Pyrazine derivatives and their use

Abstract

The present disclosure features a compound of formula I or II, or a pharmaceutically acceptable salt thereof, and a formulation containing the same. A method for treating BAF complex-related disorders such as cancer is also disclosed. 【Chemical 1】 JPEG2025516578000643.jpg39128

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. [Background technology]

[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 II, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; Each R 1 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted CH2-C3-C8 cycloalkyl; each X is independently halo; L is a linker, The present invention features a compound, or a pharmaceutically acceptable salt thereof, wherein B is a degrading moiety.

[0005] In some embodiments, the compound has Formula I or II: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; L is a linker, B is the decomposition part, Each R 1is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heterocyclyl; Formula I or II, wherein each X is independently halo; or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the compound has Formula I or II: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; L is a linker 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 C3-C 10cycloalkyl, optionally substituted C2-C9 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 2~6 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; B is the decomposition part, Each R 1 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heterocyclyl; Formula I or II, wherein each X is independently halo; or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the compound has formula IA or II-A: [ka] Formula IA or II-A, wherein the dashed bond represents a single or double bond; or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the compound has formula IG or II-G: [ka] or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound has formula IH or II-H: [ka] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, m is 0 or 1.

[0011] In some embodiments, m is 1.

[0012] In some embodiments, each R 1 is halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl.

[0013] In some embodiments, R 1 is methyl.

[0014] In some embodiments, R 1 is cyclopropane.

[0015] In some embodiments, m is 0.

[0016] In some embodiments, k is 1.

[0017] In some embodiments, X is Cl.

[0018] In some embodiments, k is 0.

[0019] In some embodiments, the linker has the structure -(L 1 ) n wherein n is 1, 2, or 3, and each L 1 are independently O, NR N, ethynyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 Aryl or optionally substituted C3-C 10 It is cycloalkyl.

[0020] In some embodiments, at least one L 1 is optionally substituted C2 to C 10 In some embodiments, an optionally substituted C-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.

[0021] In some embodiments, optionally substituted C-C 10 The heterocyclyl is a spirocyclic heterocyclyl. In some embodiments, the spirocyclic heterocyclyl is: [ka] is.

[0022] In some embodiments, optionally substituted C-C 10 The heterocyclyl is a bridged heterocyclyl. In some embodiments, the bridged heterocyclyl is: [ka] is.

[0023] In some embodiments, optionally, C2 to C 10 The heterocyclyl is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic heterocyclyl is: [ka] is.

[0024] 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.

[0025] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is [ka] is.

[0026] In some embodiments, at least one L 1 is an optionally substituted C6-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.

[0027] In some embodiments, at least one L 1 is an optionally substituted C3-C 10 In some embodiments, optionally substituted C-C cycloalkyl. 10The cycloalkyl is a monocyclic cycloalkyl. In some embodiments, the 6-membered monocyclic cycloalkyl is: [ka] is.

[0028] In some embodiments, optionally substituted C3-C 10 The cycloalkyl is a bridged cycloalkyl. In some embodiments, the bridged cycloalkyl is: [ka] is.

[0029] In some embodiments, at least one L 1 is ethynyl.

[0030] In some embodiments, only one L 1 is O. In some embodiments, only one L 1 is NR N In some embodiments, R N is an optionally substituted C1-C4 alkyl. In some embodiments, R N is H.

[0031] 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 , In the formula, 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 C3-C10 Cycloalkyl, optionally substituted C-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N is.

[0032] In some embodiments, at least one of f, h, i, and k is 1.

[0033] 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 C3-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 O. [ka] [ka] is.

[0034] In some embodiments, B 1 teeth, [ka] [ka] is.

[0035] In some embodiments, B 4 teeth, O. [ka] [ka] is.

[0036] 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.

[0037] 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.

[0038] In some embodiments, the linker is [ka] [ka] [ka] It has the following structure.

[0039] In one aspect, the present invention provides a compound having the structure of Formula I or II, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; R 1 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C3-C 10 is a carbocyclyl, X is a halo; L is a group of formula IIIa: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 , Formula IIIa 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 being an optionally substituted C1-C4 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C-C 10 Aryl C 1~4Alkyl, 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 optionally replaced by 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 -(B2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 or a pharmaceutically acceptable salt thereof.

[0040] 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 2~10 Heterocyclyl, 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 is a chemical bond that connects

[0041] In some embodiments, B 1 , B 2 , B 3 , and B 4each 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, optionally substituted C-C 10 Cycloalkyl, optionally substituted C-C 10 Carbocyclyl, O, or NR N is.

[0042] In some embodiments, B 1 and B 4 each of which independently O. [ka] [ka] is.

[0043] In some embodiments, B 1 teeth, [ka] [ka] is.

[0044] In some embodiments, B 4 teeth, O. [ka] [ka] is.

[0045] In some embodiments, C 1 teeth, [ka] is.

[0046] In some embodiments, B 2 is an optionally substituted C1-C4 alkyl.

[0047] In some embodiments, D is an optionally substituted C1-C 10 It is alkyl.

[0048] 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.

[0049] In some embodiments, 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.

[0050] 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 10Polyethylene glycol or optionally substituted C 1~10 In some embodiments, D is an optionally substituted C-C heteroalkyl. 10 cycloalkyl, 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 10 carbocyclyl, 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, wherein 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] [ka] is.

[0051] In some embodiments, the linker is [ka] [ka] [ka] It has the following structure.

[0052] In some embodiments, the compound has the structure of formula IA or II-A: [ka] In the formula, the dashed bond represents a single bond or a double bond.

[0053] In some embodiments, the compound has the structure of formula IG or II-G: [ka] In the formula, m is 0 or 1; R 1 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C3-C 10 is a carbocyclyl, k is 0 or 1; X is a halo.

[0054] In some embodiments, the compound has the structure of formula IH or II-H: [ka] During the ceremony, m is 0 or 1; R 1 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C3-C 10is a carbocyclyl, k is 0 or 1; X is a halo.

[0055] In some embodiments, m is 0.

[0056] In some embodiments, m is 1.

[0057] In some embodiments, R 1 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is methyl.

[0058] In some embodiments, R 1 is an optionally substituted C-C cycloalkyl. In some embodiments, R 1 is an optionally substituted C3-C 10 In some embodiments, R 1 is cyclopropane.

[0059] In some embodiments, k is 0.

[0060] In some embodiments, k is 1. In some embodiments, X is Cl.

[0061] In some embodiments, the decomposition moiety B has the structure of formula A-1: [ka] During the ceremony, Y 1 but, [ka] and R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A6is 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 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; 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 these independently represents H, 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, 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 are combined with the carbon atoms to which they are attached, [ka] Forming [ka] optionally substituted C6 to C 10 Aryl, optionally substituted C3-C 10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is 2 is optionally replaced by R A1 , R A2 , R A3 , and R A4 One of them is A 2 or [ka] But, A 2 is replaced by

[0062] A 2 is the bond between the degradation moiety and the linker.

[0063] In some embodiments, R A5 is H or methyl. In some embodiments, R A5 is H.

[0064] In some embodiments, R A1 , R A2 , R A3 , and R A4 each independently represents H or A 2 is.

[0065] In some embodiments, R A1 is A 2 and R A2 , R A3 , and R A4 Each of is H.

[0066] In some embodiments, R A2 is A 2 and R A1 , R A3 , and R A4 Each of is H.

[0067] In some embodiments, R A3 is A 2 and R A1 , R A2 , and R A4 Each of is H.

[0068] In some embodiments, R A4 is A 2 and R A1 , R A2 , and R A3 Each of is H.

[0069] In some embodiments, Y 1 teeth, [ka] is.

[0070] In some embodiments, R A6 is H. In some embodiments, R A7 is H.

[0071] In some embodiments, Y 1 teeth, [ka] is.

[0072] 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.

[0073] In some embodiments, the decomposition moiety comprises a structure of formula A2 [ka]

[0074] In some embodiments, the degradation moiety is [ka] is.

[0075] In some embodiments, the degrading moiety comprises a structure of formula A4 [ka]

[0076] In some embodiments, the degradation moiety is [ka] is.

[0077] In some embodiments, the degrading moiety has the structure of formula A5: [ka]

[0078] In some embodiments, the degrading moiety has the structure of formula A6: [ka]

[0079] In some embodiments, the degrading moiety has the structure of formula A8: [ka]

[0080] In some embodiments, the degrading moiety has the structure of formula A10: [ka]

[0081] In some embodiments, the degradation moiety has the structure [ka]

[0082] In some embodiments, the degradation moiety has the structure [ka]

[0083] In some embodiments, the decomposition moiety has formula C: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-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 C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C10 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 But 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 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; A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 Formula C or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the decomposition moiety has formula C: [ka] During the ceremony, L 4 But -N(RB1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-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 C6-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 But independently, 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, 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 Formula C or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the degrading moiety has the structure of formula C3. [ka]

[0086] In some embodiments, the degrading moiety has the structure of formula C4. [ka]

[0087] In some embodiments, the degrading moiety has the structure of formula C1: [ka]

[0088] In some embodiments, the degradation moiety is [ka] is.

[0089] In some embodiments, the degradation moiety is [ka] is.

[0090] In some embodiments, the degradation moiety is [ka] is.

[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 degrading moiety has the structure of formula C2: [ka]

[0095] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0096] In some embodiments, R B9 is attached to the (S)-steric center.

[0097] 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.

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

[0099] In some embodiments, the degradation moiety has a structure of formula Ca2: [ka]

[0100] In some embodiments, the degrading moiety has the structure of formula Cb2: [ka]

[0101] In some embodiments, the degrading moiety has the structure of formula Cc2: [ka]

[0102] In some embodiments, the decomposition moiety has the structure of formula Cd2: [ka]

[0103] In some embodiments, the decomposition moiety has the structure of formula Ce2: [ka]

[0104] In some embodiments, the decomposition moiety has the structure of formula Cf2: [ka]

[0105] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0106] In some embodiments, R B9 is attached to the (S)-steric center.

[0107] 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 B3is 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.

[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 is [ka] is.

[0117] In some embodiments, the decomposition moiety has formula C5: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C10 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 But 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 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 B11 is H, alcohol, boronic acid, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 Formula C5 or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, R B11 is boric acid.

[0119] In some embodiments, the degrading moiety has the structure of formula C6. [ka]

[0120] In some embodiments, the degrading moiety has the structure of formula C1: [ka]

[0121] In some embodiments, the degrading moiety has the structure of formula C8: [ka]

[0122] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0123] In some embodiments, R B9 is attached to the (S)-steric center.

[0124] 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, RB8 is H. In some embodiments, R B2 is H.

[0125] In some embodiments, the degradation moiety is [ka] is.

[0126] In some embodiments, the decomposition moiety has formula D: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-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 C6-C 10Aryl, 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 But 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 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 Formula D or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the degrading moiety has the structure of formula D3. [ka]

[0128] In some embodiments, the degrading moiety has the structure of formula D1: [ka]

[0129] In some embodiments, the degradation moiety is [ka] is.

[0130] In some embodiments, the degradation moiety is [ka] is.

[0131] In some embodiments, the degradation moiety is [ka] is.

[0132] In some embodiments, the degrading moiety has the structure of formula D2: [ka]

[0133] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0134] In some embodiments, R B9 is attached to the (S)-stereocenter. In some embodiments, R B9 is H.

[0135] 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 B3is 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, R B6 is 3-methoxy-1-propanoxy.

[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] 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 is [ka] is.

[0143] In some embodiments, the degradation moiety is [ka] is.

[0144] In some embodiments, the degradation moiety is [ka] is.

[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 degradation moiety is [ka] is.

[0149] In some embodiments, the degradation moiety is [ka] is.

[0150] In some embodiments, the degradation moiety is [ka] is.

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

[0152] In some embodiments, the degradation moiety is [ka] is.

[0153] In some embodiments, the degradation moiety is [ka] is.

[0154] In some embodiments, the degradation moiety is [ka] is.

[0155] In some embodiments, the degradation moiety is [ka] is.

[0156] In some embodiments, the degradation moiety is [ka] is.

[0157] In some embodiments, the degradation moiety is [ka] is.

[0158] In some embodiments, the degradation moiety is [ka] is.

[0159] In some embodiments, the degradation moiety is [ka] is.

[0160] In some embodiments, the degradation moiety has formula Da: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-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 C6-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 But 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 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 The formula Da or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the degradation moiety has the structure of formula Da3. [ka]

[0162] In some embodiments, the degradation moiety has the structure of formula Da1: [ka]

[0163] In some embodiments, the degradation moiety has the structure of formula Da2: [ka]

[0164] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0165] In some embodiments, R B9 is attached to the (S)-steric center.

[0166] 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.

[0167] In some embodiments, the degradation moiety is [ka] is.

[0168] In some embodiments, the decomposition moiety has formula E: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C10 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 C6-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 B9 is 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 C2-C 10 heterocyclyl, optionally substituted amino, or cyano; A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 is the formula E or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the degrading moiety has the structure of formula E3. [ka]

[0170] In some embodiments, the degrading moiety has the structure of formula E1: [ka]

[0171] In some embodiments, the degradation moiety is [ka] is.

[0172] In some embodiments, the degradation moiety is [ka] is.

[0173] In some embodiments, the degrading moiety has the structure of formula E2: [ka]

[0174] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0175] In some embodiments, R B9 is attached to the (S)-steric center.

[0176] 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, RB9 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, R B10 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.

[0177] In some embodiments, the degradation moiety is [ka] is.

[0178] In some embodiments, the degradation moiety is [ka] is.

[0179] In some embodiments, the degradation moiety is [ka] is.

[0180] In some embodiments, the degradation moiety is [ka] is.

[0181] In some embodiments, the degradation moiety is [ka] is.

[0182] In some embodiments, the degradation moiety is [ka] is.

[0183] In some embodiments, the degradation moiety is [ka] is.

[0184] In some embodiments, the degradation moiety is [ka] is.

[0185] In some embodiments, the degradation moiety is [ka] is.

[0186] In some embodiments, the decomposition moiety has formula F: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, 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 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-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 C6-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 is the formula F or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the decomposition moiety has the structure of formula F3. [ka]

[0188] In some embodiments, the degrading moiety has the structure of formula F1: [ka]

[0189] In some embodiments, the degradation moiety is [ka] is.

[0190] In some embodiments, the degradation moiety is [ka] is.

[0191] In some embodiments, the degradation moiety is [ka] is.

[0192] In some embodiments, the degrading moiety has the structure of formula F2: [ka]

[0193] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. In some embodiments, R B9 is methyl.

[0194] 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 B2is H.

[0195] In some embodiments, the degradation moiety is [ka] is.

[0196] In some embodiments, the linker has 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 Nare 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.

[0197] 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 2~10 Heterocyclyl, 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 is a chemical bond that connects

[0198] 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, optionally substituted C-C 10 Cycloalkyl, optionally substituted C-C 10 Carbocyclyl, O, or NR N is.

[0199] In some embodiments, B1 and B 4 each of which independently O. [ka] [ka] is.

[0200] In some embodiments, B 1 teeth, [ka] [ka] is.

[0201] In some embodiments, B 4 teeth, O. [ka] [ka] is.

[0202] In some embodiments, C 1 teeth, [ka] is.

[0203] In some embodiments, B 2 is an optionally substituted C1-C4 alkyl.

[0204] In some embodiments, D is an optionally substituted C1-C 10 It is alkyl.

[0205] 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.

[0206] In some embodiments, 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.

[0207] 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, 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 10cycloalkyl, 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 10 carbocyclyl, 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, wherein 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] [ka] is.

[0208] In some embodiments, the linker is [ka] [ka] [ka] It has the following structure.

[0209] 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 C3-C 10 Cycloalkyl, optionally substituted C-C 10 Carbocyclyl, optionally substituted C2-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; B is the decomposition part, Each R 1 are independently selected from halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C 10 is heterocyclyl, Each X is independently halo.

[0210] In some embodiments, the linker has the structure -(L 1 ) n wherein n is 1, 2, or 3, and each L 1 are independently O, NR N , ethynyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 Aryl or optionally substituted C3-C 10 It is cycloalkyl.

[0211] In some embodiments, at least one L 1 is optionally substituted C2 to C 10 In some embodiments, an optionally substituted C-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.

[0212] In some embodiments, optionally substituted C-C 10The heterocyclyl is a spirocyclic heterocyclyl. In some embodiments, the spirocyclic heterocyclyl is: [ka] is.

[0213] In some embodiments, optionally substituted C-C 10 The heterocyclyl is a bridged heterocyclyl. In some embodiments, the bridged heterocyclyl is: [ka] is.

[0214] In some embodiments, optionally, C2 to C 10 The heterocyclyl is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic heterocyclyl is: [ka] is.

[0215] 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.

[0216] In some embodiments, at least one L 1is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is [ka] is.

[0217] In some embodiments, at least one L 1 is an optionally substituted C6-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.

[0218] In some embodiments, at least one L 1 is an optionally substituted C3-C 10 In some embodiments, optionally substituted C-C cycloalkyl. 10 The cycloalkyl is a monocyclic cycloalkyl. In some embodiments, the 6-membered monocyclic cycloalkyl is: [ka] is.

[0219] In some embodiments, optionally substituted C3-C 10 The cycloalkyl is a bridged cycloalkyl. In some embodiments, the bridged cycloalkyl is: [ka] is.

[0220] In some embodiments, at least one L 1 is ethynyl.

[0221] In some embodiments, only one L 1 is O. In some embodiments, only one L 1 is NRN In some embodiments, R N is an optionally substituted C1-C4 alkyl. In some embodiments, R N is H.

[0222] 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 , In the formula, 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 C3-C 10 Cycloalkyl, optionally substituted C-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N is.

[0223] In some embodiments, at least one of f, h, i, and k is 1.

[0224] 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 C3-C 10 Cycloalkyl or optionally substituted C-C 10 In some embodiments, B is aryl. 1 , B 2 , B 3 , and B 4each 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 O. [ka] [ka] is.

[0225] In some embodiments, B 1 teeth, [ka] [ka] is.

[0226] In some embodiments, B 4 teeth, O. [ka] [ka] is.

[0227] 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.

[0228] 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.

[0229] In some embodiments, the linker is [ka] [ka] [ka] It has the following structure.

[0230] 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.

[0231] In some embodiments, the linker is any one of compounds 1-121 in Table 1 (e.g., BRG1 IC 50 BRM IC 50 In some embodiments, the linker has the structure of any one of compounds 1-121 in Table 1 (e.g., BRM IC 50 In some embodiments, the linker has the structure of any one of compounds 1-121 in Table 1 (e.g., BRM IC 50is ++ or higher (e.g., +++ or ++++ (e.g., ++++)), and BRG1 IC 50 BRM IC 50 to at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30).

[0232] In one aspect, the invention features a compound selected from the group consisting of 1-121 in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a BRG1 IC 50 BRM IC 50 In some embodiments, the compound is any one of compounds 1-121 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 shown in Table 15. 50 In some embodiments, the compound is any one of compounds 1-121 in Table 1, or a pharmaceutically acceptable salt thereof, having a BRM IC of ++ or higher (e.g., +++ or ++++ (e.g., ++++)). In some embodiments, the compound is any one of compounds 1-121 in Table 1, or a pharmaceutically acceptable salt thereof, as seen in Table 15. 50 is ++ or higher (e.g., +++ or ++++ (e.g., ++++)), and BRG1 IC 50 BRM IC 50 or a pharmaceutically acceptable salt thereof, wherein the ratio of

[0233] In one aspect, the invention features a compound selected from the group consisting of 1-103 in Table 1, and pharmaceutically acceptable salts thereof.

[0234] [Table 1-1]

[0235] [Table 1-2]

[0236]

Table 1-3

[0237]

Table 1-4

[0238]

Table 1-5

[0239]

Table 1-6

[0240]

Table 1-7

[0241]

Table 1-8

[0242]

Table 1-9

[0243]

Table 1-10

[0244]

Table 1-11

[0245]

Table 1-12

[0246]

Table 1-13

[0247]

Table 1-14

[0248]

Table 1-15

[0249]

Table 1-16

[0250]

Table 1-17

[0251]

Table 1-18

[0252]

Table 1-19

[0253]

Table 1-20

[0254]

Table 1-21

[0255]

Table 1-22

[0256] [Table 1-23]

[0257] [Table 1-24]

[0258] [Table 1-25]

[0259] [Table 1-26]

[0260] [Table 1-27]

[0261] [Table 1-28]

[0262] 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 50 In 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

[0263] In one aspect, the invention features a pharmaceutical composition including any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0264] 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.

[0265] In some embodiments, the cells are cancer cells.

[0266] 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 aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0267] In some embodiments, the BAF complex-associated disorder is cancer.

[0268] In a further aspect, the invention features a method of inhibiting BRM, 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 pharmaceutical composition thereof.

[0269] In some embodiments, the cells are cancer cells.

[0270] 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.

[0271] In some embodiments, the cells are cancer cells.

[0272] 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 aforementioned compounds or a pharmaceutical composition thereof.

[0273] In some embodiments, the cells are cancer cells.

[0274] 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 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 disorder associated with BRG1 loss-of-function mutation is cancer. In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, for example, determined to have a BRG1 loss-of-function cancer (for example, determined that the cancer comprises cancer cells with BRG1 loss-of-function).

[0276] 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.

[0277] In some embodiments, the cells are cancer cells.

[0278] 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 aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0279] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, 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.

[0280] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0281] 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, and have not responded to prior chemotherapy or chemotherapy regimens (taxanes such as fluoxetine 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, fosbretabulin, or PDL1 inhibitors).

[0282] 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.

[0283] 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 disorder is a retrovirus from the family Retroviridae, such as lentivirus (e.g., human immunodeficiency virus (HIV)) and deltaretrovirus (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)), or any of the following viruses: 2, HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K *The viral infection is an infection by a virus of the family Papillomaviridae (e.g., human papillomavirus (HPV), HPV E1), family Parvoviridae (e.g., parvovirus B19), family Polyomaviridae (e.g., JC virus and BK virus), family Paramyxoviridae (e.g., measles virus), or family 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.

[0284] In another aspect, the present 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).

[0285] 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 50 At 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

[0286] 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.

[0287] 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.

[0288] 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 preceding compounds or a pharmaceutical composition thereof.

[0289] 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 preceding compounds or a pharmaceutical composition thereof.

[0290] 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.

[0291] 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.

[0292] 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%).

[0293] 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.

[0294] 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%).

[0295] 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.

[0296] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein, and / or the cell or subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein, and / or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein, and / or the cell or subject has 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, the metastatic cancer can be a cancer that spreads via the lymphatic system or a cancer that spreads hematogenously. In some embodiments, an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colonization of the cancer in the liver.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other and in amounts of each that are together effective to treat the subject.

[0301] In some embodiments, the subject or cancer has and / or has been identified as having a loss-of-function mutation in BRG1.

[0302] 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 or cytotoxic agents. In some embodiments, the cancer is resistant to or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0303] 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).

[0304] In certain aspects, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in therapy.

[0305] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in reducing the activity of a BAF complex in a cell.

[0306] In some embodiments, the BAF complex is in a cancer cell.

[0307] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a BAF complex-associated disorder.

[0308] In some embodiments, the BAF complex-associated disorder is cancer or a viral infection.

[0309] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inhibiting a BRM in a cell.

[0310] In some embodiments, the cells are cancer cells.

[0311] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in the treatment of a disorder associated with a loss-of-function mutation in BRG1.

[0312] In some embodiments, the disorder associated with a loss-of-function mutation in BRG1 is cancer.

[0313] In one aspect, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inducing apoptosis in a cell.

[0314] In some embodiments, the cells are cancer cells.

[0315] In certain aspects, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in the treatment of cancer.

[0316] In some embodiments, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, 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.

[0317] In some embodiments, the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0318] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0319] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0320] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in reducing tumor growth of a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0321] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inhibiting the metastatic progression of a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0322] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inhibiting metastatic colonization of a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0323] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in reducing the level and / or activity of a BRM in a cancer cell selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0324] In some embodiments, the cell is in a subject.

[0325] In some embodiments, the cancer is metastatic.

[0326] In some embodiments, the use further comprises an anti-cancer therapy.

[0327] In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation.

[0328] In some embodiments, the anti-cancer therapy is surgery.

[0329] In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent.

[0330] In some embodiments, the chemotherapeutic or cytotoxic agent is an antimetabolite, an antimitotic, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an anti-neoplastic agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulatory agent, a Janus-related kinase inhibitor, a phosphinositide 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor.

[0331] In some embodiments, the one or more chemotherapeutic or cytotoxic agents are dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and / or a protein kinase C inhibitor.

[0332] In some embodiments, the anti-cancer therapy and the compound or pharmaceutical composition thereof are administered within 28 days of each other and in amounts of each that are together effective to treat the subject.

[0333] In some embodiments, the subject or cancer has and / or has been identified as having a loss-of-function mutation in BRG1.

[0334] In some embodiments, the cancer has failed to respond to or progressed after administration of one or more chemotherapeutic or cytotoxic agents.

[0335] In some embodiments, the cancer is resistant or predicted to be resistant to one or more chemotherapeutic agents.

[0336] In some embodiments, the one or more chemotherapeutic or cytotoxic agents are dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and / or a protein kinase C inhibitor.

[0337] In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is uveal melanoma. In some embodiments, the melanoma is mucosal melanoma. In some embodiments, the melanoma is cutaneous melanoma. In some embodiments, the cancer is a hematological cancer. In some embodiments, the hematological cancer is 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, diffuse large cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is 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. In some embodiments, the bone cancer is Ewing's sarcoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the renal cell carcinoma is microphthalmia transcription factor (MITF) family translocation renal cell carcinoma.

[0338] In certain aspects, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in the treatment of a viral infection.

[0339] In some embodiments, the viral infection is an infection with a virus of the family Retroviridae, Hepadnaviridae, Flaviviridae, Adenoviridae, Herpesviridae, Papillomaviridae, Parvoviridae, Polyomaviridae, Paramyxoviridae, or Togaviridae.

[0340] In certain aspects, the invention provides the use of any of the foregoing compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound), or a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutical compositions, in the manufacture of a medicament. In some embodiments, the use is as described for the methods described herein.

[0341] chemical terms The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0342] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in a particular chemical moiety. As understood, other atoms, such as H atoms, or substituents described herein, may be present, if necessary, to satisfy the valence of the atom. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. 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.

[0343] 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.

[0344] 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).

[0345] 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).

[0346] 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).

[0347] 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 N1Each of the groups may be optionally substituted, or two R N1 combine to form an alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino group of the present invention can be unsubstituted amino (i.e., —NH) or substituted amino (i.e., —N(R N1 )2).

[0348] 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.

[0349] 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 1, 2, 3, or 4 substituents, as defined herein for each group, where valencies allow.

[0350] As used herein, the term "azido" refers to an -N3 group.

[0351] 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.

[0352] As used herein, the term "cyano" refers to a -CN group.

[0353] As used herein, the term "carbocyclyl" refers to a non-aromatic C-C ring 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.

[0354] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent monocyclic, bicyclic, or tricyclic group of 3 to 10, preferably 3 to 6, carbon atoms. Cycloalkyl groups may be fully saturated or 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 "CH-cycloalkyl" refers to a cycloalkyl-CH- group (e.g., cyclopropylmethyl and cyclobutylmethyl).

[0355] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0356] 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 one, two, three, or four 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. 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, the heteroalkenyl group is further substituted with one, two, three, or four substituents, where valence allows, 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. 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, as described herein for alkynyl groups, where valency allows. An example of a heteroalkynyl group is "alkynoxy," which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0357] 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 one, two, or three ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of a heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0358] 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 alkyl, C2-C9, heteroaryl, etc., containing 7-16 or 7-20 carbons. In some embodiments, alkyl and heteroaryl are each further substituted with 1, 2, 3, or 4 substituents, valences allowed, as defined herein for each group.

[0359] 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.

[0360] 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 10alkyl 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.

[0361] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0362] As used herein, the term "hydroxyl" refers to an --OH group.

[0363] 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, e.g., sulfonyl-containing groups, such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy ... ,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).

[0364] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0365] 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).

[0366] As used herein, the term "thiol" refers to a -SH group.

[0367] 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, unless otherwise specified, where valences allow. 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.

[0368] 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 chiral adsorbents or eluents). Thus, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of stereoisomers 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 stereoisomers that are not related as mirror images, most commonly 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 those skilled 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 isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration. * "," "R *"," "E," "Z," "cis," and "trans" indicate configurations relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers 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 isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving isomeric mixtures 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 indicated by structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. 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. Where the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to other stereoisomers.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 diastereomer, or moles of 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 with respect 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 any diastereomer free of the other diastereomer, any diastereomer free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer with respect to the other, or mixtures of diastereomers enriched in one or more diastereomers with respect to the other. The present invention encompasses all of these forms.

[0369] 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.

[0370] 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. 15 O. 13 N, 11 C, and 18Positron-emitting isotopes, such as F, are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparation of isotopically labeled compounds is 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.

[0371] 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.

[0372] As used herein, the terms "about" and "approximately" refer to values ​​within 10% above and below the stated value. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0373] 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.

[0374] As used herein, the term "BAF complex" refers to the BRG1 or HRBM-associated factor complex in human cells.

[0375] As used herein, the term "BAF complex-associated disorder" refers to a disorder caused by or affected by the level of activity of the BAF complex.

[0376] 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.

[0377] 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).

[0378] The term "cancer" refers to conditions caused by the proliferation of malignant cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0379] 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). The 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.

[0380] "Determining the level" of protein or RNA refers to detecting the protein or RNA, either directly or indirectly, by methods 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 known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0381] "Reducing the activity of the BAF complex" means reducing the level of activity associated with the BAF complex or an associated downstream effect. A non-limiting example of reducing the activity of the BAF complex is activation of Sox2. The activity level of the 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.

[0382] As used herein, the term "degrading agent" 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).

[0383] 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).

[0384] "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.

[0385] "Reducing the activity of BRG1 and / or BRM" means reducing the level of BRG1 and / or BRM-associated activity or associated downstream effect. A non-limiting example of inhibiting BRG1 and / or BRM activity 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 BRG1 and / or BRM activity is a small molecule BRG1 and / or BRM degrader.

[0386] "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.

[0387] By "level" is meant 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), or an increase or decrease of about 10% compared to a reference material. , about 15%, about 20%, about 50%, about 75%, about 100%, or about 200% decrease or increase, 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 decrease or increase, or 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 increase. 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.

[0388] 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 known in the art, such as a BRM ATPase assay, a Nano DSF assay, or a BRM luciferase cellular assay.

[0389] 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 can 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.

[0390] 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, coating agents, 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.

[0391] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I or II. Pharmaceutically acceptable salts of any of the compounds described herein may include salts that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response, and are within the scope of sound medical judgment and 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.

[0392] 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.

[0393] "Reference material" refers to any useful reference material used to compare protein or RNA levels. A reference material can be any sample, standard, standard curve, or level used for comparison purposes. A reference material can be a normal reference sample or reference standard or level. A "reference sample" can be, for example, a control, 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 ("below X"), or a low threshold ("above X"). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as being "within the normal range" 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) and 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 within the normal reference range, such as any of those described herein, can also be used as a reference.

[0394] As used herein, the term "subject" refers to any 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.

[0395] As used herein, the terms "treat," "treated," or "treating" refer to therapeutic treatment or any procedure where the purpose is to slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, a decrease in the extent 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 the 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 excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not receiving treatment. The compounds of the invention may also be used to "prophylactically treat" or "prevent" a disorder, for example, in subjects at increased risk of developing the disorder.

[0396] 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

[0397] 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 II: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; Each R 1 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted CH2-C3-C8 cycloalkyl; each X is independently halo; L is a linker, a compound in which B is a decomposition moiety; or a pharmaceutically acceptable salt thereof.

[0398] Exemplary compounds described herein include compounds having a structure according to Formula I or II: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; L is a linker, B is the decomposition part, Each R 1is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heterocyclyl; compounds wherein each X is independently halo; or a pharmaceutically acceptable salt thereof.

[0399] Exemplary compounds described herein include compounds having a structure according to Formula I or II: [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl; m is 0, 1, 2, or 3; k is 0, 1, or 2; L is a linker 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 C3-C 10cycloalkyl, optionally substituted C2-C9 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 2~6 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; B is the decomposition part, Each R 1 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heterocyclyl; compounds wherein each X is independently halo; or a pharmaceutically acceptable salt thereof.

[0400] In some embodiments, the compound has the structure of any one of compounds 1-103 in Table 1, or a pharmaceutically acceptable salt thereof.

[0401] Other embodiments, and exemplary methods for synthesis of the production of these compounds, are described herein.

[0402] 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.

[0403] 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 rate; or (i) an increase in the subject's progression-free survival.

[0404] 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.

[0405] Treating cancer may also result in a reduction in tumor number. For example, after treatment, the 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 tumor number may be measured by any reproducible means of measurement, for example, the tumor number may be measured by counting tumors visible to the naked eye or at a particular magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0406] Treatment of 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).

[0407] 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 the average survival time of a population may be measured by any reproducible means. The increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for a population after the start of treatment with a compound of the present invention. The increase in the average survival time of a population may also be measured, for example, by calculating the average length of survival for a population after the completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0408] 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.

[0409] 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 tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0410] 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.

[0411] 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 symptoms, or in combination with other types of treatment for 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.

[0412] 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); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adolescent and pediatric analogs, such as adzesin and carzesin); 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;Nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gammaol and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed. Engl. 33:183-186 (1994); dynemicins, including dynemicin A; bisphosphonates, e.g., clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pi doxorubicin, including lorizino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogues, for example, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, for example, calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenal drugs, for example, aminoglutethimide, mitotane, trilostane; folic acid supplements, for example, furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine ( defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verraculin A, roridin A, and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa;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); the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine, as well as 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 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.

[0413] 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. Such agents include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab); Synagis (palivizumab); Remicade (infliximab); Herceptin (trastuzumab); Mylotarg (gemtuzumab ozogamicin); Campath (alemtuzumab); Zevalin (ibritumomab tiuxetan); Humira (adalimumab); Xolair (omalizumab); Bexxar (tositumomab-I-131); Raptiva (efalizumab); Erbitux (cetuximab); Avastin (bevacizumab); Tysabri (natalizumab); Actemra (tocilizumab); Vectibix (panitumumab); Lucentis (ranibizumab); Soliris (eculizumab); Cimzia (certolizumab pegol); Simponi (golimumab); Ilaris (canakinumab); Stelara (ustekinumab); Arzerra (ofatumumab); Prolia (denosumab); Numax (motavizumab); ABThrax (raxibacumab); Benlysta (belimumab); Yervoy (ipilimumab); Adcetris (brentuximab vedotin); Perjeta (pertuzumab); Kadcyla (Ado-trastuzumab emtansine); and Gazyva (obinutuzumab). Antibody-drug conjugates are also included.

[0414] 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.

[0415] 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 can be, for example, humanized or fully human. 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.

[0416] 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, 1-14, 1-21, or 1-30 days before or after the second therapeutic agent.

[0417] Pharmaceutical Compositions 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.

[0418] 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 route of administration. 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.

[0419] 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 storage and use conditions. 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 multi-dose sterile form in a sealed container, which may 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, which is 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.

[0420] 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.

[0421] 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; and the clearance rate of the compound in the treated animal. Those skilled in the art will be able to determine the appropriate dosage based on the above factors. The compounds of the present invention may be administered initially at a suitable dosage, which may be adjusted as necessary depending on the clinical response. In general, 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.

[0422] 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]

[0423] The following abbreviations are used throughout the examples below:

[0424] [Table 2-1]

[0425] [Table 2-2]

[0426] Example 1. Preparation of Compounds Preparation of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (I-1) [ka]

[0427] Step 1: Preparation of 2-(3-bromoisoxazol-5-yl)ethan-1-ol [ka]

[0428] A solution of 3-butyn-1-ol (552.89 g, 7888.26 mmol, 4 equiv.) and KHCO (592.30 g, 5916.197 mmol, 3 equiv.) in EtOAc (2600 mL) and HO (260 mL) was stirred at room temperature. 1-Bromo-N-hydroxymethanecarbonimidoyl bromide (400.00 g, 1972.066 mmol, 1.00 equiv. in EA (840 mL)) was added dropwise to the above mixture at room temperature over 60 minutes. The resulting mixture was stirred overnight at room temperature. The reaction mixture was washed with water (500 mL × 2), and the combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (30:1) to give the intermediate title compound (338.2 g, 88.98%) as an off-white solid. LCMS (ESI) m / z [M+H] + =192.

[0429] Step 2: Preparation of 2-(3-bromoisoxazol-5-yl)acetic acid [ka]

[0430] A solution of 2-(3-bromoisoxazol-5-yl)ethan-1-ol (360.00 g) in acetone (3600 mL) was stirred at 0° C. under a nitrogen atmosphere. To the above mixture, Jones reagent (1760 mL) was added dropwise over 1 hour at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water / ice at 0° C. The resulting mixture was extracted with EtOAc (1000 mL×3). The combined organic layers were washed with water (500 mL×2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (348.6 g, crude) as a green solid, which was used directly without further purification. (LCMS (ESI) m / z [M+H] + =206.

[0431] Step 3: Preparation of ethyl 2-(3-bromoisoxazol-5-yl)acetate [ka]

[0432] A solution of 2-(3-bromoisoxazol-5-yl)acetic acid (397.6 g, 1930.144 mmol, 1.00 equiv) and H2SO4 (18.92 g, 193.014 mmol, 0.1 equiv) in EtOH (2000 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (3000 mL), washed with water (500 mL × 2), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (35:1) to give the title compound (355 g, 78.61%) as a colorless oil. (LCMS (ESI) m / z [M+H] + =234.

[0433] Step 4: Preparation of ethyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate [ka]

[0434] To a stirred solution of t-BuOK (244.51 g, 2179.031 mmol, 1.5 equiv) and ethyl 2-(3-bromoisoxazol-5-yl)acetate (340.00 g, 1452.687 mmol, 1.00 equiv) in THF (2000 mL) was added 2-iodopropane (321.03 g, 1888.493 mmol, 1.3 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then diluted with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with water (500 mL × 1) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (10:1) to give the title compound (284.1 g, 70.82%) as a colorless oil. (LCMS (ESI) m / z [M+H] + =276.

[0435] Step 5: Preparation of 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid [ka]

[0436] To a stirred solution of the preparation ethyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (90.00 g, 325.933 mmol, 1.00 equiv) in MeOH (270 mL) was added a solution of KOH (274.30 g, 4888.995 mmol, 15.00 equiv) in MeOH (210 mL) at 0 °C. The reaction mixture was stirred at 80 °C overnight. The resulting solution was acidified to pH 4 with a 1 M solution of HCl (aq) and concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (1800 mL) and filtered. The filter cake was washed with EtOAc (100 mL × 3). The filtrate was concentrated under reduced pressure to give the title compound (62.9 g, 96.88%) as a yellow oil, which was used directly without further purification. LCMS (ESI) m / z: [M+H] + =200.

[0437] Step 6: Preparation of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid [ka]

[0438] To a stirred solution of 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (62.90 g, 315.754 mmol, 1.00 equiv) in HOAc (450.00 mL) was added 48% HBr (450.00 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by flash C18-flash chromatography using an elution gradient of 0-100% MeCN in water (containing 0.05% FA). Pure fractions were evaporated to dryness to give the title compound (43.3 g, 74.05%) as a white solid. LCMS (ESI) m / z: [M+H] + =186.

[0439] Step 7: Preparation of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (I-1) [ka]

[0440] To a stirred solution of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (20 g, 108.004 mmol, 1.00 equiv) in MeOH (72 mL) was added SOCl2 (35.26 mL, 486.059 mmol, 4.50 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an elution gradient of 0–100% THF in petroleum ether. Pure fractions were evaporated to dryness to give compound I-1 (15.1 g, 70.18%) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ11.24(s,1H),5.95(s,1H),3.71-3.58(m,4H),2.32-2.20(m,1H),0.88(dd,J=34.2,6.7Hz,6H). LCMS(ESI)m / z:[M+H] + =200.

[0441] Preparation of methyl 2-(3-((2-chloropyrimidin-4-yl)oxy)isoxazol-5-yl)-3-methylbutanoate (Intermediate 2) [ka]

[0442] A solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (200 mg, 1.004 mmol, 1 equiv.), 4-bromo-2-chloropyrimidine (233.04 mg, 1.205 mmol, 1.2 equiv.), and CsCO (981.9 mg, 3.012 mmol, 3.0 equiv.) in DMF (5 mL) was stirred at 100 °C under a nitrogen atmosphere for 1 h. 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, 10% to 100% gradient in 20 min; detector, UV 254 nm. The mixture was concentrated to give intermediate 2 (258 mg, crude material). LCMS (ESI) m / z: [M+H] + =312.

[0443] Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. (I-2) [ka]

[0444] Step 1: Preparation of (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine. [ka]

[0445] 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.

[0446] Step 2: Preparation of (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride. [ka]

[0447] 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 NaSO. 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.

[0448] Step 3: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate. [ka]

[0449] 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.

[0450] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid. [ka]

[0451] 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.

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

[0453] 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 min. 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.

[0454] Step 6: Preparation of methyl 2-[3-(2-methoxypyrimidin-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]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 minutes, 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 hours. 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.

[0456] Step 7: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. [ka]

[0457] 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 for 3 h under a dry nitrogen atmosphere. 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) as a brown oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =296.

[0458] Preparation of tert-butyl (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-(2R)-3-methyl-2-[3-(piperidin-4-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-3) [ka]

[0459] Step 1: Preparation of tert-butyl 4-[(1E)-(hydroxyimino)methyl]piperidine-1-carboxylate (Intermediate 2) [ka]

[0460] To a stirred solution of 4-formylpiperidine-1-carboxylic acid (5 g, 23.444 mmol, 1.00 equiv.) in MeOH (10 mL) and HO (10 mL) was added hydroxylamine hydrochloride (1.95 g, 28.133 mmol, 1.2 equiv.) and NaCO (1.24 g, 11.722 mmol, 0.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature overnight. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 20 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 2 (6 g, crude) as a colorless oil. LCMS (ESI) m / z: [M+H] + =229.

[0461] Step 2: Preparation of tert-butyl 4-[(1Z)-chloro(hydroxyimino)methyl]piperidine-1-carboxylate (Intermediate 3) [ka]

[0462] A mixture of intermediate 2 and NCS (3.5 g, 26.282 mmol, 1.0 equiv) in DMF (20 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with water (50.00 mL) and extracted with EtOAc (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 3 (7.8 g, crude) as a colorless oil. LCMS (ESI) m / z [M+H]+ =263.

[0463] Step 3: Preparation of tert-butyl 4-[5-(2-methoxy-2-oxoethyl)-1,2-oxazol-3-yl]piperidine-1-carboxylate (Intermediate 4) [ka]

[0464] A mixture of intermediate 3 (7.8 g, crude) and NaHCO3 (3.8 g, 45.675 mmol, 1.5 equiv.) in EtOAc (100 mL) was stirred at room temperature for 30 minutes. To the above mixture, methyl but-3-ynoate (2.99 g, 30.450 mmol, 1 equiv.) was added at 0 °C. The resulting mixture was stirred at room temperature overnight. 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 (0.05% FA), gradient 0% to 100% in 30 minutes; Detector: UV 254 nm. The resulting mixture was concentrated under reduced pressure to give intermediate 4 (4.1 g, 41.51%) as a pale yellow oil. LCMS (ESI) m / z: [M+H] + =325.

[0465] Step 4: Preparation of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperidine-1-carboxylate (Intermediate 5) [ka]

[0466] To a mixture of intermediate 4 (1.0 g, 3.083 mmol, 1.5 equiv.) and NaSO (1.0 g) in THF (10 mL) was added t-BuOK (518.90 mg, 4.625 mmol, 1.5 equiv.) and 2-iodopropane (628.87 mg, 3.700 mmol, 1.2 equiv.) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 3 h under a nitrogen atmosphere. The desired product could be detected by LCMS. 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 (0.05% FA) in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give intermediate 5 (330 mg, 29.21%) as a pale yellow oil. LCMS(ESI)m / z:[M+H] + =367.

[0467] Step 5: Preparation of 2-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,2-oxazol-5-yl}-3-methylbutanoic acid (Intermediate 6) [ka]

[0468] To a stirred solution of intermediate 5 (320 mg, 0.873 mmol, 1.00 equiv) in MeOH (5 mL) was added LiOH (62.74 mg, 2.619 mmol, 3 equiv) in HO (5 mL) dropwise 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. Aqueous HCl (6 M) was added to the above mixture to adjust the pH to about 5. The resulting mixture was extracted with EtOAc (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 (316 mg crude) as an off-white solid. LCMS (ESI) m / z: [M+H] + =353.

[0469] Step 6: 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)piperidine-1-carboxylate (Intermediate 7) [ka]

[0470] A mixture of intermediate 6 (310 mg, 0.880 mmol, 1.00 equiv.) and HATU (668.90 mg, 1.760 mmol, 2 equiv.) in DMF (5 mL) was stirred at room temperature for 30 min. To the above mixture, (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (291.53 mg, 0.880 mmol, 1 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for another 2 h. 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 (0.05% FA), gradient from 0% to 100% in 30 min; Detector: UV 254 nm. The resulting mixture was concentrated under reduced pressure to give Intermediate 7 (242 mg, 37.31%) as a light brown solid. LCMS (ESI) m / z: [M+H] + =666.

[0471] Step 7: Preparation of tert-butyl 4-{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}piperidine-1-carboxylate (Intermediate 8) [ka]

[0472] The product was purified under the following conditions (column: CHIRAL ART Amylose-SA, 3 * Purification by preparative SFC on a 25 cm column, 5 μm column; mobile phase A: CO₂, mobile phase B: MeOH-HPLC; flow rate: 50 mL / min; gradient: isocratic 45% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 205 nm; RT1 (min): 3.65; RT2 (min): 4.88; sample solvent: MeOH-HPLC; injection volume: 1 mL gave intermediate 8 (second peak) (208.1 mg, 43.52%) as a light brown solid. LCMS (ESI) m / z: [M+H] + =666.

[0473] Step 8: Preparation of tert-butyl (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperidin-4-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (Intermediate 9) [ka]

[0474] To a stirred solution of intermediate 8 (200 mg, 0.300 mmol, 1.00 equiv) in DCM (2 mL) was added dropwise 1M HCl in 1,4-dioxane (2 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 intermediate 9 (247.5 mg) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =566.

[0475] 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) and (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-5) [ka]

[0476] 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 (Intermediate 2). [ka]

[0477] 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), and the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give Intermediate 2 (217 mg, crude) as a white solid. LCMS(ESI)m / z:[M+H] + =482.

[0478] Step 2: Preparation of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate (Intermediate 3). [ka]

[0479] To a stirred solution of intermediate 2 (217.00 mg, 0.451 mmol, 1.00 equiv) in DMF (3.00 mL) was added tert-butyl piperazine-1-carboxylate (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 in water (0.1% FA), 0-100% gradient in 30 min. This afforded intermediate 3 (54 mg, 32.59%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =368.

[0480] Step 3: Preparation of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 4). [ka]

[0481] To a stirred solution of intermediate 3 (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). The resulting mixture was stirred at room temperature for an additional 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 saturated brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. This afforded intermediate 4 (52 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =354.

[0482] 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-carboxylate (Intermediate 6). [ka]

[0483] To a stirred solution of Intermediate 4 (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 an additional hour. The mixture was directly purified by reverse-phase flash chromatography under the following conditions. Column: C18 silica gel; Mobile phase: MeCN in water (0.1% FA), 0-100% gradient in 30 min. This gave intermediate 6 (73 mg, 92.12%) as a white solid. LCMS (ESI) m / z: [M+H] + =667.

[0484] Step 5: 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 (Intermediate 7), (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 (Intermediate 8). [ka]

[0485] Intermediate 6 (73 mg) was purified by SFC under the following conditions: column, CHIRAL ART Amylose-C NEO, 3 * 25 cm, 5 um, mobile phase, MeOH. This gave intermediate 7 (37 mg, second peak). LCMS (ESI) m / z: [M+H] + = 667, and intermediate 8 (34 mg, first peak). LCMS (ESI) m / z: [M+H] + =667.

[0486] 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-4). [ka]

[0487] To a stirred solution of intermediate 7 (37.00 mg, 0.055 mmol, 1.00 equiv) in DCM (1.50 mL) was added HCl in 1,4-dioxane (1.50 mL, 26.276 mmol, 473.57 equiv) at 0° C. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. This afforded I-4 (45 mg, crude) as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0488] Step 7: 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-5). [ka]

[0489] To a stirred solution of intermediate 8 (34.00 mg, 0.051 mmol, 1.00 equiv) in DCM (1.50 mL) was added HC in 1,4-dioxane (1.50 mL, 26.276 mmol, 515.35 equiv) at 0° C. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. This afforded I-5 (45 mg, crude) as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0490] Preparation of 2-[6-(azetidin-3-yl)thieno[2,3-c]pyridazin-3-yl]phenol (I-6) [ka]

[0491] Step 1: Preparation of tert-butyl 3-[2-(3,6-dichloropyridazin-4-yl)ethynyl]azetidine-1-carboxylate [ka]

[0492] To a stirred mixture of 3,6-dichloro-4-iodopyridazine (200 mg, 0.728 mmol, 1.00 equiv.) and tert-butyl 3-ethynylazetidine-1-carboxylate (145.06 mg, 0.801 mmol, 1.1 equiv.) in toluene (5.00 mL), Pd(PPh3)2Cl2 (76.61 mg, 0.109 mmol, 0.15 equiv.), CuI (27.71 mg, 0.146 mmol, 0.2 equiv.), and TEA (220.88 mg, 2.184 mmol, 3 equiv.) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 2 h at room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions. Column: C18; Mobile phase: MeCN (0.05% FA) in water, 40% to 60% gradient. This gave the title compound (170 mg, 64.07%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =328.

[0493] Step 2: Preparation of tert-butyl 3-{3-chlorothieno[2,3-c]pyridazin-6-yl}azetidine-1-carboxylate [ka]

[0494] To a stirred mixture of tert-butyl 3-[2-(3,6-dichloropyridazin-4-yl)ethynyl]azetidine-1-carboxylate (160 mg, 0.488 mmol, 1.00 equiv.) in NMP (5 mL) was added sodium hydrogen sulfide (32.80 mg, 0.586 mmol, 1.2 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours, cooled, and filtered. The filtrate was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN (0.05% FA) in water, 30% to 50% gradient. This afforded the title compound (122 mg, 71.43%) as a white solid. LCMS (ESI) m / z [M+H] + =326.

[0495] Step 3: Preparation of tert-butyl 3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]azetidine-1-carboxylate [ka]

[0496] To a stirred mixture of tert-butyl 3-{3-chlorothieno[2,3-c]pyridazin-6-yl}azetidine-1-carboxylate (122 mg, 0.374 mmol, 1.00 equiv.) and 2-hydroxyphenylboronic acid (154.94 mg, 1.122 mmol, 3 equiv.) in dioxane (4 mL) and HO (1 mL), CsCO (244.01 mg, 0.748 mmol, 2 equiv.) and XPhos Pd G (63.39 mg, 0.075 mmol, 0.2 equiv.) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80 °C for 2 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions. Column: C18; Mobile phase: MeCN (0.05% FA) in water, 40% to 60% gradient. This gave the title compound (85 mg, 53.28%) as a white solid. LCMS (ESI) m / z: [M+H] + =384.

[0497] Step 4: Preparation of 2-[6-(azetidin-3-yl)thieno[2,3-c]pyridazin-3-yl]phenol [ka]

[0498] To a stirred mixture of tert-butyl 3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]azetidine-1-carboxylate (85 mg, 0.222 mmol, 1.00 equiv.) in DCM (4 mL) was added TFA (1 mL) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =284.

[0499] Preparation of 2-(6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol (I-7). [ka]

[0500] Step 1: Preparation of tert-butyl 4-((3,6-dichloropyridazin-4-yl)ethynyl)piperidine-1-carboxylate (Intermediate 2). [ka]

[0501] To a stirred mixture of tert-butyl 4-ethynylpiperidine-1-carboxylate (1.00 g, 4.778 mmol, 1.00 equiv.) and 4-bromo-3,6-dichloropyridazine (1.20 g, 5.256 mmol, 1.1 equiv.) in toluene (10.00 mL), Pd(PPh)Cl (0.50 g, 0.717 mmol, 0.15 equiv.), CuI (0.18 g, 0.956 mmol, 0.2 equiv.), and TEA (1.45 g, 14.334 mmol, 3 equiv.) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in DMF (15.00 mL) and purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (0.05% FA), gradient 0% to 100% in 25 min to give intermediate 2 (596 mg, 33.61%) as a brown solid. LCMS (ESI) m / z: [M+H]+ = 356.25.

[0502] Step 2: Preparation of tert-butyl 4-(3-chlorothieno[2,3-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 3). [ka]

[0503] To a stirred solution of intermediate 2 (596.00 mg, 1.673 mmol, 1.00 equiv) in NMP (10.00 mL) was added NaSH (93.79 mg, 1.673 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 1 h and then allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (10.00 mL) and purified by reverse-phase flash chromatography (C18 column; mobile phase, MeCN in water (0.05% FA), 0% to 100% gradient in 30 min) to give intermediate 3 (356 mg, 49.91%) as a brown solid. LCMS(ESI) m / z: [M+H]+ = 353.87.

[0504] Step 3: Preparation of tert-butyl 4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 4). [ka]

[0505] To a solution of Intermediate 3 (350.00 mg, 0.989 mmol, 1.00 equiv) and 2-hydroxyphenylboronic acid (204.63 mg, 1.484 mmol, 1.5 equiv) in dioxane (5.00 mL) and HO (1.00 mL) was added CsCO (644.51 mg, 1.978 mmol, 2.0 equiv) and XPhos Pd G (83.72 mg, 0.099 mmol, 0.1 equiv). After stirring overnight at 90 °C under a nitrogen atmosphere, the mixture was concentrated under reduced pressure. The residue was dissolved in DMF (10.00 mL) and purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (0.05% FA), gradient 0% to 100% in 20 min, to give intermediate 4 (188 mg, 44.85%) as a brown solid. LCMS (ESI) m / z: [M+H]+ = 411.52.

[0506] Step 4: Preparation of 2-(6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol (I-7). [ka]

[0507] To a stirred solution of intermediate 4 (188.00 mg, 0.457 mmol, 1.00 equiv) in DCM (9.00 mL) was added TFA (3.00 mL) at room temperature. The resulting mixture was stirred for 4 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (0.05% FA), gradient 0% to 100% in 20 minutes, to give the title compound (130 mg, 91.38%) as a light brown solid. LCMS (ESI) m / z: [M+H]+ = 311.40.

[0508] Preparation of 2-(5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol (I-8). [ka]

[0509] Step 1: Preparation of tert-butyl 4-((3,6-dichloropyridazin-4-yl)ethynyl)piperidine-1-carboxylate (Intermediate 2) [ka]

[0510] To a mixture of tert-butyl 4-ethynylpiperidine-1-carboxylate (8.00 g, 38.225 mmol, 1.00 equiv.) and 4-bromo-3,6-dichloropyridazine (10.45 g, 45.870 mmol, 1.20 equiv.) in toluene (80 mL), Pd(PPh)Cl (4.02 g, 5.734 mmol, 0.15 equiv.), CuI (14.56 g, 76.450 mmol, 2.00 equiv.), and TEA (11.60 g, 114.675 mmol, 3.00 equiv.) were added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 50% EtOAc in petroleum ether to give intermediate 2 (5.00 g, 36.7%) as a yellow solid. LCMS (ESI) m / z: [M+H]+ = 356.

[0511] Step 2: Preparation of tert-butyl 4-(3-chlorothieno[2,3-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 3). [ka]

[0512] To a mixture of intermediate 2 (5.00 g, 14.035 mmol, 1.00 equiv) in NMP (50 mL) was added NaSH (0.79 g, 14.035 mmol, 1.0 equiv). The resulting mixture was stirred at 100 °C for 1 h, cooled, and filtered. The filtrate was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeOH in water, gradient 10% to 50% in 10 min to give intermediate 3 (1.80 g, 36.2%) as a yellow solid. LCMS (ESI) m / z: [M+H] = 354.

[0513] Step 3: Preparation of tert-butyl 4-(5-bromo-3-chlorothieno[2,3-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 4). [ka]

[0514] To a mixture of intermediate 3 (1.80 g, 5.087 mmol, 1.00 equiv) in CHCl (20 mL) was added Br (8.13 g, 50.870 mmol, 10.00 equiv). The resulting mixture was stirred at room temperature overnight and then basified with aqueous NaHCO. BocO (2.21 g, 10.174 mmol, 2.00 equiv) was then added and the mixture was stirred for 2 h. The mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeOH in water, gradient 10% to 50% in 10 min to give intermediate 4 (710.0 mg, 32.4%) as a yellow solid. LCMS(ESI) m / z: [M+H]+ = 432.

[0515] Step 4: Preparation of tert-butyl 4-(3-chloro-5-methylthieno[2,3-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 5). [ka]

[0516] To a mixture of Intermediate 4 (710.0 mg, 1.641 mmol, 1.00 equiv), KPO (696.50 mg, 3.282 mmol, 2.00 equiv), and Pd(AMPhos)Cl (174.25 mg, 0.246 mmol, 0.15 equiv) in dioxane (10 mL) and HO (2 mL) was added trimethyl-1,3,5,2,4,6-trioxatriborinane (411.90 mg, 3.282 mmol, 2.00 equiv), and the resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 1 h. The reaction mixture was filtered through a short pad of Celite and eluted with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeOH in water, gradient 10% to 50% in 10 min to give intermediate 5 (450.0 mg, 74.5%) as a yellow solid. LCMS (ESI) m / z: [M+H]+ = 368.

[0517] Step 5: Preparation of tert-butyl 4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 6) [ka]

[0518] To a mixture of intermediate 5 (450.0 mg, 1.223 mmol, 1.00 equiv) and 2-hydroxyphenylboronic acid (337.43 mg, 2.446 mmol, 2.00 equiv) in dioxane (10 mL) and HO (2 mL) was added XPhos Pd G (155.31 mg, 0.183 mmol, 0.15 equiv) and CsCO (1.2 g, 3.669 mmol, 3.00 equiv), and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction mixture was filtered through a short pad of Celite and eluted with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeOH in water, gradient 10% to 50% in 10 min to give intermediate 6 (380.0 mg, 73.0%) as a yellow solid. LCMS (ESI) m / z: [M+H]+ = 426.

[0519] Step 6: Preparation of 2-(5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol (I-8). [ka]

[0520] To a mixture of intermediate 6 (380.0 mg, 0.893 mmol, 1.00 equiv) in DCM (6 mL) was added TFA (3 mL, 40.389 mmol, 45.23 equiv), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeOH in water, gradient 10% to 50% in 10 min to give I-8 (246.4 mg, 84.7%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.22-8.11(m,1H),7.43-7.34(m,1H),7.07-6.99(m,2H),3.67-3 .53(m,1H),3.43-3.35(m,2H),3.10-3.00(m,2H),2.46(s,3H),2.13-2.04(m,2H),1.91-1.78(m,2H). LCMS(ESI)m / z:[M+H]+=326.10.

[0521] Preparation of methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (I-9) [ka]

[0522] Step 1: Preparation of (Z)-N-[(6-fluoro-5-methylpyridin-3-yl)methylidene]hydroxylamine (Intermediate 2) [ka]

[0523] A solution of 6-fluoro-5-methylpyridine-3-carbaldehyde (10 mg, 0.072 mmol, 1 equiv.), hydroxylamine hydrochloride (9.99 mg, 0.144 mmol, 2 equiv.), and NaCO (22.85 mg, 0.216 mmol, 3 equiv.) in MeOH (0.5 mL) and HO (0.5 mL) was added and the resulting solution was stirred at 25 °C overnight. The mixture was diluted with EtOAc (200 mL) and washed with water (200 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 2 (2.2 mg, 99.29%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =155.

[0524] Step 2: Preparation of (E)-6-fluoro-N-hydroxy-2-methylpyridine-3-carbonimidoyl chloride (Intermediate 3) [ka]

[0525] A solution of intermediate 2 (2.2 g, 14.272 mmol, 1 equiv.), NCS (2.86 g, 21.408 mmol, 1.5 equiv.) in EtOAc (20 mL) was added and the resulting solution was stirred at 25° C. overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 3 (3.6 g, crude) as a white solid. LCMS (ESI) m / z: [M+H] + =189.

[0526] Step 3: Preparation of methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]acetate (Intermediate 4) [ka]

[0527] To a solution of intermediate 3 (3.6 g, 19.089 mmol, 1 equiv.) in EtOAc (14 mL) was added methyl but-3-ynate (3.75 g, 38.178 mmol, 2 equiv.) and NaHCO3 (4.81 g, 57.267 mmol, 3 equiv.) at 0 °C. The resulting solution was stirred at 25 °C overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL × 3). 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 under the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, gradient 0% to 100% in 30 min to give intermediate 4 (2.5 g, 52.34%) as a white solid. LCMS (ESI) m / z: [M+H] + =251.

[0528] Step 4: Preparation of methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (I-9) [ka]

[0529] To a solution of intermediate 4 (500 mg, 1.998 mmol, 1 equiv.), 2-iodopropane (679.35 mg, 3.996 mmol, 2 equiv.), and CsCO (1.3 g, 3.996 mmol, 2 equiv.) in THF (5 mL) was added the resulting solution, which was stirred at 60 °C overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography using an elution gradient of 0-60% ACN in HO to give the title compound (288 mg, 49.31%) as a white solid. LCMS (ESI) m / z: [M+H] + =293.

[0530] Preparation of 2-(5-cyclopropyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)thieno[2,3-c]pyridazin-3-yl)phenol (I-11) [ka]

[0531] Step 1: Preparation of tert-butyl 2-cyano-2-cyclopropylacetate (Intermediate 2) [ka]

[0532] To a solution of 2-cyclopropylacetonitrile (10.00 g, 123.277 mmol, 1 equiv.) and BocO (53.81 g, 246.554 mmol, 2 equiv.) in THF (100 mL) was added LDA (26.41 g, 246.554 mmol, 2 equiv.) at −78 °C. After stirring at −78 °C for 2 h, the reaction was quenched with water (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 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 0% to 20% EtOAc in PE to give intermediate 2 (20.00 g, 80.57%) as a yellow solid. No MS signal was observed by H-NMR.

[0533] Step 2: tert-butyl 2-cyano-2-cyclopropyl-2-(3,6-dichloropyridazin-4-yl)acetate (Intermediate 3). [ka]

[0534] To a solution of intermediate 2 (15.00 g, 82.765 mmol, 1 equiv.) and 3,4,6-trichloropyridazine (15.18 g, 82.765 mmol, 1 equiv.) in DMSO (100 mL) was added DIEA (32.09 g, 248.295 mmol, 3 equiv.). After stirring overnight at room temperature under a nitrogen atmosphere, the resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 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 0% to 50% EtOAc in PE to give intermediate 3 (18.00 g, 59.64%) as a pink solid. LCMS (ESI) m / z: [M+H] + =328.

[0535] Step 3: Preparation of 2-cyclopropyl-2-(3,6-dichloropyridazin-4-yl)acetonitrile (Intermediate 4). [ka]

[0536] To a solution of intermediate 3 (10.00 g, 30.470 mmol, 1 equiv.) in DMSO (50 mL) and HO (5 mL) was added NaCl (3.56 g, 60.940 mmol, 2 equiv.). After stirring at 100 °C for 3 h, the resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 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 0% to 50% EtOAc in PE to give intermediate 4 (5.00 g, 64.7%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =228.

[0537] Step 4: Preparation of 3-chloro-5-cyclopropylthieno[2,3-c]pyridazin-6-amine (Intermediate 5). [ka]

[0538] To a solution of intermediate 4 (3.00 g, 13.153 mmol, 1 equiv.) in NMP (50 mL) was added NaHS.2H2O (1.21 g, 13.153 mmol, 1 equiv.). After stirring at 100 °C for 20 min, the resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (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 0% to 50% EtOAc in PE to give intermediate 5 (2.00 g, 60.6%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =226.

[0539] Step 5: Preparation of 3,6-dichloro-5-cyclopropylthieno[2,3-c]pyridazine (Intermediate 6). [ka]

[0540] To a solution of intermediate 5 (2.00 g, 8.862 mmol, 1 equiv.) and CuCl (2.38 g, 17.724 mmol, 2 equiv.) in ACN (50 mL) was added t-BuNO (1.83 g, 17.724 mmol, 2 equiv.). After stirring at 50 °C for 3 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 50% EtOAc in PE to give intermediate 6 (1.00 g, 41.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =245.

[0541] Step 6: Preparation of tert-butyl 6-(3-chloro-5-cyclopropylthieno[2,3-c]pyridazin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 7). [ka]

[0542] To a solution of intermediate 6 (1.00 g, 4.080 mmol, 1 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.62 g, 8.160 mmol, 2 equiv.) in DMSO (20 mL) was added DIEA (1.58 g, 12.240 mmol, 3 equiv.). After stirring at 100 °C under a nitrogen atmosphere for 3 h, the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (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 0% to 50% EtOAc in PE to give intermediate 7 (900.0 mg, 48.7%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =407.

[0543] Step 7: Preparation of tert-butyl 6-(5-cyclopropyl-3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 7). [ka]

[0544] To a solution of Intermediate 7 (900.0 mg, 2.212 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (610.11 mg, 4.424 mmol, 2 equiv.) in dioxane (20 mL) and HO (4 mL), CsCO (2161.8 mg, 6.636 mmol, 3 equiv.) and XPhos Pd G (187.2 mg, 0.221 mmol, 0.1 equiv.) were added. After stirring at 80 °C under a nitrogen atmosphere for 1 h, the resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using the following conditions: column, C 18 Purification by reverse-phase flash chromatography on silica gel; mobile phase, ACN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm, gave intermediate 8 (800.0 mg, 70.0%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =465.

[0545] Step 8: Preparation of 2-(5-cyclopropyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)thieno[2,3-c]pyridazin-3-yl)phenol (I-11). [ka]

[0546] To a solution of intermediate 8 (500.0 mg, 1.076 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL, 40.389 mmol, 37.53 equiv). After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure to give I-11 (700.0 mg, crude) as a semi-solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =365.

[0547] Preparation of 2-(6-{2,6-diazaspiro[3.3]heptan-2-yl}-5-methylthieno[2,3-c]pyridazin-3-yl)phenol (I-12) [ka]

[0548] Step 1: Preparation of tert-butyl 6-{3-chloro-5-methylthieno[2,3-c]pyridazin-6-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 2) [ka]

[0549] To a solution of 3,6-dichloro-5-methylthieno[2,3-c]pyridazine (639.12 mg, 2.916 mmol, 2.41 equiv.) in DMSO (8 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (240 mg, 1.210 mmol, 1.00 equiv.) and DIEA (469.36 mg, 3.630 mmol, 3 equiv.). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 6 h. 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), 10% to 80% gradient in 30 min; detector, UV 254 nm. This gave intermediate 2 (280 mg, 42.51%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =381.

[0550] Step 2: Preparation of tert-butyl 6-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 3) [ka]

[0551] To a solution of tert-butyl 6-{3-chloro-5-methylthieno[2,3-c]pyridazin-6-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 0.788 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (217.28 mg, 1.576 mmol, 2 equiv.) in dioxane (6 mL) and HO (1 mL) was added CsCO (769.87 mg, 2.364 mmol, 3 equiv.) and XPhos Pd G (66.67 mg, 0.079 mmol, 0.1 equiv.). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give intermediate 3 (160 mg, 46.32%) as a yellow solid. LCMS (ESI) m / z [M+H]+ =439.

[0552] Step 3: Preparation of 2-(6-{2,6-diazaspiro[3.3]heptan-2-yl}-5-methylthieno[2,3-c]pyridazin-3-yl)phenol (I-12) [ka]

[0553] A solution of intermediate 3 (150 mg, 0.342 mmol, 1 equiv.) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. This gave I-12 (100 mg, 86.39%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =339.

[0554] Preparation of 2-(6-{2,6-diazaspiro[3.3]heptan-2-yl}thieno[3,2-c]pyridazin-3-yl)phenol) (I-13) [ka]

[0555] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (Intermediate 2) [ka]

[0556] To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (43.00 g, 206.294 mmol, 1 equiv.) and CHCl (66.30 g, 247.553 mmol, 1.2 equiv.) in THF (300 mL) was added CuI (47.15 g, 247.553 mmol, 1.2 equiv.) and t-BuNO (25.53 g, 247.553 mmol, 1.2 equiv.). The resulting mixture was stirred at 60 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give intermediate 2 (25.00 g, 58.1%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =319.

[0557] Step 2: Preparation of 4-(tert-butylsulfanyl)-6-chloro-3-iodopyridazine (Intermediate 3) [ka]

[0558] To a stirred solution of intermediate 2 (25.00 g, 78.291 mmol, 1 equiv.) and 2-methyl-2-propanethiol (7.77 g, 86.120 mmol, 1.1 equiv.) in DMF (300 mL) was added CsCO (76.3 g, 234.873 mmol, 3 equiv.). The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 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 / EtOAc (10:1) to give intermediate 3 (16.00 g, 62.2%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =329.

[0559] Step 3: Preparation of tert-butyl 2-[4-(tert-butylsulfanyl)-6-chloropyridazin-3-yl]-2-cyanoacetate (Intermediate 4) [ka]

[0560] A solution of intermediate 3 (16.00 g, 48.691 mmol, 1 equiv.), tert-butyl 2-cyanoacetate (13.75 g, 97.382 mmol, 2 equiv.), and CsCO (47.4 g, 146.073 mmol, 3 equiv.) in 1,4-dioxane was stirred at room temperature for 30 minutes. To the above mixture was added picolinic acid (3.00 g, 24.346 mmol, 0.5 equiv.). The resulting mixture was stirred at 80 °C for an additional 2 hours. 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 4 (5.30 g, 33.1%) as a tan solid. LCMS (ESI) m / z: [M+H] + =342.

[0561] Step 4: Preparation of 3-chlorothieno[3,2-c]pyridazin-6-amine (Intermediate 5) [ka]

[0562] A solution of intermediate 4 (5.3 g, 15.504 mmol, 1 equiv) and 6 N HCl (50 mL) in AcOH (50 mL) was stirred at 80° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was neutralized to pH 7 with saturated sodium carbonate solution. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 5 (3.60 g, crude) as a yellow solid. The crude material was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =186.

[0563] Step 5: Preparation of 3,6-dichlorothieno[3,2-c]pyridazine (Intermediate 6) [ka]

[0564] To a solution of intermediate 5 (3.60 g, 19.393 mmol, 1 equiv.) and CuCl (3.84 g, 38.786 mmol, 2 equiv.) in MeCN (50 mL) was added tert-butyl nitrite (4.00 g, 38.789 mmol, 2 equiv.) in portions at 0° C. The resulting mixture was stirred at 50° C. 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 intermediate 6 (543.0 mg, 15.0%) as a light brown solid. LCMS (ESI) m / z: [M+H] + =205.

[0565] Step 6: Preparation of tert-butyl 6-(3-chlorothieno[3,2-c]pyridazin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 7) [ka]

[0566] To a stirred solution of Intermediate 6 (543.0 mg, 2.648 mmol, 1 equiv.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (525.01 mg, 2.648 mmol, 1 equiv.) in DMSO (8 mL) was added DIEA (1.03 g, 7.944 mmol, 3 equiv.). The resulting mixture was stirred at 100° C. for 1 h. 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, 10% to 50% gradient in 10 min; detector, UV 254 nm. This afforded intermediate 7 (253.0 mg, 46.5%) as a tan solid. LCMS (ESI) m / z: [M+H] + =367.

[0567] Step 7: Preparation of tert-butyl 6-[3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 8) [ka]

[0568] To a solution of Intermediate 7 (253.0 mg, 0.690 mmol, 1 equiv.) and 2-(methoxymethoxy)phenylboronic acid (125.5 mg, 0.690 mmol, 1 equiv.) in 1,4-dioxane (4 mL) and HO (1 mL) was added KPO (292.7 mg, 1.380 mmol, 2 equiv.) and (DiMeIHeptCl)Pd(cinnamyl)Cl (80.5 mg, 0.069 mmol, 0.1 equiv.). The resulting mixture was stirred for 2 h, and the mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate 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, 10% to 50% gradient in 10 min; detector, UV 254 nm. This afforded intermediate 8 (98.0 mg, 41.8%) as a tan solid. LCMS (ESI) m / z: [M+H] + =469.

[0569] Step 8: Preparation of 2-(6-{2,6-diazaspiro[3.3]heptan-2-yl}thieno[3,2-c]pyridazin-3-yl)phenol) (I-13) [ka]

[0570] A solution of intermediate 8 (98.0 mg, 0.213 mmol, 1 equiv.) and TFA (0.30 mL, 4.039 mmol, 19.31 equiv.) in DCM (0.9 mL) was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure to give I-13 (106.0 mg, crude) as a reddish oil. The crude material was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =325.

[0571] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{4-[2-(4-{3-[(3Z)-2-hydroxypenta-1,3-dien-3-yl]-5-methylthieno[2,3-c]pyridazin-6-yl}piperidin-1-yl)pyrimidin-5-yl]piperazin-1-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 14). [ka]

[0572] Step 1: Preparation of tert-butyl 4-(2-methoxypyrimidin-5-yl)piperazine-1-carboxylate (Intermediate 2) [ka]

[0573] A solution of 5-bromo-2-methoxypyrimidine (9 g, 47.616 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (13.30 g, 71.424 mmol, 1.5 equiv.), Pd(dba) (2.18 g, 2.381 mmol, 0.05 equiv.), and BINAP (2.96 g, 4.762 mmol, 0.1 equiv.) in toluene (75 mL) was added and the resulting solution was stirred at 80 °C for 6 h. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, gradient 0% to 25% in 30 min, to give intermediate 2 (4.2 g, 29.97%) as a white solid. LCMS (ESI) m / z: [M+H] + =295.

[0574] Step 2: Preparation of 2-methoxy-5-(piperidin-1-yl)pyrimidine (Intermediate 3) [ka]

[0575] A solution of intermediate 2 (4.2 g, 14.268 mmol, 1 equiv.) in TFA (10 mL) and DCM (30 mL) was added and the resulting solution was stirred at 25° C. for 5 h. The DCM in the reaction solution was removed by rotation in vacuo to give crude intermediate 3 (10.0 g, crude material) as a yellow oil. LCMS (ESI) m / z: [M+H] + =195.

[0576] Step 3: Preparation of methyl 2-{3-[4-(2-dioxolan-5-yl)piperidin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 4) [ka]

[0577] To a solution of intermediate 3 (10 g, 51.483 mmol, 1 equiv.), methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (24.78 g, 51.483 mmol, 1 equiv.), and DIEA (19.96 g, 154.449 mmol, 3 equiv.) in DMSO (40 mL) was added, and the resulting solution was stirred at 100 °C overnight. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 30% gradient in 30 min; detector, UV 220 / 200 nm, to give intermediate 4 (3.7 g, 19.14%). LCMS(ESI)m / z:[M+H] + =376.

[0578] Step 4: Preparation of methyl 2-{3-[4-(2-chloropyrimidin-5-yl)piperazin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 5) [ka]

[0579] A solution of intermediate 4 (900 mg, 2.397 mmol, 1 equiv.) in POCl3 (6 mL) was added and the resulting solution was stirred at 110 °C for 18 h. 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 58% in 30 min; detector, UV 220 / 200 nm. This gave intermediate 5 (360 mg, 39.53%) as a yellow solid.

[0580] Step 5: Preparation of methyl 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperazin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 6) [ka]

[0581] To a solution of intermediate 5 (200 mg, 0.527 mmol, 1 equiv.) and 2-[5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (342.69 mg, 1.054 mmol, 2 equiv.) in dioxane (4 mL) was added CsCO (343.10 mg, 1.054 mmol, 2 equiv.) and Pd-PEPPSI-IPentCl-2-methylpyridine (o-picomethylpyridine). Phosphorus (88.58 mg, 0.105 mmol, 0.2 equiv.) was added, and the resulting solution was stirred at 90° C. overnight. The desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography under the following conditions: column, silica gel; mobile phase, PE in EA, 0% to 56%, to give intermediate 6 (100 mg, 28.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =668.

[0582] Step 6: Preparation of 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperazin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoic acid (Intermediate 7) [ka]

[0583] To a solution of methyl intermediate 6 (95 mg, 0.142 mmol, 1 equiv.) in MeOH (4 mL) and HO (1 mL) was added LiOH (27.22 mg, 1.136 mmol, 8 equiv.), and the resulting solution was stirred at room temperature for 16 h. The mixture was acidified to pH 5 with 1 M HCl (aq.). The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 7 (98 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =655.

[0584] Step 7: Preparation of (2S,4R)-4-hydroxy-1-(2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperazin-1-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 8) [ka]

[0585] To a solution of intermediate 7 (98 mg, 0.150 mmol, 1 equiv.), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (99.21 mg, 0.300 mmol, 2 equiv.), and PyBOP (155.77 mg, 0.300 mmol, 2 equiv.) in DMF (2 mL) was added the resulting solution. The resulting solution was stirred at 25 °C for 10 min, and then DIEA (96.72 mg, 0.750 mmol, 5 equiv.) was added to the mixture. The resulting solution was stirred at 25 °C for 2 h. The reaction was purified by flash C18 chromatography using an elution gradient of 0–83% ACN in HO to give intermediate 8 (87 mg, 59.28%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =968.

[0586] Step 8: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{4-[2-(4-{3-[(3Z)-2-hydroxypenta-1,3-dien-3-yl]-5-methylthieno[2,3-c]pyridazin-6-yl}piperidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka]

[0587] Intermediate 8 (94 mg) was purified under the following conditions (column: CHIRAL ART Cellulose-SB, 2* Purification by chiral HPLC (25 cm, 5 μm column; Mobile phase A: MtBE (10 mM NH3-MeOH), Mobile phase B: MeOH-HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 20 min; Wavelength: 270 / 212 nm; RT1 (min): 10.4; RT2 (min): 14.3; Sample solvent: MeOH-HPLC; Injection volume: 0.5 mL; Run number: 6) afforded the title compound (second peak) (37.6 mg, 25.62%) as an off-white solid. The resulting solid was dried by lyophilization. 1 H NMR(300MHz,DMSO-d6)δ12.79(s,1H),8.99(s,1H),8.71(s,1H),8.42(d,J =7.6Hz,1H),8.28(s,2H),8.17(d,J=7.4Hz,1H),7.52-7.41(m,2H),7.40-7 .33(m,3H),7.08-6.97(m,2H),6.25(s,1H),5.12(d,J=3.7Hz,1H),5.01-4. 86(m,1H),4.75(d,J=13.1Hz,2H),4.38(t,J=7.8Hz,1H),4.30(s,1H),3.73 (dd,J=10.4,4.3Hz,1H),3.60(d,J=10.0Hz,2H),3.45(d,J=10.1Hz,1H),3. 41-3.36(m,4H),3.16-2.97(m,6H),2.49(s,3H),2.46(s,3H),2.24-2.19(m ,1H),2.18-1.92(m,3H),1.87-1.78(m,1H),1.71-1.55(m,2H),1.47(d,J=7 .0Hz,1H),1.39(d,J=7.0Hz,2H),0.97(d,J=6.5Hz,3H),0.87-0.77(m,3H). LCMS(ESI)m / z:[M+H] + =968.40.

[0588] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]ethynyl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 37) [ka]

[0589] Step 1: Preparation of (E)-N-[2-(benzyloxy)ethylidene]hydroxylamine (intermediate 2) [ka]

[0590] To a stirred mixture of 2-(benzyloxy)acetaldehyde (10 g, 66.588 mmol, 1 equiv.) and Na2CO3 (3.53 g, 33.294 mmol, 0.5 equiv.) in EtOH (100 mL) was added NH2OH.HCl (5.09 g, 73.247 mmol, 1.1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 2 (13.196 g, crude material) as a colorless liquid. LCMS (ESI) m / z: [M+H] + =166.

[0591] Step 2: Preparation of (Z)-2-(benzyloxy)-N-hydroxyethanecarbonimidoyl chloride (Intermediate 3) [ka]

[0592] A mixture of intermediate 2 (12 g, 72.643 mmol, 1 eq.) and NCS (10.67 g, 79.907 mmol, 1.1 eq.) in DMF (100 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with brine (200 mL). The resulting mixture was extracted with EtOAc (3×200 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 to give intermediate 3 (18.1 g, crude material) as a pale blue liquid. LCMS (ESI) m / z [M+H] + =200.

[0593] Step 3: Preparation of methyl 2-{3-[(benzyloxy)methyl]-1,2-oxazol-5-yl}acetate (Intermediate 4) [ka]

[0594] A mixture of intermediate 3 (12 g, 60.111 mmol, 1 equiv.) and NaHCO3 (7.57 g, 90.166 mmol, 1.5 equiv.) in EA (100 mL) was stirred at room temperature for 30 min. To the above mixture, methyl but-3-ynate (5.90 g, 60.111 mmol, 1 equiv.) was added dropwise at 0 °C. The resulting mixture was further stirred at room temperature overnight. 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 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 220 nm to give intermediate 4 (8.3 g, crude material) as a yellow liquid. LCMS (ESI) m / z: [M+H] + =262.

[0595] Step 4: Preparation of methyl 2-{3-[(benzyloxy)methyl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 5) [ka]

[0596] To a stirred mixture of intermediate 4 (8 g, 30.619 mmol, 1 equiv.) and MgSO (7.37 g, 61.238 mmol, 2 equiv.) in THF (80 mL) was added t-BuOK (15.31 mL, 15.309 mmol, 0.5 equiv.) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added 2-iodopropane (6.25 g, 36.743 mmol, 1.2 equiv.) at 0° C. The resulting mixture was further stirred overnight at room temperature. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with DMF (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 220 nm to give intermediate 5 (4.18 g, 45.00%) as a brown liquid. LCMS (ESI) m / z: [M+H] + =304.

[0597] Step 5: Preparation of methyl 2-[3-(hydroxymethyl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 6) [ka]

[0598] A mixture of intermediate 5 and BBr3 (9.91 g, 39.558 mmol, 3 equiv.) in DCM (40 mL) was stirred under nitrogen atmosphere at 0 °C for 2 h. The desired product could be detected by LCMS. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with CHCl (3 × 200 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 6 (1.5 g, pure) as a yellow oil. LCMS (ESI) m / z: [M+H] + =214.

[0599] Step 6: Preparation of methyl 2-(3-formyl-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 7) [ka]

[0600] A mixture of methyl intermediate 6 and Dess-Martin (1193.46 mg, 2.814 mmol, 1.2 equiv) in DCM (5 mL) was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The reaction was quenched by adding NaHCO3 (aq) and Na2S2O3 (aq) (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 7 (530 mg, crude) as a pale yellow liquid. LCMS (ESI) m / z: [M+H] + =212.

[0601] Step 7: Preparation of methyl 2-(3-ethynyl-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 8) [ka]

[0602] To a stirred mixture of intermediate 7 (500 mg, 2.367 mmol, 1 equiv.) and K2CO3 (981.49 mg, 7.101 mmol, 3 equiv.) in MeOH (5 mL) was added Seyfarth-Gilbert homologation (682.16 mg, 3.550 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CHCl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm to give intermediate 8 (320 mg, 65.23%) as a pale yellow oil. LCMS (ESI) m / z: [M+H] + =208.

[0603] Step 8: Preparation of methyl 2-[3-(2-{3-chloro-5-methylthieno[2,3-c]pyridazin-6-yl}ethynyl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 9) [ka]

[0604] A mixture of intermediate 8 (165.33 mg, 0.627 mmol, 1 equiv.), [1,3-bis[2,6-bis(propan-2-yl)phenyl]-2,3-dihydro-1H-imidazol-2-yl]dichloro(3-chloropyridin-1-ium-1-yl)palladium (42.62 mg, 0.063 mmol, 0.1 equiv.), CuI (11.95 mg, 0.063 mmol, 0.1 equiv.), and DIEA (405.40 mg, 3.135 mmol, 5 equiv.) in DMF (4 mL) was stirred at 80° C. under a nitrogen atmosphere for 3 h. The residue was purified by reverse-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 nm to give intermediate 9 (150 mg, 61.33%) as a brown solid. LCMS (ESI) m / z: [M+H] + =389.

[0605] Step 9: Preparation of methyl 2-(3-{2-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]ethynyl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 10) [ka]

[0606] A mixture of intermediate 9 (159.21 mg, 1.155 mmol, 3 equiv.), XPhos Pd G3 (65.14 mg, 0.077 mmol, 0.2 equiv.), and CsCO3 (376.09 mg, 1.155 mmol, 3 equiv.) in dioxane (3 mL) and HO (0.6 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. 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 × 10 mL) and dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm to give intermediate 10 (109 mg, 63.30%) as a reddish-brown solid. LCMS (ESI) m / z: [M+H] + =448.

[0607] Step 10: Preparation of 2-(3-{2-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]ethynyl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 11) [ka]

[0608] A mixture of intermediate 10 (100 mg, 0.223 mmol, 1 equiv.) and LiOH.HO (26.76 mg, 1.115 mmol, 5 equiv.) in THF (3 mL) and HO (3 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 intermediate 11 (400 mg, crude) as a brown solid. LCMS (ESI) m / z: [M+H] + =434.

[0609] Step 11: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{2-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]ethynyl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 12) [ka]

[0610] A mixture of Intermediate 11 (100 mg, 0.231 mmol, 1 equiv.), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (76.46 mg, 0.231 mmol, 1 equiv.), PyBOP (180.08 mg, 0.347 mmol, 1.5 equiv.), and DIEA (119.26 mg, 0.924 mmol, 4 equiv.) in DMF (2 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions. Purification by reverse-phase flash chromatography using a column of C18 silica gel; a mobile phase of MeCN (10 mmol / L NH4HCO3) in water, a gradient of 0% to 100% in 30 min; and a UV detector at 254 nm gave intermediate 12 (150 mg, 87.06%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =747.

[0611] Step 12: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]ethynyl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka]

[0612] The crude product, Intermediate 12, was purified under the following conditions (column: CHIRALPAK IA, 3 *Purification by SFC-HPLC using a 25 cm column, 5 μm column; mobile phase A: CO2, mobile phase B: MeOH:DCM=1:1 HPLC; flow rate: 60 mL / min; gradient: isocratic 55% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 274 nm; RT1 (min): 4.27; RT2 (min): 7.20; sample solvent: MeOH:DCM=1:1 HPLC; injection volume: 1.6 mL) gave the title compound (second peak) (38.1 mg, 38.73%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ12.09(s,1H),9.01-8.94(m,1H),8.88-8.81(m,1H),8.45(d,J=7.6Hz,1H),8.16-8.09(m ,1H),7.50-7.34(m,5H),7.09-7.00(m,2H),6.92(s,1H),5.14-5.09(m,1H),4.97-4.89(m,1H),4.40(t,J=8.0Hz, 1H),4.30(s,1H),3.97(d,J=9.6Hz,1H),3.77-3.47(m,2H),2.68-2.62(m,3H),2.47-2.45(m,3H),2.40-2.25(m,1 H),2.10-2.01(m,1H),1.85-1.74(m,1H),1.44(dd,J=37.1,7.0Hz,3H),1.01(d,J=6.4Hz,3H),0.88-0.79(m,3H). LCMS(ESI)m / z:[M+H] + =747.20.

[0613] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperidin-1-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 60) [ka]

[0614] Step 1: Preparation of tert-butyl 4-(2-methoxypyrimidin-5-yl)piperidine-1-carboxylate (Intermediate 2). [ka] To a solution of 5-bromo-2-methoxypyrimidine (10.0 g, 52.907 mmol, 1.00 equiv.) and tert-butyl 4-iodopiperidine-1-carboxylate (19.8 g, 63.488 mmol, 1.20 equiv.), dtbpy (1.4 g, 5.291 mmol, 0.10 equiv.), Mn (5.8 g, 105.814 mmol, 2.00 equiv.), KI (8.8 g, 52.907 mmol, 1 equiv.), and NiBr2.DME (1.9 g, 5.291 mmol, 0.10 equiv.) in DMA (100.0 mL) was added pyridine (4.6 g, 58.198 mmol, 1.10 equiv.). After stirring overnight at 80 °C under a nitrogen atmosphere, the desired product was detected by LCMS. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.05% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give intermediate 2 (6.4 g, 75.16%) as a red oil. LCMS (ESI) m / z [M+H] + =294. Step 2: Preparation of 2-methoxy-5-(piperidin-4-yl)pyrimidine (Intermediate 3). [ka]

[0615] To a solution of intermediate 2 (6.4 g, 21.816 mmol, 1.00 equiv) in DCM (60.0 mL) and TFA (20.0 mL), after stirring at room temperature for 1 hour, the desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo to give intermediate 3 (5.3 g, crude material) as a green oil. LCMS (ESI) m / z: [M+H] + =194.

[0616] Step 3: Preparation of methyl 2-{3-[4-(2-methoxypyrimidin-5-yl)piperidin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 4). [ka]

[0617] To a solution of intermediate 3 (5.3 g, crude material) and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (21.3 g, 44.150 mmol, 2.00 equiv.) in DMF (60 mL), DIEA (14.3 g, 110.375 mmol, 5.00 equiv.) was added. After stirring at 130 °C for 3 h, the desired product could be detected by LCMS. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% FA), gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give intermediate 4 (736 mg, 8.90%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =375.

[0618] Step 4: Preparation of methyl 2-{3-[4-(2-chloropyrimidin-5-yl)piperidin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoate. Preparation of (Intermediate 5). [ka]

[0619] To a solution of POCl3 (904.1 mg, 5.898 mmol, 3.00 equiv.) in DMF (8.0 mL) was added intermediate 4 (736.0 mg, 1.966 mmol, 1.00 equiv.). After stirring at 100 °C for 2 h, the desired product could be detected by LCMS. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% FA), gradient 0% to 100% in 30 min; detector, UV 254 nm) to give intermediate 5 (75.0 mg, 10.07%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =379.

[0620] Step 5: Preparation of methyl 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperidin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 6). [ka]

[0621] To a solution of intermediate 5 (75.0 mg, 0.198 mmol, 1.00 equiv.) and 2-[5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (77.3 mg, 0.238 mmol, 1.20 equiv.) in NMP (2 mL) was added KCO (54.7 mg, 0.396 mmol, 2.00 equiv.). After stirring at 100 °C for 3 h, the desired product could be detected by LCMS. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% FA), gradient from 0% to 100% FA in 30 min; detector, UV at 254 nm) to give intermediate 6 (58.0 mg, 43.87%) as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =668.

[0622] Step 6: Preparation of 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperidin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoic acid (Intermediate 7). [ka]

[0623] To a solution of intermediate 6 (58.0 mg, 0.087 mmol, 1.00 equiv) and LiOH (6.3 mg, 0.261 mmol, 3.00 equiv) in MeOH (1.0 mL) and HO (1.0 mL). After stirring at room temperature for 1 h, the desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 × 3.0 mL). The combined organic layers were washed with water (1 × 3.0 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 7 (48.0 mg, crude) as a white solid. LCMS (ESI) m / z: [M+H] + =654.

[0624] Step 7: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-{3-[4-(2-{4-[(4Z)-4-[2-(2-hydroxyphenyl)-2-iminoethylidene]-3-methyl-5H-thiophen-2-yl]piperidin-1-yl}pyrimidin-5-yl)piperidin-1-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 8). [ka]

[0625] To a solution of intermediate 7 (45 mg, 0.069 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (22.8 mg, 0.069 mmol, 1.00 equiv.) in DMF (2.0 mg) was added DIEA (26.7 mg, 0.207 mmol, 3.00 equiv.) and HATU (31.4 mg, 0.083 mmol, 1.20 equiv.). After stirring at room temperature for 1 hour, the desired product could be detected by LCMS. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.05% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give intermediate 8 (48.0 mg, 72.93%) as a white solid. LCMS (ESI) m / z: [M+H] + =966.

[0626] Step 8: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)piperidin-1-yl]-1,2-oxazol-5-yl}-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide. [ka]

[0627] Intermediate 8 (48.0 mg) was purified under the following conditions (column, CHIRALPAK ID, 2 * Purification by chiral HPLC using a column of 25 cm, 5 μm column; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: EtOH-HPLC; flow rate: 18 mL / min; gradient: 30% B to 30% B in 24 min; wavelength: 253 / 210 nm; RT1 (min): 11.24; RT2 (min): 18.89; sample solvent: MeOH:DCM = 1:1-HPLC; injection volume: 1.5 mL, number of runs: 4) gave the title compound (second peak) (4.6 mg, 29.11%) as an off-white solid.

[0628] 1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),8.99(s,1H),8.71(s,1H),8.41(d,J=7.7Hz,1H),8.35-8.29(m,2H),8.17(d,1H),7.49-7.41(m,2H),7.40- 7.33(m,3H),7.07-6.97(m,2H),6.12(s,1H),5.12(d,J=3.6Hz,1H),5.02 -4.63(m,3H),4.38(t,J=7.8Hz,1H),4.33-4.24(m,1H),3.83-3.66(m,3H) ),3.66-3.53(m,2H),3.51(s,1H),3.47-3.39(m,1H),3.06(t,J=12.4Hz ,2H),2.86(t,J=12.0Hz,2H),2.70-2.56(m,1H),2.46(s,3H),2.37-2.12 (m,2H),2.09-1.97(m,3H),1.88-1.74(m,3H),1.76-1.53(m,5H),1.42(d ,J=32.3,7.0Hz,3H),0.97(d,J=7.0Hz,3H),0.83(d,J=15.7,6.6Hz,3H). LCMS(ESI)m / z:[M+H] + =967.25.

[0629] 2S,4R)-4-Hydroxy-1-((R)-2-(3-((1s,4S)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide and (2S,4R)- Preparation of 4-hydroxy-1-((R)-2-(3-((1r,4R)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 64 and Compound 65) [ka]

[0630] Step 1: Preparation of ethyl 4-(2-methoxypyrimidin-5-yl)cyclohex-3-ene-1-carboxylate (Intermediate 2). [ka]

[0631] To a stirred solution of 5-bromo-2-methoxypyrimidine (3.37 g, 17.846 mmol, 1 equiv.) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (5 g, 17.846 mmol, 1.00 equiv.) in 1,4-dioxane (40 mL) and HO (10 mL) was added Pd(dppf)Cl 2.CHCl (1.45 g, 1.785 mmol, 0.1 eq.) and KCO (7.40 g, 53.538 mmol, 3 eq.) were added at room temperature. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 2) to give intermediate 2 (3.8, 81.4%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =263.

[0632] Step 2: Preparation of ethyl 4-(2-methoxypyrimidin-5-yl)cyclohexane-1-carboxylate (Intermediate 3). [ka]

[0633] To a stirred solution of intermediate 2 (3.8 g, 14.50 mmol, 1 equiv.) in THF (50 mL) was added Pd(OH)2 / C (2 g) at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This gave intermediate 3 (3.1 g, 81.0%) as a gray oil. LCMS (ESI) m / z: [M+H] + =265.

[0634] Step 3: Preparation of [4-(2-methoxypyrimidin-5-yl)cyclohexyl]methanol (Intermediate 4). [ka]

[0635] To a stirred solution of intermediate 3 (4 g, 15.133 mmol, 1 equiv.) in THF (50 mL) was added LiAlH (0.57 g, 15.133 mmol, 1 equiv.) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. The reaction was quenched with water at 0° C. The resulting mixture was extracted with DCM (2×100 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 4 (566 mg, 16.83%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =223.

[0636] Step 4: Preparation of 4-(2-methoxypyrimidin-5-yl)cyclohexane-1-carbaldehyde (Intermediate 5). [ka]

[0637] To a stirred solution of (COCl) (969.51 mg, 7.638 mmol, 3 equiv) in DCM (10 mL) was added DMSO (795.75 mg, 10.184 mmol, 4 equiv) under a nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added Intermediate 4 (566 mg, 2.546 mmol, 1 equiv) under a nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 minutes under a nitrogen atmosphere. To the above mixture was added EtN (1.29 g, 12.730 mmol, 5 equiv) under a nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. to room temperature for an additional 1 hour under a nitrogen atmosphere. The reaction was quenched with water at room temperature and extracted with DCM (2×100 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 5 (450 mg, 79.5%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =221.

[0638] Step 5: Preparation of (Z)-N-{[4-(2-methoxypyrimidin-5-yl)cyclohexyl]methylidene}hydroxylamine (Intermediate 6). [ka]

[0639] To a stirred solution of hydroxylamine hydrochloride (2.46 g, 35.412 mmol, 3 equiv) in MeOH (8 mL) and HO (8 mL) was added NaCO (3.75 g, 35.412 mmol, 3 equiv) at 0 °C. To the above mixture was added Intermediate 5 (2.6 g, 11.804 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave Intermediate 6 (2.8 g, crude) as a yellow oil. LCMS (ESI) m / z: [M+H] + =236.

[0640] Step 6: Preparation of (Z)-N-hydroxy-4-(2-methoxypyrimidin-5-yl)cyclohexane-1-carbimidoyl chloride (Intermediate 7). [ka]

[0641] To a stirred solution of intermediate 6 (2.8 g, 11.900 mmol, 1 equiv) in EA (30 mL) was added NCS (1.91 g, 14.280 mmol, 1.2 equiv) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The mixture was diluted with EtOAc (80 mL) and washed with water (80 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product intermediate 7 (3.2 g, crude material) as a yellow solid. LCMS (ESI) m / z: [M+H] + =270.

[0642] Step 7: Preparation of methyl 2-{3-[4-(2-methoxypyrimidin-5-yl)cyclohexyl]-1,2-oxazol-5-yl}acetate (Intermediate 8). [ka]

[0643] To a stirred solution of intermediate 7 (3.2 g, 11.864 mmol, 1 equiv) in EA (30 mL) was added NaHCO3 (2.99 g, 35.592 mmol, 3 equiv) at 0 °C. To the above mixture, methyl but-3-ynoate (4.66 g, 47.456 mmol, 4 equiv) was added at 0 °C. The resulting mixture was stirred at room temperature for an additional 16 h. The reaction was quenched with water. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were 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 100% in 30 min; detector, UV 254 / 220 nm. This gave intermediate 8 (2.7 g, 68.68%) as a brown oil. LCMS (ESI) m / z: [M+H] + =332.

[0644] Step 8: Preparation of methyl 2-(3-(4-(2-methoxypyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 9). [ka]

[0645] To a stirred solution of Intermediate 8 (2.7 g, 8.148 mmol, 1 equiv) in THF (15 mL) was added t-BuOK (2.74 g, 24.444 mmol, 3 equiv) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added 2-iodopropane (2.77 g, 16.296 mmol, 2 equiv) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with water at 0° C. The resulting mixture was extracted with DCM (2×200 mL). The combined organic layers were concentrated under reduced pressure. This afforded 2-{3-[4-(2-methoxypyrimidin-5-yl)cyclohexyl]-1,2-oxazol-5-yl}-3-methylbutanoic acid (2 g, crude) as a brown oil. The product was dissolved in DCM (16 mL) and MeOH (4 mL), and TMSCHN2 (1.91 g, 16.692 mmol, 3 equiv.) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with DCM (2 × 100 mL). The combined organic layers were 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 / 220 nm. This gave intermediate 9 (795 mg, 38.26%) as a brown oil. LCMS (ESI) m / z: [M+H] + =374.

[0646] Step 9: Preparation of methyl 2-(3-(4-(2-chloropyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 10). [ka]

[0647] To a stirred solution of intermediate 9 (795 mg, 2.129 mmol, 1 equiv.) in DMF (5 mL) was added POCl3 (979.15 mg, 6.387 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 16 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 in water (0.1% FA), gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm. This gave intermediate 10 (154 mg, 19.14%) as a brown oil. LCMS (ESI) m / z: [M+H] + =378.

[0648] Step 10: Preparation of methyl 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)cyclohexyl]-1,2-oxazol-5-yl}-3-methylbutanoate (Intermediate 11). [ka]

[0649] To a stirred solution of intermediate 10 (100 mg, 0.265 mmol, 1 equiv.) and 2-[5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (103.35 mg, 0.318 mmol, 1.2 equiv.) in DMSO (5 mL), DIEA (102.61 mg, 0.795 mmol, 3.0 equiv.) was added 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 residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), gradient from 0% to 100% in 25 min; detector, UV 254 nm. This gave intermediate 11 (105 mg, 59.50%) as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =667.

[0650] Step 11: Preparation of methyl 2-(3-(4-(2-chloropyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 12). [ka]

[0651] To a stirred solution of intermediate 11 (100 mg, 0.150 mmol, 1 equiv) in MeOH (5 mL) was added LiOH (17.96 mg, 0.750 mmol, 5.0 equiv) in HO (2 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was extracted with EtOAc (3 x 100 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. This gave intermediate 12 (85 mg, 86.83%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =653.

[0652] Step 12: Preparation of (2S,4R)-4-hydroxy-1-(2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)cyclohexyl]-1,2-oxazol-5-yl}-3-methylbutanoyl)-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 13). [ka]

[0653] To a solution of intermediate 12 (85 mg, 0.130 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (61.99 mg, 0.195 mmol, 1.5 equiv.) in DMF (5 mL), PyBOP (101.64 mg, 0.195 mmol, 1.5 equiv.) and DIEA (50.49 mg, 0.390 mmol, 3.0 equiv.) were added at room temperature. The resulting mixture was stirred for 4 h at room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water (0.1% TFA), gradient from 0% to 100% in 30 min; detector, UV 254 nm. This gave compound 13 (106 mg, 84.25%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =966.

[0654] Step 13: (2S,4R)-4-hydroxy-1-((R)-2-(3-((1s,4S)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-((1r,4R)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0655] Intermediate 13 was purified under the following conditions: column, CHIRAL ART Cellulose-SB, 2 * Purification by chiral preparative HPLC using 25 cm, 5 μm; mobile phase, MtBE (10 mM NH3-MeOH) and MeOH- (20% MeOH held for 12 min); detector, UV 254 nm, to give the compound (2S,4R)-4-hydroxy-1-((R)-2-(3-((1s,4S)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (28.1 mg) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ12.79(s,1H),8.96(d,J=15.7Hz,1H),8.70(d,J=2.5H z,1H),8.43(d,J=7.7Hz,1H),8.24(d,J=5.2Hz,2H),8.20-8.13(m,1H),7.47-7 .30(m,5H),7.06-6.98(m,2H),6.35(s,1H),5.10(d,J=3.6Hz,1H),4.91(h,J=6 .7Hz,1H),4.80(t,J=14.7Hz,2H),4.38(t,J=7.9Hz,1H),4.32-4.27(m,1H),3. 80-3.68(m,2H),3.65-3.54(m,1H),3.47(d,J=10.6Hz,1H),3.12-2.93(m,3H) ,2.59(d,J=12.9Hz,1H),2.48(d,J=8.0Hz,3H),2.44(d,J=11.0Hz,3H),2.33-2 .21(m,1H),2.11-1.96(m,5H),1.87-1.75(m,3H),1.73-1.69(m,2H),1.66-1.5 2(m,4H),1.41(d,J=16.1Hz,3H),0.98(d,J=6.7Hz,3H),0.79(d,J=6.7Hz,3H). LCMS(ESI)m / z:[M+H] + =966.55.

[0656] and the compound (2S,4R)-4-hydroxy-1-((R)-2-(3-((1r,4R)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)cyclohexyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9.1 mg) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ12.79(s,1H),9.00(d,J=4.8Hz,1H),8.71(s,1H),8. 44(d,J=7.7Hz,1H),8.33(s,2H),8.17(d,J=7.8Hz,1H),7.51-7.42(m,2H),7. 38(t,J=6.5Hz,3H),7.03(d,J=7.8Hz,2H),6.33(s,1H),5.12(d,J=3.6Hz,1H) ,4.93(q,J=6.8Hz,1H),4.84(d,J=13.2Hz,2H),4.38(t,J=7.9Hz,1H),4.30(s ,1H),3.79-3.68(m,2H),3.66-3.56(m,1H),3.53-3.45(m,1H),3.05(t,J=12. 5Hz,2H),2.74(s,1H),2.46(d,J=2.6Hz,3H),2.32-2.14(m,2H),2.04(d,J=12 .3Hz,5H),1.89-1.85(m,2H),1.84-1.74(m,1H),1.67-1.51(m,7H),1.39(d,J =7.0Hz,3H),1.26-1.09(m,2H),0.98(d,J=6.3Hz,3H),0.79(d,J=6.7Hz,3H). LCMS(ESI)m / z:[M+H] + =966.60.

[0657] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[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 1) [ka]

[0658] Step 1: Preparation of tert-butyl 6-[2-(3,6-dichloropyridazin-4-yl)ethynyl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 2) [ka]

[0659] To a solution of 3,6-dichloro-4-iodopyridazine (1 g, 3.638 mmol, 1 equiv.) and tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (0.81 g, 3.638 mmol, 1 equiv.) in toluene (10 mL) was added Pd(PPh3)2Cl2 (0.26 g, 0.364 mmol, 0.1 equiv.) and TEA (1.10 g, 10.914 mmol, 3 equiv.), and the resulting solution was stirred at 60 °C for 6 h. The mixture was diluted with EtOAc (400 mL) and washed with water (400 mL × 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 with an elution gradient of 0-43% PE in EA to give intermediate 2 (1.11 g, 82.85%) as a brown solid. LCMS (ESI) m / z: [M+H] + =368.

[0660] Step 2: Preparation of tert-butyl 6-{3-chlorothieno[2,3-c]pyridazin-6-yl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 3) [ka]

[0661] To a solution of intermediate 2 (1.1 g, 2.987 mmol, 1 equiv.) in NMP (10 mL) was added NaSH (0.17 g, 2.987 mmol, 1 equiv.), and the resulting solution was stirred at 100 °C for 6 h. Without further workup, the crude reaction solution was purified by flash C18 chromatography with an elution gradient of 0% to 46% ACN in HO to give intermediate 3 (422 mg, 38.61%) as a brown solid. LCMS (ESI) m / z: [M+H] + =366.

[0662] Step 3: Preparation of tert-butyl 6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 4) [ka]

[0663] To a solution of tert-butyl intermediate 3 (400 mg, 1.093 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (226.19 mg, 1.639 mmol, 1.5 equiv.) in 1,4-dioxane (4 mL) and HO (1 mL), XPhos Pd G3 (92.54 mg, 0.109 mmol, 0.1 equiv.) and CsCO3 (712.41 mg, 2.186 mmol, 2 equiv.) were added, and the resulting solution was stirred at 80 °C for 3 h. The mixture was diluted with EtOAc (300 mL) and washed with water (300 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography using an elution gradient of 0–41% ACN in HO to give intermediate 4 (347 mg, 74.94%) as a brown solid. LCMS(ESI)m / z:[M+H] + =424.

[0664] Step 4: Preparation of 2-(6-{2-azaspiro[3.3]heptan-6-yl}thieno[2,3-c]pyridazin-3-yl)phenol (Intermediate 5) [ka]

[0665] To a solution of intermediate 4 (347 mg, 0.819 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) and the resulting solution was stirred at 25° C. for 2 h. The resulting mixture was concentrated under reduced pressure to give intermediate 5 (308 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =324.

[0666] Step 5: Preparation of methyl 2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 6) [ka]

[0667] To a solution of intermediate 5 (250 mg, 0.773 mmol, 1 equiv.) and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (372.04 mg, 0.773 mmol, 1 equiv.) in DMSO (3 mL), DIEA (299.73 mg, 2.319 mmol, 3 equiv.) was added, and the resulting solution was stirred at 100 °C for 5 h. The crude reaction solution was purified by flash C18 chromatography using an elution gradient of 0-45% ACN in HO to give intermediate 6 (203 mg, 52.04%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =505.

[0668] Step 6: Preparation of 2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 7) [ka]

[0669] To a solution of intermediate 6 (200 mg, 0.396 mmol, 1 equiv) in MeOH (2 mL) and HO (0.5 mL), LiOH (47.46 mg, 1.980 mmol, 5 equiv) was added, and the resulting solution was stirred at 25 °C for 2 h. The mixture was acidified with HCl (1 M in HO) to pH 5-6. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 7 (297 mg, crude) as a brown solid. LCMS (ESI) m / z: [M+H] + =491.

[0670] Step 7: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[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 (Intermediate 8) [ka]

[0671] To a solution of intermediate 7 (200 mg, 0.408 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (270.24 mg, 0.816 mmol, 2 equiv.) in DMF (3 mL) was added PyBOP (424.31 mg, 0.816 mmol, 2 equiv.) and DIEA (263.46 mg, 2.040 mmol, 5 equiv.), and the resulting solution was stirred at 25° C. for 2 h. Without further workup, the crude reaction solution was purified by flash C18 chromatography using an elution gradient of 0% to 52% ACN in HO to give intermediate 8 (184 mg, 56.2%). LCMS(ESI)m / z:[M+H] + =804.

[0672] Step 7: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[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 [ka]

[0673] Intermediate 8 (184 mg) was purified by chiral HPLC (column: CHIRALPAK ID, 2 * Purification by HPLC (25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 30% B to 30% B in 17 min; wavelength: 208 / 272 nm; RT1 (min): 6.345; RT2 (min): 8.7275; sample solvent: MeOH; injection volume: 0.7 mL; number of runs: 7) gave the title compound (30.5 mg, 16.57%) as an off-white solid (second peak). 1H NMR (400MHz, methanol-d4) δ8.87(s,1H),8.58(s,1H),7.95(d,J=8.1Hz,1H),7.61-7.31(m,5H),7.27(s,1H),7.01 (d,J=8.0Hz,2H),5.88(s,1H),5.03(q,J=7.3Hz,1H),4.51(t,J=8.2Hz,1H),4.44(s,1H),4.11(s,2H),3.93(s, 2H),4.03-3.89(m,2H),3.62(t,J=12.1Hz,2H),2.83(s,2H),2.57(t,J=10.2Hz,2H),2.48(s,3H),2.41-2.29(m ,1H),2.23-2.08(m,1H),2.03-1.81(m,1H),1.52(d,J=7.1Hz,3H),1.05(d,J=6.5Hz,3H),0.89(d,J=7.2Hz,3H). LCMS(ESI)m / z:[M+H] + =804.20.

[0674] The compounds in Table 2 were prepared using a procedure similar to that used above to prepare (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[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 1).

[0675] [Table 3-1]

[0676] [Table 3-2]

[0677] [Table 3-3]

[0678] [Table 3-4]

[0679] [Table 3-5]

[0680] [Table 3-6]

[0681] Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonan-7-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 12) [ka]

[0682] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (Intermediate 2) [ka]

[0683] The resulting solution was stirred at 25 °C for 0.5 h, after which t-BuNO (2.47 g, 23.988 mmol, 1 equiv.) was added to a solution of 4-bromo-6-chloropyridazin-3-amine (5 g, 23.988 mmol, 1 equiv.) and CuI (5.48 g, 28.786 mmol, 1.2 equiv.) in THF (60 mL) and CHCl (7.71 g, 28.786 mmol, 1.2 equiv.). The crude product was purified by silica column chromatography using an elution gradient of 0–80% EA in PE to give intermediate 2 (2.9 g, 37.86%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =319.

[0684] Step 2: Preparation of tert-butyl 2-((4-bromo-6-chloropyridazin-3-yl)ethynyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 3) [ka]

[0685] To a solution of intermediate 2 (2 g, 6.263 mmol, 1 eq.) and tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate (1.56 g, 6.263 mmol, 1 eq.), Pd(PPh3)2Cl2 (0.88 g, 1.253 mmol, 0.2 eq.) and CuI (0.24 g, 1.253 mmol, 0.2 eq.) in methylbenzene (15 mL, 0.011 mmol) and TEA (1.90 g, 18.789 mmol, 3 eq.), the resulting solution was stirred at 25 °C for 2 h. The crude product was purified by silica column chromatography using an elution gradient of 0–17% EA in PE to give intermediate 3 (1.6 g, 57.96%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =441.

[0686] Step 3: Preparation of tert-butyl 2-(3-chlorothieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 4) [ka]

[0687] A solution of intermediate 3 (1.6 g, 3.630 mmol, 1 equiv.) and NaSH (203.50 mg, 3.630 mmol, 1 equiv.) in NMP (10 mL, 51.850 mmol) was added and the resulting solution was stirred at 100 °C for 2 h. The resulting mixture was diluted with EA (400 mL) and washed with water (3 × 400 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of 0–34% EA in PE to give intermediate 4 (890 mg, 62.24%) as an orange solid. LCMS (ESI) m / z: [M+H] = 394.

[0688] Step 4: Preparation of tert-butyl 2-(3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 5) [ka]

[0689] A solution of intermediate 4 (890 mg, 2.259 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (467.43 mg, 3.388 mmol, 1.5 equiv.), CsCO (1.47 g, 4.518 mmol, 2 equiv.), XPhos Pd G (191.24 mg, 0.226 mmol, 0.1 equiv.) in 1,4-dioxane (4 mL) and HO (1 mL) was added and the resulting solution was stirred at 80 °C for 2 h. The resulting mixture was diluted with EA (400 mL) and washed with water (3 × 400 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 using an elution gradient of 0–15% EA in PE to give intermediate 5 (571 mg, 55.97%) as a brown oil. LCMS(ESI)m / z:[M+H] + =452.

[0690] Step 5: Preparation of 2-(6-(7-azaspiro[3.5]nonan-2-yl)thieno[3,2-c]pyridazin-3-yl)phenol (Intermediate 6) [ka]

[0691] To a solution of intermediate 5 (571 mg, 1.264 mmol, 1 equiv) in TFA (1 mL) and DCM (3 mL) was added the resulting solution, which was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure to give intermediate 6 (667 mg, crude) as a brown oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =352.

[0692] Step 6: Preparation of methyl 3-methyl-2-{3-[2-(3-{2-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]phenyl}thieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonan-7-yl]-1,2-oxazol-5-yl}butanoate (Intermediate 7a) [ka]

[0693] To a solution of intermediate 6 (300 mg, 0.854 mmol, 1 equiv.) and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (410.81 mg, 0.854 mmol, 1.0 equiv.) in DMSO (5 mL), DIEA (330.96 mg, 2.562 mmol, 3.0 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 0% to 100% gradient in 10 min; detector, UV 254 nm. This gave intermediate 7a (181 mg, 26.03%) as a tan solid. LCMS (ESI) m / z: [M+H] + =815.

[0694] Step 7: Preparation of 2-(3-(2-(3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonan-7-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 8) [ka]

[0695] A solution of intermediate 7 (170 mg, 0.209 mmol, 1 equiv) and NaOH (83.46 mg, 2.090 mmol, 10 equiv) in MeOH (4 mL) and HO (1 mL) was added and the resulting solution was stirred at 25 °C for 4 h. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 8 (155 mg, crude) as a brown solid. LCMS (ESI) m / z: [M+H] + =519.

[0696] Step 8: Preparation of (2S,4R)-4-hydroxy-1-(2-(3-(2-(3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonan-7-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 9) [ka]

[0697] To a solution of intermediate 8 (155 mg, 0.299 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (99.05 mg, 0.299 mmol, 1 equiv.) and PyBOP (311.06 mg, 0.598 mmol, 2 equiv.) in DMF (2 mL) and DIEA (193.14 mg, 1.495 mmol, 5 equiv.) was added the resulting solution, which was stirred for 2 hours at 25° C. Without further workup, the crude reaction solution was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 * Purification by LCMS (ESI) m / z: [M+H] (150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 70% B, 70% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.55) gave intermediate 9 (30 mg, 34.72%) as a yellow solid. + =832.

[0698] Step 9: Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl)-7-azaspiro[3.5]nonan-7-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] Intermediate 9 was purified by chiral preparative HPLC under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 * 25 cm, 5 μm; Mobile phase A: MtBE (10 mM NH3-MeOH), Mobile phase B: MeOH - HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 13 min; Wavelength: 270 / 212 nm; RT1 (min): 7.8; RT2 (min): 10.4; Sample solvent: MeOH:DCM = 1:2; Injection volume: 0.5 mL; Number of runs: 4. This gave the title compound (second peak) (11.8 mg, 4.51%) as a white solid. ( 11H NMR (300 MHz, methanol-d4) δ 8.92 (d, J = 15.4 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.52 - 7.37 (m, 4H), 7.04 (d, J = 7.8 Hz, 2H), 6.11 (d, J = 16.1 Hz, 1H), 5.12 - 5.02 (m, 1H), 4.54 (t, J = 8.1 Hz, 1H), 4.46 (s, 1H), 4.07 - 4.42 (m, 1H), 4.05 (dd, J = 10.8, 4.1 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.64 (dd, J = 10.4, 6.1 Hz, 2H), 3.45 (s, 2H), 3.35 (m, 2H), 3.18 (d, J = 6.3 Hz, 2H), 2.56 (t, J = 10.3 Hz, 2H), 2.50 (s, 3H), 2.39 (s, 1H), 2.20 (t, J = 10.3 Hz, 3H), 2.06 - 1.93 (m, 1H), 1.91 (s, 2H), 1.75 (s, 2H), 1.58 (dd, J = 20.1, 7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H). LCMS (ESI) m / z: [M + H] + = 832.35 Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 2)

Chem.

[0699] Step 1: Preparation of methyl 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoate

Chem.

[0700] To a stirred solution of intermediate 3 (200 mg, 0.642 mmol, 1 equiv.) and intermediate 7 (187.74 mg, 0.642 mmol, 1 equiv.) in DMSO (4 mL), DIEA (249.04 mg, 1.926 mmol, 3 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 36 h under a nitrogen atmosphere. 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 (10 mmol / L NH4HCO3) in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This gave methyl 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoate (50 mg) as a yellow solid. LCMS (ESI) m / z: [M+H] + =384.

[0701] Step 2: Preparation of 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoic acid [ka]

[0702] A solution of methyl 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoate (50 mg, 0.086 mmol, 1 equiv) in MeOH (2 mL) was treated with LiOH.HO (20.52 mg, 0.860 mmol, 10 equiv) at room temperature, followed by the dropwise addition of HO (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq). The precipitated solid was collected by filtration and washed with HO (3 × 10 mL). This gave 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoic acid (47 mg) as a yellow solid. LCMS (ESI) m / z: [M+H] + =570.

[0703] Step 3: Preparation of (2S,4R)-4-hydroxy-1-(2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0704] To a stirred solution of 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoic acid (40 mg, 0.070 mmol, 1 equiv.) and Intermediate 8 (27.93 mg, 0.084 mmol, 1.2 equiv.) in DMF (0.5 mL) was added PyBOP (73.08 mg, 0.140 mmol, 2 equiv.) and DIEA (27.23 mg, 0.210 mmol, 3 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: MeCN (10 mmol / L NH4HCO3) in water, 0% to 100% gradient in 30 min; Detector: UV 254 nm. The resulting mixture was concentrated under reduced pressure to give (2S,4R)-4-hydroxy-1-(2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (35 mg) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =883.

[0705] Step 6: Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0706] The above product was purified by chiral preparative HPLC under the following conditions: Column, CHIRALPAK ID, 2 * 25 cm, 5 μm; mobile phase, MtBE:DCM=2:1 (10 mM / L) and MeOH (50% MeOH held for 12 min); detector, UV 254. This gave the title compound (second peak) (14.3 mg) as an off-white solid. 1H NMR(300MHz,DMSO-d6)δ12.38(s,1H),8.99(s,1H),8.74(s,1H),8.60(d,J=2.3Hz,1H),8.46(t,J=8.1Hz,1H),8.07-7.96(m,2H) ),7.48-7.34(m,6H),7.09-6.97(m,2H),6.87(d,J=39.5Hz,1H),5.13(s,1H),5.02-4.88(m,1H),4.40(t,J=7.9Hz,1H),4.31(s, 1H),3.86(d,J=9.6Hz,1H),3.78-3.68(m,3H),3.53(d,J=7.6Hz,2H),3.00(t,J=12.1Hz,2H),2.47(s,3H),2.37-2.33(m,3H),2. 22(d,J=12.5Hz,3H),2.11-1.89(m,3H),1.82(d,J=8.7Hz,1H),1.54-1.36(m,3H),1.02(d,J=6.4Hz,3H),0.84(d,J=6.8Hz,3H). LCMS(ESI)m / z:[M+H] + =883.25.

[0707] The compounds in Table 3 were prepared using a procedure similar to that used above to prepare (2S,4R)-4-hydroxy-1-((R)-2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidin-1-yl)-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 2) using the appropriate fluoropyridine and 2-(5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol.

[0708] [Table 4-1]

[0709] [Table 4-2]

[0710] [Table 4-3]

[0711] [Table 4-4]

[0712] [Table 4-5]

[0713] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 3) [ka]

[0714] Step 1: Preparation of ethyl (E)-N-[(4-bromo-3-methylphenyl)methylidene]hydroxylamine (Intermediate 2) [ka]

[0715] A solution of 4-bromo-3-methylbenzaldehyde (4 g, 20.096 mmol, 1 equiv.) and hydroxylamine hydrochloride (2.79 g, 40.192 mmol, 2.0 equiv.) in MeOH (20 mL) and HO (20 mL) was stirred at room temperature for 4 hours. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CHCl (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 2 (4.5 g, 104.61%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =214.

[0716] Step 2: Preparation of (Z)-4-bromo-N-hydroxy-3-methylbenzenecarbonimidoyl chloride (Intermediate 3) [ka]

[0717] A solution of intermediate 2 (4.4 g, 20.555 mmol, 1 eq.) and NCS (4.12 g, 30.832 mmol, 1.5 eq.) in EtOAc (40 mL) was stirred at room temperature for 12 h. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 3 (3.0 g, 58.73%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =248.

[0718] Step 3: Preparation of methyl 2-[3-(4-bromo-3-methylphenyl)-1,2-oxazol-5-yl]acetate (Intermediate 4) [ka]

[0719] A solution of intermediate 3 (3.0 g, 12.072 mmol, 1 equiv.) and methyl but-3-ynate (1.18 g, 12.072 mmol, 1.0 equiv.) in EtOAc (2 mL) was stirred at room temperature for 12 h. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give intermediate 4 (3.0 g, 80.12%) as a yellow solid. LCMS (ESI) m / z [M+H] + =310.

[0720] Step 4: Preparation of ethyl methyl 2-[3-(4-bromo-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 5) [ka]

[0721] A solution of intermediate 4 (3.0 g, 9.673 mmol, 1 equiv.) and 2-iodopropane (3.29 g, 19.346 mmol, 2.0 equiv.) in THF (20 mL) was stirred at 60° C. for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (7:3) to give intermediate 5 (1.7 g, 49.90%) as a yellow oil. LCMS (ESI) m / z [M+H] + =352.

[0722] Step 5: Preparation of methyl 2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 6) [ka]

[0723] To a solution of Intermediate 5 (200 mg, 0.568 mmol, 1 equiv.) and 2-[5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (221.74 mg, 0.682 mmol, 1.2 equiv.) in dioxane (1 mL) was added CsCO (555.01 mg, 1.704 mmol, 3.0 equiv.), Pd(dba) (311.98 mg, 0.341 mmol, 0.6 equiv.), and BINAP (106.07 mg, 0.170 mmol, 0.3 equiv.). After stirring at 100 °C under a nitrogen atmosphere for 6 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (7:3) to give intermediate 6 (80 mg, 23.61%) as a yellow solid. LCMS (ESI) m / z [M+H] + =597.

[0724] Step 6: Preparation of 2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 7) [ka]

[0725] A solution of intermediate 6 (80 mg, 0.134 mmol, 1 equiv.) and LiOH (64.21 mg, 2.680 mmol, 20 equiv.) in MeOH (4 mL) was stirred at 60 °C for 1 h. 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 60% in 40 min; detector, UV 254 nm. This gave intermediate 7 (45 mg, 57.60%) as a white solid. LCMS (ESI) m / z [M+H] + =583.

[0726] Step 7: Preparation of tert-butyl (2S,4R)-4-hydroxy-1-{2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 8) [ka]

[0727] A solution of intermediate 7 (45 mg, 0.077 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (30.71 mg, 0.092 mmol, 1.2 equiv.), PyBOP (80.37 mg, 0.154 mmol, 2.0 equiv.), and DIEA (29.94 mg, 0.231 mmol, 3.0 equiv.) in DMF (1 mL) was stirred at room temperature for 1 h. 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 80% in 40 min; detector, UV 254 nm. This gave intermediate 8 (34 mg, 49.13%) as a white solid. LCMS (ESI) m / z [M+H] + =896.

[0728] Step 8: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka]

[0729] Intermediate 8 (34 mg) was purified by the following conditions (column: CHIRALPAK ID-3, 4.6 *Purification by chiral preparative HPLC using a 50 mm column, 3 μm column; mobile phase A: MtBE (0.1% DEA):MeOH = 70:30; flow rate: 1 mL / min; gradient: 0% B to 0% B; injection volume: 5 μl mL) gave the title compound (second peak) (11.3 mg, 33.24%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.81(d,J=3.3Hz,1H),8.99(s,1H),8.72(s,1H),8.44(d,J=7.6Hz,1H),8.22-8.15(m,1H),7.73-7.64(m,2H),7.48-7 .42(m,2H),7.39(t,J=6.8Hz,3H),7.16(dd,J=8.5,3.9Hz,1H),7.07-6.99(m,2H),6.86(s,1H),5.11(d,J=3.7Hz,1H),4.93(p,J=7.2Hz,1H),4. 40(t,J=7.9Hz,1H),4.30(brs,1H),3.84(d,J=9.7Hz,1H),3.76(dd,J=10.7,4.3Hz,1H),3.68-3.38(m,3H),3.33-3.32(m,3H),2.89(t,J=11.6H) z,2H),2.63-2.53(m,1H),2.45(s,3H),2.37(s,3H),2.18-1.72(m,7H), 1.39(d,J=7.0Hz,3H),1.05-0.98(m,3H),0.85(dd,J=11.6,6.6Hz,3H). LCMS(ESI)m / z[M+H] + =896.25.

[0730] The compounds in Table 4 were prepared using a procedure similar to that used above to prepare (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidin-1-yl}-3-methylphenyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 3) using the appropriate aryl bromide and 2-(5-methyl-6-(piperidin-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol.

[0731] [Table 5-1]

[0732] [Table 5-2]

[0733] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-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]

[0734] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2) [ka]

[0735] A mixture of 2-{6-[(3S)-pyrrolidin-3-yl]thieno[2,3-c]pyridazin-3-yl}phenol (400 mg, 1.345 mmol, 1 equiv.), methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (397.77 mg, 1.345 mmol, 1 equiv.), and DIEA (869.24 mg, 6.725 mmol, 5 equiv.) in DMSO (4 mL) was stirred under a nitrogen atmosphere at 100° C. for 3 h. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm to give intermediate 2 (130 mg, 17.36%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =557.

[0736] Step 2: Preparation of 2-(3-{2-[(3R)-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 (Intermediate 3) [ka]

[0737] A mixture of intermediate 2 (130 mg, 0.234 mmol, 1 equiv.) and LiOH (16.78 mg, 0.702 mmol, 3 equiv.) in MeOH (2 mL), THF (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 intermediate 3 (142 mg, crude) as a yellow solid. LCMS (ESI) m / z [M+H] + =543.

[0738] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-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]

[0739] A mixture of intermediate 3 (142 mg, 0.262 mmol, 1 equiv.), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (86.73 mg, 0.262 mmol, 1 equiv.), PyBOP (204.28 mg, 0.393 mmol, 1.5 equiv.), and DIEA (169.12 mg, 1.310 mmol, 5 equiv.) in DMF (3 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm to give intermediate 4 (100 mg, 44.64%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =856.

[0740] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-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 [ka]

[0741] The product intermediate 4 was purified under the following conditions (column: CHIRAL ART Cellulose-SB, 3 * Purification by preparative SFC on a 25 cm column, 5 μm column; mobile phase A:CO2, mobile phase B:IPA:DCM=1:1 HPLC; flow rate: 90 mL / min; gradient: isocratic 60% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 277 nm; RT1 (min): 3.33; RT2 (min): 4.28; sample solvent: MeOH:DCM=1:1 HPLC; injection volume: 1 mL gave the title compound (second peak) (36.9 mg, 35.46%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.30-12.25(m,1H),9.01-8.96(m,1H),8.89-8.79(m,2H),8.75(s,1H),8.44(d,J=7.7Hz,1H),8.01(d,J=7 .9,1.7Hz,1H),7.50(s,1H),7.47-7.42(m,2H),7.40-7.34(m,3H),7.07-6.92(m,3H),5.11(d,J=3.6Hz,1H),4.94(q,J=7.2,6.5Hz,1 H),4.39(t,J=7.9Hz,1H),4.30(s,1H),4.24-4.07(m,2H),3.93-3.59(m,5H),3.51(d,J=10.7Hz,1H),2.65-2.56(m,1H),2.48-2.42( m,3H),2.38-2.23(m,2H),2.10-1.99(m,1H),1.85-1.69(m,1H),1.44(dd,J=40.6,7.0Hz,3H),1.05-0.98(m,3H),0.89-0.81(m,3H). LCMS(ESI)m / z:[M+H] + =856.40.

[0742] The compounds in Table 5 were prepared using a procedure similar to that used above to prepare (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-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) using the appropriate aryl chloride and amine.

[0743] [Table 6-1]

[0744] [Table 6-2]

[0745] [Table 6-3]

[0746] [Table 6-4]

[0747] [Table 6-5]

[0748] [Table 6-6]

[0749] [Table 6-7]

[0750] [Table 6-8]

[0751]

Table 6-9

[0752]

Table 6-10

[0753]

Table 6-11

[0754]

Table 6-12

[0755]

Table 6-13

[0756]

Table 6-14

[0757]

Table 6-15

[0758]

Table 6-16

[0759]

Table 6-17

[0760]

Table 6-18

[0761] [Table 6-19]

[0762] Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{4-[3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl]piperazin-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 9) [ka]

[0763] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (Intermediate 2) . [ka]

[0764] To a solution of 4-bromo-6-chloropyridazin-3-amine (20.00 g, 95.951 mmol, 1.00 equiv) in THF (200.00 mL) was added CuI (21.93 g, 115.141 mmol, 1.20 equiv) and CHCl (30.84 g, 115.141 mmol, 1.20 equiv) at room temperature. To the above mixture was added t-BuNO (11.87 g, 115.141 mmol, 1.20 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C for an additional 6 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with saturated brine (1 x 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 (1:1) to give intermediate 2 (15 g, 48.96%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =319.

[0765] Step 2: Preparation of 4-(tert-butylsulfanyl)-6-chloro-3-iodopyridazine (Intermediate 4) . [ka]

[0766] To a solution of intermediate 2 (15.00 g, 46.975 mmol, 1.00 equiv) in THF (100.00 mL) was added 2-methyl-2-propanethiol (5.08 g, 56.370 mmol, 1.20 equiv) and NaH (2.25 g, 93.950 mmol, 2.00 equiv, 60%) at 0 °C. The resulting mixture was stirred at 60 °C for 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were washed with saturated brine (1 × 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 (1:1) to give intermediate 4 (6.4 g, 41.46%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =329.

[0767] Step 3: Preparation of tert-butyl 2-[4-(tert-butylsulfanyl)-6-chloropyridazin-3-yl]-2-cyanoacetate (Intermediate 6). [ka]

[0768] To a stirred solution of Intermediate 4 (6.40 g, 19.477 mmol, 1.00 equiv.) and tert-butyl 2-cyanoacetate (5.50 g, 38.954 mmol, 2.00 equiv.) in 1,4-dioxane (60.00 mL), CuI (0.74 g, 3.895 mmol, 0.20 equiv.), picolinic acid (1.20 g, 9.739 mmol, 0.50 equiv.), and CsCO (19.04 g, 58.431 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. 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: HO in ACN (0.1% FA), gradient 0% to 100% in 30 min; Detector: UV 254 / 220 nm. This gave intermediate 6 (5 g, 75.10%) as a brown oil. LCMS (ESI) m / z: [M+H] + =342.

[0769] Step 4: Preparation of 2-[4-(tert-butylsulfanyl)-6-chloropyridazin-3-yl]acetonitrile (Intermediate 7). [ka]

[0770] Intermediate 6 (5.00 g, 14.626 mmol, 1.00 equiv) was added to HFIP (50.00 mL) at room temperature. The resulting mixture was stirred at 60° C. for 16 hours. The residue was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, HO in ACN (0.1% FA), gradient 0% to 100% in 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 7 (1.2 g, 33.94%) as a brown oil. LCMS (ESI) m / z: [M+H] + =242.

[0771] Step 5: Preparation of 3-chlorothieno[3,2-c]pyridazin-6-amine (Intermediate 8). [ka]

[0772] Intermediate 7 (1.20 g, 4.964 mmol, 1.00 equiv) was added to trifluoroacetaldehyde (10.00 mL) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, H2O in ACN (10 mmol / L NH4HCO3), gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm. This gave intermediate 8 (283 mg, 30.71%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =186.

[0773] Step 6: Preparation of 3,6-dichlorothieno[3,2-c]pyridazine (Intermediate 9). [ka]

[0774] To a stirred solution of intermediate 8 (283.00 mg, 1.525 mmol, 1.00 equiv) in ACN (10.00 mL) was added CuCl (301.86 mg, 3.050 mmol, 2.00 equiv) at 0 °C. To the above mixture was added t-BuNO (314.42 mg, 3.050 mmol, 2.00 equiv) at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was quenched with water 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, HO in ACN (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 / 220 nm. This afforded intermediate 9 (153 mg, 48.94%) as a brown solid. LCMS(ESI)m / z:[M+H] + =205.

[0775] Step 7: Preparation of 1-{3-chlorothieno[3,2-c]pyridazin-6-yl}piperazine (Intermediate 11). [ka]

[0776] To a stirred solution of intermediate 9 (153.00 mg, 0.746 mmol, 1.00 equiv) in DMSO (5.00 mL) was added piperazine (192.81 mg, 2.238 mmol, 3.00 equiv) and DIEA (482.17 mg, 3.730 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 100 °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, HO in ACN (0.1% FA), gradient 0% to 100% in 30 min; detector, UV 254 / 220 nm. This afforded intermediate 11 (114 mg, 59.98%) as a brown solid. LCMS (ESI) m / z: [M+H] + =255.

[0777] Step 8: Preparation of 2-[6-(piperazin-1-yl)thieno[3,2-c]pyridazin-3-yl]phenol (Intermediate 13). [ka]

[0778] To a stirred solution of Intermediate 11 (114.00 mg, 0.448 mmol, 1.00 equiv) and 2-hydroxyphenylboronic acid (185.18 mg, 1.344 mmol, 3.00 equiv) in 1,4-dioxane (8.00 mL) and HO (2.00 mL) was added XPhos Pd G (37.88 mg, 0.045 mmol, 0.10 equiv) and CsCO (437.43 mg, 1.344 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 6 hours under a nitrogen atmosphere. 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: HO in ACN (0.1% FA), gradient 0% to 100% in 30 min; Detector: UV 254 / 220 nm. This afforded intermediate 13 (44 mg, 31.47%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =313.

[0779] Step 9: Preparation of methyl 2-[3-(2-{4-[3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 15). [ka]

[0780] To a stirred solution of intermediate 13 (44.00 mg, 0.141 mmol, 1.00 equiv.) in DMSO (5.00 mL), methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (41.74 mg, 0.141 mmol, 1.00 equiv.) and DIEA (54.57 mg, 0.423 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C for 1 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, HO in ACN (0.1% FA), gradient from 0% to 100% in 30 min; detector, UV 254 / 220 nm. This afforded intermediate 15 (19 mg, 23.75%) as a brown solid. LCMS(ESI)m / z:[M+H] + =572.

[0781] Step 10: Preparation of 2-[3-(2-{4-[3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 16). [ka]

[0782] To a stirred solution of Intermediate 15 (19.00 mg, 0.033 mmol, 1.00 equiv) in MeOH (2.00 mL) and HO (2.00 mL) was added LiOH . HO (14.52 mg, 0.330 mmol, 10.00 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was acidified to pH 3 with HCl (1 M). The resulting mixture was concentrated in vacuo. This gave intermediate 16 (20 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =558.

[0783] Step 11: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{4-[3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl]piperazin-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 [ka]

[0784] To a stirred solution of Intermediate 16 (20.00 mg, 0.036 mmol, 1.00 equiv.) in DMF (1.00 mL), PyBOP (55.99 mg, 0.108 mmol, 3.00 equiv.) and DIEA (23.18 mg, 0.180 mmol, 5.00 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 (11.89 mg, 0.036 mmol, 1.00 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 16 hours. The residue was purified by preparative HPLC under the following conditions. Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 65% B in 9 min; Wavelength: 254 / 220 nm; RT1 (min): 8.47; Run count: 0. This afforded the title compound (0.7 mg, 2.16%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ 13.81 - 13.76 (m, 1H), 9.01 - 8.87 (m, 3H), 8.84 (s, 1H), 8.45 - 8.23 (m, 1H), 7.98 - 7.93 (m, 1H), 7.51 - 7.42 (m, 1H), 7.40 - 7.26 (m, 4H), 7.01 - 6.94 (m, 3H), 6.71 (s, 1H), 6.15 - 4.98 (m, 1H), 4.99 - 4.84 (m, 1H), 4.60 - 4.36 (m, 1H), 4.34 - 4.22 (m, 1H), 4.10 - 3.99 (m, 4H), 3.99 - 3.82 (m, 1H), 3.68 - 3.57 (m, 5H), 3.40 - 3.34 (m, 1H), 2.48 - 2.43 (m, 2H), 2.40 (s, 2H), 2.11 - 1.99 (m, 1H), 1.85 - 1.73 (m, 1H), 1.34 (d, J = 7.0Hz, 3H), 1.01 (d, J = 6.6Hz, 3H), 0.86 (d, J = 6.6Hz, 3H). LCMS(ESI) m / z: [M + H] + = 871.20。

[0785] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{5-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]pyrimidin-2-yl}piperazin-1-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 31)

Chem.

[0786] Step 1: Preparation of ethyl 2-cyano-2-(3,6-dichloropyridazin-4-yl)-2-methylacetate (Intermediate 2).

Chem.

[0787] To a solution of 3,4,6-trichloropyridazine (10 g, 54.520 mmol, 1 equiv.) and ethyl 2-cyanopropionate (6.93 g, 54.520 mmol, 1 equiv.) in DMSO (80 mL) was added DIEA (21.14 g, 163.560 mmol, 3 equiv.), and the resulting solution was stirred at 100 °C for 3 h. The mixture was diluted with EtOAc (200 mL) and washed with water (200 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography using an elution gradient of 0–35% ACN in HO to give intermediate 2 (7.3 g, 48.85%) as a brown oil. LCMS (ESI) m / z: [M+H] + =274.

[0788] Step 2: Preparation of 2-(3,6-dichloropyridazin-4-yl)propanenitrile (Intermediate 3). [ka]

[0789] To a solution of intermediate 2 (7.3 g, 26.633 mmol, 1 equiv.) and NaCl (3.11 g, 53.266 mmol, 2 equiv.) in DMSO (50 mL) and HO (10 mL) was added, and the resulting solution was stirred at 120° C. for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography, elution gradient 0 to 42% ACN in HO to give intermediate 3 (2.8 g, 52.04%) as a brown oil. LCMS (ESI) m / z: [M+H] + =202.

[0790] Step 3: Preparation of 3-chloro-5-methylthieno[2,3-c]pyridazin-6-amine (Intermediate 4). [ka]

[0791] To a solution of intermediate 3 (2.8 g, 12.374 mmol, 1 equiv.) and CuI (235.66 mg, 1.237 mmol, 0.1 equiv.) in DMF (25 mL) was added TMEDA (287.59 mg, 2.475 mmol, 0.20 equiv.) and NaSO.9HO (8.92 g, 37.122 mmol, 3 equiv.), and the resulting solution was stirred at 80 °C for 2 h (under N atmosphere). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by flash C18 chromatography using an elution gradient of 0–42% MeOH in HO to give intermediate 4 (1.1 g, 44.52%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =200.

[0792] Step 4: Preparation of 6-bromo-3-chloro-5-methylthieno[2,3-c]pyridazine (Intermediate 5). [ka]

[0793] To a solution of intermediate 4 (1.1 g, 5.509 mmol, 1 equiv.) and CuBr (1.48 g, 6.611 mmol, 1.2 equiv.) in MeCN (10 mL) was added 2-methyl-2-propyl nitrite (681.76 mg, 6.611 mmol, 1.2 equiv.), and the resulting solution was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (200 mL) and washed with water (200 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography, elution gradient 0 to 64% ACN in HO to give intermediate 5 (693 mg, 47.73%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =263.

[0794] Step 5: Preparation of 5-{3-chloro-5-methylthieno[2,3-c]pyridazin-6-yl}-2-methoxypyrimidine (Intermediate 6). [ka]

[0795] To a solution of Intermediate 5 (693 mg, 2.630 mmol, 1 equiv.) and 2-methoxypyrimidin-5-ylboronic acid (404.77 mg, 2.630 mmol, 1 equiv.) in dioxane (6 mL) and HO (1.5 mL), dichloropalladium, bis(triphenylphosphane) (184.57 mg, 0.263 mmol, 0.1 equiv.) and KPO (1.12 g, 5.260 mmol, 2 equiv.) were added, and the resulting solution was stirred at 80 °C for 16 h (under N atmosphere). The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0-67% ACN in HO to give intermediate 6 (253 mg, 32.87%) as a brown solid. LCMS (ESI) m / z: [M+H] + =293.

[0796] Step 6: Preparation of 2-[6-(2-methoxypyrimidin-5-yl)-5-methylthieno[2,3-c]pyridazin-3-yl]phenol (Intermediate 7). [ka]

[0797] To a solution of intermediate 6 (271 mg, 0.926 mmol, 1 equiv.) and 2-hydroxyphenylboronic acid (191.53 mg, 1.389 mmol, 1.5 equiv.) in dioxane (6 mL) and HO (1.5 mL), XPhos Pd G3 (78.36 mg, 0.093 mmol, 0.1 equiv.) and CsCO3 (603.24 mg, 1.852 mmol, 2 equiv.) were added, and the resulting solution was stirred at 80 °C for 2 h (under N2 atmosphere). The mixture was diluted with EtOAc (80 mL) and washed with water (80 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography using an elution gradient of 0–51% EA in PE to give intermediate 7 (234 mg, 72.14%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =351.

[0798] Step 7: Preparation of 2-[6-(2-chloropyrimidin-5-yl)-5-methylthieno[2,3-c]pyridazin-3-yl]phenol (Intermediate 8). [ka]

[0799] To a solution of intermediate 7 (323 mg, 0.922 mmol, 1 equiv) in POCl3 (0.5 mL) was added DMF (3 mL) dropwise at 0 °C, and the resulting solution was stirred at 60 °C for 2 h. The reaction was quenched with water at 0 °C. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0-62% ACN in HO to give intermediate 8 (108 mg, 33.02%) as a yello...

Claims

1. A compound having the structure of Formula I or II, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 in the formula ring system A is a 5- to 9-membered heterocyclyl or heteroaryl, m is 0, 1, 2, or 3, k is 0, 1, or 2, Each R １ is, independently, halo, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ２ -C ９ heterocyclyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted CH ２ -C ３ -C ８ cycloalkyl, and each X is independently halo, L is a linker, B is a cleavage moiety, the compound, or a pharmaceutically acceptable salt thereof.

2. Having the said structure of Formula I or II, wherein 【Chemical Formula 2】 in the formula ring system A is a 5- to 9-membered heterocyclyl or heteroaryl, m is 0, 1, 2, or 3, k is 0, 1, or 2, L is a linker, B is a cleavage moiety, Each R １ is, independently, halo, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ２ -C ９ heterocyclyl, and each X is independently halo, the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

3. Having the said structure of Formula I or II, wherein [Chemical Formula 3] in the formula ring system A is a 5- to 9-membered heterocyclyl or heteroaryl, m is 0, 1, 2, or 3, k is 0, 1, or 2, L is a linker 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 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 ethynyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C ３ -C １０ -cycloalkyl, optionally substituted C ２ -C ９ -heterocyclyl, optionally substituted C ２ -C ９ -heteroaryl, 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 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, B is a cleavage moiety, Each R １ is independently halo, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ２ -C ９ heterocyclyl, and each X is independently halo, the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound has the structure of Formula I-A or II-A, wherein 【Chemical Formula 4】 in the formula, the dashed bond represents a single bond or a double bond, the compound according to any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. The compound has the structure of Formula I-G or II-G, the compound according to any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 5】

6. The compound has the structure of Formula I-H or II-H, the compound according to any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 6】

7. m is 0 or 1, the compound according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. m is 1, the compound according to any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R １ is halo, optionally substituted C １ ~C ６ alkyl, or optionally substituted C ３ ~C ８ cycloalkyl, a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

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

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

12. m is 0, the compound according to any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof.

13. k is 1, the compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X is Cl.

15. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein k is 0.

16. L is a linker 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 independently being an optionally substituted ethynyl, an optionally substituted C ６ ~C １０ Aryl, optionally substituted C ３ ~C １０ Cycloalkyl, optionally substituted C ２ ~C ９ Heterocyclyl, 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 ２～６ 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, The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each of f, g, h, i, j, and k is independently 0 or 1.

17. The linker is of the following structure A １ -(B １ ) ｆ -(B ２ ) ｈ -(B ３ ) ｉ -(B ４ ) ｋ -A ２ 、 wherein each of B １ 、B ２ 、B ３ 、and B ４ is independently optionally substituted ethynyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ３ -C １０ cycloalkyl, optionally substituted C ２ -C ９ heterocyclyl, optionally substituted C ２ -C ９ heteroaryl, O, or NR Ｎ ; a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein at least one of f, h, i, and k is 1.

19. 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 ９ -heterocyclyl, optionally substituted C ３ -C １０ -cycloalkyl, or optionally substituted C ６ -C １０ -aryl, a compound according to any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof.

20. B １ and B ４ each independently O 【Chemical Formula 7】 [Chemical 8] The compound according to any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof.

21. B １ is 【Chemical Formula 9】 【Chemical 10】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

22. B ４ is O 【Chemical 11】 【Chemical 12】 The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof.

23. B ２ is NH, 【Chemical 13】 The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 16 to 23, or a pharmaceutically acceptable salt thereof, wherein g, h, i, and j are 0.

25. The cleavage moiety B has a structure of formula A-1, 【Chemical Formula 14】 Wherein Y １ is 【Chemical Formula 15】 is R Ａ５ is H, C optionally substituted with １ ~C ６ alkyl, or C optionally substituted with １ ~C ６ heteroalkyl, and R Ａ６ is H or optionally substituted C １ -C ６ -C Ａ７ -alkyl, R １ is H or optionally substituted C ６ -C Ａ６ and R Ａ７ together with the carbon atom to which each is attached combine to form optionally substituted C ３ -C ６ -carbocyclic or optionally substituted C ２ -C ５ -heterocyclic, or R Ａ６ and R Ａ７ together with the said carbon atom to which each is attached combine to form optionally substituted C ３ -C ６ -carbocyclic or optionally substituted C ２ -C ５ -heterocyclic, and R Ａ８ is H, C optionally substituted １ ~C ６ alkyl, or C optionally substituted １ ~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 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, optionally substituted -O-C ３ ~C ６ carbocyclic, 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 together with the carbon atom to which each is attached to form 【Chemical Formula 16】 to form 【Chemical 17】 is optionally substituted C ６ ~C １０ aryl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ２ ~C ９ heteroaryl, or C ２ ~C ９ heterocyclic, any one of which is optionally substituted with A ２ and R Ａ１ 、R Ａ２ 、R Ａ３ 、and R Ａ４ One of them is A ２ or 【Chemical 18】 is A ２ is replaced by A ２ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is a bond between the decomposition part and the linker.

26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety has the following structure 【Chemical 19】

27. The cleavage moiety is of formula C, 【Chemical 20】 Wherein L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 21】 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, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, C optionally substituted with １ ~C ６ alkyl, or C optionally substituted with １ ~C ６ heteroalkyl, 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 ~C ６ alkyl, or optionally substituted C ６ ~C １０ aryl, and R Ｂ９ is H or optionally substituted C １ -C ６ to C alkyl, R Ｂ１０ is H or F, and A ２ is a bond between the decomposition part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one of is A ２ The compound according to any one of claims 1 to 24 having the structure of formula C or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

28. The cleavage moiety is of formula C, 【Chemical 22】 Wherein L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 23】 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, C optionally substituted with １ -C ６ alkyl, or C optionally substituted with 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, C １ to C ６ alkyl, C ３ to C １０ carbocyclic, C ６ to C １０ aryl, C １ to C ６ alkyl C ３ to C １０ carbocyclic, or C １ to C ６ alkyl C ６ to C １０ aryl, and R Ｂ５ is H, C optionally substituted with １ ~C ６ alkyl, or C optionally substituted with 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 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, and 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 to C ６ alkyl, A ２ is a bond between the decomposition part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one of is A ２ A compound according to any one of claims 1 to 24 having the structure of formula C or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

29. The cleavage moiety is 【Chemical 24】 The compound according to claim 27 or 28, or a pharmaceutically acceptable salt thereof.

30. The cleavage moiety is 【Chemical 25】 The compound according to claim 27, or a pharmaceutically acceptable salt thereof.

31. The cleavage moiety is 【Chemical 26】 The compound according to claim 27 or 28, or a pharmaceutically acceptable salt thereof.

32. The cleavage moiety is 【Chemical 27】 The compound according to claim 27, or a pharmaceutically acceptable salt thereof.

33. The cleavage moiety is 【Chemical 28】 The compound according to claim 27, or a pharmaceutically acceptable salt thereof.

34. The cleavage moiety is 【Chemical 29】 The compound according to claim 27, or a pharmaceutically acceptable salt thereof.

35. The cleavage moiety is of formula C5, where 【Chemical 30】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 31】 where 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, C optionally substituted with １ -C ６ alkyl, or C optionally substituted with 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 -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 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 to C alkyl, R Ｂ１１ is H, an alcohol, a boronic acid, 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 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 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, having the structure of formula C5 or a pharmaceutically acceptable salt thereof

36. The cleavage moiety is 【Chemical 32】 The compound according to claim 35, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

37. The cleavage moiety is of formula D, where 【Chemical 33】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 34】 where 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 -C ６ -C 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 ~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 １ -C ６ heteroalkyl, optionally substituted C ２ -C ６ alkynyl, 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 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 is A ２ The compound according to any one of claims 1 to 24 having the structure of formula D or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

38. The cleavage moiety is 【Chemical Formula 35】 The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

39. The cleavage moiety is 【Chemical Formula 36】 【Chemical 37】 The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

40. The cleavage moiety is of formula Da, where 【Chemical Formula 38】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 39】 where 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, 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, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, C optionally substituted with １ -C ６ alkyl, or C optionally substituted with 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 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 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 is A The compound according to any one of claims 1 to 24 having the structure of formula Da or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

41. The cleavage moiety is 【Chemical 40】 The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

42. The cleavage moiety is of formula E, where 【Chemical Formula 41】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 42】 where 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, C optionally substituted １ ~C ６ alkyl, or C optionally substituted 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, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -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, and 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 heterocyclyl, optionally substituted amino, or cyano, A ２ is the bond between the decomposition part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one of is A ２ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, having the structure of formula E or a pharmaceutically acceptable salt thereof.

43. The cleavage moiety is 【Chemical Formula 43】 The compound according to claim 42, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

44. The cleavage moiety is of formula F, where 【Chemical 44】 In the formula, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 45】 where 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, C optionally substituted with １ ~C ６ alkyl, or C optionally substituted with 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, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -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 a bond between the decomposition part and the linker, R Ｂ１ or R Ｂ３ Only one of which is A ２ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, having the structure of formula F or a pharmaceutically acceptable salt thereof.

45. The cleavage moiety is 【Chemical 46】 The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

46. The cleavage moiety is 【Chemical 47】 The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein the cleavage moiety is as defined above.

47. 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, where In the formula, A １ is a bond between the linker and the ring system A, 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 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 C optionally substituted １～１０ alkyl, C optionally substituted ２～１０ alkenyl, C optionally substituted ２～１０ alkynyl, C optionally substituted ２～１０ heterocyclyl, C optionally substituted ２～６ heteroaryl, C optionally substituted ６～１２ aryl, C optionally substituted ２ -C １０ polyethylene glycol, C optionally substituted ３ -C １０ cycloalkyl, C optionally substituted ３ -C １０ carbocyclyl, or C optionally substituted 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 15 and 25 to 46, or a pharmaceutically acceptable salt thereof.

48. A １ is a bond between the linker and the benzopyridazine core ring system, 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 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 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 ２～６ 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 is 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 47, or a pharmaceutically acceptable salt thereof.

49. The compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure 【Chemical 48】 【Chemical 49】

50. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure 【Chemical Formula 50】

51. 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 where 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; B is a cleavage moiety; 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 ３ to C ８ cycloalkyl, or optionally substituted C ２ to C １０ heterocyclyl, and each X is independently halo. The compound according to any one of claims 1 to 15 and 25 to 46, or a pharmaceutically acceptable salt thereof.

52. The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure 【Chemical Formula 51】 【Chemical 52】 【Chemical 53】

53. A pharmaceutical composition comprising the compound according to any one of claims 1 to 52 and a pharmaceutically acceptable excipient.

54. A method for treating BAF complex-related disorders 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 52 or the pharmaceutical composition according to claim 53.

55. The method according to claim 54, wherein the BAF complex-related disorder is cancer or a viral infection.

56. 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 52 or the pharmaceutical composition according to claim 53.

57. The method according to claim 56, wherein the disorder associated with the loss-of-function mutation of BRG1 is cancer.

58. 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 52 or the pharmaceutical composition according to claim 53.

59. The method according to any one of claims 54 to 58, 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, esophagogastric cancer, pancreatic cancer, hepatobiliary 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 cancer, appendiceal cancer, small intestine cancer, or penile cancer.

60. The method according to claim 59, 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.

61. The method according to claim 59, wherein the cancer is non-small cell lung cancer.

62. The method according to claim 59, wherein the cancer is soft tissue sarcoma.

63. 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 52 or the pharmaceutical composition according to claim 53.

64. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 53, for use in therapy.

65. A compound according to any one of claims 1 to 252, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 53, for use in the treatment of cancer.

66. The compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 65, 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, esophagogastric cancer, pancreatic cancer, hepatobiliary 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 cancer, appendiceal cancer, small intestine cancer, or penile cancer.

67. The compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 65, 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.

68. The compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 65, wherein the cancer is non-small cell lung cancer.

69. The compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 65, wherein the cancer is soft tissue sarcoma.

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