447.27 mg, 3.661 mmol, 0.1 equiv.) in DCM (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give intermediate 8 (9.4 g, 65.58%) as a white solid. LCMS (ESI) m / z [M+H] + =391.

[0611] Step 8: Preparation of 2-(7-bromo-6-chlorocinnolin-3-yl)phenol, methyl ether (I-14) [ka]

[0612] To a solution of Intermediate 8 (3.00 g, 7.662 mmol, 1 equiv.) and 2-(methoxymethoxy)phenylboronic acid (1.39 g, 7.662 mmol, 1.0 equiv.) in dioxane (100 mL) and HO (25 mL) was added KPO (4.88 g, 22.986 mmol, 3.0 equiv.) and Pd(dppf)Cl (1.12 g, 1.532 mmol, 0.2 equiv.). After stirring at room temperature under nitrogen for 1 h, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give I-14 (960 mg, 32.83%) as a yellow solid. LCMS (ESI) m / z [M+H] + =827.

[0613] The following intermediates in Table 7 were prepared in a manner similar to that described in the preparation of intermediate I-14.

[0614] [Table 8]

[0615] Preparation of 6-chloro-7-cyclopropyl-3-[2-(methoxymethoxy)phenyl]cinnoline (I-20). [ka]

[0616] To a solution of I-14 (1 g, 2.634 mmol, 1 equiv.) and cyclopropylboronic acid (678.80 mg, 7.902 mmol, 3.0 equiv.) in dioxane (10 mL) and HO (2.5 mL) was added KPO (1677.37 mg, 7.902 mmol, 3.0 equiv.) and Pd(dppf)Cl (385.4 mg, 0.527 mmol, 0.2 equiv.). After stirring at 60 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-20 (380.0 mg, 42.3%) as a yellow solid. LCMS (ESI) m / z [M+H] + =341.

[0617] Preparation of tert-butyl 6-{6-chloro-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2-azaspiro[3.3]heptane-2-carboxylate (I-21). [ka]

[0618] A solution of Zn (413.32 mg, 6.324 mmol, 6 equiv.), I2 (133.71 mg, 0.527 mmol, 0.5 equiv.), and tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (681.01 mg, 2.108 mmol, 2 equiv.) in DMF was stirred at 30 °C under a nitrogen atmosphere for 2 h. To the above mixture, I-14 (400 mg, 1.054 mmol, 1 equiv.), XPhos Pd G3 (178.37 mg, 0.211 mmol, 0.2 equiv.), and XPhos (100.46 mg, 0.211 mmol, 0.2 equiv.) were added portionwise over 5 min at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (3×20 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 PE / EA (3:1) to afford I-21 (190 mg, 36.36%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =496.

[0619] Preparation of tert-butyl 6-(6-cyano-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2-azaspiro[3.3]heptane-2-carboxylate (I-22) [ka]

[0620] To a stirred solution of I-21 (220 mg, 0.444 mmol, 1 equiv.) and Zn(CN) (208.33 mg, 1.776 mmol, 4 equiv.) in DMF (3 mL) was added XPhos Pd G (75.09 mg, 0.089 mmol, 0.2 equiv.) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The combined organic layers were washed with brine (2 × 25 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 PE / EA (5:1) to afford I-22 (117 mg, 54.21%) as a yellow oil. LCMS (ESI) m / z: [M+H] = 487.

[0621] Preparation of tert-butyl 6-(6-chloro-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-23). [ka]

[0622] To a solution of I-14 (340.0 mg, 0.90 mmol, 1.00 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (435.8 mg, 0.90 mmol, 1.00 equiv.) in toluene (10 mL), BINAP (111.5 mg, 0.18 mmol, 0.20 equiv.), Pd(dba) (164.0 mg, 0.18 mmol, 0.20 equiv.), and t-BuONa (172.1 mg, 1.79 mmol, 2.00 equiv.) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: EtOAc = 10:1 to 2:1 to give I-23 (350.0 mg, 78.6%) as an orange solid. LCMS (ESI) m / z: [M+H] + =497. [ka]

[0623] tert-Butyl 6-(6-cyano-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-24) was prepared in a similar procedure to I-22 using I-23.

[0624] Preparation of tert-butyl 6-(6-ethoxy-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-25) [ka]

[0625] To a stirred solution of I-23 (300.0 mg, 0.604 mmol, 1 equiv.) and AConA (149.0 mg, 1.812 mmol, 3 equiv.) in 1,4-dioxane (2 mL) and EtOH (2 mL) was added di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (51.2 mg, 0.121 mmol, 0.2 equiv.) and Pd2(dba)3 (110.5 mg, 0.121 mmol, 0.2 equiv.). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give I-25 (210.0 mg, 68.6%) as a yellow solid. LCMS(ESI)m / z[M+H] + =507.

[0626] Preparation of tert-butyl 6-{6-cyclopropoxy-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (I-26). [ka]

[0627] To a solution of I-23 (200 mg, 0.402 mmol, 1 equiv.) and Pd(dba) (36.85 mg, 0.040 mmol, 0.1 equiv.) in dioxane (1.2 mL, 14.165 mmol), cyclopropanol (1.2 mL), CHCOONa (99.03 mg, 1.206 mmol, 3 equiv.), and t-BuXPhos (34.18 mg, 0.080 mmol, 0.2 equiv.) were added. The resulting solution was cooled under a N atmosphere. The mixture was stirred at 80°C (under air) for 16 hours. The mixture was diluted with EtOAc (150 mL) and washed with water (150 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography eluting with 0-50% EtOAc in petroleum ether to give I-26 (61 mg, 29.23%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =519.

[0628] Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}-6-(dimethylamino)cinnolin-3-yl)phenol (I-27). [ka]

[0629] A stirred solution of I-23 (66 mg, 0.131 mmol, 1 equiv) in DCM (2 mL, 31.461 mmol, 241.02 equiv) and TFA (2 mL, 26.926 mmol, 206.28 equiv) was stirred at room temperature under air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. This afforded I-27 (48 mg, 91.56%) as a red solid. LCMS (ESI) m / z: [M+H] + =362.

[0630] Preparation of tert-butyl 6-(6-cyano-3-(2-(methoxymethoxy)phenyl)quinolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-28). [ka]

[0631] To a solution of I-23 (350.0 mg, 0.70 mmol, 1.00 equiv) in DMF (7 mL) was added XPhos (67.1 mg, 0.14 mmol, 0.20 equiv), XPhos Pd G3 (119.2 mg, 0.14 mmol, 0.20 equiv), and Zn(CN)2 (248.1 mg, 2.11 mmol, 3.00 equiv) at room temperature. The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O (3 × 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 PE:EtOAc = 10:1 to 1:1 to give I-28 (150.0 mg, 43.7%) as an orange solid. LCMS(ESI)m / z:[M+H] + =488.

[0632] Synthesis of tert-butyl 6-[6-(difluoromethoxy)-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-30). [ka]

[0633] Step 1: Preparation of tert-butyl 6-{6-hydroxy-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-29). [ka]

[0634] To a stirred solution of I-23 (923.0 mg, 1.857 mmol, 1 equiv.) and KOH (0.31 g, 5.571 mmol, 3 equiv.) in 1,4-dioxane (5 mL) and HO (5 mL) was added Pd(dba) (0.34 g, 0.371 mmol, 0.2 equiv.) and di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (0.16 g, 0.371 mmol, 0.2 equiv.). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give I-29 (780.0 mg, 87.7%) as a brown solid. LCMS(ESI)m / z:[M+H] + =479.

[0635] Step 2: Preparation of tert-butyl 6-{6-difluoromethoxy-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-30). [ka]

[0636] To a stirred mixture of I-29 (300.0 mg, 0.627 mmol, 1 equiv.) and CsCO (612.76 mg, 1.881 mmol, 3 equiv.) in DMF (6 mL) was added sodium 2-chloro-2,2-difluoroacetate (286.7 mg, 1.881 mmol, 3 equiv.). The resulting mixture was stirred at 60 °C for 2 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (6:1) to afford I-30 (140.0 mg, 42.2%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =529.

[0637] Preparation of tert-butyl 6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-31). [ka]

[0638] Step 1: Preparation of tert-butyl 6-{5-chloro-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-35). [ka]

[0639] To a solution of I-17 (1.00 g, 2.634 mmol, 1 equiv.), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.52 g, 2.634 mmol, 1 equiv.), and BINAP (0.33 g, 0.527 mmol, 0.2 equiv.) in toluene (12 mL) was added Pd(dba) (0.48 g, 0.527 mmol, 0.2 equiv.) and t-BuONa (0.51 g, 5.268 mmol, 2 equiv.), and the mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 I-35 (1.00 g, 76.9%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =497.

[0640] Step 2: Preparation of tert-butyl 6-{5-ethenyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-36). [ka]

[0641] To a solution of I-35 (1.00 g, 2.012 mmol, 1 equiv.) and ethenyldifluoro-lambda 4-boranyl)-lambda 2-fluoranide (0.19 g, 2.012 mmol, 1 equiv.) in HO (2 mL) and dioxane (10 mL) was added XPhos Pd G3 (0.34 g, 0.402 mmol, 0.2 equiv.) and Cs2Co3 (1.97 g, 6.036 mmol, 3 equiv.), and the mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / HO (5:1) to give I-36 (900.0 mg, 91.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =489.

[0642] Step 3: Preparation of tert-butyl 6-{6-formyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-37). [ka]

[0643] To a solution of I-36 (840.0 mg, 1.719 mmol, 1 equiv.) and 2,6-lutidine (368.5 mg, 3.438 mmol, 2 equiv.) in dioxane (60 mL) and HO (30 mL), NaIO (1470.9 mg, 6.876 mmol, 4 equiv.) and KOsO.2HO (50.9 mg, 0.138 mmol, 0.08 equiv.) were added, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and then dried over anhydrous sodium sulfate. 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 I-37 (400.0 mg, 47.4%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =491.

[0644] Step 4: Preparation of tert-butyl 6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-31). [ka]

[0645] To a solution of intermediate 4 (400.0 mg, 0.815 mmol, 1 equiv.) and dimethyl (1-diazo-2-oxopropyl)phosphonate (234.9 mg, 1.222 mmol, 1.5 equiv.) in MeOH (6 mL) was added K2Co3 (338.1 mg, 2.445 mmol, 3 equiv.), and the mixture was stirred at room temperature for 3 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give I-31 (220.0 mg, 55.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =487. [ka]

[0646] tert-Butyl 6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-32) was prepared in a similar manner as described in the preparation of I-31. LCMS (ESI) m / z: [M+H] + =487.

[0647] Synthesis of 7-chloro-6-(difluoromethyl)-3-[2-(methoxymethoxy)phenyl]cinnoline (I-33). [ka]

[0648] Step 1: Preparation of 7-chloro-6-ethenyl-3-[2-(methoxymethoxy)phenyl]cinnoline (Intermediate 2). [ka]

[0649] To a stirred solution of J-21 (500.0 mg, 1.317 mmol, 1 equiv.) and potassium vinyltrifluoroborate (352.9 mg, 2.634 mmol, 2 equiv.) in dioxane (7.5 mL) and HO (1.5 mL), XPhos Pd G3 (222.9 mg, 0.263 mmol, 0.2 equiv.) and CsCO3 (1287.3 mg, 3.951 mmol, 3 equiv.) were added. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (9:1) to give intermediate 2 (350.0 mg, 81.2%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =327.

[0650] Step 2: Preparation of 7-chloro-3-[2-(methoxymethoxy)phenyl]cinnoline-6-carbaldehyde (Intermediate 3). [ka]

[0651] To a stirred solution of Intermediate 2 (350 mg, 1.070 mmol, 1 equiv) and NaIO (924.6 mg, 4.281 mmol, 4 equiv) in dioxane (3 mL) and HO (3 mL) was added KOsO.2HO (18.1 mg, 0.053 mmol, 0.05 equiv) and 2,6-lutidine (228.9 mg, 2.140 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated sodium hyposulfite (aq) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc 1:1) to give intermediate 3 (300 mg, 85.2%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =329.

[0652] Step 3: Preparation of 7-chloro-6-(difluoromethyl)-3-[2-(methoxymethoxy)phenyl]cinnoline (I-33). [ka]

[0653] To a solution of intermediate 3 (300 mg, 0.911 mmol, 1 equiv) in DCM (5 mL) was added BAST (1 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl (aq) at 0° C. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (1:1 PE / EtOAc) to give I-33 (250.0 mg, 78.1%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =351. [ka]

[0654] Using a procedure similar to that described above, 6-chloro-7-(difluoromethyl)-3-(2-(methoxymethoxy)phenyl)cinnoline (I-34) was prepared from I-33.

[0655] Preparation of tert-butyl 6-[5-(difluoromethyl)-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-38). [ka]

[0656] To a stirred solution of I-37 (440.0 mg, 0.897 mmol, 1 equiv) in DCM (5 mL) was added BAST (1 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with NH4Cl (aq) at 0 °C. The aqueous layer was extracted with EtOAc (2 × 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give I-38 (160.0 mg, 34.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =513.

[0657] Preparation of 2-(6-cyclopropyl-7-{2,6-diazaspiro[3.3]heptan-2-yl}cinnolin-3-yl)phenol (I-39) [ka]

[0658] Step 1: Preparation of 1,3-dimethyl 2-(5-bromo-4-chloro-2-nitrophenyl)propanedioate (Intermediate 2). [ka]

[0659] A solution of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (20 g, 78.604 mmol, 1 equiv.), dimethyl malonate (11.42 g, 86.464 mmol, 1.1 equiv.), and CsCO (51.22 g, 157.208 mmol, 2.0 equiv.) in DMF (50 mL) was stirred at room temperature for 12 h. The mixture was acidified to pH 6 with 1 N HCl (aq.). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 300 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This afforded Intermediate 2 (20 g, 69.4%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =366.

[0660] Step 2: Preparation of 5-bromo-4-chloro-2-nitrophenyl)acetic acid (Intermediate 3) [ka]

[0661] A solution of intermediate 2 (20 g, 54.563 mmol, 1 equiv.) in AcOH (250 mL) in HCl (250 mL) was stirred at 100° C. for 12 hours. The resulting mixture was diluted with water (200 mL). The precipitated solid was collected by filtration and washed with water (3×200 mL). The resulting mixture was concentrated under reduced pressure. This gave intermediate 3 (15 g, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =294.

[0662] Step 3: Preparation of methyl 2-(5-bromo-4-chloro-2-nitrophenyl)acetate (Intermediate 4) [ka]

[0663] To a stirred solution of intermediate 3 (15 g, 50.936 mmol, 1 equiv.) in MeOH (100 mL) and DCM (400 mL) was added TMSCHN2 (34.91 g, 152.807 mmol, 3 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. This afforded intermediate 4 (16 g, crude) as a pale yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =308.

[0664] Step 4: Preparation of methyl 2-(4-chloro-5-cyclopropyl-2-nitrophenyl)acetate (Intermediate 5) [ka]

[0665] To a solution of intermediate 4 (3.0 g, 9.724 mmol, 1 equiv.) and cyclopropylboronic acid (1.67 g, 19.448 mmol, 2.0 equiv.) in dioxane (20 mL) in HO (5 mL) was added KPO (6.19 g, 29.172 mmol, 3.0 equiv.) and Pd(dppf)Cl (1.42 g, 1.945 mmol, 0.2 equiv.). After stirring at 60 °C under nitrogen for 2 h, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give intermediate 5 (1.8 g, 68.6%) as a yellow solid. LCMS (ESI) m / z [M+H] + =270.

[0666] Step 5: Preparation of methyl 2-(2-amino-4-chloro-5-cyclopropylphenyl)acetate (Intermediate 6) [ka]

[0667] To a stirred solution of intermediate 5 (1.8 g, 6.675 mmol, 1 equiv.) and NH4Cl (7.14 g, 133.500 mmol, 20 equiv.) in MeOH (20 mL) was added Zn (8.73 g, 133.500 mmol, 20 equiv.) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 6 (1.4 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =240.

[0668] Step 6: Preparation of 1-amino-6-chloro-5-cyclopropyl-3H-indol-2-one (Intermediate 7) [ka]

[0669] A mixture of intermediate 6 (1.8 g, 7.509 mmol, 1 equiv.) and NOBF (1.32 g, 11.264 mmol, 1.5 equiv.) in DCM (25 mL) was stirred at 0 °C for 1 h. To the above mixture, SnCl (8.63 g, 45.054 mmol, 6.0 equiv.) in HCl (30 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C 18 Silica gel, mobile phase: MeCN in water (0.1% FA), gradient 0% to 50% in 50 min, detector: UV 254 nm. This afforded intermediate 7 (700.0 mg, 41.8%) as a yellow solid. LCMS (ESI) m / z [M+H] + =223.

[0670] Step 7: Preparation of tert-butyl 6-(6-cyclopropyl-3-hydroxycinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (Intermediate 8) [ka]

[0671] To a solution of Intermediate 7 (300.0 mg, 1.360 mmol, 1 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (539.1 mg, 2.720 mmol, 2.0 equiv.) in dioxane (5 mL), CsCO (1328.9 mg, 4.080 mmol, 3.0 equiv.) and Pd-PEPPSI-IPentCl 2-methylpyridine (215.5 mg, 0.272 mmol, 0.2 equiv.) were added. After stirring at 100 °C under a nitrogen atmosphere for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C 18 Silica gel, mobile phase: MeCN (0.1% FA) in water, gradient 0% to 50% in 50 min, detector: UV 254 nm. This gave intermediate 8 (250.0 mg, 48.0%) as a yellow solid. LCMS (ESI) m / z [M+H] + =221.

[0672] Step 8: Preparation of tert-butyl 6-(6-cyclopropyl-3-hydroxycinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 9) [ka]

[0673] To a solution of Intermediate 8 (300.0 mg, 1.360 mmol, 1 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (539.1 mg, 2.720 mmol, 2.0 equiv.) in dioxane (5 mL), CsCO (1328.9 mg, 4.080 mmol, 3.0 equiv.) and Pd-PEPPSI-IPentCl 2-methylpyridine (215.5 mg, 0.272 mmol, 0.2 equiv.) were added. After stirring at 100 °C under a nitrogen atmosphere for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C 18Silica gel, mobile phase: MeCN in water (0.1% FA), gradient 0% to 50% in 50 min, detector: UV 254 nm. This afforded intermediate 9 (250.0 mg, 48.0%) as a yellow solid. LCMS (ESI) m / z [M+H] + =383.

[0674] Step 9: Preparation of tert-butyl 6-[6-cyclopropyl-3-(trifluoromethanesulfonyloxy)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 10) [ka]

[0675] To a solution of intermediate 9 (250.0 mg, 0.654 mmol, 1 equiv.) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (467.0 mg, 1.308 mmol, 2.0 equiv.) in DCM (5 mL) was added TEA (198.4 mg, 1.962 mmol, 3.0 equiv.) and DMAP (7.9 mg, 0.065 mmol, 0.1 equiv.), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE / EA (23:67) to give intermediate 10 (270.0 mg, 80.2%) as a yellow oil. LCMS (ESI) m / z [M+H] + =515.

[0676] Step 10: Preparation of tert-butyl 6-[6-cyclopropyl-3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 11) [ka]

[0677] To a solution of Intermediate 10 (210.0 mg, 0.408 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (168.8 mg, 1.224 mmol, 3.0 equiv.) in dioxane (4 mL) and HO (1 mL) was added CsPO (259.4 mg, 1.224 mmol, 3.0 equiv.) and XPhos Pd G (59.4 mg, 0.082 mmol, 0.2 equiv.). After stirring at 60 °C under a nitrogen atmosphere for 1 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 Silica gel, mobile phase: MeCN in water (0.1% FA), gradient 0% to 60% in 40 min, detector: UV 254 nm. This gave intermediate 11 (100.0 mg, 53.4%) as a yellow oil. LCMS (ESI) m / z [M+H] + =503.

[0678] Step 11: Preparation of 2-(6-cyclopropyl-7-{2,6-diazaspiro[3.3]heptan-2-yl}cinnolin-3-yl)phenol (I-39) [ka]

[0679] A solution of intermediate 11 (70.0 mg, 0.153 mmol, 1 equiv) and TFA (0.5 mL) in DCM (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give I-39 (90 mg, crude) as a red solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =359. [ka]

[0680] 2-(5-Cyclopropyl-7-{2,6-diazaspiro[3.3]heptan-2-yl}cinnolin-3-yl)phenol (I-40) was prepared in a similar manner as described in the preparation of intermediate I-39. LCMS (ESI) m / z [M+H] + =359.

[0681] Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}-5-methylcinnolin-3-yl)phenol (I-41). [ka]

[0682] Step 1: Preparation of 1,3-dimethyl 2-(4-bromo-2-methyl-6-nitrophenyl)propanedioate (Intermediate 2) [ka]

[0683] A solution of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (30.00 g, 128.192 mmol, 1.00 equiv.) and dimethyl malonate (16.94 g, 128.192 mmol, 1.00 equiv.) in DMF (300 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water (2 L). The resulting mixture was extracted with EtOAc (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 2 (44.00 g, 96.1%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =246.

[0684] Step 2: Preparation of (4-bromo-2-methyl-6-nitrophenyl)acetic acid (Intermediate 3). [ka]

[0685] A solution of intermediate 2 (44.00 g, 127.119 mmol, 1.00 equiv) and AcOH (300 mL) in concentrated HCl (300 mL) was stirred at 100° C. overnight. The precipitated solid was collected by filtration and washed with water (3×300 mL). This gave intermediate 3 (33.00 g, 92.8%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =274.

[0686] Step 3: Preparation of methyl 2-(4-bromo-2-methyl-6-nitrophenyl)acetate (Intermediate 4). [ka]

[0687] To a stirred solution of intermediate 3 (33.00 g, 120.407 mmol, 1.00 equiv) in DCM (300 mL) was added (COCl) (30.56 g, 240.814 mmol, 2.00 equiv) dropwise under nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 1.5 h under nitrogen atmosphere. To the above mixture, MeOH (165 mL) was added dropwise over 10 min at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with sodium bicarbonate solution (3 × 1 L) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 4 (35.00 g, 98.88%) as a pale yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =288.

[0688] Step 4: Preparation of methyl 2-(2-amino-4-bromo-6-methylphenyl)acetate (Intermediate 5). [ka]

[0689] To a stirred solution of intermediate 4 (35.00 g, 121.487 mmol, 1.00 equiv) and NH4Cl (129.97 g, 2429.740 mmol, 20.00 equiv) in MeOH (400 mL) was added Zn (119.14 g, 1822.305 mmol, 15.00 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 300 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 5 (32.00 g, 63.27%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =258.

[0690] Step 5: Preparation of 1-amino-6-bromo-4-methyl-3H-indol-2-one (Intermediate 6). [ka]

[0691] To a stirred solution of intermediate 5 (32.00 g, 123.976 mmol, 1.00 equiv) in DCM (320 mL) was added NOBF (21.72 g, 185.964 mmol, 1.50 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. To the above mixture was added SnCl (118.79 g, 619.880 mmol, 5.00 equiv) and HCl (320 mL) in portions over 10 min at 0 °C. The resulting mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with water (3 × 300 mL). This gave intermediate 6 (13.00 g, 43.06%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =241.

[0692] Step 6: Preparation of 7-bromo-5-methylcinnolin-3-ol (Intermediate 7). [ka]

[0693] To a stirred solution of intermediate 6 (11.00 g, 45.626 mmol, 1.00 equiv) in toluene (200 mL) was added tert-butyl hypochlorite (3.96 g, 36.501 mmol, 0.80 equiv) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The precipitated solid was collected by filtration and washed with PE (3×300 mL). This gave intermediate 7 (11.70 g, 92.2%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =239.

[0694] Step 7: Preparation of tert-butyl 6-(3-hydroxy-5-methylcinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 8) [ka]

[0695] To a solution of Intermediate 7 (2.00 g, 8.366 mmol, 1.00 equiv.), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.32 g, 16.732 mmol, 2.00 equiv.), and CsCO (8.18 g, 25.098 mmol, 3.00 equiv.) in dioxane (25 mL), {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloro(2-methyl-1λ4-pyridin-1-yl)palladium (351.8 mg, 0.418 mmol, 0.05 equiv.) was added, and the mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×400 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 CHCl / MeOH (12:1) to give intermediate 8 (3.40 g, 62.71%) as a black solid. LCMS (ESI) m / z: [M+H] + =257.

[0696] Step 8: Preparation of tert-butyl 6-[5-methyl-3-(trifluoromethanesulfonyloxy)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 9). [ka]

[0697] To a solution of intermediate 8 (3.40 g, 9.539 mmol, 1.00 equiv) and TEA (2.90 g, 28.617 mmol, 3.00 equiv) in DCM (40 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (5.11 g, 14.308 mmol, 1.50 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 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 PE / EA (7:3) to give intermediate 9 (1.9 g, 36.7%) as an orange solid. LCMS(ESI)m / z:[M+H] + =489.

[0698] Step 9: Preparation of tert-butyl-6-{3-[2-(methoxymethoxy)phenyl]-5-methylcinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 10). [ka]

[0699] To a stirred solution of Intermediate 9 (1.90 g, 3.890 mmol, 1.00 equiv) and 2-(methoxymethoxy)phenylboronic acid (707.8 mg, 3.890 mmol, 1.00 equiv) in dioxane (20 mL) and HO (4 mL) was added Pd(dppf)Cl (569.2 mg, 0.778 mmol, 0.20 equiv) and KPO (2.48 g, 11.670 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (500 mL). The aqueous layer was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (3 × 400 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 PE / EA (2:8) to give intermediate 10 (780.0 mg, 42.1%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =477.

[0700] Step 10: Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}-5-methylcinnolin-3-yl)phenol (I-41). [ka]

[0701] A solution of Intermediate 10 (770.0 mg, 1.616 mmol, 1.00 equiv) in DCM (8 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C 18 Silica gel, mobile phase: MeOH (0.05% TFA) in water, gradient 0% to 100% in 30 min, detector: UV 254 / 220 nm. The resulting mixture was concentrated in vacuo to afford I-41 (374.0 mg, 62.6%) as a red solid. LCMS (ESI) m / z: [M+H] + =333. [ka]

[0702] 2-(6-methyl-7-(2,6-diazaspiro[3.3]heptan-2-yl)cinnolin-3-yl)phenol (I-42) was prepared in a similar manner as described in the preparation of intermediate I-41. LCMS (ESI) m / z: [M+H] + =333.

[0703] Preparation of 2-(7-{2-azaspiro[3.3]heptan-6-yl}cinnolin-3-yl)phenol (I-43) [ka]

[0704] Step 1: Ethyl (2E)-3-(4-amino-6-chloropyridazin-3-yl)prop-2-enoate (Intermediate 2) [ka]

[0705] A solution of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (4.99 g, 15.433 mmol, 1.5 equiv.), I2 (1.31 g, 5.144 mmol, 0.5 equiv.), and Zn (71.57 mg, 1.095 mmol, 3 equiv.) in DMF (20 mL) was stirred at room temperature under a nitrogen atmosphere for 1.5 h. The resulting solution was added with methyl 2-(4-bromo-2-nitrophenyl)acetate (2.82 g, 10.289 mmol, 1 equiv.), CuI (0.98 g, 5.144 mmol, 0.5 equiv.), and Pd(PPh 32 Cl2 (1.44 g, 2.058 mmol, 0.2 equiv) was added at room temperature under nitrogen atmosphere. The final reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1), to give intermediate 2 (1.87 g, 46.55%) as a yellow oil. LCMS (ESI) m / z [M+H] + =390.

[0706] Step 2: Preparation of methyl 2-(4-{2-azaspiro[3.3]heptan-6-yl}-2-nitrophenyl)acetate (Intermediate 3) [ka]

[0707] A mixture of intermediate 2 (1.87 g, 4.790 mmol, 1 eq) and TFA (5 mL) in DCM (15 mL) was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =290.

[0708] Step 3: Preparation of methyl 2-(4-{2-acetyl-2-azaspiro[3.3]heptan-6-yl}-2-nitrophenyl)acetate (Intermediate 4) [ka]

[0709] A mixture of intermediate 3 (1.37 g, 4.719 mmol, 1 equiv.) and acetic anhydride (0.96 g, 9.438 mmol, 2 equiv.) in DCM (13 mL) was stirred at room temperature for 50 min. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give intermediate 4 (1.44 g, 91.82%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =332.

[0710] Step 4: Preparation of methyl 2-(4-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-2-aminophenyl)acetate (Intermediate 5) [ka]

[0711] To a stirred mixture of intermediate 4 (1.44 g, 4.333 mmol, 1 equiv.) and NH4Cl (4.64 g, 86.660 mmol, 20 equiv.) in MeOH (15 mL) was added Zn (5.67 g, 86.660 mmol, 20 equiv.) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The residue was dissolved in EtOAc (100 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 5 mL). The resulting mixture was washed with water (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =302.

[0712] Step 5: Preparation of 6-{2-acetyl-2-azaspiro[3.3]heptan-6-yl}-1-amino-3H-indol-2-one (Intermediate 6). [ka]

[0713] A stirred mixture of intermediate 5 (1.127 g, 3.727 mmol, 1 equiv.) was suspended in DCM (12 mL) at 0 °C. NOBF (0.65 g, 5.590 mmol, 1.5 equiv.) was added to the mixture. The mixture was stirred for 1 h at 0 °C. This mixture was added directly to a vigorously stirred mixture of SnCl (5.71 g, 29.816 mmol, 8 equiv.) in HCl (6 mL, 197.477 mmol, 181.49 equiv.) at 0 °C. The resulting mixture was stirred overnight at 30 °C. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water, gradient 0% to 40% in 30 min, detector, UV 254 nm. This gave Intermediate 6 (520 mg, 48.89%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =285.

[0714] Step 6: Preparation of 1-[6-(3-hydroxycinnolin-7-yl)-2-azaspiro[3.3]heptan-2-yl]ethanone intermediate 7) [ka]

[0715] A solution of intermediate 6 (500 mg, 1.752 mmol, 1 equiv.) and Pb(OAc)4 (932.34 mg, 2.102 mmol, 1.2 equiv.) in DCM (6 mL) was stirred for 20 min at room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, ACN in water, gradient 0% to 40% in 20 min, detector, UV 254 nm. This gave intermediate 7 (232 mg, 46.73%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =283.

[0716] Step 7: Preparation of 7-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)cinnolin-3-yl trifluoromethanesulfonate (Intermediate 8) [ka]

[0717] A solution of intermediate 7 (250 mg, 0.882 mmol, 1 equiv.) and TfO (1249.68 mg, 4.429 mmol, 5.02 equiv.) in pyridine (6 mL) was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The residue was dissolved in EtOAc (50 mL). The combined organic layers were washed with water (2×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =415.

[0718] Step 8: Preparation of 1-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2-azaspiro[3.3]heptan-2-yl}ethanone (Intermediate 9) [ka]

[0719] To a stirred solution of intermediate 8 (60 mg, 0.072 mmol, 1 equiv., 50%) and 2-hydroxyphenylboronic acid (19.92 mg, 0.144 mmol, 2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added XPhos Pd G3 (12.23 mg, 0.014 mmol, 0.2 equiv.) and CsCO3 (70.59 mg, 0.216 mmol, 3 equiv.). The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The crude product (60 mg) was purified by Chiral-Prep-HPLC under the following conditions (NB-Prep-HPLC-01): Column, Xselect CSH C18 OBD column 30 * Purification with 150 mm 5 um, mobile phase water (0.1% FA) and ACN (35% ACN to 58% in 7 min) gave intermediate 9 as a light yellow solid 8.9 mg, 34.08%). 1H NMR (400MHz, DMSO-d6)δ 12.05(s, 1H), 8.90(s, 1H), 8.24(s, 1H), 8.15-8.06(m, 2H), 7.86-7.78(m, 1H), 7.41-7.33(m, 1H), 7.09-7.00(m, 2H), 4.31(s, 1 H), 4.09(s, 1H), 4.03(s, 1H), 3.81(s, 1H), 3.72(p, J=8.7Hz, 1H), 2.75-2.64(m, 2H), 2.50-2.42(m, 2H), 1.76(d, J=13.2Hz, 3H). LCMS(ESI)m / z:[M+H] + =359.16.

[0720] Step 9: Preparation of 2-(7-{2-diazaspiro[3.3]heptan-6-yl}cinnolin-3-yl)phenol (I-43) [ka]

[0721] A solution of intermediate 9 (122 mg, 0.339 mmol, 1 equiv.) and KOH (190.44 mg, 3.390 mmol, 10 equiv.) in MeOH (1.5 mL) and HO (1.5 mL) was stirred at -70 °C overnight. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 60% in 40 min; detector, UV 254 nm. This afforded I-43 (102 mg, 94.68%) as an off-white solid. LCMS (ESI) m / z [M+H] + =317.

[0722] Preparation of 1-{3-[7-bromo-3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (I-44) [ka]

[0723] Step 4: Preparation of tert-butyl 3-[2-chloro-5-(2-methoxy-2-oxoethyl)-4-nitrophenyl]azetidine-1-carboxylate (Intermediate 5) [ka]

[0724] A solution of tert-butyl 3-iodoazetidine-1-carboxylate (22.94 g, 81.035 mmol, 1 equiv.), I2 (10.28 g, 40.517 mmol, 0.5 equiv.), and Zn (15.89 g, 243.105 mmol, 3 equiv.) in DMF (250 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture was added CuI (3.09 g, 16.207 mmol, 0.2 equiv.), Pd(dppf)Cl2 (11.86 g, 16.207 mmol, 0.2 equiv.), and Intermediate 4 (25 g, 81.035 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give intermediate 5 (32 g, 97.4%) as a pale yellow oil. LCMS (ESI) m / z: [M+H] + =385.

[0725] Step 5: Preparation of methyl 2-[5-(azetidin-3-yl)-4-chloro-2-nitrophenyl]acetate (Intermediate 6). [ka]

[0726] A solution of intermediate 5 (31 g, 80.559 mmol, 1 equiv.) in TFA (30 mL) and DCM (90 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. This gave intermediate 6 (40 g, crude) as a brown oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =285.

[0727] Step 6: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-4-chloro-2-nitrophenyl]acetate (Intermediate 7). [ka]

[0728] To a stirred solution of intermediate 6 (40 g, crude) and EtN (21.33 g, 210.747 mmol, 3 equiv.) in DCM (250 mL) was added AcO (7.17 g, 70.249 mmol, 1 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 0% B to 100% B in 40 min, 254 / 220 nm) to give intermediate 7 (21 g, 86.9%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =327.

[0729] Step 7: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-2-amino-4-chlorophenyl]acetate (Intermediate 8). [ka]

[0730] To a stirred solution of intermediate 7 (10 g, 30.606 mmol, 1 equiv.) and NH4Cl (16.37 g, 306.060 mmol, 10 equiv.) in MeOH (100 mL) at 0 °C was added Zn (20.01 g, 306.060 mmol, 10 equiv.). The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered, and the filter cake was extracted with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure, and the residue was diluted with water (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 400 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This afforded intermediate 8 (9.5 g, crude) as a pale yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =297.

[0731] Step 8: Preparation of 5-(1-acetylazetidin-3-yl)-1-amino-6-chloro-3H-indol-2-one (Intermediate 9). [ka]

[0732] A solution of intermediate 8 (9.5 g, crude) and NOBF (5.61 g, 48.019 mmol, 1.5 equiv.) in DCM (100 mL) was stirred at 0 °C for 1 h. To the above mixture, SnCl (36.81 g, 192.078 mmol, 6 equiv.) in HCl (100 mL) was added dropwise at 0 °C. The resulting mixture was further stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography under the following conditions: mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 45 mL / min, gradient: 0% B to 50% B in 40 min, 254 / 220 nm), to give intermediate 9 (5.2 g, 34.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =280.

[0733] Step 9: Preparation of 1-[3-(7-chloro-3-hydroxycinnolin-6-yl)azetidin-1-yl]ethanone (Intermediate 10). [ka]

[0734] To a stirred solution of intermediate 9 (1.5 g, 4.558 mmol, 1 equiv, 85%) in DCM (20 mL) was added Pb(OAc)4 (3.03 g, 6.837 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The resulting solution was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using the following conditions: mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 0% B to 50% B in 40 min, 254 / 220 nm), to give intermediate 10 (1.5 g, 94.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =278.

[0735] Step 10: Preparation of 6-(1-acetylazetidin-3-yl)-7-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 11). [ka]

[0736] To a stirred solution of Intermediate 10 (1.5 g, 4.321 mmol, 1 equiv., 80%) and EtN (1.31 g, 12.963 mmol, 3 equiv.) in DCM (2 mL) was added DMAP (0.26 g, 2.160 mmol, 0.5 equiv.) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (1.54 g, 4.321 mmol, 1 equiv.) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give Intermediate 11 (1.5 g, 72.0%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =410.

[0737] Step 11: Preparation of 1-{3-[7-chloro-3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (Intermediate 12). [ka]

[0738] To a stirred solution of Intermediate 11 (700.0 mg, 1.708 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (353.44 mg, 2.562 mmol, 1.5 equiv.) in dioxane (70 mL) and HO (14 mL), PPd(dppf)Cl (250.00 mg, 0.342 mmol, 0.2 equiv.) and KPO (1087.85 mg, 5.124 mmol, 3 equiv.) were added. The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 300 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography under the following conditions: Mobile phase A: water (0.1% FA), Mobile phase B: ACN, Flow rate: 60 mL / min, Gradient: 0% B to 100% B in 40 min, 254 / 220 nm) to give Intermediate 12 (436.0 mg, 68.5%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =354.

[0739] Step 12: Preparation of 1-{3-[7-cyclopropyl-3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (Intermediate 13). [ka]

[0740] To a stirred solution of Intermediate 12 (25.0 mg, 0.071 mmol, 1 equiv.) and potassium cyclopropyltrifluorolambda 4-borane (52.28 mg, 0.355 mmol, 5 equiv.) in toluene (2 mL) and HO (0.4 mL), Pd(dppf)Cl (10.34 mg, 0.014 mmol, 0.2 equiv.) and KCO (29.30 mg, 0.213 mmol, 3 equiv.) were added. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions (Column: XBridge Shield RP). 18 OBD, 30 * 150 mm, 5 μm, Mobile phase A: Water (0.1% FA), Mobile phase B: ACN, Flow rate: 60 mL / min, Gradient: 35% B to 50% B in 8 min, 50% B, Wavelength: 254 / 220 nm, RT1 (min): 8.86, Number of runs: 0) to obtain Intermediate 13 (2.8 mg, 11.0%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =741.30. 1 H NMR (400MHz, methanol-d4)δ 8.80(s, 1H), 8.17-7.95(m, 3H), 7.40-7.32(m, 1H), 7.10-6.96(m, 2H), 4.79(t, J=8.5Hz, 1H), 4.68-4.48( m, 3H), 4.30(dd, J=9.4, 6.3Hz, 1H), 2.08-2.00(m, 1H), 1.96(s, 3H), 1.23-1.13(m, 2H), 0.97-0.89(m, 2H).

[0741] Step 13: Preparation of 2-[6-(azetidin-3-yl)-7-cyclopropylcinnolin-3-yl]phenol (I-44). [ka]

[0742] A solution of intermediate 13 (150.0 mg, 0.417 mmol, 1 equiv) and KOH (234.1 mg, 4.170 mmol, 10 equiv) in MeOH (2 mL) and HO (2 mL) was stirred at 60 °C overnight. The residue was purified by reverse-phase flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 35 mL / min, gradient: 0% B to 100% B in 40 min, 254 / 220 nm) to afford I-44 (61.0 mg, 44.2%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =318.

[0743] Preparation of 2-fluoro-2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-58). [ka]

[0744] Step 1: Preparation of N,3-dimethoxy-N-methyl-1,2-oxazole-5-carboxamide (Intermediate 2). [ka]

[0745] To 3-methoxy-1,2-oxazole-5-carboxylic acid (15 g, 104.823 mmol, 1 equiv.), N,O-dimethylhydroxylamine (7.68 g, 125.788 mmol, 1.2 equiv.), and HATU (47.83 g, 125.788 mmol, 1.2 equiv.) in DMF (150 mL) was added DIEA (67.74 g, 524.115 mmol, 5 equiv.). The solution was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (800 mL) and washed with HO (800 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 39% ethyl acetate in petroleum ether to give Intermediate 2 (17.6 g, 90.19%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =187.

[0746] Step 2: Preparation of 1-(3-methoxy-1,2-oxazol-5-yl)-2-methylpropan-1-one (Intermediate 3). [ka]

[0747] To a solution of intermediate 2 (16 g, 85.944 mmol, 1 equiv.) in THF (150 mL) was added bromo(isopropyl)magnesium (25.32 g, 171.888 mmol, 2 equiv.) under a N atmosphere at −78°C. The resulting solution was stirred at −78°C for 2 h. The reaction solution was diluted with MeOH (30 mL) and concentrated. The residue was diluted with EtOAc (600 mL) and washed with water (3×600 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography with an elution gradient of 0–15% ethyl acetate in petroleum ether to give intermediate 3 (9.8 g, 67.40%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =170.

[0748] Step 3: Preparation of 2-(3-methoxy-1,2-oxazol-5-yl)-3-methyl-2-[(trimethylsilyl)oxy]butanenitrile (Intermediate 4). [ka]

[0749] To a solution of intermediate 3 (9.8 g, 57.926 mmol, 1 equiv.) in THF (100 mL) was added trimethylsilyl cyanide (22.99 g, 231.704 mmol, 4 equiv.) and 18-crown-6 (1.53 g, 5.793 mmol, 0.1 equiv.). The resulting solution was stirred at 40 °C for 24 h. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with EtOAc (2 × 300 mL), and the combined organic layers were washed with saturated aqueous sodium chloride (3 × 500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using an elution gradient of 0–30% dichloromethane in petroleum ether to afford intermediate 4 (11.4 g, 73.33%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =269.

[0750] Step 4: Preparation of 2-hydroxy-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanenitrile (Intermediate 5). [ka]

[0751] To a solution of intermediate 4 (11.4 g, 42.476 mmol, 1 equiv) in DCM (50 mL) and MeOH (50 mL) was added TFA (5 mL). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0-33% ACN in water (0.1% TFA) to give intermediate 5 (7.8 g, 93.59%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =197.

[0752] Step 5: Preparation of 2-fluoro-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanenitrile (Intermediate 5). [ka]

[0753] To a solution of intermediate 5 (7.8 g, 39.754 mmol, 1 equiv) in DCM (60 mL) was added DAST (7.69 g, 47.708 mmol, 1.20 equiv) at 0 °C. The resulting solution was stirred at 0 °C for 15 min and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with DCM (2 × 200 mL), and the combined organic layers were washed with saturated aqueous sodium chloride (3 × 500 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 50% dichloromethane in petroleum ether to give intermediate 6 (4.01 g, 50.89%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =199.

[0754] Step 6: Preparation of 2-fluoro-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 7). [ka]

[0755] To a solution of intermediate 6 (200 mg, 1.009 mmol, 1 equiv) in MeOH (3 mL) and HO (3 mL) was added NaOH (403.61 mg, 10.090 mmol, 10 equiv). The resulting solution was stirred at 80 °C for 1 h. The mixture was acidified to pH 2 with 1 M HCl (aq). The solution was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 7 (220 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =218.

[0756] Step 7: Preparation of 2-fluoro-2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-58). [ka]

[0757] To a solution of intermediate 7 (220 mg, 1.013 mmol, 1 equiv) in HOAc (2.5 mL) was added HBr (48% in water, 2.5 mL). The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash C18 chromatography with an elution gradient of 0 to 25% acetonitrile in water (0.1% FA) to afford I-58 (136 mg, 66.09%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 14.12(s, 1H), 11.55(s, 1H), 6.16(s, 1H), 2.72-2.52(m, 1H), 0.97(d, J=6.9Hz, 3H), 0.88(d, J=6.8Hz, 3H). LCMS(ESI)m / z:[M+H] + =204.

[0758] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 51). [ka]

[0759] Step 1: Preparation of tert-butyl 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 2). [ka]

[0760] To a stirred mixture of 7-chloro-3-[2-(methoxymethoxy)phenyl]cinnoline (6 g, 19.951 mmol, 1 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.58 g, 7.980 mmol, 1.2 equiv.) in dioxane (50 mL), Cs2Co3 (19.50 g, 59.853 mmol, 3 equiv.) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (1.68 g, 1.995 mmol, 0.1 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give intermediate 2 (8 g, 86.69%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =463.

[0761] Step 2: Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}cinnolin-3-yl)phenol (I-45). [ka]

[0762] To a stirred mixture of TFA (10 mL) and DCM (30 mL) was added Intermediate 2 (8 g, 17.295 mmol, 1 equiv.) and stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 60% in 30 min; detector, UV 254 nm. This afforded I-45 (4 g, 72.64%) as a red solid. LCMS (ESI) m / z: [M+H] + =319.

[0763] Step 3: Preparation of methyl 2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 4). [ka]

[0764] A stirred mixture of intermediate 3 and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (9.07 g, 18.846 mmol, 2 equiv.) in NMP (20 mL) was added dropwise to DIEA (3.65 g, 28.269 mmol, 3 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 1 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% to 90% in 40 min; detector, UV 254 nm. This afforded intermediate 4 (700 mg, 14.87%) as a red solid. LCMS (ESI) m / z: [M+H] + =500.

[0765] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (Intermediate 5). [ka]

[0766] A mixture of intermediate 4 (700 mg, 1.401 mmol, 1 equiv.) and LiOH·HO (587.94 mg, 14.010 mmol, 10 equiv.) in MeOH (8 mL) and HO (2 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was diluted with CHCl / MeOH (9:1) (100 mL). The resulting mixture was washed with 3×100 mL of brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 5 (500 mg, 73.49%) as a red solid. LCMS (ESI) m / z: [M+H] + =486.

[0767] Step 5: Preparation of (2R,4S)-4-hydroxy-1-[2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 6). [ka]

[0768] To a stirred mixture of intermediate 5 (210 mg, 0.433 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (186.35 mg, 0.563 mmol, 1.3 equiv.) in DMF (2 mL), PyBOP (450.15 mg, 0.866 mmol, 2 equiv.) and DIEA (226.01 µL, 1.299 mmol, 3 equiv.) were added dropwise at room temperature. The resulting mixture was stirred for an additional hour at room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water; gradient, 10% to 90% in 30 min; detector, UV 254 nm. This gave intermediate 6 (102 mg, 29.52%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =799.

[0769] Step 6: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 51) [ka]

[0770] Intermediate 6 was purified under the following conditions (column: CHIRALPAK ID, 2 * 25 cm, 5 μm, mobile phase: MtBE (10 mM NH 3 -MeOH) and EtOH (hold 30 min at 50% EtOH), detector: UV 254 nm. This gave 51 (second peak) (47.8 mg, 45.74%) as a red solid. 1H NMR (400 MHz, DMSO-d) δ 12.82(d, J=4.8Hz, 1H), 9.00(d, J=6.4Hz, 1H), 8.76(s, 1H), 8.42(d, J=7. 7Hz, 1H), 8.07-8.01(m, 1H), 7.96(d, J=9.0Hz, 1H), 7.50-7.42(m, 2H), 7.3 7(d, J=8.1Hz, 2H), 7.35-7.25(m, 2H), 7.01(d, J=8.0Hz, 3H), 5.87(d, J=42 .8Hz, 1H), 5.12(d, J=3.6Hz, 1H), 5.05-4.85(m, 1H), 4.37(t, J=7.7Hz, 1H) , 4.29(s, 5H), 4.13(s, 4H), 3.71(dd, J=10.6, 4.4Hz, 1H), 3.60(t, J=10.6H z, 1H), 3.45(dd, J=14.0, 10.8Hz, 1H), 2.47(d, J=4.9Hz, 3H), 2.34-2.13(m , 1H), 2.03(t, J=10.0Hz, 1H), 1.79(ddd, J=12.8, 8.2, 4.9Hz, 1H), 1.43(dd , J=32.8, 7.0Hz, 3H), 0.96(d, J=6.5Hz, 3H), 0.82(dd, J=14.9, 6.7Hz, 3H). LCMS(ESI)m / z:[M+H] + =799.15.

[0771] The compounds in Table 8 were prepared using procedures similar to those used to prepare compound 51 above, using the appropriate Boc-diamine and chloro-cinnoline.

[0772] [Table 9-1]

[0773] [Table 9-2]

[0774] [Table 9-3]

[0775]

Table 9-4

[0776]

Table 9-5

[0777]

Table 9-6

[0778]

Table 9-7

[0779]

Table 9-8

[0780]

Table 9-9

[0781]

Table 9-10

[0782]

Table 9-11

[0783]

Table 9-12

[0784]

Table 9-13

[0785]

Table 9-14

[0786]

Table 9-15

[0787]

Table 9-16

[0788]

Table 9-17

[0789]

Table 9-18

[0790]

Table 9-19

[0791]

Table 9-20

[0792]

Table 9-21

[0793]

Table 9-22

[0794]

Table 9-23

[0795]

Table 9-24

[0796] [Table 9-25]

[0797] [Table 9-26]

[0798] Preparation of (2S,4R)-1-[(2S)-2-cyclopropyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 210-001). [ka]

[0799] Step 1: Preparation of ethyl 2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclopropylacetate (I-46) [ka]

[0800] To a solution of 4-bromo-1H-1,2,3-triazole (1 g, 6.758 mmol, 1 equiv.) and ethyl 2-bromo-2-cyclopropylacetate (2.80 g, 13.516 mmol, 2 equiv.) in DMF (5 mL) was added KCO (1.87 g, 13.516 mmol, 2 equiv.). The resulting solution was stirred at 60 °C for 4 h. The resulting mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient 0% to 100% in 30 min, detector, UV 254 / 220 nm to give I-46 (611 mg, 32.98%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =274. [ka]

[0801] Ethyl 2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclobutylacetate (I-47) and ethyl 2-(4-bromo-1H-1,2,3-triazol-1-yl)-3-methylbutanoate (I-48) were prepared from 4-bromo-1H-1,2,3-triazole using a procedure similar to that for I-46.

[0802] Step 2: Preparation of 4-bromo-1,2,3-triazol-1-yl)(cyclopropyl)acetic acid intermediate 3) [ka]

[0803] A solution of intermediate 2 (489 mg, 1.784 mmol, 1 equiv) and LiOH (213.62 mg, 8.920 mmol, 5 equiv) in MeOH (4 mL) and HO (1 mL) was stirred at room temperature for 3 h. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 3 (481 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] = 245.

[0804] Step 3: Preparation of (2S,4R)-1-[2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclopropylacetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4). [ka]

[0805] To a stirred solution of Intermediate 3 (481 mg, 1.955 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol)]-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (971.81 mg, 2.933 mmol, 1.5 equiv.), HOBT (528.28 mg, 3.910 mmol, 2 equiv.), and EDCI (749.46 mg, 3.910 mmol, 2 equiv.) in DMF (2 mL) was added DIEA (1263.24 mg, 9.775 mmol, 5 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% NH4HCO3) in water, gradient 0% to 100% in 30 min, detector, UV 254 / 220 nm to give intermediate 4 (291 mg, 26.61%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =559.

[0806] Step 4: Preparation of tert-butyl 6-(1-{1-cyclopropyl-2-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl))phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-2-oxoethyl}-1,2,3-triazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 5). [ka]

[0807] A solution of Intermediate 4 (281 mg, 0.502 mmol, 1 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (199.16 mg, 1.004 mmol, 2 equiv.), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (42.25 mg, 0.050 mmol, 0.1 equiv.), and Cs2Co3 (327.29 mg, 1.004 mmol, 2 equiv.) in 1,4-dioxane (2 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm to give intermediate 5 (116 mg, 34.12%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =677.

[0808] Step 5: Preparation of (2S,4R)-1-[2-cyclopropyl-2-(4-{2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 6). [ka]

[0809] To a solution of intermediate 5 (106 mg, 0.157 mmol, 1 equiv.) in DCM (1.5 mL) was added TFA (0.5 mL) and stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% NH4HCO3) in water, gradient 0% to 100% in 30 min, detector, UV 254 / 220 nm to give intermediate 6 (61 mg, 67.54%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =577.

[0810] Step 6: Preparation of (2S,4R)-1-[2-{cyclopropyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl}-2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 7) [ka]

[0811] A solution of Intermediate 6 (51 mg, 0.088 mmol, 1 equiv.), I-12 (22.70 mg, 0.088 mmol, 1 equiv.), Pd-PEPPSI-IPentCl 2-methylpyridine (9 mg, 0.009 mmol, 0.1 equiv.), and Cs2Co3 (57.63 mg, 0.176 mmol, 2 equiv.) in 1,4-dioxane (1 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm to give intermediate 7 (43 mg, 61.01%) as a red solid. LCMS (ESI) m / z: [M+H] + =797.

[0812] Step 7: Preparation of (2S,4R)-1-(2S)-2-cyclopropyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 210-001). [ka]

[0813] Intermediate 7 (36 mg) was purified by HPLC under the following conditions: column, CHIRAL ART Amylose-C NEO, 2 *25 cm, 5 μm, Mobile phase A: MtBE (10 mM NH3-MeOH), Mobile phase B: MeOH, Flow rate: 20 mL / min, Gradient: Isocratic 50% B Wavelength: 272 / 210 nm, RT1 (min): 6.75, RT2 (min): 10, Sample solvent: MeOH, Injection volume: 0.7 mL, Run number: 4, Obtained 210-001 (second peak) (9.5 mg, 26.39%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.83(s, 1H), 8.99(s, 1H), 8.76(s, 1H), 8.42(d, J=7.6Hz, 1H), 8.11-7.90(m, 2H), 7.5 5(s, 1H), 7.49-7.27(m, 6H), 7.01(d, J=8.4Hz, 3H), 5.16(s, 1H), 5.04(d, J=8.7Hz, 1H) , 4.93(s, 1H), 4.35(d, J=27.2Hz, 6H), 4.05(s, 4H), 3.65(s, 1H), 3.52(s, 1H), 2.46(s, 3H), 2.04(s, 1H), 1.80(s, 1H), 1.53(s, 1H), 1.38(d, J=7.1Hz, 3H), 0.73-0.44(m, 4H). LCMS(ESI)m / z:[M+H] + =797.30.

[0814] The compounds in Table 9 were prepared by procedures similar to those used to prepare compound 210-001 above.

[0815] [Table 10-1]

[0816] [Table 10-2]

[0817] [Table 10-3]

[0818] [Table 10-4]

[0819] [Table 10-5]

[0820] [Table 10-6]

[0821] [Table 10-7]

[0822] Preparation of 2-(4-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoic acid (I-49) [ka]

[0823] Step 1: Preparation of tert-butyl 6-(1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 2) [ka]

[0824] To a stirred solution of I-48 (1.58 g, 5.722 mmol, 1 equiv.) and intermediate 6 (3.40 g, 17.166 mmol, 3 equiv.) in 1,4-dioxane (30 mL), Cs2Co3 (5.59 g, 17.166 mmol, 3 equiv.) and Pd-PEPPSI-IPentCl 2-methylpyridine (0.19 g, 0.229 mmol, 0.04 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 25 min; detector, UV 254 nm. This afforded intermediate 2 (2.1 g, 92.10%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =394.

[0825] Step 2: Preparation of ethyl 2-(4-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoate Intermediate 3) [ka]

[0826] To a solution of intermediate 2 (2.1 g, 5.340 mmol, 1 equiv.) in DCM (6 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water, gradient 10% to 100% in 30 min, detector, UV 254 nm. This gave intermediate 3 (1.4 g, 89.17%) as a colorless oil. LCMS (ESI) m / z [M+H] + =294.

[0827] Step 3: Preparation of ethyl 2-(4-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoate (Intermediate 4) [ka]

[0828] To a stirred solution of intermediate 3 (1 g, 3.409 mmol, 1 equiv.) and I-12 (1.31 g, 5.114 mmol, 1.5 equiv.) in dioxane (10 mL), Cs2Co3 (3.34 g, 10.227 mmol, 3 equiv.) and Pd-PEPPSI-IPentCl 2-methylpyridine (2.87 mg, 0.003 mmol, 0.1 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This gave intermediate 4 (985 mg, 56.26%) as a yellow solid. LCMS (ESI) m / z [M+H] + =514.

[0829] Step 4: Preparation of 2-(4-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoic acid (I-49) [ka]

[0830] A mixture of intermediate 4 (985 mg, 1.918 mmol, 1 equiv) and LiOH·HO (459.32 mg, 19.180 mmol, 10 equiv) in MeOH (4 mL) and HO (2 mL) was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The mixture was acidified to pH 6 with HCl (aq). The resulting mixture was diluted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave I-49 (498 mg, 53.48%) as a red solid. LCMS (ESI) m / z [M+H] + =486.

[0831] Preparation of (2S,4R)-N-[(2-chloro-4-ethynylphenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide (I-50) [ka]

[0832] Step 1: Preparation of tert-butyl N-({2-chloro-4-[2-(trimethylsilyl)ethynyl]phenyl}methyl)carbamate (Intermediate 2) [ka]

[0833] A mixture of tert-butyl N-[(4-bromo-2-chlorophenyl)methyl]carbamate (1 g, 3.119 mmol, 1 equiv.), trimethylsilylacetylene (919.06 mg, 9.357 mmol, 3 equiv.), Pd(dppf)Cl2.CHCl2 (127.04 mg, 0.156 mmol, 0.05 equiv.), and CuI (59.40 mg, 0.312 mmol, 0.1 equiv.) in TEA (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 4 h. The desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (3 × 50 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 / EA (4:1) to give Intermediate 2 (1.15 g, crude) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =338.

[0834] Step 2: Preparation of tert-butyl N-[(2-chloro-4-ethynylphenyl)methyl]carbamate (Intermediate 3) [ka]

[0835] A mixture of intermediate 2 (1.1 g, 3.255 mmol, 1 equiv.) and K2CO3 (1349.66 mg, 9.765 mmol, 3 equiv.) in MeOH (10 mL) was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 3 (860 mg, 99.42%) as a brown oil. LCMS (ESI) m / z [M+H] + =266.

[0836] Step 3: Preparation of 1-(2-chloro-4-ethynylphenyl)methanamine (Intermediate 4). [ka]

[0837] To a stirred solution of intermediate 3 (850 mg, 3.199 mmol, 1 equiv.) in DCM (5 mL) was added dropwise HCl (gas) in 1,4-dioxane (4 M) (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give intermediate 4 (670 mg, hydrochloride salt) as an off-white solid. LCMS (ESI) m / z: [M+H] + =166.

[0838] Step 4: Preparation of tert-butyl (2S,4R)-2-{[(2-chloro-4-ethynylphenyl)methyl]carbamoyl}-4-hydroxypyrrolidine-1-carboxylate (Intermediate 5). [ka]

[0839] A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.865 mmol, 1.00 equiv.), EDCI (248.69 mg, 1.297 mmol, 1.5 equiv.), and HOBT (175.30 mg, 1.297 mmol, 1.5 equiv.) in DMF (3 mL) was stirred at room temperature for 15 minutes. To the above mixture, Intermediate 4 (171.89 mg, 1.038 mmol, 1.2 equiv.) and DIEA (335.35 mg, 2.595 mmol, 3 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for another 2 hours. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 15 min, detector, UV 254 to give intermediate 5 (320 mg, 97.66%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =379.

[0840] Step 5: Preparation of (2S,4R)—N-[(2-chloro-4-ethynylphenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide (I-50). [ka]

[0841] To a stirred solution of intermediate 5 (310 mg, 0.818 mmol, 1 equiv.) in DCM (3 mL) was added dropwise HCl (gas) in 1,4-dioxane (4 M) (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give I-50 (310 mg, HCl salt) as an off-white solid. LCMS (ESI) m / z: [M+H] + =279.

[0842] Preparation of 2-(3-{2-[(3S)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-52) [ka]

[0843] Step 1: Preparation of tert-butyl 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 2) [ka]

[0844] To a stirred mixture of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (1.45 g, 4.489 mmol, 1.5 equiv.), I2 (0.38 g, 1.496 mmol, 0.5 equiv.), and Zn (0.59 g, 8.979 mmol, 3 equiv.) in DMF (9 mL) was added I-12 (900 mg, 2.993 mmol, 1 equiv.), XPhos (0.29 g, 0.599 mmol, 0.2 equiv.), and XPhos Pd G3 (0.51 g, 0.599 mmol, 0.2 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. This afforded intermediate 2 (1 g, 72.40%) as a brown solid. LCMS(ESI)m / z[M+H] + =462.

[0845] Step 2: Preparation of 2-(7-{2-azaspiro[3.3]heptan-6-yl}cinnolin-3-yl)phenol (I-51) [ka]

[0846] A mixture of Intermediate 2 (1 g, 2.167 mmol, 1 equiv.) in TFA (7.5 mL) and DCM (2.5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give I-51 (1.4 g, 91.62%) as a brown oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =318.

[0847] Step 3: Preparation of ethyl 2-cyclobutyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)acetate (Intermediate 4). [ka]

[0848] To a stirred mixture of I-51 (200 mg, 0.630 mmol, 1 equiv.) and I-47 (217.88 mg, 0.756 mmol, 1.2 equiv.) in DMSO (3 mL), CuI (24.00 mg, 0.126 mmol, 0.2 equiv.), K2CO3 (261.26 mg, 1.890 mmol, 3 equiv.), and L-proline (14.51 mg, 0.126 mmol, 0.2 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% in 10 min; detector, UV 254 nm. This afforded intermediate 4 (60 mg, 18.1%) as a brown solid. LCMS (ESI) m / z: [M+H] + =525.

[0849] Step 4: Preparation of 2-(3-{2-[(3S)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-52) [ka]

[0850] A mixture of intermediate 4 (60 mg, 0.12 mmol, 1 equiv.) and LiOH (24.91 mg, 1.240 mmol, 3 equiv.) in MeOH (2 mL) and HO (1 mL) was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was concentrated under reduced pressure to give I-52 (40 mg, crude) as a brown solid. LCMS (ESI) m / z [M+H] + =497.

[0851] Preparation of 2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoic acid (I-53). [ka]

[0852] Using I-46 and I-51, intermediate I-53 was prepared as a brown solid using a procedure similar to that used above for the preparation of I-52. LCMS (ESI) m / z [M+H] + =485.

[0853] Preparation of (2S,4R)-N-[(2-chloro-4-ethynylphenyl)methyl]-4-hydroxy-1-[(2S)-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoyl]pyrrolidine-2-carboxamide (compound 223-001). [ka]

[0854] A mixture of I-50 (60.28 mg, 0.216 mmol, 1.50 equiv.), I-53 (70 mg, 0.144 mmol, 1.00 equiv.), PyBOP (112.54 mg, 0.216 mmol, 1.5 equiv.), and DIEA (55.90 mg, 0.432 mmol, 3 equiv.) in DMF (1 mL) was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The crude product was purified by Prep-HPLC under the following conditions: CHIRALPAK IA-3 Column, 4.6 * 50 mm, 3 mm, mobile phase A: MtBE (0.1% DEA): EtOH = 50:50, gradient), the final compound mixture (60 mg, 55.77%) was obtained as a reddish-brown solid. LCMS (ESI) m / z: [M+H] + =746.

[0855] The above mixture was separated by chiral HPLC using the following conditions: Column: CHIRALPAK IA-3, 4.6 * Purification by 50 mm, 3 μm, mobile phase A: MtBE (0.1% DEA):MeOH=70:30 gave 223-001 (23.5 mg, 38.70%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 12.82(s, 1H), 8.76(s, 1H), 8.67(t, J=5.9Hz, 1H), 8.03(d, J=8.2, 1.6Hz, 1H), 7.96(d, J=9.1Hz, 1H), 7.60-7 .54(m, 1H), 7.51-7.37(m, 3H), 7.36-7.25(m, 2H), 7.05-6.96(m, 3H), 5.20(d, J=3.6Hz, 1H), 5.11(d, J=10.4 Hz, 1H), 4.44-4.31(m, 4H), 4.30(d, J=4.2Hz, 5H), 4.09-3.99(m, 4H), 3.86-3.78(m, 1H), 3.62(d, J=10.9Hz, 1H), 2.34-2.28(m, 1H), 2.13-2.03(m, 1H), 1.97-1.86(m, 1H), 0.99(d, J=6.5Hz, 3H), 0.67(d, J=6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + =746.25.

[0856] The compounds in Table 10 were prepared using procedures similar to those used above for the preparation of compound 223-001, using the appropriate amine and acid (I-53 or analog).

[0857] [Table 11-1]

[0858] [Table 11-2]

[0859] [Table 11-3]

[0860] Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]spiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 208-001). [ka]

[0861] Step 1: Preparation of methyl 6-hydroxyspiro[3.3]heptane-2-carboxylate (Intermediate 2). [ka]

[0862] To a stirred solution of methyl 6-oxospiro[3.3]heptane-2-car...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 in the formula,[[]]END]] m is 0, 1, 2, or 3,[[]]END]] k is 0, 1, or 2,[[]]END]] Each R １ is, independently, halo, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ２ to C ９ heterocyclyl, optionally substituted C ３ to C ８ cycloalkyl, optionally substituted C ３ to C ８ cycloalkoxy, optionally substituted C ２ to C ６ alkynyl, optionally substituted amino, or cyano, Each X is, independently, halo or optionally substituted C １ ~C ６ heteroalkyl, L is a linker,[[]]END]] B is a cleavage moiety, a compound of formula I, or a pharmaceutically acceptable salt thereof.[[]]END]]

2. Each R １ is, independently, halo, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ２ to C ９ heterocyclyl, or optionally substituted C ３ to C ８ cycloalkyl, and The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each X is independently halo.[[]]END]]

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound has a structure of formula I-A:[[]]END]] [Chemical Formula 2]

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound has a structure of formula I-B:[[]]END]] 【Chemical Formula 3】

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein m is 1.[[]]END]]

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein m is 2.[[]]END]]

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein m is 3.[[]]END]]

8. R １ is optionally substituted C １ -C ６ heteroalkyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. R １ is optionally substituted C １ -C ６ alkoxy or halo, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

10. R １ The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein R is methoxy or difluoromethoxy.

11. R １ The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R is F or Cl.

12. R １ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

13. R １ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R is methyl or difluoromethyl.

14. R １ is optionally substituted C ２ to C ６ alkynyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

15. R １ The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein R is methine.

16. R １ is optionally substituted C ３ to C ８ cycloalkyl or optionally substituted C ３ to C ８ cycloalkoxy, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

17. R １ The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R is cyclopropane or cyclopropoxy.

18. R １ is optionally substituted C ２ to C ９ heterocyclyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

19. R １ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is amino or cyano which is optionally substituted.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein m is 0.[[]]END]]

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein k is 0.[[]]END]]

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein k is 1.[[]]END]]

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein k is 2.[[]]END]]

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 and 22 to 23, wherein X is methoxy or F.[[]]END]]

25. The cleavage moiety B has a structure of formula A-1, wherein 【Chemical Formula 4】 in the formula,[[]]END]] Y １ is [Chemical Formula 5] and R Ａ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ａ６ is H or optionally substituted C １ -C ６ -C alkyl, R Ａ７ is H or optionally substituted C １ -C ６ -C alkyl, or R Ａ６ and R Ａ７ each combine with the carbon atom to which they are attached to form an optionally substituted C ３ -C ６ -C carbocyclic or an optionally substituted C ２ -C ５ -C heterocyclic, or R Ａ６ and R Ａ７ each combine with the carbon atom to which they are attached to form an optionally substituted C ３ -C ６ -C carbocyclic or an optionally substituted C ２ -C ５ -C heterocyclic, R Ａ８ is H, optionally substituted C １ to C ６ alkyl, or optionally substituted C １ to C ６ heteroalkyl, and R Ａ１ 、 R Ａ２ 、 R Ａ３ 、 and R Ａ４ each independently is H, A ２ 、 halogen, optionally substituted C １ ~C ６ alkyl, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted C ３ ~C １０ carbocyclyl, optionally substituted C ２ ~C ９ heterocyclyl, optionally substituted C ６ ~C １０ aryl, optionally substituted C ２ ~C ９ heteroaryl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ heteroalkenyl, optionally substituted -O-C ３ ~C ６ carbocyclyl, hydroxyl, thiol, or optionally substituted amino, or R Ａ１ and R Ａ２ 、 R Ａ２ and R Ａ３ 、 and / or R Ａ３ and R Ａ４ together with the carbon atom to which each is attached combine to form [Chemical Formula 6] forms 【Chemical Formula 7】 is optionally substituted C ６ to C １０ aryl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ２ to C ９ heteroaryl, or C ２ to C ９ heterocyclic, any of which is optionally substituted by A ２ and R Ａ１ 、R Ａ２ 、R Ａ３ 、and R Ａ４ one of which is A ２ or 【Chemical 8】 is A ２ is replaced by A ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, which is a bond between the decomposition part and the linker.

26. R Ａ５ The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein R is H or methyl.

27. R Ａ１ is A ２ and R Ａ２ R Ａ３ and R Ａ４ each of which is H, the compound according to any one of claims 25 to 26 or a pharmaceutically acceptable salt thereof.

28. R Ａ２ is A ２ and R Ａ１ R Ａ３ and R Ａ４ each of which is H, the compound according to any one of claims 25 to 26 or a pharmaceutically acceptable salt thereof.

29. R Ａ３ is A ２ and R Ａ１ R Ａ２ and R Ａ４ each of which is H, a compound according to any one of claims 25 to 26 or a pharmaceutically acceptable salt thereof.

30. R Ａ４ is A ２ and R Ａ１ R Ａ２ and R Ａ３ each of which is H, the compound according to any one of claims 25 to 26 or a pharmaceutically acceptable salt thereof.

31. Y １ is 【Chemical Formula 9】 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein

32. R Ａ６ is H, and R Ａ７ is H, the compound according to claim 31 or a pharmaceutically acceptable salt thereof.

33. Y １ is 【Chemical 10】 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein

34. R Ａ８ The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein R is H or methyl.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 28, wherein the decomposition moiety has a structure of formula A2 or formula A4: 【Chemical 11】

36. The decomposition moiety is 【Chemical 12】 The compound or a pharmaceutically acceptable salt thereof according to claim 35.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein the decomposition moiety has a structure of formula A5, formula A6, formula A8, or formula A10: 【Chemical 13】

38. The decomposition moiety is 【Chemical Formula 14】 The compound or a pharmaceutically acceptable salt thereof according to claim 25, which has a structure of

39. The decomposition moiety has a structure of formula C, 【Chemical 15】 wherein L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 16】 is R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ４ is H, optionally substituted C １ -C ６ -C ３ -C １０ -C ６ -C １０ -C １ -C ６ alkyl C ３ -C １０ -C １ -C ６ alkyl C ６ -C １０ -C aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is, independently, A ２ , halogen, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ２ to C ９ heterocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C ２ to C ９ heteroaryl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ each independently is H, halogen, optionally substituted C １ to C ６ alkyl, or optionally substituted C ６ to C １０ aryl, and R Ｂ９ is H or optionally substituted C １ ~C ６ alkyl, R Ｂ１０ is H or F, A ２ is a bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one of them is A ２ structure or the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, which has a pharmaceutically acceptable salt thereof.

40. The decomposition moiety has a structure of formula C, 【Chemical 17】 wherein L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 18】 is R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, optionally substituted C １ ~C ６ alkyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ６ ~C １０ aryl, optionally substituted C １ ~C ６ alkyl C ３ ~C １０ carbocyclic, or optionally substituted C １ ~C ６ alkyl C ６ ~C １０ aryl, and R Ｂ５ is H, optionally substituted C １ to C ６ alkyl, or optionally substituted C １ to C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is, independently, A ２ , halogen, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclyl, optionally substituted C ２ -C ９ heterocyclyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ heteroalkenyl, hydroxy, thiol, or optionally substituted amino, R Ｂ７ and R Ｂ８ each independently is H, halogen, optionally substituted C １ ~C ６ alkyl, or optionally substituted C ６ ~C １０ aryl, and R Ｂ９ is H or optionally substituted C １ ~C ６ alkyl, A ２ is the bond between the decomposition part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one of them is A ２ structure or the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, which has a pharmaceutically acceptable salt thereof.

41. The compound or a pharmaceutically acceptable salt thereof according to claim 39 or 40, wherein the decomposition moiety has a structure of formula C3 or formula C1: 【Chemical 19】

42. The compound or a pharmaceutically acceptable salt thereof according to claim 39, wherein the decomposition moiety has a structure of formula C4: 【Chemical 20】

43. The decomposition moiety is 【Chemical 21】 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 or 40.

44. The decomposition moiety is 【Chemical 22】 The compound or a pharmaceutically acceptable salt thereof according to claim 39.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 to 40, wherein the decomposition moiety has a structure of formula C2: 【Chemical 23】

46. The compound or a pharmaceutically acceptable salt thereof according to claim 39, wherein the decomposition moiety has a structure of formula Ca2, formula Cb2, formula Cc2, formula Cd2, formula Ce2, or formula Cf2: 【Chemical 24】

47. R Ｂ９ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 39 to 42 and 45 to 46 or a pharmaceutically acceptable salt thereof.

48. R Ｂ９ The compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

49. R Ｂ９ which is attached to the (S)-stereocenter and is a compound according to any one of claims 39 to 42 and 45 to 48 or a pharmaceutically acceptable salt thereof.

50. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 to 42 and 45 to 49, wherein v2 is 0.

51. R Ｂ４ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 to 42 and 45 to 50, wherein R is H.

52. R Ｂ５ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 to 42 and 45 to 51, wherein R is H.

53. R Ｂ７ is optionally substituted C １ to C ６ alkyl, a compound according to any one of claims 39 to 42 and 45 to 52 or a pharmaceutically acceptable salt thereof.

54. R Ｂ７ The compound according to claim 53, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

55. R Ｂ３ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 39 to 42 and 45 to 54 or a pharmaceutically acceptable salt thereof.

56. R Ｂ３ The compound or a pharmaceutically acceptable salt thereof according to claim 55, wherein R is isopropyl or fluoro-2-methylpropane.

57. R Ｂ３ is optionally substituted C ３ -C １０ carbocyclic, the compound according to any one of claims 39 to 42 and 45 to 54 or a pharmaceutically acceptable salt thereof.

58. R Ｂ３ The compound or a pharmaceutically acceptable salt thereof according to claim 57, wherein R is cyclopropane.

59. R Ｂ８ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 to 42 and 45 to 58, wherein R is H.

60. R Ｂ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 39 to 42 and 45 to 59, wherein R is H.

61. The decomposition moiety is 【Chemical Formula 25】 The compound according to any one of claims 39 to 40, or a pharmaceutically acceptable salt thereof.

62. wherein the decomposable moiety is 【Chemical 26】 The compound according to claim 39, or a pharmaceutically acceptable salt thereof.

63. wherein the decomposable moiety is 【Chemical 27】 The compound according to claim 39, or a pharmaceutically acceptable salt thereof.

64. wherein the decomposable moiety is 【Chemical formula 28】 The compound according to claim 39, or a pharmaceutically acceptable salt thereof.

65. wherein the decomposable moiety has the structure of Formula C5, 【Chemical 29】 wherein in the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 30】 and R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is independently A ２ , halogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ２ -C ９ heterocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ each independently is H, halogen, optionally substituted C １ to C ６ alkyl, or optionally substituted C ６ to C １０ aryl, and R Ｂ９ is H or optionally substituted C １ -C ６ -C alkyl, and R Ｂ１１ is H, an alcohol, a boronic acid, optionally substituted C １ to C ６ alkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and and A ２ is the bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one of ２ is A or a pharmaceutically acceptable salt thereof, the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

66. R Ｂ１１ The compound according to claim 65, or a pharmaceutically acceptable salt thereof, wherein R is a boronic acid.

67. The compound according to any one of claims 65 to 66, or a pharmaceutically acceptable salt thereof, wherein the decomposable moiety has the structure of Formula C6, Formula C7, or Formula C8. 【Chemical Formula 31】

68. R Ｂ９ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 65 to 66 or a pharmaceutically acceptable salt thereof.

69. R Ｂ９ The compound or a pharmaceutically acceptable salt thereof according to claim 68, wherein R is methyl.

70. R Ｂ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 65 to 69, wherein R is attached to the (S)-stereocenter.

71. The compound according to any one of claims 65 to 70, or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

72. R Ｂ５ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 65 to 71, wherein R is H.

73. R Ｂ７ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 65 to 72 or a pharmaceutically acceptable salt thereof.

74. In some embodiments, R Ｂ７ is methyl, the compound according to claim 73 or a pharmaceutically acceptable salt thereof.

75. R Ｂ３ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 65 to 74 or a pharmaceutically acceptable salt thereof.

76. R Ｂ３ The compound according to claim 75, or a pharmaceutically acceptable salt thereof, wherein R is isopropyl.

77. R Ｂ８ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 65 to 76, wherein R is H.

78. R Ｂ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 65 to 77, wherein R is H.

79. wherein the decomposable moiety is 【Chemical Formula 32】 The compound according to any one of claims 65 and 66, or a pharmaceutically acceptable salt thereof.

80. wherein the decomposable moiety has the structure of Formula D, 【Chemical 33】 wherein in the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 34】 and R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ４ is H, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, optionally substituted C １ to C ６ alkyl, or optionally substituted C １ to C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is independently A ２ , halogen, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ２ to C ９ heterocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C ２ to C ９ heteroaryl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ９ is H or optionally substituted C １ -C ６ to C alkyl, A ２ is a bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one of them is A ２ structure or a pharmaceutically acceptable salt thereof, the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

81. The compound according to claim 80, or a pharmaceutically acceptable salt thereof, wherein the decomposable moiety has the structure of Formula D3 or Formula D1: 【Chemical 35】

82. wherein the decomposable moiety is 【Chemical 36】 The compound according to any one of claims 80 to 81, or a pharmaceutically acceptable salt thereof.

83. The compound according to claim 80, or a pharmaceutically acceptable salt thereof, wherein the decomposable moiety has the structure of Formula D2: 【Chemical 37】

84. R Ｂ９ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 80 and 83 or a pharmaceutically acceptable salt thereof.

85. R Ｂ９ The compound according to claim 84, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

86. R Ｂ９ The compound according to any one of claims 80 and 83 to 85, or a pharmaceutically acceptable salt thereof, wherein R is attached to the (S)-stereocenter.

87. R Ｂ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83, wherein R is H.

88. The compound according to any one of claims 80 and 83 to 87, or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

89. The compound according to any one of claims 80 and 83 to 87, or a pharmaceutically acceptable salt thereof, wherein v2 is 1.

90. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83 to 87, wherein v2 is 2.

91. R Ｂ４ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83 to 90, wherein R is H.

92. R Ｂ５ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83 to 91, wherein R is H.

93. R Ｂ３ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 80 and 83 to 92 or a pharmaceutically acceptable salt thereof.

94. R Ｂ３ The compound or a pharmaceutically acceptable salt thereof according to claim 93, wherein R is isopropyl.

95. R Ｂ６ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83 to 94, wherein R is H.

96. R Ｂ６ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83 to 94, wherein R is fluorine, chlorine, or bromine.

97. R Ｂ６ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 80 and 83 to 94, wherein R is cyano.

98. R Ｂ６ is optionally substituted C １ -C ６ heteroalkyl, a compound according to any one of claims 80 and 83 to 94 or a pharmaceutically acceptable salt thereof.

99. R Ｂ６ The compound according to claim 98, or a pharmaceutically acceptable salt thereof, wherein R is methoxy or 3-methoxy-1-propoxy.

100. R Ｂ６ is optionally substituted C ３ -C ６ -alkynyl, a compound according to any one of claims 80 and 83 to 94 or a pharmaceutically acceptable salt thereof.

101. The decomposition moiety is 【Chemical 38】 【Chemical Formula 39】 The compound or a pharmaceutically acceptable salt thereof according to claim 80.

102. The decomposition moiety has a structure of formula Da, wherein 【Chemical Formula 40】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 41】 and R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ４ is H, optionally substituted C １ to C ６ alkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and X １ and X ２ each independently is C, N, or O, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is, independently, A ２ , halogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclyl, optionally substituted C ２ -C ９ heterocyclyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ９ is H or optionally substituted C １ -C ６ -C alkyl, A ２ is a bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one of ２ them is A or a pharmaceutically acceptable salt thereof, of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24.

103. The compound or a pharmaceutically acceptable salt thereof according to claim 102, wherein the decomposition moiety has a structure of formula Da3, formula Da1, or formula Da2. 【Chemical 42】

104. R Ｂ９ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 102 to 103 or a pharmaceutically acceptable salt thereof.

105. R Ｂ９ The compound according to claim 104, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

106. R Ｂ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 102 to 105, wherein R is attached to the (S)-stereocenter.

107. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 102 to 106, wherein v2 is 0.

108. R Ｂ４ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 102 to 107, wherein R is H.

109. R Ｂ５ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 102 to 108, wherein R is H.

110. R Ｂ３ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 102 to 109 or a pharmaceutically acceptable salt thereof.

111. R Ｂ３ The compound or a pharmaceutically acceptable salt thereof according to claim 110, wherein R is isopropyl.

112. X １ is C, and X ２ is N, the compound according to any one of claims 102 to 111, or a pharmaceutically acceptable salt thereof.

113. The decomposition moiety is 【Chemical 43】 The compound or a pharmaceutically acceptable salt thereof according to claim 102.

114. The decomposition moiety has a structure of formula E, wherein 【Chemical 44】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 45】 and R Ｂ１ is H, A ２ optionally substituted C １ to C ６ alkyl, or optionally substituted C １ to C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, optionally substituted C １ to C ６ alkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ９ is H, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ alkynyl, optionally substituted C ３ -C １０ carbocyclic, or optionally substituted C ２ -C １０ heterocyclic, B １０ is H, optionally substituted C １ ~C ６ alkyl, optionally substituted C ３ ~C ６ alkynyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ２ ~C １０ heterocyclic, optionally substituted amino, or cyano, and A ２ is the bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one of them is A ２ structure, or a pharmaceutically acceptable salt thereof, of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24.

115. The compound or a pharmaceutically acceptable salt thereof according to claim 114, wherein the decomposition moiety has a structure of formula E3 or formula E1. 【Chemical 46】

116. The decomposition moiety is 【Chemical 47】 The compound or a pharmaceutically acceptable salt thereof according to claim 114.

117. The compound or a pharmaceutically acceptable salt thereof according to claim 114, wherein the decomposition moiety has a structure of formula E2: 【Chemical 48】

118. R Ｂ９ is optionally substituted C １ -C ６ alkyl, the compound according to any one of claims 114 to 115, or a pharmaceutically acceptable salt thereof.

119. R Ｂ９ The compound according to claim 118, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

120. R Ｂ９ is optionally substituted C ３ -C ６ -alkynyl, a compound according to any one of claims 114 to 115 or a pharmaceutically acceptable salt thereof.

121. R Ｂ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 114 to 115, wherein R is [1.1.1] pentane, cyclopropane, cyclobutene, or cyclopentane.

122. R Ｂ９ which is attached to an (S)-stereocenter, a compound according to any one of claims 114 to 115 and 117 to 121 or a pharmaceutically acceptable salt thereof.

123. R Ｂ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 114 to 115, wherein R is H.

124. R Ｂ４ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 114 to 115 and 117 to 123, wherein R is H.

125. R Ｂ５ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 114 to 115 and 117 to 124, wherein R is H.

126. R Ｂ３ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 114 to 115 and 117 to 125 or a pharmaceutically acceptable salt thereof.

127. R Ｂ３ The compound according to claim 126, or a pharmaceutically acceptable salt thereof, wherein R is isopropyl.

128. R Ｂ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 114 to 115 and 117 to 127, wherein R is H.

129. R Ｂ１０ which is non-existent, a compound according to any one of claims 114 to 115 and 117 to 128 or a pharmaceutically acceptable salt thereof.

130. R Ｂ１０ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 114 to 115 and 117 to 128, wherein R is H or cyano.

131. R Ｂ１０ is optionally substituted C ３ -C １０ carbocyclic, a compound according to any one of claims 114 to 115 and 117 to 128 or a pharmaceutically acceptable salt thereof.

132. R Ｂ１０ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 114 to 115 and 117 to 128 or a pharmaceutically acceptable salt thereof.

133. R Ｂ１０ The compound or a pharmaceutically acceptable salt thereof according to claim 132, wherein R is methyl.

134. The decomposition moiety is 【Chemical 49】 The compound or a pharmaceutically acceptable salt thereof according to claim 114.

135. The decomposition moiety has a structure of formula F, wherein 【Chemical Formula 50】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 51】 and R Ｂ１ is H, A ２ , optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ４ is H, optionally substituted C １ to C ６ alkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C １ to C ６ alkyl C ３ to C １０ carbocyclic, or optionally substituted C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and A ２ is the bond between the decomposition part and the linker, R Ｂ１ or R Ｂ３ Only one of them is A ２ structure The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof having or its pharmaceutically acceptable salt.

136. The compound according to claim 135 or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety has the structure of formula E3 or formula E1. 【Chemical 52】

137. The cleavage moiety is 【Chemical Formula 53】 The compound according to claim 135 or a pharmaceutically acceptable salt thereof which is as follows.

138. The compound according to claim 135 or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety has the structure of formula F2: 【Chemical 54】

139. R Ｂ９ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 135 and 138 or a pharmaceutically acceptable salt thereof.

140. R Ｂ９ The compound according to claim 139, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

141. R Ｂ４ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138 to 140, wherein R is H.

142. R Ｂ５ wherein R is H, a compound according to any one of claims 135 and 138 to 141, or a pharmaceutically acceptable salt thereof.

143. R Ｂ３ is optionally substituted C １ -C ６ alkyl, a compound according to any one of claims 135 and 138 to 142 or a pharmaceutically acceptable salt thereof.

144. R Ｂ３ The compound according to claim 143, or a pharmaceutically acceptable salt thereof, wherein R is isopropyl.

145. R Ｂ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138 to 144, wherein R is H.

146. The cleavage moiety is 【Chemical Formula 55】 The compound according to claim 135 or a pharmaceutically acceptable salt thereof which is as follows.

147. The linker has the structure of formula II: A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(D)-(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ 、 Formula II or a pharmaceutically acceptable salt thereof, and wherein A １ is a bond between the linker and ring system A, A ２ is a bond between the decomposition part and the linker, B １ 、B ２ 、B ３ 、and B ４ each of which is, independently, optionally substituted C １ ~C ４ alkyl, optionally substituted C ６ ~C １０ aryl, optionally substituted C ６ ~C １０ arylC １～４ alkyl, optionally substituted C １ ~C ４ heteroalkyl, optionally substituted C ３ ~C １０ cycloalkyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ２ ~C １０ heterocyclic, optionally substituted C ２ ~C ６ heteroaryl, optionally substituted C ６～１２ aryl, O, S, S(O) ２ or NR Ｎ and Each R Ｎ is, independently, H, optionally substituted C １～４ alkyl, optionally substituted C ２～４ alkenyl, optionally substituted C ２～４ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ２～６ heteroaryl, or optionally substituted C １～７ heteroalkyl, and C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, D is optionally substituted C １～１０ alkyl, optionally substituted C ２～１０ alkenyl, optionally substituted C ２～１０ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ２～６ heteroaryl, optionally substituted C ６～１２ aryl, optionally substituted C ２ ~C １０ polyethylene glycol, optionally substituted C ３ ~C １０ cycloalkyl, optionally substituted C ３ ~C １０ carbocyclyl, or optionally substituted C １～１０ heteroalkyl, or D is absent, and the linker is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ The compound according to any one of claims 1 to 146 or a pharmaceutically acceptable salt thereof.

148. A １ is a bond between the linker and the benzopyridazine core ring system, A ２ is the bond between the decomposition part and the linker, B １ 、 B ２ 、 B ３ 、 and B ４ each of which is independently optionally substituted C １ -C ４ alkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ６ -C １０ arylC １～４ alkyl, optionally substituted C １ -C ４ heteroalkyl, optionally substituted C ３ -C １０ cycloalkyl, optionally substituted C ２ -C ８ heterocyclyl, optionally substituted C ２ -C ６ heteroaryl, optionally substituted C ６～１２ aryl, O, S, S(O) ２ or NR Ｎ wherein Each R Ｎ is, independently, H, optionally substituted C １～４ alkyl, optionally substituted C ２～４ alkenyl, optionally substituted C ２～４ alkynyl, optionally substituted C ２～６ heterocyclyl, optionally substituted C ２～６ heteroaryl, or optionally substituted C １～７ heteroalkyl, and C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, D is optionally substituted C １～１０ alkyl, optionally substituted C ２～１０ alkenyl, optionally substituted C ２～１０ alkynyl, optionally substituted C ２～６ heterocyclyl, optionally substituted C ２～６ heteroaryl, optionally substituted C ６～１２ aryl, optionally substituted C ２ ~C １０ polyethylene glycol, or optionally substituted C １～１０ heteroalkyl, or D is absent and the linker is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ The compound according to claim 147 or a pharmaceutically acceptable salt thereof.

149. B １ 、 B ２ 、 B ３ 、 and B ４ each of which is independently optionally substituted C １ to C ２ alkyl, optionally substituted C １ to C ３ heteroalkyl, optionally substituted C ２ to C １０ heterocyclyl, optionally substituted C ２～６ heteroaryl, O, or NR Ｎ The compound according to any one of claims 147 to 148 or a pharmaceutically acceptable salt thereof.

150. B １ , B ２ , B ３ , and B ４ each independently is optionally substituted C １ -C ２ alkyl, optionally substituted C １ -C ３ heteroalkyl, optionally substituted C ２ -C ８ heterocyclyl, optionally substituted C ２～６ heteroaryl, or O, a compound according to any one of claims 147 to 148 or a pharmaceutically acceptable salt thereof.

151. B １ and B ４ each independently 【Chemical Formula 56】 【Chemical 57】 The compound according to any one of claims 147 to 150 or a pharmaceutically acceptable salt thereof which is as follows.

152. B １ and B ４ each independently 【Chemical Formula 58】 The compound according to any one of claims 147 to 150 or a pharmaceutically acceptable salt thereof which is as follows.

153. B １ is 【Chemical Formula 59】 【Chemical Formula 60】 The compound according to any one of claims 147 to 151 or a pharmaceutically acceptable salt thereof which is as follows.

154. B ４ is 【Chemical Formula 61】 【Chemical Formula 62】 The compound according to any one of claims 147 to 151 and 153 or a pharmaceutically acceptable salt thereof which is as follows.

155. C １ is 【Chemical Formula 63】 The compound according to any one of claims 147 to 154 or a pharmaceutically acceptable salt thereof which is as follows.

156. B ２ is optionally substituted C １ to C ４ alkyl, a compound according to any one of claims 147 to 155 or a pharmaceutically acceptable salt thereof.

157. D is optionally substituted C １ ~C １０ The compound according to any one of claims 147 to 156, or a pharmaceutically acceptable salt thereof, wherein D is alkyl.

158. The compound according to any one of claims 147 to 157 or a pharmaceutically acceptable salt thereof, wherein f is 1.

159. The compound according to any one of claims 147 to 158 or a pharmaceutically acceptable salt thereof, wherein g, h, i, and j are 0.

160. The compound according to any one of claims 147 to 159 or a pharmaceutically acceptable salt thereof, wherein k is 0.

161. The compound according to any one of claims 147 to 159 or a pharmaceutically acceptable salt thereof, wherein k is 1.

162. D is absent and the linker is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ and is a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

163. D is optionally substituted C １～１０ alkyl, optionally substituted C ２～１０ alkenyl, optionally substituted C ２～１０ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ２～６ heteroaryl, optionally substituted C ６～１２ aryl, optionally substituted C ２ ~C １０ polyethylene glycol, or optionally substituted C １～１０ heteroalkyl, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

164. D is optionally substituted C ３ ~C １０ is cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, k is 1, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

165. D is optionally substituted C ３ ~C １０ is cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, k is 0, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

166. D is optionally substituted C ３ ~C １０ is cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, k is 1, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

167. D is optionally substituted C ３ ~C １０ a cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, k is 0, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

168. D is optionally substituted C ３ ~C １０ a carbocyclic ring, f is 1, g is 0, h is 0, i is 0, j is 0, k is 1, the compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

169. D is optionally substituted C ３ ~C １０ is carbocyclic, f is 1, g is 0, h is 0, i is 0, j is 0, k is 0, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

170. D is optionally substituted C ３ ~C １０ is carbocyclic, f is 0, g is 0, h is 0, i is 0, j is 0, k is 1, the compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

171. D is optionally substituted C ３ ~C １０ is carbocyclic, f is 0, g is 0, h is 0, i is 0, j is 0, k is 0, a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

172. D is 【Chemical Formula 64】 【Chemical Formula 65】 a compound according to any one of claims 147 to 156 and 158 to 161 or a pharmaceutically acceptable salt thereof.

173. wherein the linker is 【Chemical Formula 66】 【Chemical Formula 67】 a compound according to claim 147 or a pharmaceutically acceptable salt thereof having the structure of.

174. wherein the linker is 【Chemical Formula 68】 a compound according to any one of claims 147 to 148 or a pharmaceutically acceptable salt thereof having the structure of.

175. wherein the linker has the structure of formula III, A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ , Formula III wherein A １ is a bond between the linker and ring system A, A ２ is a bond between the decomposition part and the linker, B １ 、B ２ 、B ３ 、and B ４ each of which is, independently, optionally substituted ethynyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C ３ -C １０ -cycloalkyl, optionally substituted C ３ -C １０ -carbocyclic, optionally substituted C ２ -C １０ -heterocyclic, optionally substituted C ２ -C ９ -heteroaryl, O, S, S(O) ２ , or NR Ｎ and Each R Ｎ is, independently, H, optionally substituted C １～４ alkyl, optionally substituted C ２～４ alkenyl, optionally substituted C ２～４ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ６～１２ aryl, or optionally substituted C １～７ heteroalkyl, and C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, a compound according to any one of claims 1 to 146 or a pharmaceutically acceptable salt thereof.

176. wherein the linker is of the structure -(L １ ) ｎ -, n is 1, 2, or 3, and each L １ is independently O, NR Ｎ , ethynyl, optionally substituted C ２ -C １０ heterocyclyl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ６ -C １０ aryl, or optionally substituted C ３ -C １０ cycloalkyl, and the compound according to claim 175 or a pharmaceutically acceptable salt thereof.

177. At least one L １ is optionally substituted C ２ to C １０ is a heterocyclyl, the compound according to claim 176 or a pharmaceutically acceptable salt thereof.

178. The optionally substituted C ２ -C １０ The compound or a pharmaceutically acceptable salt thereof according to claim 177, wherein the heterocyclyl is a 4-membered, 5-membered or 6-membered monocyclic heterocyclyl, a spirocyclic heterocyclyl, a bridged heterocyclyl, or a fused bicyclic heterocyclyl.

179. Said C ２ ~C １０ The heterocyclyl is 【Chemical Formula 69】 a compound according to claim 178 or a pharmaceutically acceptable salt thereof.

180. At least one L １ is optionally substituted C ２ to C ９ is heteroaryl, a compound according to any one of claims 176 to 179 or a pharmaceutically acceptable salt thereof.

181. wherein the linker is -(L １ ), ｑ -(optionally substituted C ２ to C ９ heteroaryl)-(L １ ), ｑ -; each q is independently 0 or 1; a compound according to any one of claims 176 to 180 or a pharmaceutically acceptable salt thereof.

182. The optionally substituted C ２ -C ９ The compound or a pharmaceutically acceptable salt thereof according to claim 180 or 181, wherein the heteroaryl is a 6-membered monocyclic heteroaryl.

183. wherein the 6-membered monocyclic heteroaryl is 【Chemical 70】 a compound according to claim 182 or a pharmaceutically acceptable salt thereof.

184. At least one L １ is optionally substituted C ６ to C １０ is aryl, a compound according to any one of claims 176 to 183 or a pharmaceutically acceptable salt thereof.

185. The optionally substituted C ６ -C １０ The compound according to claim 184, wherein the aryl is optionally substituted phenyl.

186. At least one L １ is optionally substituted C ３ to C １０ is cycloalkyl, a compound according to any one of claims 176 to 185 or a pharmaceutically acceptable salt thereof.

187. said optionally substituted C ３ -C １０ wherein the cycloalkyl is 【Chemical 71】 a compound according to claim 186 or a pharmaceutically acceptable salt thereof.

188. At least one L １ The compound according to any one of claims 176 to 187 or a pharmaceutically acceptable salt thereof, wherein is ethynyl.

189. Only one L １ is O, a compound according to any one of claims 176 to 188 or a pharmaceutically acceptable salt thereof.

190. only one L １ is NR Ｎ A compound or a pharmaceutically acceptable salt thereof according to any one of claims 176 to 188, wherein

191. R Ｎ is H or optionally substituted C １ -C ４ -alkyl, the compound according to claim 190 or a pharmaceutically acceptable salt thereof.

192. wherein the linker has the following structure, A １ - (B １ ) ｆ - (B ２ ) ｈ - (B ３ ) ｉ - (B ４ ) ｋ - A ２ and wherein B １ , B ２ B ３ and B ４ each independently is optionally substituted ethynyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ３ -C １０ cycloalkyl, optionally substituted C ２ -C １０ heterocyclyl, optionally substituted C ２ -C ９ heteroaryl, O, or NR Ｎ ; a compound according to claim 175 or a pharmaceutically acceptable salt thereof.

193. at least one of f, h, i, and k is 1, a compound according to claim 175 or 192 or a pharmaceutically acceptable salt thereof.

194. B １ 、 B ２ 、 B ３ 、 and B ４ each independently is O, ethynyl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ２ -C １０ heterocyclyl, optionally substituted C ３ -C １０ cycloalkyl, or optionally substituted C ６ -C １０ aryl, a compound according to any one of claims 175 or 192 to 193 or a pharmaceutically acceptable salt thereof.

195. B １ , B ２ , B ３ , and B ４ each independently is optionally substituted C ２ to C ９ heteroaryl or optionally substituted C ２ to C １０ heterocyclyl, a compound according to any one of claims 175 and 192 to 194 or a pharmaceutically acceptable salt thereof.

196. B １ and B ４ each independently 【Chemical 72】 【Chemical Formula 73】 a compound according to any one of claims 175 and 192 to 195 or a pharmaceutically acceptable salt thereof.

197. B １ is 【Chemical 74】 【Chemical 75】 a compound according to claim 196 or a pharmaceutically acceptable salt thereof.

198. B ４ is 【Chemical 76】 【Chemical 77】 a compound according to claim 196 or 197 or a pharmaceutically acceptable salt thereof.

199. B ２ is NH, 【Chemical Formula 78】 a compound according to any one of claims 175 and 192 to 198 or a pharmaceutically acceptable salt thereof.

200. f is 0, a compound according to any one of claims 175 and 192 to 199 or a pharmaceutically acceptable salt thereof.

201. f is 1, a compound according to any one of claims 175 and 191 to 199 or a pharmaceutically acceptable salt thereof.

202. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 and 192 to 201, wherein g, h, i, and j are 0.

203. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 and 192 to 202, wherein k is 0.

204. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 and 192 to 202, wherein k is 1.

205. The linker is 【Chemical Formula 79】 【Chemical Formula 80】 【Chemical 81】 The compound or a pharmaceutically acceptable salt thereof according to claim 175, which has the structure of.

206. A compound selected from the group consisting of Compounds 1 to 291 in Table 1, and a pharmaceutically acceptable salt thereof.

207. The compound has a ratio to the BRG1 IC of at least 5 ５０ and the BRM IC ５０ The compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof.

208. The compound has a ratio to at least 10 of BRG1 IC ５０ of BRM IC ５０ The compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof.

209. wherein the compound has a ratio to at least 20 BRG1 IC ５０ of BRM IC ５０ and is a compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof.

210. The compound has a ratio to at least 30 BRG1 IC ５０ of BRM IC ５０ and is the compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof.

211. A pharmaceutical composition comprising the compound according to any one of claims 1 to 210 and a pharmaceutically acceptable excipient.

212. A method for treating a BAF complex-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 210 or the pharmaceutical composition according to claim 211.

213. The method according to claim 212, wherein the BAF complex-related disorder is cancer or a viral infection.

214. A method for treating a disorder associated with a loss-of-function mutation of BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 210 or the pharmaceutical composition according to claim 211.

215. The method according to claim 214, wherein the disorder associated with the loss-of-function mutation of BRG1 is cancer.

216. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 210 or the pharmaceutical composition according to claim 211.

217. The method according to any one of claims 212 to 216, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, pancreatic cancer, hepatobiliary tract cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small intestine cancer, or penile cancer.

218. The method according to claim 217, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

219. The method according to claim 217, wherein the cancer is non-small cell lung cancer.

220. The method according to claim 217, wherein the cancer is soft tissue sarcoma.

221. A method for treating cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, and blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 210 or the pharmaceutical composition according to claim 211.

222. The compound according to any one of claims 1 to 210, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 211 for use in therapy.

223. The compound according to any one of claims 1 to 210, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 211 for use in the treatment of cancer.

224. The compound according to claim 223, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, pancreatic cancer, hepatobiliary tract cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small intestine cancer, or penile cancer.

225. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 223, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

226. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 223, wherein the cancer is non-small cell lung cancer.

227. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 223, wherein the cancer is soft tissue sarcoma.

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