Compounds and their uses

Abstract

This disclosure features compounds of formula I or pharmaceutically acceptable salts thereof that are useful for modulating BRG1 or BRM-related factor (BAF) complexes, and formulations containing the same. Methods for treating BAF complex-related disorders, such as cancer, are also disclosed. [Formula 1] TIFF2026516481000281.tif31128

Description

[Technical Field]

[0001] This invention relates to compounds useful for regulating BRG1 or BRM-associated factor (BAF) complexes. In particular, this invention relates to compounds useful for treating disorders related to 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 transcription activator BRG1 is also known as the ATP-dependent chromatin remodeler SMARCA4 and is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancerous tumors and is required for cancer cell proliferation. BRM is also known as the likely global transcription activator SNF2L2 and / or the ATP-dependent chromatin remodeler SMARCA2 and is encoded by the SMARCA2 gene on chromosome 9. It 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 results in downstream cellular effects, including cell cycle arrest and tumor suppression. [Overview of the project]

[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 of the BAF complex, such as disorders associated with alterations of 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 embodiment, the present invention relates to a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof,

[0005] [ka] During the ceremony, m is 0, 1, 2, or 3, k is 0, 1, or 2, R is either absent or optionally substituted with a C1-C6 alkyl group. Each R 1 However, independently, these are halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano. Each X is independently a halo or optionally substituted C1-C6 heteroalkyl. L is the linker, B is characterized by a compound, or a pharmaceutically acceptable salt thereof, which is the decomposition part.

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

[0007] [ka]

[0008] In some embodiments, the compound has the structure of Formula I-B.

[0009]

Chemical formula

[0010] In some embodiments, the compound has the structure of Formula I-C.

[0011]

Chemical formula

[0012] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0013] In some embodiments, R 1 is optionally substituted C1-C6 heteroalkyl.. In some embodiments, R 1 is alkoxy. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is halo. In some embodiments, R 1 is F or Cl. In some embodiments, R [[ID=3⑨]] 1 is optionally substituted C1-C6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is difluoromethoxy. In some embodiments, R 1 is difluoromethyl. In some embodiments, R 1 is optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is methine. In some embodiments, R 1 is optionally substituted C3-C8 cycloalkyl.. In some embodiments, R 1is cyclopropane. In some embodiments, R 1 is cyclopropoxy. In some embodiments, R 1 is an optionally substituted C2-C9 heterocycline. In some embodiments, R 1 is an optionally substituted amino acid. In some embodiments, R 1 It is cyano.

[0014] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, X is an optionally substituted C1-C6 heteroalkyl. In some embodiments, X is methoxy. In some embodiments, X is a halo. In some embodiments, X is F.

[0015] In some embodiments, the disassembled part B has the structure of formula A-1,

[0016] [ka] During the ceremony, Y 1 but,

[0017] [ka] And, R A5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R A6 However, H is a C1-C6 alkyl group that is optionally substituted, and R A7 However, H, or a C1-C6 alkyl group substituted by any choice, or R A6 and R A7 However, each combines with the carbon atom to which it is bonded to form a C3-C6 carbocykryl with optional substitution, or a C2-C5 heterocycline with optional substitution, or R A6and R A7 However, each combines with the carbon atom to which it is bonded to form a C3-C6 carbocyrill with optional substitution, or a C2-C5 heterocycline with optional substitution. R A8 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R A1 , R A2 , R A3 , and R A4 Each of these is independently H, A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 The aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 carbocyrill, hydroxyl, thiol, or optionally substituted amino, or R A1 and R A2 , R A2 and R A3 , and / or R A3 and R A4 However, when each of them combines with the carbon atoms it is bonded to,

[0018] [ka] Forming,

[0019] [ka] However, C6~C were replaced by arbitrary selection. 10 Arial, C3~C replaced by any choice 10 Carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, and any of these is A2 It is replaced by an optional selection, R A1 , R A2 , R A3 , and R A4 One of them is A 2 is, or

[0020] [ka] However, A 2 It has been replaced with, A 2 However, this is the connection between the decomposition part and the linker.

[0021] In some embodiments, R A5 is H or methyl. In some embodiments, R A5 H is H.

[0022] In some embodiments, R A1 , R A2 , R A3 , and R A4 Each of these is independently H or A 2 That is the case.

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

[0024] In some embodiments, R A2 is, A 2 And R A1 , R A3 , and R A4 Each of these is H.

[0025] In some embodiments, R A3 is, A 2 And R A1 , R A2 , and R A4 Each of these is H.

[0026] In some embodiments, R A4 is A 2 and each of R A1 , R A2 , and R A3 is H.

[0027] In some embodiments, Y 1 is

[0028]

Chemical formula

[0029] In some embodiments, R A6 is H. In some embodiments, R A7 is H.

[0030] In some embodiments, Y 1 is

[0031]

Chemical formula

[0032] 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.

[0033] In some embodiments, the degradation moiety comprises the structure of formula A2.

[0034]

Chemical formula

[0035] In some embodiments, the degradation moiety is

[0036]

Chemical formula

[0037] In some embodiments, the degradation moiety comprises the structure of formula A4.

[0038]

Chemical formula

[0039] In some embodiments, the degradation moiety is

[0040]

Chemical formula

[0041] In some embodiments, the degradation moiety has the structure of formula A5.

[0042]

Chemical formula

[0043] In some embodiments, the degradation moiety has the structure of formula A6.

[0044]

Chemical formula

[0045] In some embodiments, the degradation moiety has the structure of formula A8. <00009S6>

[0046] <00oo989>

Chemical formula

[0047] <000099S>In some embodiments, the degradation moiety has the structure of formula A10.

[0048] [[ID=7E]]

Chemical formula

[0049] In some embodiments, the decomposition part has the following structure.

[0050]

Chemical formula

[0051] In some embodiments, the decomposition part has the following structure.

[0052]

Chemical formula

[0053] In some embodiments, the decomposition part is formula C,

[0054]

Chemical formula

[0055]

Chemical formula

[0056] In some embodiments, the disassembled part is defined by formula C,

[0057] [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ),

[0058] [ka] And, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, RB5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. v2 is 0, 1, 2, 3, or 4, Each R B6 However, A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The aryl group is an aryl group, an optionally substituted C2-C9 heteroaryl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 heteroalkenyl group, a hydroxyl group, a thiol group, or an optionally substituted amino group. R B7 and R B8 Each of these can independently be H, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C6-C 10 It is Ariel, R B9 However, it is a C1-C6 alkyl group that is substituted with H or optionally substituted. R B10 However, it is H or F, A 2 However, it is a connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the disassembled part has the structure of formula C3.

[0060] [ka]

[0061] In some embodiments, the disassembled portion has the structure of formula C4.

[0062] [ka]

[0063] In some embodiments, the disassembled part has the structure of formula C1.

[0064] [ka]

[0065] In some embodiments, the disassembled part is

[0066] [ka] That is the case.

[0067] In some embodiments, the disassembled part is

[0068] [ka] That is the case.

[0069] In some embodiments, the disassembled part is

[0070] [ka] That is the case.

[0071] In some embodiments, the disassembled part is

[0072] [ka] That is the case.

[0073] In some embodiments, the disassembled part is

[0074] [ka] That is the case.

[0075] In some embodiments, the disassembled part is

[0076] [ka] That is the case.

[0077] In some embodiments, the disassembled part has the structure of formula C2.

[0078] [ka]

[0079] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0080] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0081] In some embodiments, v2 is 0. In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B7 is methyl. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3 is isopropyl. In some embodiments, R B8 H is H. In some embodiments, R B2 H is H.

[0082] In some embodiments, the disassembled part is

[0083] [ka] That is the case.

[0084] In some embodiments, the decomposition portion has the structure of formula Ca2.

[0085] [ka]

[0086] In some embodiments, the disassembled portion has the structure of formula Cb2.

[0087] [ka]

[0088] In some embodiments, the disassembled portion has the structure of formula Cc2.

[0089] [ka]

[0090] In some embodiments, the decomposed part has the structure of formula Cd2.

[0091] [ka]

[0092] In some embodiments, the decomposed portion has the structure of formula Ce2.

[0093] [ka]

[0094] In some embodiments, the disassembled portion has the structure of formula Cf2.

[0095] [ka]

[0096] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0097] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0098] In some embodiments, v2 is 0. In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B7 is methyl. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3 is isopropyl. In some embodiments, R B3 C3~C, which were replaced by optional selection. 10 It is carbocyclyl. In some embodiments, R B3 is cyclopropane. In some embodiments, R B3 R is cyclobutane. In some embodiments, R B3 R is fluoro-2-methylpropane. In some embodiments, R B8 H is H. In some embodiments, R B2 H is H.

[0099] In some embodiments, the disassembled part is

[0100] [ka] That is the case.

[0101] In some embodiments, the disassembled part is

[0102] [ka] That is the case.

[0103] In some embodiments, the disassembled part is

[0104] [ka] That is the case.

[0105] In some embodiments, the disassembled part is

[0106] [ka] That is the case.

[0107] In some embodiments, the disassembled part is

[0108] [ka] That is the case.

[0109] In some embodiments, the disassembled part is

[0110] [ka] That is the case.

[0111] In some embodiments, the disassembled part is

[0112] [ka] That is the case.

[0113] In some embodiments, the disassembled part is

[0114] [ka] That is the case.

[0115] In some embodiments, the disassembled part is

[0116] [ka] That is the case.

[0117] In some embodiments, the disassembled part is represented by formula C5,

[0118] [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ),

[0119] [ka] And, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. v2 is 0, 1, 2, 3, or 4, Each R B6 However, A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The compounds are 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 of these can independently be H, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C6-C 10 It is Ariel, R B9 However, it is a C1-C6 alkyl group that is substituted with H or optionally substituted. R B11 However, H, alcohol, boronic acid, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, A 2 However, it is a connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, R B11 It is boric acid.

[0121] In some embodiments, the disassembled part has the structure of formula C6.

[0122] [ka]

[0123] In some embodiments, the disassembled part has the structure of formula C1.

[0124] [ka]

[0125] In some embodiments, the disassembled part has the structure of formula C8.

[0126] [ka]

[0127] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0128] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0129] In some embodiments, v2 is 0. In some embodiments, R B5 H is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B7 is methyl. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3is isopropyl. In some embodiments, R B8 H is H. In some embodiments, R B2 H is H.

[0130] In some embodiments, the disassembled part is

[0131] [ka] That is the case.

[0132] In some embodiments, the decomposition part is given by formula D,

[0133] [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ),

[0134] [ka] And, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. v2 is 0, 1, 2, 3, or 4, Each R B6 However, A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C2-C6 alkynyls, optionally substituted C3-C 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The compounds are 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 However, it is a C1-C6 alkyl group that is substituted with H or optionally substituted. A 2 However, it is a connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the disassembled part has the structure of formula D3.

[0136] [ka]

[0137] In some embodiments, the disassembled part has the structure of formula D1.

[0138] [ka]

[0139] In some embodiments, the disassembled part is

[0140] [ka] That is the case.

[0141] In some embodiments, the disassembled part is

[0142] [ka] That is the case.

[0143] In some embodiments, the disassembled part is

[0144] [ka] That is the case.

[0145] In some embodiments, the disassembled part has the structure of formula D2.

[0146] [ka]

[0147] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0148] In some embodiments, R B9 It is bonded to the (S)-chiral center. In some embodiments, RB9 H is H.

[0149] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3 is isopropyl. In some embodiments, R B6 H is H. In some embodiments, R B6 is a 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 R is a C3-C6 alkynyl that has been optionally substituted. In some embodiments, R B6 is methoxy. In some embodiments, R B6 It is 3-methoxy-1-propanoxy.

[0150] In some embodiments, the disassembled part is

[0151] [ka] That is the case.

[0152] In some embodiments, the disassembled part is

[0153] [ka] That is the case.

[0154] In some embodiments, the disassembled part is

[0155] [ka] That is the case.

[0156] In some embodiments, the disassembled part is

[0157] [ka] That is the case.

[0158] In some embodiments, the disassembled part is

[0159] [ka] That is the case.

[0160] In some embodiments, the disassembled part is

[0161] [ka] That is the case.

[0162] In some embodiments, the disassembled part is

[0163] [ka] That is the case.

[0164] In some embodiments, the disassembled part is

[0165] [ka] That is the case.

[0166] In some embodiments, the disassembled part is

[0167] [ka] That is the case.

[0168] In some embodiments, the disassembled part is

[0169] [ka] That is the case.

[0170] In some embodiments, the disassembled part is

[0171] [ka] That is the case.

[0172] In some embodiments, the disassembled part is

[0173] [ka] That is the case.

[0174] In some embodiments, the disassembled part is

[0175] [ka] That is the case.

[0176] In some embodiments, the disassembled part is

[0177] [ka] That is the case.

[0178] In some embodiments, the disassembled part is

[0179] [ka] That is the case.

[0180] In some embodiments, the disassembled part is

[0181] [ka] That is the case.

[0182] In some embodiments, the disassembled part is

[0183] [ka] That is the case.

[0184] In some embodiments, the disassembled part is

[0185] [ka] That is the case.

[0186] In some embodiments, the disassembled part is

[0187] [ka] That is the case.

[0188] In some embodiments, the disassembled part is

[0189] [ka] That is the case.

[0190] In some embodiments, the disassembled part is

[0191] [ka] That is the case.

[0192] In some embodiments, the disassembled part is

[0193] [ka] That is the case.

[0194] In some embodiments, the disassembled part is

[0195] [ka] That is the case.

[0196] In some embodiments, the disassembled part is

[0197] [ka] That is the case.

[0198] In some embodiments, the disassembled part is

[0199] [ka] That is the case.

[0200] In some embodiments, the decomposition part is the formula Da,

[0201] [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ),

[0202] [ka] And, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. Each of X1 and X2 is independently C, N, or O. v2 is 0, 1, 2, 3, or 4, Each R B6 However, A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The compounds are aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino. R B9However, it is a C1-C6 alkyl group that is substituted with H or optionally substituted. A 2 However, it is a connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the disassembled portion has the structure of formula Da3.

[0204] [ka]

[0205] In some embodiments, the disassembled portion has the structure of formula Da1.

[0206] [ka]

[0207] In some embodiments, the disassembled portion has the structure of formula Da2.

[0208] [ka]

[0209] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0210] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0211] In some embodiments, v2 is 0. In some embodiments, R B4 H is H. In some embodiments, RB5 H is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. 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.

[0212] In some embodiments, the disassembled part is

[0213] [ka] That is the case.

[0214] In some embodiments, the disassembled part is given by formula E,

[0215] [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ),

[0216] [ka] And, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B9 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclyl, or optionally substituted C2-C 10 It is a heterocycline, B 10 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C2-C 10 Heterocyclines, optionally substituted aminos, or cyanos, A 2 However, it is a connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the disassembled part has the structure of formula E3.

[0218] [ka]

[0219] In some embodiments, the disassembled portion has the structure of formula E1.

[0220] [ka]

[0221] In some embodiments, the disassembled part is

[0222] [ka] That is the case.

[0223] In some embodiments, the disassembled part is

[0224] [ka] That is the case.

[0225] In some embodiments, the disassembled part has the structure of formula E2.

[0226] [ka]

[0227] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0228] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0229] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, R B4 H is H. In some embodiments, RB5 H is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 H is H. In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 is methyl. In some embodiments, R B9 H is H. In some embodiments, R B9 R is a C3-C6 alkynyl that has been optionally substituted. In some embodiments, R B10 It does not exist. In some embodiments, R B9 R is [1.1.1]pentane. In some embodiments, R B9 is cyclopropane. In some embodiments, R B9 R is cyclobutane. In some embodiments, R B9 R is cyclopentane. In some embodiments, R B10 H is H. In some embodiments, R B10 is cyano. In some embodiments, R B10 C3~C, which were replaced by optional selection. 10 It is carbocyclyl. In some embodiments, R B10 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B10 It is methyl.

[0230] In some embodiments, the disassembled part is

[0231] [ka] That is the case.

[0232] In some embodiments, the disassembled part is

[0233] [ka] That is the case.

[0234] In some embodiments, the disassembled part is

[0235] [ka] That is the case.

[0236] In some embodiments, the disassembled part is

[0237] [ka] That is the case.

[0238] In some embodiments, the disassembled part is

[0239] [ka] That is the case.

[0240] In some embodiments, the disassembled part is

[0241] [ka] That is the case.

[0242] In some embodiments, the disassembled part is

[0243] [ka] That is the case.

[0244] In some embodiments, the disassembled part is

[0245] [ka] That is the case.

[0246] In some embodiments, the disassembled part is

[0247] [ka] That is the case.

[0248] In some embodiments, the decomposition part is given by formula F,

[0249] [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ),

[0250] [ka] And, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. A 2 However, it is a connection between the decomposition part and the linker. R B1 or R B3 Only one of them is A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the disassembled part has the structure of formula F3.

[0252] [ka]

[0253] In some embodiments, the disassembled part has the structure of formula F1.

[0254] [ka]

[0255] In some embodiments, the disassembled part is

[0256] [ka] That is the case.

[0257] In some embodiments, the disassembled part is

[0258] [ka] That is the case.

[0259] In some embodiments, the disassembled part is

[0260] [ka] That is the case.

[0261] In some embodiments, the disassembled part has the structure of formula F2.

[0262] [ka]

[0263] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 It is methyl.

[0264] In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 H is H.

[0265] In some embodiments, the disassembled part is

[0266] [ka] That is the case.

[0267] In some embodiments, the linker has the structure of formula II, A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -(D)-(B 3 ) i-(C 2 ) j -( B 4 ) k -A 2 , Formula II or a pharmaceutically acceptable salt thereof, During the ceremony, A 1 However, this is a bond between the linker and ring system A, A 2 However, it is a connection between the decomposition part and the linker. B 1 B 2 B 3 , and B 4 Each of these can be independently and optionally substituted with C1-C4 alkyl groups, or optionally substituted with C6-C 10 Aryl, optionally substituted C6~C 10 Aryl C 1~4 Alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-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 However, independently, H and C are optionally substituted. 1~4 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkinyl, optionally substituted C 2~10 Heterocyclines, optionally substituted C 2~6 Heteroaryl or optionally substituted C 1~7 It is heteroalkyl, C 1 and C 2 Each of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. D is replaced by C by choice. 1~10 Alkyl, optionally substituted C 2~10 Alkenil, C replaced by any choice 2~10 Alkinyl, optionally replaced with C 2~10 Heterocyclines, C substituted by choice 2~6 Heteroaryl, optionally substituted C 6~12 Arial, C2~C substituted by choice 10 Polyethylene glycol, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclyl, or optionally substituted C 1~10 It 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 That is the case.

[0268] In some embodiments, B 1 B 2 B 3 , and B 4 Each of these independently consists of an optionally substituted C1-C2 alkyl group, an optionally substituted C1-C3 heteroalkyl group, and an optionally substituted C2-C3 group. 10 Heterocyclines, optionally substituted C 2~6 Heteroaryl, O, or NR N And D is C which is optionally substituted. 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkinyl, optionally substituted C 2~10 Heterocyclines, optionally substituted C 6~12 Aryl, optionally substituted C2-C10 Polyethylene glycol, or optionally substituted C 1~10 Heteroalkyl, or A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -to-(B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 It is a chemical bond that connects them.

[0269] In some embodiments, B 1 B 2 B 3 , and B 4 Each of these independently consists of an optionally substituted C1-C2 alkyl group, an optionally substituted C1-C3 heteroalkyl group, and an optionally substituted C2-C3 group. 10 Heterocyclines, C substituted by choice 2~6 Heteroaryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclyl, O, or NR N That is the case.

[0270] In some embodiments, B 1 and B 4 Each of them is independent,

[0271] [ka]

[0272] [ka] That is the case.

[0273] In some embodiments, B 1 teeth,

[0274] [ka]

[0275] [ka] That is the case.

[0276] In some embodiments, B 4 teeth,

[0277] [ka]

[0278] [ka] That is the case.

[0279] In some embodiments, C 1 teeth,

[0280] [ka] That is the case.

[0281] In some embodiments, B 2 These are C1-C4 alkyl groups that have been optionally substituted.

[0282] In some embodiments, D is optionally replaced by C1-C 10 It is alkyl.

[0283] 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.

[0284] 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 That is the case.

[0285] In some embodiments, the linker is D. In some embodiments, D is optionally replaced by C. 1~10 Alkyl, optionally substituted C 2~10 Alkenil, C replaced by any choice 2~10 Alkinyl, optionally replaced with C 2~10 Heterocyclines, C substituted by choice 2~6 Heteroaryl, optionally substituted C 6~12 Arial, C2~C substituted by choice 10 Polyethylene glycol, or optionally substituted C 1~10 It is a heteroalkyl group. In some embodiments, D is optionally substituted with C3-C 10 It is a cycloalkyl group, 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 optionally substituted with C3-C 10It is a cycloalkyl group, 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 optionally substituted with C3-C 10 It is a cycloalkyl group, 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 optionally substituted with C3-C 10 It is a cycloalkyl group, where f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is optionally substituted with C3-C 10 It is a 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 optionally replaced by C3~C 10 It is a 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 optionally replaced by C3~C 10 It is a carbocyclyl, where f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is optionally replaced by C3~C 10 It is a carbocyclyl, where f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is

[0286] [ka]

[0287] [ka] That is the case.

[0288] In some embodiments, the linker is

[0289] [ka]

[0290] [ka] It has the structure of [the object].

[0291] 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 However, this is a bond between the linker and ring system A, A 2 However, it is a connection between the decomposition part and the linker. B 1 B 2 B 3 , and B 4 Each of these is independently substituted with an optional ethynyl, and an optional C6-C. 10 Arial, C3~C replaced by any choice 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O)2, or NR N And, Each R N However, independently, H and C are substituted by choice. 1~4 Alkyl, optionally substituted C 2~4 Alkenil, C replaced by any choice 2~4 Alkinyl, optionally replaced with C 2~10 Heterocyclines, C substituted by choice 6~12 C replaced by an aryl or optional character.1~7 It is heteroalkyl, C 1 and C 2 Each of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. B is the decomposition part, Each R 1 However, independently, halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C 10 It is a heterocycline, Each X is an independent halo.

[0292] In some embodiments, the linker is structure-(L 1 ) n - is the form in which n is 1, 2, or 3, and each L 1 O, NR are independent of each other. N , ethynyl, optionally substituted C2~C 10 Heterocyclyl, C2-C9 heteroaryl with optional substitution, C6-C9 with optional substitution 10 C3-C replaced by aryl or optional substitutions. 10 It is a cycloalkyl group.

[0293] In some embodiments, at least one L 1 C2~C which were replaced by optional selection. 10 It is a heterocycline. In some embodiments, C2-C is optionally substituted. 10 A heterocyclyl is a monocyclic heterocyclyl with four, five, or six members. In some embodiments, a monocyclic heterocyclyl with four, five, or six members is,

[0294] [ka] That is the case.

[0295] In some embodiments, C2~C are optionally replaced. 10 The heterocyclil is a spirocyclic heterocyclil. In some embodiments, the spirocyclic heterocyclil is

[0296] [ka] That is the case.

[0297] In some embodiments, C2~C are optionally replaced. 10 The heterocyclil is a cross-linked heterocyclil. In some embodiments, the cross-linked heterocyclil is

[0298] [ka] That is the case.

[0299] In some embodiments, C2~C 10 A heterocyclyl is a condensed bicyclic heterocyclyl. In some embodiments, a condensed bicyclic heterocyclyl is,

[0300] [ka] That is the case.

[0301] 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 In the formula, each q is independently 0 or 1. In some embodiments, the optionally substituted C2-C9 heteroaryls are 6-membered monocyclic heteroaryls. In some embodiments, the 6-membered monocyclic heteroaryls are

[0302] [ka] That is the case.

[0303] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is

[0304] [ka] That is the case.

[0305] In some embodiments, at least one L 1 C6~C, which were replaced by optional substitution. 10 It is an aryl. In some embodiments, C6~C is optionally replaced. 10 The aryl is a six-membered monocyclic aryl. In some embodiments, the six-membered monocyclic aryl is optionally substituted with a phenyl compound.

[0306] In some embodiments, at least one L 1 C3~C, which were replaced by optional selection. 10 It is a cycloalkyl group. In some embodiments, C3-C3 is optionally substituted. 10 Cycloalkyls are monocyclic cycloalkyls. In some embodiments, a 6-membered monocyclic cycloalkyl is,

[0307] [ka] That is the case.

[0308] In some embodiments, C3~C are optionally replaced. 10 The cycloalkyl is a crosslinked cycloalkyl. In some embodiments, the crosslinked cycloalkyl is

[0309] [ka] That is the case.

[0310] In some embodiments, at least one L 1 It is ethynyl.

[0311] In some embodiments, only one L 1 is O. In some embodiments, there is only one L 1 , NR N In some embodiments, R N is an optionally substituted C1-C4 alkyl group. In some embodiments, R N H is H.

[0312] In some embodiments, the linker has 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 of these is independently an optionally substituted ethynyl, and an optionally substituted C6-C 10 Arial, C3~C replaced by any choice 10 Cycloalkyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N That is the case.

[0313] In some embodiments, at least one of f, h, i, and k is 1.

[0314] In some embodiments, B 1 B 2 B 3 , and B 4Each of these is independently O, ethynyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C 10 Heterocyclines, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C6-C 10 It is an arrow. In some embodiments, B 1 B 2 B 3 , and B 4 Each of these is independently a C2-C9 heteroaryl or C2-C9 heteroaryl substituted by choice. 10 It is a heterocycline. In some embodiments, B 1 and B 4 Each of them is independent,

[0315] [ka]

[0316] [ka] That is the case.

[0317] In some embodiments, B 1 teeth,

[0318] [ka]

[0319] [ka] That is the case.

[0320] In some embodiments, B 4 teeth,

[0321] [ka]

[0322] [ka] That is the case.

[0323] In some embodiments, B 2 , NR N In some embodiments, B 2 is NH. In some embodiments, B 2 is a C2-C9 heteroaryl that is optionally substituted. In some embodiments, B 2 teeth,

[0324] [ka] That is the case.

[0325] 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.

[0326] In some embodiments, the linker is

[0327] [ka]

[0328] [ka]

[0329] [ka] It has the structure of [the object].

[0330] In some embodiments, the shortest chain of atoms connecting the two valencies of the linker is 2 to 10 atoms long. In some embodiments, the shortest chain of atoms connecting the two valencies of the linker is 6 atoms long.

[0331] In some embodiments, the linker is one of the compounds 1 to 4 in Table 1 (e.g., BRG1 IC 50 BRM IC 50 The linker structure is in any of the compounds whose ratio to is at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30). In some embodiments, the linker is any one of the compounds 1 to 4 in Table 1 (e.g., BRM IC 50 The linker structure is in any of the compounds where is ++ or greater (e.g., +++ or ++++ (e.g., ++++)). In some embodiments, the linker is any one of the compounds 1 to 4 in Table 1 (e.g., BRM IC 50 The value is ++ or higher (for example, +++ or ++++ (for example, ++++)) and the BRG1 IC 50 BRM IC 50 The linker structure is found in any of the compounds whose ratio to is at least 5 (for example, at least 7, 10, 15, 20, 25, or 30).

[0332] In some embodiments, the present invention is characterized by compounds selected from the group consisting of 1 to 4 in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is BRG1 IC 50 BRM IC 50 The compound is one of the compounds 1-4 in Table 1 or a pharmaceutically acceptable salt thereof, having a ratio of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30). In some embodiments, the compound is BRM IC as seen in Table 2. 50The compound is one of the compounds 1-4 in Table 1 or a pharmaceutically acceptable salt thereof, with a value of ++ or higher (e.g., +++ or ++++ (e.g., ++++)). In some embodiments, the compound is BRM IC as seen in Table 2. 50 The value is ++ or higher (for example, +++ or ++++ (for example, ++++)) and the BRG1 IC 50 BRM IC 50 One of the compounds 1-4 in Table 1, or a pharmaceutically acceptable salt thereof, having a ratio of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) to .

[0333] [Table 1]

[0334] In some embodiments, the compound contains at least 5 BRG1 IC 50 BRM IC 50 It has a ratio to BRG1 IC. In some embodiments, the compound has at least 7 BRG1 IC 50 BRM IC 50 It has a ratio to . In some embodiments, the compound is at least 10 BRG1 IC 50 BRM IC 50 It has a ratio to . In some embodiments, the compound contains at least 15 BRG1 IC 50 BRM IC 50 It has a ratio to . In some embodiments, the compound has at least 20 BRG1 IC 50 BRM IC 50 It has a ratio to . In some embodiments, the compound has at least 25 BRG1 IC 50 BRM IC 50 It has a ratio to . In some embodiments, the compound has at least 30 BRG1 IC 50 BRM IC 50 It has a ratio to [the specified value].

[0335] In one embodiment, the present invention is characterized by a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0336] In another embodiment, the present invention provides a method for reducing the activity of intracellular BAF complexes, wherein the method comprises contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0337] In some embodiments, the cells are cancer cells.

[0338] In another embodiment, the present invention relates to a method for treating BAF complex-related disorder in a subject in need thereof, the method comprising administering an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof to the subject.

[0339] In some embodiments, the BAF complex-related disorder is cancer or a viral infection.

[0340] In a further embodiment, the present invention relates to a method for inhibiting BRM, characterized in that the method involves contacting cells with an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof.

[0341] In some embodiments, the cells are cancer cells.

[0342] In another aspect, the present invention provides a method for inhibiting BRG1, wherein the method comprises contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0343] In some embodiments, the cells are cancer cells.

[0344] In a further embodiment, the present invention provides a method for inhibiting BRM and BRG1, wherein the method comprises contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0345] In some embodiments, the cells are cancer cells.

[0346] In another embodiment, the present invention relates to 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 an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof to the subject.

[0347] In some embodiments, the disorder associated with loss-of-function mutations in BRG1 is cancer. In other embodiments, the subject is determined to have a loss-of-function disorder in BRG1, for example, to have cancer with loss-of-function BRG1 (for example, the cancer is determined to contain cancer cells with loss-of-function BRG1).

[0348] In another embodiment, the present invention relates to a method for inducing apoptosis in cells, the method comprising contacting cells with an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof.

[0349] In some embodiments, the cells are cancer cells.

[0350] In a further embodiment, the present invention relates to a method for treating cancer in a subject in need thereof, the method comprising administering an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof to the subject.

[0351] In some embodiments of the methods described above, cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small intestine cancer, or penile cancer.

[0352] In some embodiments of the methods described above, 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.

[0353] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0354] In some embodiments of the aforementioned methods, the cancer is either drug-resistant or has been treated with previous therapies (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiotherapy, temozolomide, irinotecan, CAR-T therapy, Herceptin®, Perjeta®, tamoxifen, Xeloda®, docetaxol, platinum-based drugs such as carboplatin, paclita The patient did not respond to taxanes such as xel 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, fosbletabrin, or PDL1 inhibitors.

[0355] In some embodiments of the methods described above, the cancer has or is determined to have a BRG1 mutation. In some embodiments of the methods described above, the BRG1 mutation is homozygous. In some embodiments of the methods described above, the cancer does not have or is determined to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of the methods described above, the cancer does not have or is determined to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of the methods described above, the cancer has or is determined to have a KRAS mutation. In some embodiments of the methods described above, the BRG1 mutation is located in the ATPase catalytic domain of the protein. In some embodiments of the methods described above, the BRG1 mutation is a C-terminal deletion of BRG1.

[0356] In another aspect, the Disclosure provides a method for treating BAF-related disorders (e.g., cancer or viral infection) in a subject requiring such treatment. This method involves contacting cells with an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, viral infections include Retroviridae viruses such as lentiviruses (e.g., human immunodeficiency virus (HIV) and delta-retroviruses (e.g., human T-cell leukemia virus I (HTLV-I) and human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae viruses (e.g., hepatitis B virus (HBV)), Flaviviridae viruses (e.g., hepatitis C virus (HCV)), Adenoviridae viruses (e.g., human adenoviruses), Herpesviridae viruses (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), and herpesvirus K * The disorders are infections caused by viruses of the following families: 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). In some embodiments, the disorder is coffin sillis, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0357] In another aspect, the Disclosure provides a method for treating a viral infection in a subject in need thereof. This method involves administering an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions to a subject. In some embodiments, viral infections include Retroviridae viruses such as lentiviruses (e.g., human immunodeficiency virus (HIV) and delta-retroviruses (e.g., human T-cell leukemia virus I (HTLV-I) and human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae viruses (e.g., hepatitis B virus (HBV)), Flaviviridae viruses (e.g., hepatitis C virus (HCV)), Adenoviridae viruses (e.g., human adenoviruses), Herpesviridae viruses (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), and herpesvirus K * It is an infectious disease caused by viruses belonging to the following families: 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).

[0358] In some embodiments of the aforementioned models, the compound is a BRM-selective compound. In some embodiments, the BRM-selective compound inhibits the level and / or activity of BRM at least 10 times more than the compound inhibits the level and / or activity of BRG1, and / or the compound binds to BRM at least 10 times more than the compound binds to BRG1. For example, in some embodiments, the BRM-selective compound is IC for BRG1. 50 or IP 50IC is at least 10 times lower 50 or IP 50 It has. In some embodiments of the above-described aspects, the compound is a BRM / BRG1 biinhibitor compound. In some embodiments, the BRM / BRG1 biinhibitor compound has similar activity against both BRM and BRG1 (e.g., activity of the compound against BRM and BRG1 of up to 10 times (e.g., less than 5 times, less than 2 times)). In some embodiments, the activity of the BRM / BRG1 biinhibitor compound is greater against BRM. In some embodiments, the activity of the BRM / BRG1 biinhibitor compound is greater against BRG1. For example, in some embodiments, the BRM / BRG1 biinhibitor compound has IC against BRM 50 or IP 50 However, IC for BRG1 50 or IP 50 It is within 10 times that amount.

[0359] In another embodiment, the present invention relates to a method for treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject in need thereof, wherein the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof to the subject.

[0360] In another embodiment, the present invention relates to a method for reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject requiring such reduction, wherein the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof to the subject.

[0361] In another embodiment, the present invention relates to a method for suppressing the metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, characterized in that the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0362] In another embodiment, the present invention relates to a method for suppressing metastatic colony formation of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, wherein the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0363] In another embodiment, the present invention relates to a method for reducing the levels and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer cells, wherein the method comprises contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0364] In some embodiments of the above-described models, melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cells are included in the scope.

[0365] In some embodiments of the above-described models, an effective amount of the 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 the 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 the 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%).

[0366] In some embodiments, an effective amount of the 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%) for at least 12 hours (e.g., 14, 16, 18, 20, 22, 24, 30, 36, 48, 72 hours, or longer) 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%) compared to a reference substance for at least 4 days (e.g., 5, 6, 7, 14, 28, or longer).

[0367] In some embodiments of the above aspects, an effective amount of the compound reduces the level and / or activity of the 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 the compound reduces the level and / or activity of the 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 the compound reduces the level and / or activity of the BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0368] In some embodiments, an effective amount of the compound reduces the level and / or activity of the 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, 16, 18, 20, 22, 24, 30, 36, 48, 72 hours, or longer) compared to a reference substance. In some embodiments, an effective amount of a compound that reduces the level and / or activity of 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 for at least 4 days (e.g., 5, 6, 7, 14, 28, or longer).

[0369] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM proteins, and / or the cells or subject are identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein, and / or the cells or subject are identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein, and / or the cells or subject are 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, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin Aλ myeloma, diffuse mixed histiocytic lymphoma 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 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 (for example, the cancer has spread to the liver). Metastatic cancer may include cells exhibiting migratory cell migration and / or invasion, and / or cells exhibiting endothelial mobilization and / or angiogenesis. In other embodiments, migratory cancer is cell-migrating cancer. In yet another embodiment, cell-migrating cancer is non-metastatic cell-migrating cancer. Metastatic cancer may be cancer that spreads by seeding on the surface of the peritoneum, pleura, pericardium, or subarachnoid space.Alternatively, metastatic cancer can be cancer that spreads via the lymphatic system or hematogenously. In some embodiments, an effective dose of a drug that reduces the levels and / or activity of BRG1 and / or BRM is an effective dose to inhibit the formation of metastatic colonies of cancer in the liver.

[0370] 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.

[0371] In some embodiments, the method further comprises administering to a subject or contacting cells with an anticancer therapy, such as a chemotherapeutic agent or cytotoxic agent, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation. In some embodiments, the anticancer therapy is a chemotherapeutic agent or cytotoxic agent, such as antimetabolites, antimitotic agents, antitumor antibiotics, asparagine-specific enzymes, bisphosphonates, anticancer agents, alkylating agents, DNA repair enzyme inhibitors, histone deacetylase inhibitors, corticosteroids, demethylating agents, immunomodulators, Janus-related kinase inhibitors, phosphinocitide 3-kinase inhibitors, proteasome inhibitors, or tyrosine kinase inhibitors.

[0372] In some embodiments, the compounds of the present invention are used in combination with other anticancer therapies used to treat uveal melanoma, such as surgery, MEK inhibitors, and / or PKC inhibitors. For example, in some embodiments, the method further includes performing surgery before, after, or concurrently with the administration of the compounds of the present invention. In some embodiments, the method further includes administering MEK inhibitors and / or PKC inhibitors before, after, or concurrently with the administration of the compounds of the present invention.

[0373] In some embodiments, the anticancer therapy and the compound of the present invention are administered within 28 days of each other, and in amounts that are effective in treating the target together.

[0374] In some embodiments, the subject or cancer has been identified as having and / or possessing a loss-of-function mutation in BRG1.

[0375] In some embodiments, the cancer is resistant to one or more chemotherapeutic agents or cytotoxic agents (for example, the cancer has been determined to be resistant to chemotherapeutic agents or cytotoxic agents (e.g., by genetic markers), or has been determined to be highly likely to be resistant to chemotherapeutic agents or cytotoxic agents (e.g., cancer that did not respond to chemotherapeutic agents or cytotoxic agents)). In some embodiments, the cancer did not respond to one or more chemotherapeutic agents. In some embodiments, the cancer was resistant to or unresponsive 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).

[0376] In some embodiments, the cancer was resistant to or unresponsive to previously administered therapeutic agents used to treat uveal melanoma, such as MEK inhibitors or PKC inhibitors. For example, in some embodiments, the cancer was resistant to or unresponsive 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).

[0377] In some embodiments, the present invention provides the use of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds), or pharmaceutically acceptable salts thereof, or any of the aforementioned pharmaceutical compositions in the manufacture of pharmaceuticals. In some embodiments, the use is as described in the methods described herein.

[0378] chemical terms The terms used herein are for the purpose of describing specific embodiments and are not intended to be limiting.

[0379] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in the particular chemical part. As to be understood, other atoms, such as H atoms, or substituents as described herein, may be present to satisfy the valence of the atoms, where necessary. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, references to the number of carbon atoms include the divalent carbons in acetal and ketal groups, but do not include the carbonyl carbons 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.

[0380] As used herein, the term “acyl” refers to a hydrogen or alkyl group bonded to a parent group via a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbon atoms.

[0381] As used herein, the term "alkyl" refers to a branched or linear monovalent saturated aliphatic hydrocarbon group having 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).

[0382] Alkylenes are divalent alkyl groups. As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon residue having a carbon-carbon double bond and containing 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), either alone or in combination with other groups.

[0383] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon residue having a carbon-carbon triple bond and containing 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), either alone or in combination with other groups.

[0384] As used herein, the term "amino" means -N(R N1 ) represents 2, and each R N1 These are independently H, OH, NO2, N(R) N2 )2, SO2OR N2 SO2R N2 SOR N2 , N protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others as specified herein), and these listed R N1Each of the elements can be replaced by any choice, or two R N1 These combine to form alkylenes or heteroalkylenes, and each R N2 The amino group is independently H, alkyl, or aryl. The amino group of the present invention is an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R) N1 )2) This could be the case.

[0385] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. When polycyclic, the aryl group contains two or three rings. Examples of such groups, but not limited to, include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0386] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Unsubstituted arylalkyls include benzyl and phenethyl, which have 7 to 30 carbon atoms (e.g., C1-C6 alkyl, C6-C6 alkyl). 10 Aryl, C1~C 10 Alkyl C6~C 10 Aryl, or C1-C 20 Alkyl C6~C 10 It contains aryl groups (7 to 16 or 7 to 20 carbon atoms). In some embodiments, the alkyl and aryl groups are further substituted with 1, 2, 3, or 4 substituents, each with an acceptable valence, as defined herein for each group.

[0387] As used herein, the term "azide" refers to the -N3 group.

[0388] As used herein, the term “crosslinked polycycloalkyl” refers to a crosslinked polycyclic group of 5 to 20 carbon atoms containing 1 to 3 crosslinks. Crosslinked polycycloalkyl groups may be unsubstituted or substituted, as defined herein for cycloalkyl groups.

[0389] As used herein, the term "cyano" refers to the -CN group.

[0390] As used herein, the term "carbocykrill" refers to a non-aromatic C3-C ring formed by carbon atoms. 12 This refers to monocyclic, bicyclic, or tricyclic structures. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl groups.

[0391] As used herein, the term “cycloalkyl” refers to a saturated, non-aromatic monocyclic, bicyclic, or tricyclic group having 3 to 10, preferably 3 to 6, carbon atoms. A cycloalkyl group may be completely saturated or contain one or more double or triple bonds, provided the ring is non-aromatic. This term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. As used herein, the term “cycloalkoxy” refers to a cycloalkyl-O group (e.g., cyclopropoxy and cyclobutoxy).

[0392] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0393] As used herein, the term “heteroalkyl” refers to an alkyl group as defined herein, in which one or more of its constituent carbon atoms are replaced by 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). A heteroalkylene is a divalent heteroalkyl group.

[0394] As used herein, the term “heteroalkenyl” refers to an alkenyl group, as defined herein, in which one or more of its constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group is further substituted with 1, 2, 3, or 4 substituents, of which valence is permitted, as described herein for an alkenyl group. An example of a heteroalkenyl group is “alkenoxy,” which, as used herein, refers to an alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.

[0395] As used herein, the term “heteroalkynyl” refers to an alkynyl group, as defined herein, in which one or more of its constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group is further substituted with 1, 2, 3, or 4 substituents, as described herein for alkynyl groups, with acceptable valences. An example of a heteroalkynyl group is “alkynoxy,” which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0396] 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 the heteroaryl group may be replaced by carbonyl groups. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0397] As used herein, the term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups consist of 7 to 30 carbon atoms (e.g., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 heteroaryl, or C1-C20 The alkyl C2-C9 heteroaryl groups contain 7-16 or 7-20 carbon atoms. In some embodiments, the alkyl and heteroaryl groups are further substituted with 1, 2, 3, or 4 substituents, each with an acceptable valence, as defined herein for each group.

[0398] As used herein, the term “heterocyclyl” refers to a monocyclic, bicyclic, or tricyclic group having 3 to 12 atoms and having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, wherein the rings are not aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperadinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0399] As used herein, the term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl group. Unsubstituted heterocyclylalkyl groups consist of 7 to 30 carbon atoms (e.g., C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 Alkyl C2-C9 heterocyclyl, or C1-C 20 The alkyl C2-C9 heterocyclyl groups contain 7-16 or 7-20 carbon atoms. In some embodiments, the alkyl and heterocyclyl groups are further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0400] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0401] As used herein, the term "hydroxyl" refers to the -OH group.

[0402] As used herein, the term “N protecting group” refers to a group intended to protect an amino group from undesirable reactions during a synthetic procedure. Commonly used N protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999).The N protecting group is not limited to acyl, allyl, 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 additives, such as protected or unprotected D,L, or D,L-amino acids, for example. For example, alanine, leucine, and phenylalanine; sulfonyl-containing groups, e.g., benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups, e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2 ,4-20-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl Examples include carbonyl, 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).

[0403] As used herein, the term "nitro" refers to the -NO2 group.

[0404] The term "oxo," as used herein, represents a divalent oxygen atom (for example, the structure of an oxo may be shown as =O). For example, a carbonyl group is a carbon substituted with an oxo (e.g., an alkyl carbon, alkenyl carbon, alkynyl carbon, heteroalkyl carbon, heteroalkenyl carbon, heteroalkynyl carbon, carbocyclyl carbon, etc.). Alternatively, sulfur may be substituted with one or two oxo groups (e.g., -SO- or -SO2- in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group).

[0405] As used herein, the term "thiol" refers to the -SH group.

[0406] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. If substituted, unless otherwise specified, there are 1, 2, 3, 4, or 5 substituents with acceptable valencies. Each of the 1 to 5 substituents is independently selected from the group consisting of acyl, alkyl (e.g., unsubstituted and substituted, the substituent being any group described herein, e.g., aryl, halo, hydroxy), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyryl (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., NH2 or monoalkylamino or dialkylamino), azide, cyano, nitro, thiol, and oxo. Each substituent is either unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl groups 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), carbocyryl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH2 or mono or dialkylamino), azide, cyano, nitro, thiol, and oxo groups. Each substituent is either unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, the substituents are themselves unsubstituted.

[0407] The compounds of the present invention may have one or more chiral carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomer racemates, or mixtures of diastereomer racemates. Optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography using chiral adsorbents or eluents). In other words, a particular disclosed compound may exist in various stereoisomer forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of stereoisomers whose mirror images cannot be superimposed because they contain asymmetrically substituted carbon atoms that function as chiral centers. Enantiomers mean one of a pair of molecules that are mirror images of each other and cannot be superimposed. 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 stereoconfiguration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomer from a racemic mixture using one or more known techniques and methods, such as chiral chromatography and separation methods thereunder. Appropriate techniques and / or methods for separating the enantiomers of the compounds described herein from a racemic mixture can be readily determined by those skilled in the art. "Racemic mixture" means a compound containing two enantiomers, such a mixture is not optically active; that is, they do not rotate the plane of polarization. "Geometric isomer" means an isomer in which the orientation of the substituted atom differs in relation to a carbon-carbon double bond, cycloalkyl ring, or bridging bicyclic system. The atoms on each side of the carbon-carbon double bond (other than H) may be in either an E configuration (substituents are on opposite sides of the carbon-carbon double bond) or a Z configuration (substituents are oriented on the same side). * "R *"E", "Z", "cis", and "trans" indicate the stereoconfiguration relative to the core molecule. Certain disclosed compounds may exist in atropisomer form. Atropisomers are stereoisomers arising from hindered rotations around a single bond where the steric strain barrier against rotation is high enough to allow isolation of the conformational isomer. The compounds of the present invention may be prepared as individual isomers by isomer-specific synthesis or by separation from an isomer mixture. Conventional resolution methods include forming salts of the free bases of each isomer of an isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free bases), forming salts of the acidic forms of each isomer of an isomer pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each isomer of an isomer pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliaries), or resolving a mixture of isomers of either the starting material or the final product using various well-known chromatographic methods. Where the stereochemistry of a disclosed compound is named or indicated by structure, the named or indicated stereoisomer is present in at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight relative to the other stereoisomers. If a single enantiomer is named or indicated by its structure, the indicated or named enantiomer is optically pure to at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight. If a single diastereomer is named or indicated by its structure, the indicated or named diastereomer is pure to at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight. Optical purity percentage is the weight of the enantiomer, or the ratio of the weight of the enantiomer to the weight of its optical isomers. Diastereomer purity by weight is the weight of one diastereomer or the ratio to the weight of all diastereomers. If the stereochemistry of a disclosed compound is named or indicated by its structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction relative to the other stereoisomers.If a single enantiomer is named or indicated by its structure, the indicated or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction. If a single diastereomer is named or indicated by its structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction. The purity percentage in mole fraction is the number of moles of the enantiomer, or the ratio of the number of moles of the enantiomer to the number of moles of its optical isomer. Similarly, the purity percentage in mole fraction is the number of moles of the diastereomer, or the ratio of the number of moles of the diastereomer to the number of moles of its isomer. If a disclosed compound is named or indicated by its structure without showing its stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass either an enantiomer of the compound that does not contain a corresponding optical isomer, a racemic mixture of the compound, a mixture of the compound, or a mixture in which one enantiomer is concentrated relative to its corresponding optical isomer. If a disclosed compound is named or indicated by its structure without showing its stereochemistry, and has two or more chiral centers, the name or structure should be understood to encompass a diastereomer that does not contain another diastereomer, several diastereomers that do not contain another diastereomer pair, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is concentrated relative to another diastereomer, or a mixture of diastereomers in which one or more diastereomers are concentrated relative to another diastereomer. The present invention encompasses all of these forms.

[0408] The compounds of this disclosure also include all isotopes of atoms present in the intermediate or final compounds. “Isotopes” refer to atoms that have the same atomic number but different mass numbers, resulting from different numbers of neutrons in their nuclei. For example, isotopes of hydrogen include tritium and deuterium.

[0409] Unless otherwise specified, the structures described herein also mean that they may include different compounds, differing only by the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of the present 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 This includes hydrogen isotopes such as I, carbon isotopes, nitrogen isotopes, oxygen isotopes, phosphorus isotopes, sulfur isotopes, fluorine isotopes, chlorine isotopes, and iodine isotopes. Isotope-labeled compounds (e.g., 3 H and 14 Those labeled with 1C may be useful in compound or substrate tissue distribution assays. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes may be useful due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes such as H) may yield certain therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dose). In some embodiments, one or more hydrogen atoms are replaced with 2 H or 3 Replaced by H, or one or more carbon atoms 13 C or 14 It is replaced by carbon-rich carbon. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as 14F are useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. The preparation of isotope-labeled compounds is known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by substituting an isotope-labeled reagent with an unisotope-labeled reagent, following a procedure similar to that disclosed for the compounds of the present invention described herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled 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 may also be used. Those materials, methods, and examples are illustrative and not intended to limit. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated in their entirety by reference. In case of any conflict, this specification, including definitions, shall prevail.

[0410] definition In this application, unless otherwise evident 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"; (iii) the terms "comprising" and "including," whether presented alone or together with one or more additional components or steps, may be understood to encompass the components or steps of the list.

[0411] As used herein, the terms “about” and “approximately” refer to values ​​within 10% above or below the described value. For example, the term “about 5 nM” refers to a range of 4.5 to 5.5 nM.

[0412] As used herein, the term “administration” means the administration of a composition (e.g., a compound or a preparation containing a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any suitable route. For example, in some embodiments, administration may be by the bronchus (including by bronchial infusion), buccal, enteral, interdermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, nasal cavity, intraperitoneal, subarachnoid, intratumoral, intravenous, intraventricular, mucosa, nasal cavity, oral, rectal, subcutaneous, sublingual, topical, trachea (including by intratracheal infusion), percutaneous, vaginal, and vitreous humor.

[0413] As used herein, the term "BAF complex" refers to the BRG1 or HRBM-related factor complex in human cells.

[0414] As used herein, the term "BAF complex-related disorder" refers to a disorder caused by or affected by the level of activity of the BAF complex.

[0415] As used herein, the term “loss-of-function mutation of BRG1” refers to a mutation in BRG1 that results in a protein with reduced activity (e.g., a reduction of at least 1% of BRG1 activity, e.g., a reduction of 2%, 5%, 10%, 25%, 50%, or 100% of BRG1 activity). Exemplary loss-of-function mutations of BRG1 include, but are not limited to, mutations and deletions of homozygous BRG1 at the C-terminus of BRG1.

[0416] As used herein, the term “BRG1 loss of function disorder” refers to a disorder (e.g., cancer) that presents with reduced BRG1 activity (e.g., a reduction of at least 1% of BRG1 activity, e.g., a reduction of 2%, 5%, 10%, 25%, 50%, or 100% of BRG1 activity).

[0417] The term "cancer" refers to a condition caused by the proliferation of malignant tumor cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0418] As used herein, “combination therapy” or “administered in combination” means that two (or more) different drugs 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 dose and periodicity of administration of each drug so that the effects of the separate drugs on the subject overlap. In some embodiments, the delivery of two or more drugs may be simultaneous or parallel, and the drugs may be co-formulated. In some embodiments, the two or more drugs are not co-formulated and are administered sequentially as part of a prescribed regimen. In some embodiments, the administration of two or more drugs or a combination treatment results in a greater reduction of symptoms or other parameters related to the disorder than that observed with a single drug or treatment delivered alone or in the absence of one of them. The effects of the two treatments may be partially additive, fully additive, or more than additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent may be brought about by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered via the same route or via different routes. For example, the first therapeutic agent in the combination may be administered by intravenous injection, while the second therapeutic agent in the combination may be administered orally.

[0419] "Determining the level" of a protein or RNA means the detection of the protein or RNA, either directly or indirectly, by methods known in the art. "Direct determination" 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 the term is defined herein). "Indirect determination" means receiving a physical entity or value from another entity 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 the properties of the protein, including enzyme activity or interactions with other protein partners. Methods for measuring RNA levels are known in the art and are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blotting.

[0420] "Decreasing the activity of the BAF complex" means reducing the level of activity associated with the BAF complex, or associated downstream effects. A non-limiting example of decreasing the activity of the BAF complex is the 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.

[0421] As used herein, the term “degradant” refers to a small molecule compound containing a degradation moiety that interacts with a protein (e.g., BRG1 and / or BRM) in such a way that it results in the degradation of the protein (e.g., the binding of the compound results in a reduction of at least 5% of the protein level in a cell or subject).

[0422] As used herein, the term “degradation moiety” refers to a moiety that, upon binding, results in the degradation of a protein (e.g., BRG1 and / or BRM). For example, this moiety binds to a protease or ubiquitin ligase that metabolizes the protein (e.g., BRG1 and / or BRM).

[0423] "Modifying the activity of the BAF complex" means altering the level of activity associated with the BAF complex (e.g., GBAF) or associated downstream effects. 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 153:71-85 (2013), which is incorporated herein by reference.

[0424] "Reducing the activity of BRG1 and / or BRM" means reducing the level of activity or associated downstream effects related to BRG1 and / or BRM. A non-limiting example of inhibiting the activity of BRG1 and / or BRM is reducing the level of BAF complex in cells. The activity level of BRG1 and / or BRM can be measured using any method known in the art. In some embodiments, the agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrading agent.

[0425] "To reduce BRG1 and / or BRM levels" means to decrease the levels of BRG1 and / or BRM in cells or subjects. BRG1 and / or BRM levels can be measured using any method known in the art.

[0426] "Level" means the level of protein or protein-coding mRNA compared to a reference substance. The reference substance may be any useful reference substance as defined herein. A "decreased level" or "increased level" of protein means a decrease or increase in the protein level compared to a reference substance (e.g., a decrease or increase of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more), compared to a reference substance by about 10% This means a decrease or increase of more than approximately 15%, 20%, 50%, 75%, 100%, or 200%, a decrease or increase of less than approximately 0.01 times, 0.02 times, 0.1 times, 0.3 times, 0.5 times, or less than approximately 0.8 times, or an increase of approximately 1.2 times, 1.4 times, 1.5 times, 1.8 times, 2.0 times, 3.0 times, 3.5 times, 4.5 times, 5.0 times, 10 times, 15 times, 20 times, 30 times, 40 times, 50 times, 100 times, 1000 times, or more. Protein levels may be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of total protein or mRNA in the sample.

[0427] As used herein, the term "inhibit BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition may be determined using methods known in the art, such as BRM ATPase assays, Nano DSF assays, or BRM luciferase cell assays.

[0428] As used herein, the term “pharmaceutical composition” refers to a composition containing the compounds described herein, formulated with pharmaceutically acceptable excipients and suitable for administration to mammals, such as humans. Typically, pharmaceutical compositions are manufactured or marketed with the approval of a government regulatory body as part of a therapeutic regimen for the treatment of diseases in mammals. Pharmaceutical compositions may be formulated, for example, in unit dosage forms for oral administration (e.g., tablets, capsules, caplets, gel caps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as sterile solutions without particulate stumps and in solvent systems suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0429] As used herein, “pharmaceutically acceptable excipients” means any component other than the compounds described herein that has the property of being substantially non-toxic and non-inflammatory in the patient (e.g., a vehicle capable of suspending or dissolving the active compound). Excipients may include, for example, anti-adhesion agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, lubricants (flow enhancers), preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, and hydration water.

[0430] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, e.g., any compound of formula I. Any pharmaceutically acceptable salt of any of the compounds described herein may be suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reactions, within the bounds of sound medical judgment, and may include salts that are balanced by 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. PHStahl and CGWermuth), 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.

[0431] 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 containing inorganic or organic acids, or, in the case of the acidic form of the compounds of the present invention, the salts may be prepared from inorganic or organic bases. More 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, and appropriate methods for preparing salts are well known in the art. Salts can be prepared from pharmaceutically acceptable, non-toxic acids and bases, including inorganic and organic acids and bases.

[0432] "Reference material" means any useful reference material used to compare protein or RNA levels. A reference material may be any sample, standard, standard curve, or level used for comparison purposes. A reference material may be a normal reference sample or reference standard or level. A "reference sample" may be, for example, a control, a predetermined negative control value such as "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 from a subject without disease (e.g., cells or tissue), a sample from a subject diagnosed with disease but not yet treated with the compound of the present invention, a sample from a subject treated with the compound of the present invention, or a sample of purified protein or RNA (e.g., any of those described herein) at a known normal concentration. "Reference standard or level" means a value or numerical value derived from a reference sample. A "normal control value" is a predetermined value that indicates a non-disease state, for example, 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 ("less than or equal to X"), or a low threshold ("greater than or equal to X"). A subject having a measurement value for a particular biomarker within the normal control range is typically referred to as being "within the normal range" for that biomarker. Normal reference standards or levels may be values ​​or numbers derived from a healthy subject without disease or disorder (e.g., cancer) or from a subject being treated with the compounds of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the sample subject by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of purified protein or RNA within the normal reference range, e.g., any of those described herein, may also be used as a reference.

[0433] As used herein, the term “subject” means any organism to which a composition according to the present invention may 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 that is seeking or in need of treatment, requesting treatment, receiving treatment, may receive treatment in the future, or is receiving treatment from a specialist trained for a particular disease or condition.

[0434] As used herein, the terms “to treat,” “to be treated,” or “to treat” mean a therapeutic procedure or any means, the purpose of which is to slow (reduce) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, reduction of the severity of a condition, disorder, or disease, a stable (i.e., non-worsening) state of a condition, disorder, or disease, delay or slowing of the onset of the progression of a condition, disorder, or disease, improvement or remission (partial or overall) of a condition, disorder, or disease state, improvement of at least one measurable physical parameter, which is not necessarily identifiable by the patient, or enhancement or improvement of a condition, disorder, or disease. Treatment includes inducing a clinically significant response without excessive levels of side effects. Treatment also includes extending survival compared to the predicted survival without treatment. The compounds of the present invention may also be used, for example, to “preventively treat” or “prevent” a disorder in subjects with an increased risk of developing the disorder.

[0435] Details of one or more embodiments of the present invention are shown in the following description. Other features, purposes, and advantages of the present invention will become apparent from the description and the claims. [Modes for carrying out the invention]

[0436] This disclosure features compounds useful for inhibiting BRG1 and, optionally, BRM. These compounds may be used to modulate the activity of the BAF complex for the treatment of BAF-related disorders (e.g., BRG1 loss-of-function disorders), such as cancer. Exemplary compounds described herein include compounds having the structure of formula I or a pharmaceutically acceptable salt thereof.

[0437] The compound of formula I is as follows:

[0438] [ka] During the ceremony, m is 0, 1, 2, or 3, k is 0, 1, or 2, R is either absent or optionally substituted with a C1-C6 alkyl group. Each R 1 However, independently, these are halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano. Each X is independently a halo. L is the linker, B is the part that is broken down.

[0439] In some embodiments, the compound has the structure of one of the compounds 1 to 4 in Table 1, or a pharmaceutically acceptable salt thereof.

[0440] Other embodiments and exemplary methods for the synthesis of these compounds are described herein.

[0441] Pharmaceutical use The compounds described herein are useful in the methods of the present invention and are not theoretically constrained, but are thought to exert their ability to modulate the level, state, 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-related disorders include, but are not limited to, loss-of-function mutation-related disorders of BRG1.

[0442] One aspect of the present invention relates to a method for treating BRG1 loss-of-function mutation-related disorders in subjects in need, such as cancer (e.g., 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). In some embodiments, the compound is administered in amounts and for a time that is effective in producing one or more of the following (e.g., two or more, three or more, four or more) results: (a) reduction in tumor size, (b) reduction in tumor growth rate, (c) increase in tumor cell death, (d) reduction in tumor progression, (e) reduction in the number of metastases, (f) reduction in the rate of metastasis, (g) reduction in tumor recurrence, (h) increase in the subject's survival rate, and (i) increase in the subject's progression-free survival.

[0443] Cancer treatment can result in a reduction in tumor size or volume. For example, after treatment, tumor size may be reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to its size before treatment. Tumor size may be measured by any reproducible means. For example, tumor size may be measured as the diameter of the tumor.

[0444] Cancer treatment can lead to a further reduction in the number of tumors. For example, after treatment, the number of tumors may be reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the number before treatment. The number of tumors may be measured by any reproducible means, for example, by counting tumors visible to the naked eye or visible at a specific magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0445] Cancer treatment can result in a reduction 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 may be reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the pre-treatment number. The number of metastatic nodules may be measured by any reproducible measurement method. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or visible at a specific magnification (e.g., 2x, 10x, or 50x).

[0446] Treating cancer may result in an increase in the mean survival time of a population treated according to the present invention compared to an untreated population. For example, the mean survival time may increase by more than 30 days (more than 60, 90, or 120 days). The increase in the mean survival time of the population may be measured by any reproducible means. The increase in the mean survival time of the population may be measured, for example, by calculating the length of the mean survival period for the population after the initiation of treatment with the compound of the present invention. The increase in the mean survival time of the population may also be measured, for example, by calculating the length of the mean survival period for the population after the completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0447] Furthermore, treating cancer may result in a reduction in mortality in the treated population compared to the untreated population. For example, mortality may be reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in mortality in the treated population may be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time after the start of treatment with the pharmaceutically acceptable salt of the present invention for the population. The reduction in mortality in the population may also be measured, for example, by calculating the average number of disease-related deaths per unit time after the completion of the first round of treatment with the pharmaceutically acceptable salt of the present invention for the population.

[0448] Exemplary cancers that can be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin 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, appendiceal cancer, small intestine cancer, and penile cancer.

[0449] Combination formulations and their use The compounds of the present invention can be combined with one or more therapeutic agents. In particular, the therapeutic agents may treat or prevent any of the cancers described herein.

[0450] Combination therapy The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as other agents that treat cancer or related conditions, or in combination with other types of treatments 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, the dosage may be determined empirically from the combination and permutation of drugs, 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.

[0451] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful for treating cancer). These include alkylating agents, antimetabolites, folate analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracendione-substituted ureas, methylhydrazine derivatives, adrenocortican inhibitors, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-exclusive examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocon, metadopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analog topotecan); briostatin; calistatin; CC-1065 (its adzeresin, carzeresin) Including cin and bizeresin synthetic analogs); cryptophycin (especially cryptophycin 1 and cryptophycin 8); drastatin; duocalmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodicin; spongistatin; nitrogen mustard, e.g., chlorambutyl, chlornafadin, colophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobemchkin, fenesterine, prednimustine, trophosfamide, uracil mustard;Nitrosoureas, such as carmustine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as engine antibiotics (e.g., calicheamicin, especially calicheamicin gammaol and calicheamicin omegall) (e.g., Agnew, Chem. Intl. Ed.) See Engl. 33:183-186 (1994); Dynemicins including Dynemicin A; Bisphosphonates, e.g., clodronate; Esperamicin; and neocarcinostatin chromophores and related pigment proteins enediin antibiotics); aclasinomycin, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, carabicin, kaminomycin, cardinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin (registered trademark) (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-p Doxorubicin (including loridino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zorubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folic acid analogs, e.g., denopterin, methotrexate, pteropterin, trimethrexate; purine analogs, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal drugs, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., floric acid; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin; bestrabusil; bisanthren; edatraxate; defofamine ( defofamine; demecolsin; diaziquan; elfomithine; eriptinium acetate; epotilone; etogluside; gallium nitrate; hydroxyurea; lentinan; lonidainine; mayansinoids, e.g., maytansine and anthamitosine; mitogwazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); Lazoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; Triadicone; 2,2',2''-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, verlaculin A, loridine A and angidin); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxoids, such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane® albumin-modified nanoparticle formulations of paclitaxel that do not contain cremofol (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® doxetaxel (Rhone-Poulenc Examples include Rorer, Antony, France; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum-coordinated 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); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, e.g., retinoic acid; capecitabine, and any 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 the first therapeutic agent described herein. Suitable administration 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.

[0452] In some embodiments, the second therapeutic agent is a biological agent such as a cytokine used in cancer treatment (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-VEGF agent, such as an anti-angiogenic agent such as bevacizumab (Avastin®). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., 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. Examples of such drugs include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab); Synagis (palivizumab); Remicade (infliximab); Herceptin (trastuzumab); Mylotarg (gemtuzumab ozogamicin); Camppath (alemtuzumab); Zevalin (ibritumomab tiuxetan); Humira (adalimumab); Xolair (omalizumab); Bexxar (tositumomab-I-131); Raptiva (efalizumab); Erbitux (cetuximab); Avastin (bevacizumab); Tysabri (natalizumab); and Actemra. Examples include (tocilizumab); Vectibix (panitumumab); Lucentis (ranibizumab); Soliris (eculizumab); Cimzia (certolizumab pegol); Simponi (golimumab); Ilaris (canakinumab); Stelara (ustekinumab); Arzerra (ofatumumab); Prolia (denosumab); Numax (motabizumab); ABThrax (laxibakumab); Benlysta (belimumab); Yervoy (ipilimumab); Adcetris (brentuximab vedotin); Perjeta (pertuzumab); Kadcyla (Ado-trastuzumab emtansine); and Gazyva (obinutuzumab). Antibody-drug conjugates are also included.

[0453] The second agent may be a non-pharmacological treatment. For example, the second agent may be radiotherapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue.

[0454] The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, 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 the checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with the ligand of the checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 (e.g., nivolumab / Opdivo®; pembrolizumab / Keytruda®; pizilizumab / CT-011) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL1 (e.g., MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224) (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof (e.g., an inhibitory antibody or small molecule inhibitor).

[0455] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, or in any order. The first therapeutic agent may 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 to 7, 1 to 14, 1 to 21, or 1 to 30 days before or after the second therapeutic agent.

[0456] Pharmaceutical composition The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biocompatible form suitable for in vivo administration. Accordingly, in some embodiments, the present invention provides pharmaceutical compositions comprising the compounds of the present invention mixed with a suitable diluent, carrier, or excipient.

[0457] The compounds of the present invention may be in the form of free bases, salts, solvates, and prodrugs. All forms are within the scope of the present invention. As can be understood by those skilled in the art, according to the methods of the present invention, the compounds described, or their salts, solvates, or prodrugs, may be administered to a patient in various forms depending on the selected route of administration. The compounds of the present invention may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and pharmaceutical compositions may be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, subarachnoid, rectal, and topical administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0458] The compounds of the present invention can be administered orally, for example, with an inert diluent or an assimilated edible carrier, or encapsulated in hard or soft shell gelatin capsules, or compressed into tablets, or directly incorporated with food in a meal. For oral therapeutic administration, the compounds of the present invention may be incorporated with excipients and may be used in the form of digestible tablets, buccal tablets, lozenges, 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 hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and in oil. These preparations may contain preservatives to prevent microbial growth under normal storage and use conditions. Conventional procedures and components 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. Suitable pharmaceutical forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and fluid enough to be readily administered via syringe. Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are supplied in a sterile form in single or multiple doses in a sealed container that can take the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container may be a single-dose dispensing device, such as a nasal inhaler or aerosol dispenser fitted with a metering valve, intended for disposal after use.If the dosage form includes an aerosol dispenser, it contains a propellant which may be a compressed gas such as compressed air or an organic propellant such as a fluorochloro hydrocarbon. The aerosol dosage form may also take the form of a pump 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, as an intratumor injection. Intratumor injection is a direct injection into the tumor blood vessels and is particularly intended for individual solid, accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein can be advantageously brought into contact with the tumor by injection or multiple injections administered at intervals of approximately 1 cm, for example. In the case of surgical intervention, the present invention can be used preoperatively, such as for the resection of an inoperable tumor. Continuous administration may also be applied, if appropriate, for example, by implanting a catheter into the tumor or tumor blood vessel.

[0459] The compounds of the present invention may be administered to animals, such as humans, alone or in combination with pharmaceutically acceptable carriers, as described herein, in proportion to the solubility and chemical properties of the compounds, the selected route of administration, and standard pharmacopoeias.

[0460] Dosage The dosage of the compound of the present invention and / or a composition containing the compound of the present invention may 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, if any, the type of concurrent treatment; and the clearance rate of the compound in the treated animal. Those skilled in the art can determine an appropriate dosage based on the above factors. The compound of the present invention may be administered initially at a preferred dosage, and this amount may be adjusted as needed in accordance with the clinical response. Generally, satisfactory results can be obtained when the compound of the present invention is administered to humans in daily doses of, for example, 0.05 mg to 3000 mg (measured in solid form). The dose range includes, 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.

[0461] Alternatively, the dosage can be calculated using the patient's body weight. For example, the dose of a compound or its pharmaceutical composition 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 and 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). [Examples]

[0462] The following abbreviations will be used throughout the following examples.

[0463] [Table 2-1]

[0464] [Table 2-2]

[0465] Example 1. Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)-6-methylpyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 3)

[0466] [ka]

[0467] Step 1: Preparation of methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]aminopyridazine-3-carboxylate (intermediate 2)

[0468] [ka]

[0469] A mixture of methyl 4,6-dichloropyridazine-3-carboxylate (10 g, 48.307 mmol, 1 equivalent), 1-(2,4-dimethoxyphenyl)methaneamine (8.08 g, 48.307 mmol, 1 equivalent), and DIEA (12.49 g, 96.614 mmol, 2 equivalents) in NMP (50 mL) was stirred at 60°C for 2 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with brine (400 mL). The resulting mixture was extracted with SiO (3 × 300 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 2 (15.6 g, 95.61%) as a yellow solid. LC-MS(ESI)m / z:[M+H] + = 338.

[0470] Step 2: Preparation of methyl 4-amino-6-chloropyridazine-3-carboxylate (intermediate 3)

[0471] [ka]

[0472] The mixture of intermediate 2 (5 g, 14.803 mmol, 1 equivalent) in TFA (10 mL) was stirred at 80°C for 1 hour under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was diluted with MeCN (40 mL). The precipitated solid was collected by filtration and washed with MeCN (3 × 10 mL). The resulting mixture was concentrated under reduced pressure to obtain intermediate 3 (4.1 g, TFA salt) as a light purple solid. LC-MS (ESI) m / z [M + H] + = 188.

[0473] Step 3: Preparation of (4-amino-6-chloropyridazine-3-yl)methanol (intermediate 4)

[0474] [ka]

[0475] To a mixture of intermediate 3 (4 g, 21.324 mmol, 1 equivalent) and CaCl2 (4.73 g, 42.648 mmol, 2 equivalents) in EtOH (40 mL), NaBH4 (1.61 g, 42.648 mmol, 2 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product was detected by LC-MS. The reaction was quenched at room temperature by adding water (100 mL). The resulting mixture was filtered, and the filter cake was washed with MeCN (3 × 100 mL). The filtrate was concentrated under reduced pressure to obtain intermediate 4 (960 mg, 28.21%) as a white solid. LC-MS(ESI)m / z:[M+H] + = 160.

[0476] Step 4: Preparation of 4-amino-6-chloropyridazine-3-carbaldehyde (intermediate 5)

[0477] [ka]

[0478] A mixture of intermediate 4 and MnO2 (1.55 g, 17.862 mmol, 3 equivalents) in DCM (10 mL) was stirred at room temperature for 4 hours. The desired product was detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure to obtain intermediate 5 (100 mg, 10.66%) as a white solid. LC-MS(ESI)m / z:[M+H] + = 158.

[0479] Step 5: Preparation of tert-butyl6-{3-chloro-6-methylpyrido[3,2-c]pyridazin-7-yl}-2,6-diazaspiro[3.3]heptan-2-carboxylate (intermediate 6)

[0480] [ka]

[0481] A mixture of intermediate 5 (150 mg, 0.952 mmol, 1 equivalent), tert-butyl 6-(2-oxopropyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (266.34 mg, 1.047 mmol, 1.1 equivalents), and pyridine (150.61 mg, 1.904 mmol, 2 equivalents) in EtOH (3 mL) was stirred at 60°C for 5 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain intermediate 6 (70 mg, 19.56%), a brownish-yellow solid. LCMS(ESI)m / z:[M+H] +=376.

[0482] Step 6: Preparation of tert-butyl6-[3-(2-hydroxyphenyl)-6-methylpyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3.3]heptan-2-carboxylate (intermediate 7)

[0483] [ka]

[0484] A mixture of intermediate 6 (65 mg, 0.173 mmol, 1 equivalent), 2-hydroxyphenylboronic acid (71.56 mg, 0.519 mmol, 3 equivalents), XPhos Pd G3 (29.28 mg, 0.035 mmol, 0.2 equivalents), and Cs2CO3 (169.04 mg, 0.519 mmol, 3 equivalents) in dioxane (2 mL) and H2O (0.4 mL) was stirred at 80°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to obtain intermediate 7 (72.6 mg, 96.84%), a yellow solid. LC-MS(ESI)m / z:[M+H] + = 434.

[0485] Step 7: Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}-6-methylpyrido[3,2-c]pyridazine-3-yl)phenol (intermediate 8)

[0486] [ka]

[0487] A mixture of intermediate 7 (67.6 mg, 0.156 mmol, 1 equivalent) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 0.5 hours. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure to obtain a dark red solid intermediate 8 (75 mg, TFA salt). LC-MS (ESI) m / z: [M + H] + = 334.

[0488] Step 8: Preparation of methyl 2-(3-{6-[3-(2-hydroxyphenyl)-6-methylpyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoate (intermediate 9)

[0489] [ka]

[0490] Intermediate 8 (70 mg, 0.210 mmol, 1 equivalent), methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl}butanoate (202.10 mg, 0.420 mmol, 2 equivalents), and DIEA (81.41 mg, 0.630 mmol, 3 equivalents) were mixed in DMSO (3 mL) and stirred at 120 °C for 1 hour under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain intermediate 9 (70 mg, 64.79%), a yellow solid. LCMS(ESI)m / z:[M+H] + = 515.

[0491] Step 9: Preparation of 2-(3-{6-[3-(2-hydroxyphenyl)-6-methylpyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoic acid (intermediate 9)

[0492] [ka]

[0493] The mixture of intermediate 9 (65 mg, 0.126 mmol, 1 equivalent) and LiOH·H2O (26.50 mg, 0.630 mmol, 5 equivalents) in MeOH (1 mL), THF (1 mL), and H2O (0.5 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure to obtain intermediate 10 (72.3 mg, crude), a dark red solid. LC-MS(ESI)m / z:[M+H] + = 501.

[0494] Step 10: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{6-[3-(2-hydroxyphenyl)-6-methylpyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 11)

[0495] [ka]

[0496] A mixture of intermediate 10 (70 mg, 0.140 mmol, 1 equivalent), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (46.35 mg, 0.140 mmol, 1 equivalent), PyBOP (87.33 mg, 0.168 mmol, 1.2 equivalents), and DIEA (54.22 mg, 0.420 mmol, 3 equivalents) in DMF (2 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The crude product was analyzed under the following conditions (column: XBridge Shield RP18 OBD column, 30 * The sample was purified by preparative HPLC (150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 51% B in 10 minutes; wavelength: 254 / 220 nm), and intermediate 11 (23 mg, 20.21%) was obtained as a yellow solid. LC-MS (ESI) m / z: [M + H] + = 814.

[0497] Step 11: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)-6-methylpyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 3)

[0498] [ka]

[0499] Intermediate 11 was prepared under the following conditions (column: CHIRALPAK IA, 2 *The sample was purified by chiral HPLC using a 25cm, 5μm microscope; mobile phase A: MtBE (10mM NH3-MeOH), mobile phase B: ACN:DCM=2:1 (0.1% 2M NH-MeOH); flow rate: 20mL / min; gradient: constant composition 30; wavelength: 212 / 262nm; RT1 (min): 9; RT2 (min): 17.25; sample solvent: MeOH:DCM=1:1 --HPLC; injection volume: 1.2mL) to obtain compound 3 (6.4mg, 31.74%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),9.00(s,1H),8.69(s,1H),8.43(d,J=7.7Hz,1H),8.19-8.12(m,1H),7.51-7.28(m, 6H),7.06-6.96(m,2H),5.88(s,1H),5.07(dd,J=43.2,3.2Hz,1H),4.88(dp,1H),4.44(s,4H),4.37(t,J=7.9Hz,1H),4.2 9(s,1H),4.12(s,4H),3.75-3.67(m,1H),3.65-3.55(m,1H),3.53-3.40(m,1H),2.70(s,3H),2.47(s,3H),2.24-2.19(m, 1H),2.08-1.98(m,1H),1.84-1.73(m,1H),1.43(dd,J=33.4,7.0Hz,3H),1.01-0.93(m,3H),0.82(dd,J=14.7,6.7Hz,3H). LCMS(ESI)m / z:[M+H] + = 814.35.

[0500] Step 12: Preparation of tert-butyl 6-(2-oxopropyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (intermediate 13)

[0501] [ka]

[0502] A mixture of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5 g, 25.219 mmol, 1 equivalent), bromoacetone (3.8 g, 27.741 mmol, 1.1 equivalents), and K2CO3 (6.97 g, 50.438 mmol, 2 equivalents) in MeCN (50 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water in MeCN (0.1% FA), with a gradient from 0% to 20% over 20 minutes, to obtain a brownish oily intermediate 13 (580 mg, 9.04%). LC-MS(ESI) m / z: [M+H] + = 255.

[0503] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1)

[0504] [ka]

[0505] Step 1: Preparation of methylethyl(2E)-3-(4-amino-6-chloropyridazine-3-yl)prop-2-enoate (intermediate 2)

[0506] [ka]

[0507] A mixture of 3,6-dichloropyridazine-4-amine (5 g, 30.490 mmol, 1 equivalent), ethyl(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (8.27 g, 36.588 mmol, 1.2 equivalents), Pd(PPh3)4 (3.52 g, 3.049 mmol, 0.1 equivalent), and Na2CO3 (6.46 g, 60.980 mmol, 2 equivalents) in DME (30 mL) and H2O (10 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with ELISA (3 × 300 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (1:3) elution to obtain intermediate 2 (6.5 g, 93.65%), a yellow solid. LCMS(ESI)m / z:[M+H] + = 228.

[0508] Step 2: Preparation of 3-chloropyrido[3,2-c]pyridazine-6-ol (intermediate 3)

[0509] [ka]

[0510] A mixture of intermediate 2 (3 g, 13.178 mmol, 1 equivalent) and DIEA (3 mL) in DBU (15 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (19:1) to obtain intermediate 3 (3.2 g, crude), a yellow solid. LC-MS (ESI) m / z [M+H] + = 182.

[0511] Step 3: Preparation of 3-[2-(methoxymethoxy)phenyl]pyrido[3,2-c]pyridazine-6-ol (intermediate 4)

[0512] [ka]

[0513] A mixture of intermediate 3 (1 g, 5.507 mmol, 1 equivalent), 2-(methoxymethoxy)phenylboronic acid (1.50 g, 8.261 mmol, 1.5 equivalents), XPhos Pd G3 (466.16 mg, 0.551 mmol, 0.1 equivalent), and Cs2CO3 (2.69 g, 8.261 mmol, 1.5 equivalents) in dioxane (10 mL) and H2O (2 mL) was stirred at 80°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (20:1) to obtain intermediate 4 (1.5 g, 96.15%), a yellow solid. LC-MS(ESI)m / z:[M+H] + = 284.

[0514] Step 4: Preparation of 3-[2-(methoxymethoxy)phenyl]pyrido[3,2-c]pyridazine-6-yltrifluoromethanesulfonate (intermediate 5)

[0515] [ka]

[0516] A mixture of intermediate 4 (1.5 g, 5.295 mmol, 1 equivalent), 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (2.84 g, 7.942 mmol, 1.5 equivalents), DMAP (64.69 mg, 0.529 mmol, 0.1 equivalent), and Et3N (1.61 g, 15.885 mmol, 3 equivalents) in DCM (10 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to obtain intermediate 5 (690 mg, 31.37%) as a brown oily substance. LC-MS (ESI) m / z: [M + H]+ = 416.

[0517] Step 5: Preparation of tert-butyl6-{3-[2-(methoxymethoxy)phenyl]pyrido[3,2-c]pyridazin-6-yl}2,6-diazaspiro[3.3]heptan-2-carboxylate (intermediate 6)

[0518] [ka]

[0519] Intermediate 5 (500 mg, 1.204 mmol, 1 equivalent), tert-butyl 2,6-diazaspiro[3.3]heptan-2-carboxylate (358.02 mg, 1.806 mmol, 1.5 equivalents), Pd-PEPPSI-IPentCl A mixture of 2-methylpyridine (o-picoline (50.63 mg, 0.060 mmol, 0.05 equivalents) and Cs2CO3 (1.18 g, 3.612 mmol, 3 equivalents)) in dioxane (0.5 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain a brownish oily intermediate 6 (350 mg, crude). LC-MS (ESI) m / z: [M+H] + = 464.

[0520] Step 6: Preparation of 2-(6-{2,6-diazaspiro[3,3]heptan-2-yl}pyrido[3,2-c]pyridazine-3-yl)phenol (intermediate 7)

[0521] [ka]

[0522] A mixture of intermediate 6 (340 mg, 0.733 mmol, 1 equivalent) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm to obtain intermediate 7 (35 mg, 14.94%), a yellow solid. LC-MS (ESI) m / z: [M+H] + =320.

[0523] Step 7: Preparation of methyl 2-(3-{6-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoate (intermediate 8)

[0524] [ka]

[0525] A mixture of intermediate 7 (35 mg, 0.110 mmol, 1 equivalent), methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl}butanoate (105.49 mg, 0.220 mmol, 2 equivalents), and DIEA (42.49 mg, 0.330 mmol, 3 equivalents) in DMSO (1 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ELISA (3 × 20 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 to obtain intermediate 8 (106 mg, crude) as a brown solid. LCMS(ESI)m / z:[M+H] + = 501.

[0526] Step 8: Preparation of 2-(3-{6-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoic acid (intermediate 9)

[0527] [ka]

[0528] A mixture of intermediate 8 (30 mg, 0.060 mmol, 1 equivalent) and LiOH·H2O (7.18 mg, 0.300 mmol, 5 equivalents) in MeOH (1 mL), THF (1 mL), and H2O (0.5 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm to obtain intermediate 9 (16 mg, 54.87%) as a yellow solid. LC-MS(ESI) m / z:[M+H] + = 487.

[0529] Step 9: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{6-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 9)

[0530] [ka]

[0531] The mixture of intermediate 9 (11 mg, 0.023 mmol, 1 equivalent), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,1-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (11.24 mg, 0.035 mmol, 1.5 equivalents), PyBOP (17.65 mg, 0.035 mmol, 1.5 equivalents), and DIEA (11.69 mg, 0.092 mmol, 4 equivalents) in DMF (3 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The crude product was analyzed under the following conditions (column: XBridge Shield RP18 OBD column, 30 * The sample was purified by preparative HPLC (150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 52% B in 10 minutes; wavelength: 254 / 220 nm), and intermediate 10 (10 mg, 55.29%) was obtained as a yellow solid. LC-MS (ESI) m / z: [M + H] + = 800.

[0532] Step 10: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1)

[0533] [ka]

[0534] Intermediate 10 (10 mg) was processed under the following conditions (column, CHIRALPAK ID, 2 *The sample was purified by chiral HPLC using a 25cm, 5μm microscope; mobile phase A: MtBE (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: MeOH-HPLC; flow rate: 20 mL / min; gradient: constant composition 30; wavelength: 276 / 214 nm; RT1 (min): 9.766; RT2 (min): 16.448; sample solvent: MeOH:DCM = 4:1; injection volume: 1.5 mL) to obtain compound 1 (3.3 mg, 32.87%) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.99(s,1H),8.43-8.30(m,3H),8.17(dd,J=8.0,1.7Hz,1H),7.51-7.41(m,2H),7 .45-7.31(m,3H),7.13(d,J=9.4Hz,1H),7.03-6.92(m,2H),5.92(s,1H),5.13-4.88(m,2H),4.56-4.32(m,5H),4.29(s, 1H),4.12(s,4H),3.75-3.67(m,1H),3.61(d,J=9.8Hz,1H),3.46(dd,J=25.9,11.4Hz,1H),2.46(s,3H),2.27-2.17(m,1 H),2.07-1.98(m,1H),1.85-1.74(m,1H),1.42(dd,J=32.3,7.0Hz,3H),1.00-0.93(m,3H),0.82(dd,J=14.6,6.6Hz,3H). LCMS(ESI)m / z:[M+H] + = 800.20.

[0535] Preparation of tert-butyl(S)-3-methyl-2-(4-(tributylstannyl)-1H-1,2,3-triazole-1-yl)butanoate

[0536] [ka]

[0537] Step 1: Preparation of tert-butyl(S)-2-azido-3-methylbutanoate (intermediate 2)

[0538] [ka]

[0539] To a stirred mixture of tert-butyl L-valinate hydrochloride (5 g, 28.859 mmol, 1 equivalent) and CuSO4·5H2O (1.44 g, 5.772 mmol, 0.1 equivalent) in MeOH (80 mL), imidazole-1-sulfonyl azide (9.99 g, 57.718 mmol, 1 equivalent) and K2CO3 (24.11 g, 173.154 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (300 mL) and extracted with SiO2 (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 2 (11.3 g) as a pale yellow oily substance. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 200.

[0540] Step 2: Preparation of tert-butyl(S)-3-methyl-2-(4-(tributylstannyl)-1H-1,2,3-triazole-1-yl)butanoate (intermediate 3)

[0541] [ka]

[0542] A mixture of intermediate 2 (4 g, 20.075 mmol, 1 equivalent) and tributyl(ethynyl) stannane (6.33 g, 20.075 mmol, 1 equivalent) in toluene (20 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / PE (1:1) to obtain intermediate 3 (6.5 g, 62.95%) as a colorless liquid. LC-MS(ESI) m / z[M+H] + = 515.

[0543] Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-{4-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-1,2,3-triazole-1-yl}-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 2)

[0544] [ka]

[0545] Step 1: Preparation of tert-butyl(2S)-2-(4-{3-[2-(methoxymethoxy)phenyl]pyrido[3,2-c]pyridazin-6-yl}-1,2,3-triazole-1-yl)-3-methylbutanoate (intermediate 2)

[0546] [ka]

[0547] A mixture of 3-[2-(methoxymethoxy)phenyl]pyrido[3,2-c]pyridazine-6-yltrifluoromethanesulfonate (300 mg, 0.722 mmol, 1 equivalent), tert-butyl(2S)-3-methyl-2-[4-(tributylstannyl)-1,2,3-triazole-1-yl]butanoate (445.81 mg, 0.866 mmol, 1.2 equivalents), and bis(tri-tert-butylphosphane)palladium (36.91 mg, 0.072 mmol, 0.1 equivalent) in NMP (3 mL) was stirred at 100°C for 1 hour under a nitrogen atmosphere. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain a yellow solid intermediate 2 (85 mg, 23.99%). LCMS(ESI) m / z:[M+H] + =491.

[0548] Step 2: Preparation of (2S)-2-{4-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-1,2,3-triazole-1-yl}-3-methylbutanoic acid (intermediate 3)

[0549] [ka]

[0550] A mixture of intermediate 2 (85 mg, 0.173 mmol, 1 equivalent) and TFA (0.5 mL) in DCM (1.5 mL) was stirred overnight at room temperature. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm to obtain intermediate 3 (30 mg, 44.35%), a yellow solid. LC-MS (ESI) m / z [M+H] + =391.

[0551] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-{4-[3-(2-hydroxyphenyl)pyrido[3,2-c]pyridazin-6-yl]-1,2,3-triazole-1-yl}-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 2)

[0552] [ka]

[0553] A mixture of intermediate 3 (25 mg, 0.064 mmol, 1 equivalent), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,1-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (31.84 mg, 0.096 mmol, 1.5 equivalents), HATU (36.52 mg, 0.096 mmol, 1.5 equivalents), and DIEA (24.83 mg, 0.192 mmol, 3 equivalents) in DMF (3 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The crude product was purified using C18 silica gel to obtain compound 2 (10.3 mg, 21.94%), a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.46(s,1H),9.06(s,1H),9.01-8.88(m,3H),8.65-8.57(m,1H),8.54(d,J=7.6Hz,1H ),8.25(dd,J=7.9,1.7Hz,1H),7.49-7.34(m,5H),7.14-7.02(m,2H),5.53(d,J=10.0Hz,1H),5.25-5.10(m,1H) ,5.02-4.89(m,1H),4.43(t,J=8.1Hz,1H),4.35(s,1H),3.84-3.57(m,2H),2.65-2.56(m,1H),2.45(s,3H),2. 13-2.04(m,1H),1.86-1.75(m,1H),1.49(dd,J=73.1,7.0Hz,3H),1.12(d,J=6.5Hz,3H),0.79(d,J=6.6Hz,3H). LCMS(ESI)m / z:[M+H] + = 704.20.

[0554] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)-5-methyl-6-oxopyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 4).

[0555] [ka]

[0556] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (intermediate 2).

[0557] [ka]

[0558] 4-bromo-6-chloropyridazine-3-amine (20 g, 95.951 mmol, 1 equivalent) and CuI (21.93 g, 115.141 mmol, 1.2 equivalents) were stirred in THF (60 mL) to which CH2I2 (30.84 g, 115.141 mmol, 1.2 equivalents) and t-BuNO2 (9.89 g, 95.951 mmol, 1 equivalent) were added. The resulting solution was stirred at 60°C for 5 hours. The reaction mixture was diluted with HCl (500 mL) and washed with water (3 × 500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with HCl in petroleum ether with a 0% to 80% gradient to obtain intermediate 2 (7.5 g, 24.41%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =319.

[0559] Step 2: Preparation of 6-chloro-3-iodo-N-methylpyridazine-4-amine (intermediate 3).

[0560] [ka]

[0561] To a solution of intermediate 2 (7.5 g, 23.487 mmol, 1 equivalent) and methanamine hydrochloride (1.90 g, 28.184 mmol, 1.2 equivalents) in NMP (50 mL), DIEA (6.07 g, 46.974 mmol, 2 equivalents) was added. The resulting solution was stirred at 80°C for 2 hours. The resulting mixture was diluted with ethyl acetate (300 mL) and washed with water (3 × 300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography eluting with SiO2 in petroleum ether with a 0% to 55% gradient to obtain intermediate 3 (4.15 g, 65.57%) as a white solid. LCMS(ESI)m / z:[M+H] + =270.

[0562] Step 3: Preparation of 6-chloro-4-(methylamino)pyridazine-3-carbaldehyde (intermediate 4).

[0563] [ka]

[0564] To a solution of intermediate 3 (4.15 g, 15.401 mmol, 1 equivalent) and Pd(dppf)Cl2 (1.13 g, 1.540 mmol, 0.1 equivalent) in DMF (30 mL), triethylsilane (5.37 g, 46.202 mmol, 3 equivalents) and TEA (4.68 g, 46.202 mmol, 3 equivalents) were added. The mixture was pressurized to 40 atm with carbon monoxide. The resulting solution was stirred at 40°C for 3 hours. The reaction solution was purified by flash C18 chromatography with an elution gradient of 0-50% acetonitrile in water to obtain intermediate 4 (997 mg, 30.11%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 172.

[0565] Step 4: Preparation of ethyl 3-chloro-5-methyl-6-oxopyrido[3,2-c]pyridazine-7-carboxylate (intermediate 5).

[0566] [ka]

[0567] To a solution of intermediate 4 (0.993 g, 5.787 mmol, 1 equivalent) and diethyl malonate (1.11 g, 6.944 mmol, 1.2 equivalents) in THF (10.00 mL, 123.437 mmol, 21.33 equivalents), TiCl4 (2.20 g, 11.574 mmol, 2 equivalents) and pyridine (0.92 g, 11.574 mmol, 2 equivalents) were added at 0°C. The resulting solution was stirred at 40°C for 3 hours. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography eluting with ethyl acetate in petroleum ether at a 0% to 55% gradient to obtain intermediate 5 (1.01 g, 65.20%) as a grayish-white solid. LCMS(ESI)m / z:[M+H] + = 268.

[0568] Step 5: Preparation of 3-[2-(methoxymethoxy)phenyl]-5-methyl-6-oxopyrido[3,2-c]pyridazine-7-carboxylic acid (intermediate 6).

[0569] [ka]

[0570] To a solution of intermediate 5 (1 g, 3.736 mmol, 1 equivalent) and 2-(methoxymethoxy)phenylboronic acid (1.02 g, 5.604 mmol, 1.5 equivalents) in dioxane (8 mL, 94.432 mmol, 25.28 equivalents) and H2O (2 mL, 111.019 mmol, 29.72 equivalents), XPhos Pd G3 (0.32 g, 0.374 mmol, 0.1 equivalent) and Cs2CO3 (2.43 g, 7.472 mmol, 2 equivalents) was added. The resulting solution was stirred at 100°C for 5 hours under an N2 atmosphere. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by flash C18 chromatography with an elution gradient of 0-72% acetonitrile in water to obtain intermediate 6 (890 mg, 69.79%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =342.

[0571] Step 6: Preparation of 7-bromo-3-[2-(methoxymethoxy)phenyl]-5-methylpyrido[3,2-c]pyridazin-6-one (intermediate 7).

[0572] [ka]

[0573] To a solution of intermediate 6 (890 mg, 2.608 mmol, 1 equivalent) in pyridine (10 mL), Br2 (833.40 mg, 5.216 mmol, 2 equivalents) was added. The resulting solution was stirred at 60°C for 2 hours. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography eluting with ethyl acetate in petroleum ether at a 0% to 45% gradient to obtain intermediate 7 (930 mg, 94.80%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =376.

[0574] Step 7: Preparation of tert-butyl 6-{3-[2-(methoxymethoxy)phenyl]-5-methyl-6-oxopyrido[3,2-c]pyridazin-7-yl}-2,6-diazaspiro[3.3]heptan-2-carboxylate (intermediate 8).

[0575] [ka]

[0576] To a solution of intermediate 7 (700 mg, 1.861 mmol, 1 equivalent) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (553.36 mg, 2.792 mmol, 1.5 equivalents) in dioxane (10 mL), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (156.51 mg, 0.186 mmol, 0.1 equivalent) and Cs2CO3 (1212.48 mg, 3.722 mmol, 2 equivalents) were added. The resulting solution was stirred at 100°C for 2 hours under an N2 atmosphere. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography using ethyl acetate in petroleum ether with a 0% to 52% gradient to obtain intermediate 8 (705 mg, 76.77%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 494.

[0577] Step 8: Preparation of 7-{2,6-diazaspiro[3.3]heptan-2-yl}-3-(2-hydroxyphenyl)-5-methylpyrido[3,2-c]pyridazin-6-one (intermediate 9).

[0578] [ka]

[0579] To a solution of intermediate 8 (705 mg, 1.428 mmol, 1 equivalent) in DCM (6 mL), TFA (2 mL) was added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain intermediate 9 (647 mg, crude), a yellow solid. LCMS(ESI)m / z:[M+H] + =350.

[0580] Step 9: Preparation of methyl 2-(3-{6-[3-(2-hydroxyphenyl)-5-methyl-6-oxopyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoate (intermediate 10).

[0581] [ka]

[0582] Intermediate 9 (647 mg, 1.852 mmol, 1 equivalent) and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl}butanoate (1336.86 mg, 2.778 mmol, 1.5 equivalents) were dissolved in DMSO (10 mL), to which DIEA (718.01 mg, 5.556 mmol, 3 equivalents) was added. The resulting solution was stirred at 100 °C for 5 hours. The reaction mixture was purified by flash C18 chromatography with an elution gradient of 0-63% acetonitrile in water to obtain intermediate 10 (420 mg, 42.75%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 531.

[0583] Step 10: Preparation of 2-(3-{6-[3-(2-hydroxyphenyl)-5-methyl-6-oxopyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoic acid (intermediate 11).

[0584] [ka]

[0585] To a solution of intermediate 10 (420 mg, 0.322 mmol, 1 equivalent) in H2O (1 mL) and MeOH (4 mL), LiOH (94.79 mg, 3.957 mmol, 5 equivalents) was added. The resulting solution was stirred at room temperature for 2 hours. The reaction solution was acidified to pH 5 with 1 M HCl (aqueous solution). The mixture was extracted with RINKAN (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 11 (345 mg, 84.37%), a yellow solid. LCMS(ESI)m / z:[M+H] + = 517.

[0586] Step 11: Preparation of (2S,4R)-4-hydroxy-1-[(2)-2-(3-{6-[3-(2-hydroxyphenyl)-5-methyl-6-oxopyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 12).

[0587] [ka]

[0588] Intermediate 11 (345 mg, 0.668 mmol, 1 equivalent) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (332.03 mg, 1.002 mmol, 1.5 equivalents) were dissolved in DMF (3 mL), to which PyBOP (695.13 mg, 1.336 mmol, 2 equivalents) and DIEA (431.61 mg, 3.340 mmol, 5 equivalents) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was then subjected to the following conditions (column: Xbridge Phenyl OBD column, 19 *The mixture was purified by preparative HPLC using a 150 mm, 5 m mobile phase (10 mmol / L NH4HCO3 + 0.05% NH3H2O, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 52% B over 10 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 9.57) to obtain a yellow solid intermediate 12 (92 mg, 16.60%). LC-MS (ESI) m / z: [M + H] + = 830.

[0589] Step 12: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)-5-methyl-6-oxopyrido[3,2-c]pyridazin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 4).

[0590] [ka]

[0591] Intermediate 12 (92 mg) was purified by SFC under the following conditions: column, CHIRAL ART Cellulose-SB, 3 * Column: 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH:DCM=1:1 (20 mMNH3); Flow rate: 100 mL / min; Gradient: Isocratic 55% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 260 / 240 nm; RT1 (min): 3; RT2 (min): 5.17; Sample solvent: HFIP; Injection volume: 4 mL. Compound 4 (second peak) (44 mg, 47.83%) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ13.57(d,J=3.4Hz,1H),8.99(d,J=4.7Hz,1H),8.41(d,J=7.7Hz,1H),8.21-8.14(m,1H),8.08(s,1H),7.51-7.4 1(m,2H),7.41-7.31(m,3H),7.00(ddd,J=8.2,6.5,1.3Hz,2H),6.65(s,1H),5.90(s,1H),5.11(d,J=3.6Hz,1H),4.91(q,J=6.9Hz,1H),4 .61-4.15(s,6H),4.08(s,4H),3.76-3.65(m,4H),3.63-3.54(m,1H),3.45(dd,J=16.1,9.9Hz,1H),2.46(d,J=4.4Hz,3H),2.28-2.15(m ,1H),2.03(t,J=8.8Hz,1H),1.79(ddd,J=12.8,8.0,4.8Hz,1H),1.46-1.24(m,3H),0.96(t,J=6.5Hz,3H),0.82(dd,J=19.3,6.9Hz,3H). LCMS(ESI)m / z:[M+H] + = 830.30.

[0592] Example 2. Decomposition of BRM and BRG1 by the compound of the present invention. This example demonstrates the ability of the compounds of this disclosure to degrade HiBit-BRM or HiBit-BRG1 fusion proteins in cell-based degradation assays.

[0593] Procedure: A stable HeLa cell line expressing HiBiT-BRM was generated. On day 0, 5000 cells were seeded in 40 μL of medium into each well of a 384-well cell culture plate. On day 1, the cells were treated with 120 nL of DMSO or 120 nL of 3x serially diluted DMSO compound (10 points in pairs, with a final maximum dose of 30 μM). Subsequently, the plates were incubated in a standard tissue culture incubator for 24 hours and equilibrated at room temperature for 15 minutes. A fresh Nano-Glo HiBiT Lytic Detection System (Promega N3050) reagent was prepared and 20 μL was added to each well. Upon addition of this LgBit-containing reagent, HiBiT and LgBiT proteins associate to form a luminescent NanoBiT luciferase. The plates were shaken at room temperature for 10 minutes, and bioluminescence was read using an EnVision plate reader (PerkinElmer).

[0594] To measure BRG1 degradation, stable HeLa cell lines expressing HiBit-BRG1 and LgBit were generated. The same protocol as described above was then followed.

[0595] The decomposition of % is given by the following formula: Decomposition % = 100% - 100% × (Lum 試料 -Lum LC ) / (Lum HC -Lum LC The calculations were performed using DMSO-treated cells as the high control (HC), and cells treated with 2 μM of a known BRM / BRG1 degrader as the standard as the low control (LC). As shown in Table 2, the data were fitted to a four-parameter nonlinear curve fit to obtain the IC. 50 The (μM) value was calculated.

[0596] Results: As shown in Table 2 below, the compounds of the present invention decomposed BRM and / or BRG1.

[0597] [Table 3] "+" indicates that DC50 is ≥1000nM. "++" indicates that DC50 is <1000nM and ≥100nM. "+++" indicates that DC50 is <100nM and ≥10nM. "++++" indicates an inhibitory effect of less than 10nM. "NT" indicates not tested. "NC" indicates not calculated. "A" indicates maximum resolution ≥ 75%. "B" indicates maximum resolution ≥ 50%. "C" indicates maximum resolution < 50%.

[0598] Other Embodiments All publications, patents, and patent applications referenced in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being incorporated herein by reference. Where it is found that a term in this application is defined differently in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

[0599] The present invention is described in relation to its specific embodiments, The present invention is subject to further modifications, and this application is intended to cover any modifications, uses, or adaptations of the present invention, including deviations from this disclosure that generally adhere to the principles of the present invention and fall within the scope of known or customary practices in the art to which the invention relates, and which may be applied to the essential features set forth herein and are understood to be subject to the claims.

[0600] Other embodiments are described in the claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, m is 0, 1, 2, or 3, k is 0, 1, or 2, R is either absent or C is optionally substituted. １ ~C ６ It is alkyl, Each R １ is, independently, halo, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ２ to C ９ heterocyclyl, optionally substituted C ３ [[ID=十六]]to C[[ET]] ８ cycloalkyl, optionally substituted C ３ to C ８ cycloalkoxy, optionally substituted C ２ to C ６ alkynyl, optionally substituted amino, or cyano, and Each X can be independently replaced by a halo or optionally replaced by a C. １ ~C ６ It is heteroalkyl, L is the linker, B is the compound, or a pharmaceutically acceptable salt thereof, which is the decomposition part.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-A or I-B. 【Chemistry 2】

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-C. 【Transformation 3】

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein m is 1.

5. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein m is 2.

6. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein m is 3.

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

8. R １ However, C １ ~C ６ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is an alkoxy or a halo.

9. R １ The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound is methoxy or difluoromethoxy.

10. R １ The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound is F or Cl.

11. R １ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is alkyl.

12. R １ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl or difluoromethyl.

13. R １ However, C is optionally substituted. ２ ~C ６ A compound according to any one of claims 1 to 6, which is an alkynyl compound, or a pharmaceutically acceptable salt thereof.

14. R １ The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound is methine.

15. R １ However, C is optionally substituted. ３ ~C ８ Cycloalkyl or optionally substituted C ３ ~C ８ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is a cycloalkoxy.

16. R １ The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropane or cyclopropoxy.

17. R １ However, C is optionally substituted. ２ ~C ９ A compound according to any one of claims 1 to 6, which is a heterocycline, or a pharmaceutically acceptable salt thereof.

18. R １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with an amino or cyano.

19. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein m is 0.

20. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein k is 0.

21. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein k is 1.

22. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein k is 2.

23. X is replaced by C in an arbitrary choice. １ ~C ６ A compound according to any one of claims 1 to 19 and 21 to 22, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl or halo.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein X is methoxy or F.

25. The disassembled part B has the structure of formula A-1, 【Chemistry 4】 During the ceremony, Y １ but, 【Transformation 5】 And, R Ａ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ａ６ However, C is replaced by H or by any other choice. １ ~C ６ It is alkyl, R Ａ７ However, C is replaced by H or by any other choice. １ ~C ６ Alkyl or R Ａ６ and R Ａ７ However, each combines with the carbon atom to which it is bonded, and is optionally substituted with C ３ ~C ６ Carbocyclyl, or optionally substituted C ２ ~C ５ Forms heterocyclines, or R Ａ６ and R Ａ７ However, each combines with the carbon atom to which it is bonded, and is optionally substituted with C ３ ~C ６ Carbocyclyl, or optionally substituted C ２ ~C ５ Forming heterocyclines, R Ａ８ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, 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<000096>~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 when combined together with the carbon atoms to which each is attached, 【Transformation 6】 Forming, 【Transformation 7】 However, C was replaced by an arbitrary choice. ６ ~C １０ Aaryl, replaced by C of any choice ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heteroaryl, or C ２ ~C ９ They are heterocyclines, and all of them are A ２ It is replaced by an optional selection, R Ａ１ , R Ａ２ , R Ａ３ , and R Ａ４ One of them is A ２ is, or 【Transformation 8】 However, A ２ It has been replaced with, A ２ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein the bond between the decomposition portion and the linker is.

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

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

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

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

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

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

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

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

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

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

36. The aforementioned disassembled part 【Chemistry 12】 The compound according to claim 35 or a pharmaceutically acceptable salt thereof.

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

38. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the following structure. 【Chemistry 14】

39. The aforementioned disassembled part has the structure of formula C, 【Chemistry 15】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Chemistry 16】 And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, A ２ , halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkinyl, optionally replaced with C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ Each of these can be independently replaced by H, halogen, or C of any choice. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ９ However, C is replaced by H or of any choice. １ ~C ６ It is alkyl, R Ｂ１０ However, it is H or F, A ２ However, this is a connection between the disassembled 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, or a pharmaceutically acceptable salt thereof.

40. The aforementioned disassembled part has the structure of formula C, 【Chemistry 17】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), [Chemistry 18] And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, 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 replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, or optionally substituted amino acids, R Ｂ７ and R Ｂ８ Each of these can be independently replaced by H, halogen, or C of any choice. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ９ However, C is replaced by H or of any choice. １ ~C ６ It is alkyl, A ２ However, this is a connection between the disassembled 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, or a pharmaceutically acceptable salt thereof.

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

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

43. The aforementioned disassembled part 【Chemistry 21】 The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof.

44. The aforementioned disassembled part 【Chemistry 22】 The compound according to claim 39 or a pharmaceutically acceptable salt thereof.

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

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

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

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

49. R Ｂ９ However, the compound according to any one of claims 39 to 42 and 45 to 48 or a pharmaceutically acceptable salt thereof, wherein the compound is bonded to the (S)-steric center.

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

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

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

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

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

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

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

57. R Ｂ３ However, C is optionally substituted. ３ ~C １０ A compound according to any one of claims 39 to 42 and 45 to 54, which is a carbocyclyl, or a pharmaceutically acceptable salt thereof.

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

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

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

61. The aforementioned disassembled part 【Chemistry 25】 The compound according to any one of claims 39 to 40 or a pharmaceutically acceptable salt thereof.

62. The aforementioned disassembled part 【Chemistry 26】 The compound according to claim 39 or a pharmaceutically acceptable salt thereof.

63. The aforementioned disassembled part 【Chemistry 27】 The compound according to claim 39 or a pharmaceutically acceptable salt thereof.

64. The aforementioned disassembled part 【Chemistry 28】 The compound according to claim 39 or a pharmaceutically acceptable salt thereof.

65. The aforementioned disassembled part has the structure of formula C5, 【Chemistry 29】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Transformation 30】 And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, A ２ , halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkinyl, optionally replaced with C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ Each of these can be independently replaced by H, halogen, or C of any choice. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ９ However, C is replaced by H or of any choice. １ ~C ６ It is alkyl, R Ｂ１１ However, H, alcohol, boronic acid, and C are optionally substituted. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, A ２ However, this is a connection between the disassembled 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, or a pharmaceutically acceptable salt thereof.

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

67. The compound according to any one of claims 65 to 66 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula C6, formula C7, or formula C8. 【Chemistry 31】

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

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

70. R Ｂ９ However, the compound according to any one of claims 65 to 69 or a pharmaceutically acceptable salt thereof, wherein it is bonded to the (S) stereocenter.

71. A compound according to any one of claims 65 to 70 or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

72. R Ｂ５ A compound according to any one of claims 65 to 71 or a pharmaceutically acceptable salt thereof, wherein H is present.

73. R Ｂ７ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 65 to 72, or a pharmaceutically acceptable salt thereof, which is alkyl.

74. In some embodiments, R Ｂ７ The compound according to claim 73 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

75. R Ｂ３ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 65 to 74, or a pharmaceutically acceptable salt thereof, which is alkyl.

76. R Ｂ３ The compound according to claim 75 or a pharmaceutically acceptable salt thereof, wherein the compound is isopropyl.

77. R Ｂ８ A compound according to any one of claims 65 to 76, wherein H is present, or a pharmaceutically acceptable salt thereof.

78. R Ｂ２ A compound according to any one of claims 65 to 77, wherein H is present, or a pharmaceutically acceptable salt thereof.

79. The aforementioned disassembled part 【Chemistry 32】 The compound according to any one of claims 65 to 664 or a pharmaceutically acceptable salt thereof.

80. The disassembled part has the structure of formula D, 【Transformation 33】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Transformation 34】 And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, A ２ , halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ２ ~C ６ Alkinyl, optionally replaced with C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, cyano, or optionally substituted amino, R Ｂ９ However, C is replaced by H or of any choice. １ ~C ６ It is alkyl, A ２ However, this is a connection between the disassembled 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, or a pharmaceutically acceptable salt thereof.

81. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula D3 or formula D1. 【Chemistry 35】

82. The aforementioned disassembled part 【Transformation 36】 The compound according to any one of claims 80 to 81 or a pharmaceutically acceptable salt thereof.

83. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula D2. 【Chemistry 37】

84. R Ｂ９ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 80 and 83, or a pharmaceutically acceptable salt thereof, which is alkyl.

85. R Ｂ９ The compound according to claim 84 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

86. R Ｂ９ The compound according to any one of claims 80 and 83 to 85, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded to the (S)-steric center.

87. R Ｂ９ The compound according to any one of claims 80 and 83, or a pharmaceutically acceptable salt thereof, wherein H is present.

88. A compound according to any one of claims 80 and 83 to 87, or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

89. A compound according to any one of claims 80 and 83 to 87, or a pharmaceutically acceptable salt thereof, wherein v2 is 1.

90. A compound according to any one of claims 80 and 83 to 87, or a pharmaceutically acceptable salt thereof, wherein v2 is 2.

91. R Ｂ４ The compound according to any one of claims 80 and 83 to 90, or a pharmaceutically acceptable salt thereof, wherein H is present.

92. R Ｂ５ The compound according to any one of claims 80 and 83 to 91, or a pharmaceutically acceptable salt thereof, wherein H is present.

93. R Ｂ３ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 80 and 83 to 92, or a pharmaceutically acceptable salt thereof, which is alkyl.

94. R Ｂ３ The compound according to claim 93 or a pharmaceutically acceptable salt thereof, wherein the compound is isopropyl.

95. R Ｂ６ The compound according to any one of claims 80 and 83 to 94, or a pharmaceutically acceptable salt thereof, wherein H is present.

96. R Ｂ６ The compound according to any one of claims 80 and 83 to 94, or a pharmaceutically acceptable salt thereof, wherein the compound is fluorine, chlorine, and bromine.

97. R Ｂ６ The compound according to any one of claims 80 and 83 to 94, or a pharmaceutically acceptable salt thereof, wherein the compound is cyano.

98. R Ｂ６ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 80 and 83 to 94, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl compound.

99. R Ｂ６ The compound according to claim 98 or a pharmaceutically acceptable salt thereof, wherein the compound is methoxy or 3-methoxy-1-propanoxy.

100. R Ｂ６ However, C is optionally substituted. ３ ~C ６ A compound according to any one of claims 80 and 83 to 94, or a pharmaceutically acceptable salt thereof, which is an alkynyl.

101. The aforementioned disassembled part 【Transformation 38】 【Chemistry 39】 The compound according to claim 80 or a pharmaceutically acceptable salt thereof.

102. The disassembled part has the structure of formula Da, 【Chemistry 40】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Chemistry 41】 And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, X １ and X ２ Each of these is independently C, N, or O, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, A ２ , halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkinyl, optionally replaced with C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, cyano, or optionally substituted amino, R Ｂ９ However, C is replaced by H or of any choice. １ ~C ６ It is alkyl, A ２ However, this is a connection between the disassembled 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, or a pharmaceutically acceptable salt thereof.

103. The compound according to claim 102 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula Da3, formula Da1, or formula Da2. 【Chemistry 42】

104. R Ｂ９ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 102 to 103, or a pharmaceutically acceptable salt thereof, which is alkyl.

105. R Ｂ９ The compound according to claim 104 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

106. R Ｂ９ The compound according to any one of claims 102 to 105 or a pharmaceutically acceptable salt thereof, wherein the compound is bonded to the (S)-steric center.

107. A compound according to any one of claims 102 to 106 or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

108. R Ｂ４ A compound according to any one of claims 102 to 107, wherein H is present, or a pharmaceutically acceptable salt thereof.

109. R Ｂ５ A compound according to any one of claims 102 to 108 or a pharmaceutically acceptable salt thereof, wherein H is present.

110. R Ｂ３ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 102 to 109, or a pharmaceutically acceptable salt thereof, which is alkyl.

111. R Ｂ３ The compound according to claim 110 or a pharmaceutically acceptable salt thereof, wherein the compound is isopropyl.

112. X １ C is X ２ A compound according to any one of claims 102 to 111, or a pharmaceutically acceptable salt thereof, wherein is N.

113. The aforementioned disassembled part 【Chemistry 43】 The compound according to claim 102 or a pharmaceutically acceptable salt thereof.

114. The aforementioned disassembled part has the structure of formula E, 【Chemistry 44】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Chemistry 45】 And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ９ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ６ Alkinyl, optionally replaced with C ３ ~C １０ Carbocyclyl, or optionally substituted C ２ ~C １０ It is a heterocycline, B １０ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ６ Alkinyl, optionally replaced with C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C １０ Heterocyclines, optionally substituted aminos, or cyanos, A ２ However, this is a connection between the disassembled 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, or a pharmaceutically acceptable salt thereof.

115. The compound according to claim 114 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula E3 or formula E1. 【Chemistry 46】

116. The aforementioned disassembled part 【Chemistry 47】 The compound according to claim 114 or a pharmaceutically acceptable salt thereof.

117. The compound according to claim 114 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula E2. 【Chemistry 48】

118. R Ｂ９ However, C is optionally substituted. １ ~C ６ A compound according to claims 114 to 115, or a pharmaceutically acceptable salt thereof, which is alkyl.

119. R Ｂ９ The compound according to claim 118 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

120. R Ｂ９ However, C is optionally substituted. ３ ~C ６ A compound according to any one of claims 114 to 115, or a pharmaceutically acceptable salt thereof, which is an alkynyl.

121. R Ｂ９ The compound according to any one of claims 114 to 115, wherein the compound is [1.1.1]pentane, cyclopropane, cyclobutene, or cyclopentane, or a pharmaceutically acceptable salt thereof.

122. R Ｂ９ The compound according to any one of claims 114-115 and 117-121, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded to the (S)-steric center.

123. R Ｂ９ A compound according to any one of claims 114 to 115, wherein H is present, or a pharmaceutically acceptable salt thereof.

124. R Ｂ４ The compound according to any one of claims 114-115 and 117-123, or a pharmaceutically acceptable salt thereof, wherein H is present.

125. R Ｂ５ The compound according to any one of claims 114-115 and 117-124, or a pharmaceutically acceptable salt thereof, wherein H is present.

126. R Ｂ３ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 114-115 and 117-125, or a pharmaceutically acceptable salt thereof, which is alkyl.

127. R Ｂ３ The compound according to claim 126 or a pharmaceutically acceptable salt thereof, wherein the compound is isopropyl.

128. R Ｂ２ The compound according to any one of claims 114-115 and 117-127, or a pharmaceutically acceptable salt thereof, wherein H is present.

129. R Ｂ１０ However, the compound or pharmaceutically acceptable salt thereof described in any one of claims 114-115 and 117-1285 does not exist.

130. R Ｂ１０ The compound according to any one of claims 114-115 and 117-128, or a pharmaceutically acceptable salt thereof, wherein the compound is H or cyano.

131. R Ｂ１０ However, C is optionally substituted. ３ ~C １０ A compound according to any one of claims 114-115 and 117-128, or a pharmaceutically acceptable salt thereof, which is a carbocyclyl.

132. R Ｂ１０ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 114-115 and 117-128, or a pharmaceutically acceptable salt thereof, which is alkyl.

133. R Ｂ１０ The compound according to claim 132 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

134. The aforementioned disassembled part 【Chemistry 49】 The compound according to claim 114 or a pharmaceutically acceptable salt thereof.

135. The aforementioned disassembled part has the structure of formula F, [Transformation 50] During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Chemistry 51】 And, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, A ２ However, this is a connection between the disassembled part and the linker, R Ｂ１ or R Ｂ３ Only one of them is A ２ The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

136. The compound according to claim 135 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula E3 or formula E1. 【Chemistry 52】

137. The aforementioned disassembled part 【Chemistry 53】 The compound according to claim 135 or a pharmaceutically acceptable salt thereof.

138. The compound according to claim 135 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula F2. 【Chemistry 54】

139. R Ｂ９ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 135 and 138, or a pharmaceutically acceptable salt thereof, which is alkyl.

140. R Ｂ９ The compound according to claim 139 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

141. R Ｂ４ The compound according to any one of claims 135 and 138 to 140, or a pharmaceutically acceptable salt thereof, wherein H is present.

142. R Ｂ５ The compound according to any one of claims 135 and 138 to 141, or a pharmaceutically acceptable salt thereof, wherein H is present.

143. R Ｂ３ However, C is optionally substituted. １ ~C ６ A compound according to any one of claims 135 and 138 to 142, or a pharmaceutically acceptable salt thereof, which is alkyl.

144. R Ｂ３ The compound according to claim 143 or a pharmaceutically acceptable salt thereof, wherein the compound is isopropyl.

145. R Ｂ２ The compound according to any one of claims 135 and 138 to 144, or a pharmaceutically acceptable salt thereof, wherein H is present.

146. The aforementioned disassembled part 【Transformation 55】 The compound according to claim 135 or a pharmaceutically acceptable salt thereof.

147. The linker has the structure of formula II. A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(D)-(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ 、 Formula II Having or a pharmaceutically acceptable salt thereof, During the ceremony, A １ However, this is a bond between the linker and the ring system A, A ２ However, this is a connection between the disassembled part and the linker, B １ , B ２ , B ３ , and B ４ Each of these is independently and arbitrarily substituted C １ ~C ４ Alkyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ６ ~C １０ Aryl C １～４ Alkyl, optionally substituted C １ ~C ４ Heteroalkyl, optionally substituted C ３ ~C １０ Cycloalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally substituted C ２ ~C １０ Heterocyclyl, optionally substituted C ２ ~C ６ Heteroaryl, optionally substituted C ６～１２ Ariel, O, S, S(O) ２ , or NR Ｎ And, Each R Ｎ However, independently, H and C are optionally substituted. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, optionally substituted C ２～４ Alkinyl, optionally substituted C ２～１０ Heterocyclyl, optionally substituted C ２～６ Heteroaryl or optionally substituted C １～７ It is heteroalkyl, C １ and C ２ Each of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. D is replaced by C by arbitrary choice. １～１０ Alkyl, optionally substituted C ２～１０ Alkenyl, C substituted by choice ２～１０ Alkinyl, optionally replaced with C ２～１０ Heterocycline, C by optional substitution ２～６ Heteroaryl, optionally substituted C ６～１２ Aaryl, replaced by C of any choice ２ ~C １０ Polyethylene glycol, optionally substituted C ３ ~C １０ Cycloalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C １～１０ It 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 any one of claims 1 to 146 or a pharmaceutically acceptable salt thereof.

148. A １ However, this is a bond between the linker and the benzopyridazine core ring system, A ２ However, this is a connection between the disassembled part and the linker, B １ 、 B ２ 、 B ３ 、 and B ４ each of which is, independently, optionally substituted C １ to C ４ alkyl, optionally substituted C ６ to C １０ aryl, optionally substituted C ６ to C １０ arylC １～４ alkyl, optionally substituted C １ to C ４ heteroalkyl, optionally substituted C ３ [[ID=?]]to C １０ cycloalkyl, optionally substituted C ２ to C ８ heterocyclyl, optionally substituted C ２ to C ６ heteroaryl, optionally substituted C<000090?aryl, O, S, S(O)<000?904>or NR Ｎ wherein It seems there are some formatting or content issues in the original text which made the translation a bit tricky in some parts. The "?904" and "?90?" in the translated text are placeholders for the unclear parts in the original. 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 of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. D is replaced by C by arbitrary choice. １～１０ Alkyl, optionally substituted C ２～１０ Alkenyl, C substituted by choice ２～１０ Alkinyl, optionally replaced with C ２～６ Heterocycline, C by optional substitution ２～６ Heteroaryl, optionally substituted C ６～１２ Aaryl, replaced by C of any choice ２ ~C １０ Polyethylene glycol, or optionally substituted C １～１０ It 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 147 or a pharmaceutically acceptable salt thereof.

149. B １ , B ２ , B ３ , and B ４ Each of these is independently and arbitrarily substituted C １ ~C ２ Alkyl, optionally substituted C １ ~C ３ Heteroalkyl, optionally substituted C ２ ~C １０ Heterocyclyl, optionally substituted C ２－６ Heteroaryl, O, or NR Ｎ The compound according to any one of claims 147 to 148 or a pharmaceutically acceptable salt thereof.

150. B １ , B ２ , B ３ , and B ４ Each of these is independently and arbitrarily substituted C １ ~C ２ Alkyl, optionally substituted C １ ~C ３ Heteroalkyl, optionally substituted C ２ ~C ８ Heterocyclyl, optionally substituted C ２－６ A compound according to any one of claims 147 to 148, or a pharmaceutically acceptable salt thereof, wherein the compound is heteroaryl or O.

151. B １ and B ４ Each of them, independently, 【Transformation 56】 【Chemistry 57】 The compound according to any one of claims 147 to 150 or a pharmaceutically acceptable salt thereof.

152. B １ and B ４ Each of them, independently, 【Chemistry 58】 The compound according to any one of claims 147 to 150 or a pharmaceutically acceptable salt thereof.

153. B １ but, 【Chemistry 59】 【Transformation 60】 The compound according to any one of claims 147 to 151 or a pharmaceutically acceptable salt thereof.

154. B ４ but, 【Chemistry 61】 【Transformation 62】 The compound according to any one of claims 147 to 151 and 153, or a pharmaceutically acceptable salt thereof.

155. C １ but, 【Transformation 63】 The compound according to any one of claims 147 to 154 or a pharmaceutically acceptable salt thereof.

156. B ２ is optionally substituted C １ -C ４ alkyl, a compound according to any one of claims 147 to 155 or a pharmaceutically acceptable salt thereof.

157. D is replaced by C in an arbitrary choice. １ ~C １０ A compound according to any one of claims 147 to 156, or a pharmaceutically acceptable salt thereof, which is alkyl.

158. A compound according to any one of claims 147 to 157 or a pharmaceutically acceptable salt thereof, wherein f is 1.

159. A compound according to any one of claims 147 to 158 or a pharmaceutically acceptable salt thereof, wherein g, h, I, and j are 0.

160. A compound according to any one of claims 147 to 159 or a pharmaceutically acceptable salt thereof, wherein k is 0.

161. A compound according to any one of claims 147 to 159 or a pharmaceutically acceptable salt thereof, wherein k is 1.

162. D does not exist, 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 147 to 156 and 158 to 161, or a pharmaceutically acceptable salt thereof.

163. D is replaced by C in an arbitrary choice. １－１０ Alkyl, optionally substituted C ２－１０ Alkenyl, optionally substituted C ２－１０ Alkinyl, optionally substituted C ２－１０ Heterocyclyl, optionally substituted C ２－６ Heteroaryl, optionally substituted C ６－１２ Aryl, optionally substituted C ２ ~C １０ Polyethylene glycol, or optionally substituted C １－１０ A compound according to any one of claims 147 to 156 and 158 to 161, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl compound.

164. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound according to any one of claims 147 to 156 and 158 to 161, or a pharmaceutically acceptable salt thereof, wherein the compound is cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1.

165. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound according to any one of claims 147 to 156 and 158 to 161, or a pharmaceutically acceptable salt thereof, wherein the compound is cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0.

166. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound according to any one of claims 147 to 156 and 158 to 161, or a pharmaceutically acceptable salt thereof, wherein the compound is cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1.

167. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound according to any one of claims 147 to 156 and 158 to 161, or a pharmaceutically acceptable salt thereof, wherein the compound is cycloalkyl and f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0.

168. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound or pharmaceutically acceptable salt according to any one of claims 147 to 156 and 158 to 161, wherein the compound is a carbocyclyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1.

169. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound or pharmaceutically acceptable salt according to any one of claims 147 to 156 and 158 to 161, wherein the compound is a carbocyclyl, f is 1, g is 0, h is 0, I is 0, j is 0, and k is 0.

170. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound or pharmaceutically acceptable salt according to any one of claims 147 to 156 and 158 to 161, wherein f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1.

171. D is replaced by C in an arbitrary choice. ３ ~C １０ A compound or pharmaceutically acceptable salt according to any one of claims 147 to 156 and 158 to 161, wherein f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0.

172. D is 【Chemistry 64】 【Transformation 65】 The compound or pharmaceutically acceptable salt according to any one of claims 147 to 156 and 158 to 161.

173. The aforementioned linker, 【Chemical 66】 【Transformation 67】 A compound according to claim 147 or a pharmaceutically acceptable salt thereof having the structure of the compound.

174. The aforementioned linker, 【Transformation 68】 A compound according to any one of claims 147 to 148, having the structure of the compound or a pharmaceutically acceptable salt thereof.

175. 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 However, this is a bond between the linker and ring system A, A ２ However, this is a connection between the disassembled part and the linker, B １ , B ２ , B ３ , and B ４ Each of these is independently substituted with an optionally substituted ethynyl and an optionally substituted C. ６ ~C １０ Aaryl, replaced by C of any choice ３ ~C １０ Cycloalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C １０ Heterocycline, C by optional substitution ２ ~C ９ Heteroaryl, O, S, S(O) ２ , or NR Ｎ And, Each R Ｎ However, independently, H and C are substituted by choice. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, C substituted by choice ２～４ Alkinyl, optionally replaced with C ２～１０ Heterocycline, C by optional substitution ６～１２ C replaced by an aryl or of any choice １～７ It is heteroalkyl, C １ and C ２ Each of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. B is the decomposition part, Each R １ However, independently, halo, and C are replaced by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C ８ Cycloalkyl or optionally substituted C ２ ~C １０ It is a heterocycline, Each X is independently a halo, the compound according to any one of claims 1 to 146 or a pharmaceutically acceptable salt thereof.

176. The linker has structure - (L １ ) ｎ - is such that n is 1, 2, or 3, and each L １ However, independently, O, NR Ｎ , ethynyl, optionally substituted C ２ ~C １０ Heterocyclyl, optionally substituted C ２ ~C ９ Heteroaryl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ３ ~C １０ A cycloalkyl compound or a pharmaceutically acceptable salt thereof according to claim 175.

177. at least one L １ However, C is optionally substituted. ２ ~C １０ A compound according to claim 176, or a pharmaceutically acceptable salt thereof, which is a heterocycline.

178. The optionally substituted C ２ ~C １０ The compound according to claim 177, or a pharmaceutically acceptable salt thereof, wherein the heterocyclil is a four-membered, five-membered, or six-membered monocyclic heterocyclil, a spirocyclic heterocyclil, a cross-linked heterocyclil, or a condensed bicyclic heterocyclil.

179. Said C ２ ~C １０ Heterocyclines, 【Transformation 69】 The compound according to claim 178, or a pharmaceutically acceptable salt thereof.

180. at least one L １ However, C is optionally substituted. ２ ~C ９ A compound according to any one of claims 176 to 179, or a pharmaceutically acceptable salt thereof, which is a heteroaryl compound.

181. The linker is -(L １ ) ｑ - (C that has been optionally replaced) ２ ~C ９ (heteroaryl)-(L １ ) ｑ A compound or pharmaceutically acceptable salt according to any one of claims 176 to 180, wherein each q is independently 0 or 1.

182. The optionally substituted C ２ ~C ９ The compound according to claim 180 or 181, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is a six-membered monocyclic heteroaryl.

183. The aforementioned six-membered monocyclic heteroaryl, 【Transformation 70】 The compound according to claim 182, or a pharmaceutically acceptable salt thereof.

184. at least one L １ However, C is optionally substituted. ６ ~C １０ A compound according to any one of claims 176 to 183, or a pharmaceutically acceptable salt thereof, which is an aryl compound.

185. The optionally substituted C ６ ~C １０ The compound according to claim 184, wherein the aryl is optionally substituted with a phenyl compound.

186. at least one L １ However, C is optionally substituted. ３ ~C １０ A compound according to any one of claims 176 to 185, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

187. The optionally substituted C ３ ~C １０ Cycloalkyl, 【Chemistry 71】 The compound according to claim 186 or a pharmaceutically acceptable salt thereof.

188. at least one L １ The compound according to any one of claims 176 to 187, or a pharmaceutically acceptable salt thereof, wherein the compound is ethinyl.

189. Only one L １ A compound according to any one of claims 176 to 188 or a pharmaceutically acceptable salt thereof, wherein the compound is O.

190. Only one L １ However, NR Ｎ The compound according to any one of claims 176 to 188 or a pharmaceutically acceptable salt thereof.

191. R Ｎ However, H or C which is optionally substituted. １ ~C ４ The compound according to claim 190 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

192. The linker has 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 of them independently has an optionally substituted ethynyl and an optionally substituted C. ６ ~C １０ Aaryl, replaced by C of any choice ３ ~C １０ Cycloalkyl, optionally substituted C ２ ~C １０ Heterocycline, C by optional substitution ２ ~C ９ Heteroaryl, O, or NR Ｎ The compound according to claim 175 or a pharmaceutically acceptable salt thereof.

193. A compound according to claim 175 or 192, or a pharmaceutically acceptable salt thereof, wherein at least one of f, h, i, and k is 1.

194. B １ , B ２ , B ３ , and B ４ Each of these can be independently replaced by O, ethynyl, or optionally substituted C. ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C １０ Heterocyclyl, optionally substituted C ３ ~C １０ Cycloalkyl or optionally substituted C ６ ~C １０ A compound according to any one of claims 175 or 192-193, or a pharmaceutically acceptable salt thereof, which is an aryl compound.

195. B １ , B ２ , B ３ , and B ４ Each of these is independently and arbitrarily substituted C ２ ~C ９ Heteroaryl or optionally substituted C ２ ~C １０ A compound or pharmaceutically acceptable salt according to any one of claims 175 and 192-194, which is a heterocycline.

196. B １ and B ４ Each of them, independently, 【Chemistry 72】 【Transformation 73】 The compound according to any one of claims 175 and 192-195, or a pharmaceutically acceptable salt thereof.

197. B １ but, 【Chemistry 74】 The compound or pharmaceutically acceptable salt according to claim 196.

198. B ４ but, 【Chemistry 75】 【Transformation 76】 The compound according to claim 196 or 197, or a pharmaceutically acceptable salt thereof.

199. B ２ However, NH, 【Chemical 77】 The compound according to any one of claims 175 and 192-198, or a pharmaceutically acceptable salt thereof.

200. A compound according to any one of claims 175 and 192 to 199, or a pharmaceutically acceptable salt thereof, wherein f is 0.

201. A compound according to any one of claims 175 and 191 to 199, or a pharmaceutically acceptable salt thereof, wherein f is 1.

202. A compound according to any one of claims 175 and 192-201, or a pharmaceutically acceptable salt thereof, wherein g, h, I, and j are 0.

203. A compound according to any one of claims 175 and 192 to 202, or a pharmaceutically acceptable salt thereof, wherein k is 0.

204. A compound according to any one of claims 175 and 192 to 202, or a pharmaceutically acceptable salt thereof, wherein k is 1.

205. The aforementioned linker, 【Transformation 78】 【Chemistry 79】 【Chemistry 80】 A compound or pharmaceutically acceptable salt according to claim 175 having the structure of the compound or pharmaceutically acceptable salt.

206. A compound selected from the group consisting of compounds 1 to 291 in Table 1 and their pharmaceutically acceptable salts.

207. The compound contains at least 5 BRG1 IC ５０ BRM IC ５０ A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof having a ratio to .

208. The compound is at least 10 BRG1 IC ５０ BRM IC ５０ A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof having a ratio to .

209. The compound contains at least 20 BRG1 IC ５０ BRM IC ５０ A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof having a ratio to .

210. The compound is at least 30 BRG1 IC ５０ BRM IC ５０ A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof having a ratio to .

211. A pharmaceutical composition comprising a compound according to any one of claims 1 to 210 and a pharmaceutically acceptable excipient.

212. A method for treating BAF complex-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 210 or a pharmaceutical composition according to claim 211.

213. The method according to claim 212, wherein the BAF complex-related disorder is cancer or a viral infection.

214. A method for treating a disorder related to a loss-of-function mutation of BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 210 or a pharmaceutical composition according to claim 211.

215. The method according to claim 214, wherein the disorder associated with a loss-of-function mutation in BRG1 is cancer.

216. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 210 or a pharmaceutical composition according to claim 211.

217. The method according to any one of claims 212 to 216, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary tract cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small intestine cancer, or penile cancer.

218. The method according to claim 217, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

219. The method according to claim 217, wherein the cancer is non-small cell lung cancer.

220. The method according to claim 217, wherein the cancer is a soft tissue sarcoma.

221. A method for treating a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 210 or a pharmaceutical composition according to claim 211.

222. A compound according to any one of claims 1 to 210, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 211, for use in therapy.

223. A compound according to any one of claims 1 to 210, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 211, for use in the treatment of cancer.

224. The compound for use according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary tract cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenal cortical cancer, appendiceal cancer, small intestine cancer, or penile cancer.

225. The compound for use according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

226. The compound for use according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is non-small cell lung cancer.

227. The compound for use according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is a soft tissue sarcoma.

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