Pyrazine derivatives and their use

Abstract

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

Description

[Technical Field]

[0001] 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 II, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl. m is 0, 1, 2, or 3, k is 0, 1, or 2, Each R 1 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, or optionally substituted CH2-C3-C8 cycloalkyl. Each X is independently a halo. L is the linker, B is characterized by a compound, or a pharmaceutically acceptable salt thereof, which is the decomposition part.

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

[0006] In some embodiments, the compound is of formula I or II,

Chemical formula

[0007] In some embodiments, the compound is of formula IA or II-A, [ka] In the formula, the dashed line represents a single bond or a double bond, as in formula IA or II-A. or having the structure of a pharmaceutically acceptable salt thereof.

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

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

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

[0011] In some embodiments, m is 1.

[0012] Several embodiments, each R 1 This is a halo, an optionally substituted C1-C6 alkyl, or an optionally substituted C3-C8 cycloalkyl.

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

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

[0015] In some embodiments, m is 0.

[0016] In some embodiments, k is 1.

[0017] In some embodiments, X is Cl.

[0018] In some embodiments, k is 0.

[0019] In some embodiments, the linker 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.

[0020] 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 four-, five-, or six-membered monocyclic heterocyclyl is, [ka] That is the case.

[0021] In some embodiments, C2~C are optionally replaced. 10 The heterocyclil is a spirocyclic heterocyclil. In some embodiments, the spirocyclic heterocyclil is [ka] That is the case.

[0022] In some embodiments, C2~C are optionally replaced. 10 The heterocyclil is a cross-linked heterocyclil. In some embodiments, the cross-linked heterocyclil is [ka] That is the case.

[0023] In some embodiments, C2~C 10 A heterocyclyl is a condensed bicyclic heterocyclyl. In some embodiments, a condensed bicyclic heterocyclyl is, [ka] That is the case.

[0024] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is -(L 1 ) q -(Optionally substituted C2~C9 heteroaryl)-(L 1 ) q 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 [ka] That is the case.

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

[0026] In some embodiments, at least one L 1 C6~C, which were replaced by optional selection. 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.

[0027] 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. 10Cycloalkyls are monocyclic cycloalkyls. In some embodiments, a 6-membered monocyclic cycloalkyl is, [ka] That is the case.

[0028] In some embodiments, C3~C are optionally replaced. 10 The cycloalkyl is a crosslinked cycloalkyl. In some embodiments, the crosslinked cycloalkyl is [ka] That is the case.

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

[0030] 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.

[0031] 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 choice10 Cycloalkyl, optionally substituted C2-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N is.

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

[0033] In some embodiments, B 1 , B 2 , B 3 , and B 4 each independently is O, ethynyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C 10 heterocyclyl, optionally substituted C3-C 10 cycloalkyl, or optionally substituted C6-C 10 aryl. In some embodiments, B 1 , B 2 , B 3 , and B 4 each independently is optionally substituted C2-C9 heteroaryl or optionally substituted C2-C 10 heterocyclyl. In some embodiments, B 1 and B 4 each independently is O,

Chemical Structure

Chemical Structure

[0034] In some embodiments, B 1 is

Chemical Structure

Chemical Structure

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

[0036] 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, [ka] That is the case.

[0037] In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

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

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

[0040] 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, O, or NR N And 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 6~12 Arial, C2~C substituted by choice 10 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.

[0041] In some embodiments, B 1 B 2 B 3 , and B 4Each 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.

[0042] In some embodiments, B 1 and B 4 Each of them is independent, O, [ka] [ka] That is the case.

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

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

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

[0046] In some embodiments, B 2 These are C1-C4 alkyl groups that have been optionally substituted.

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

[0048] In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0049] In some embodiments, D is absent, and the linker is A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -( B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 That is the case.

[0050] 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 10Polyethylene glycol, or optionally substituted C 1~10 It is heteroalkyl. 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 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 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 [ka] [ka] [ka] That is the case.

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

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

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

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

[0055] In some embodiments, m is 0.

[0056] In some embodiments, m is 1.

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

[0058] In some embodiments, R 1 is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 1 C3~C, which were replaced by optional selection. 10 It is carbocyclyl. In some embodiments, R 1 It is cyclopropane.

[0059] In some embodiments, k is 0.

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

[0061] In some embodiments, the disassembled part B has the structure of formula A-1, [ka] During the ceremony, Y 1 but, [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 A6is a C1-C6 alkyl group that is substituted with H or optionally, and R A7 is either H or a C1-C6 alkyl group substituted with any choice, or R A6 and R A7 Each combines with the carbon atom to which it is bonded to form an optionally substituted C3-C6 carbocykryl or an optionally substituted C2-C5 heterocycline, or R A6 and R A7 These combine with the carbon atoms to which they are bonded to form optionally substituted C3-C6 carbocyryls or optionally substituted C2-C5 heterocyclyls. 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, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 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 to which it is bonded, [ka] Forming, [ka] However, C6~C was replaced by arbitrary selection. 10 Arial, C3~C replaced by any choice 10 Carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any one of which is 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 [ka] However, A 2 It has been replaced with,

[0062] A 2 However, this is the connection between the decomposition part and the linker.

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

[0064] 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.

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

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

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

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

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

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

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

[0072] In some embodiments, R A8 is H or optionally substituted C1-C6 alkyl. In some embodiments, R A8 is H or methyl. In some embodiments, R A8 It is methyl.

[0073] In some embodiments, the disassembled portion includes the structure of formula A2. [ka]

[0074] In some embodiments, the disassembled part is [ka] That is the case.

[0075] In some embodiments, the disassembled portion includes the structure of formula A4. [ka]

[0076] In some embodiments, the disassembled part is [ka] That is the case.

[0077] In some embodiments, the disassembled part has the structure of formula A5: [ka]

[0078] In some embodiments, the disassembled part has the structure of formula A6: [ka]

[0079] In some embodiments, the disassembled part has the structure of formula A8: [ka]

[0080] In some embodiments, the disassembled part has the structure of formula A10: [ka]

[0081] In some embodiments, the disassembled part has the following structure [ka]

[0082] In some embodiments, the disassembled part has the following structure [ka]

[0083] In some embodiments, the disassembled part is defined by formula C, [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ), [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, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C10 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 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. 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 Equation C is such that or having the structure of a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the disassembled part is defined by formula C, [ka] During the ceremony, L 4 However, -N(RB1 )(R B2 ), [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, 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 C3-C 10Carbocyclyl, 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, 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 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 Equation C is such that or having the structure of a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the disassembled portion has the structure of formula C3. [ka]

[0086] In some embodiments, the disassembled portion has the structure of formula C4. [ka]

[0087] In some embodiments, the disassembled part has the structure of formula C1: [ka]

[0088] In some embodiments, the disassembled part is [ka] That is the case.

[0089] In some embodiments, the disassembled part is [ka] That is the case.

[0090] In some embodiments, the disassembled part is [ka] That is the case.

[0091] In some embodiments, the disassembled part is [ka] That is the case.

[0092] In some embodiments, the disassembled part is [ka] That is the case.

[0093] In some embodiments, the disassembled part is [ka] That is the case.

[0094] In some embodiments, the disassembled part has the structure of formula C2: [ka]

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

[0096] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0097] 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.

[0098] In some embodiments, the disassembled part is [ka] That is the case.

[0099] In some embodiments, the decomposition portion has the structure of formula Ca2: [ka]

[0100] In some embodiments, the disassembled part has the structure of formula Cb2: [ka]

[0101] In some embodiments, the disassembled part has the structure of formula Cc2: [ka]

[0102] In some embodiments, the decomposed part has the structure of formula Cd2: [ka]

[0103] In some embodiments, the disassembled part has the structure of formula Ce2: [ka]

[0104] In some embodiments, the disassembled part has the structure of formula Cf2: [ka]

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

[0106] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0107] 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 B3is 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.

[0108] In some embodiments, the disassembled part is [ka] That is the case.

[0109] In some embodiments, the disassembled part is [ka] That is the case.

[0110] In some embodiments, the disassembled part is [ka] That is the case.

[0111] In some embodiments, the disassembled part is [ka] That is the case.

[0112] In some embodiments, the disassembled part is [ka] That is the case.

[0113] In some embodiments, the disassembled part is [ka] That is the case.

[0114] In some embodiments, the disassembled part is [ka] That is the case.

[0115] In some embodiments, the disassembled part is [ka] That is the case.

[0116] In some embodiments, the disassembled part is [ka] That is the case.

[0117] In some embodiments, the disassembled part is represented by formula C5, [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ), [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-C10 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 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 Equation C5 or having the structure of a pharmaceutically acceptable salt thereof.

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

[0119] In some embodiments, the disassembled part has the structure of formula C6. [ka]

[0120] In some embodiments, the disassembled part has the structure of formula C1: [ka]

[0121] In some embodiments, the disassembled part has the structure of formula C8: [ka]

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

[0123] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0124] 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 B3 is isopropyl. In some embodiments, RB8 H is H. In some embodiments, R B2 H is H.

[0125] In some embodiments, the disassembled part is [ka] That is the case.

[0126] In some embodiments, the decomposition part is given by formula D, [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ), [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, 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. 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 Equation D is such that or having the structure of a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the disassembled part has the structure of formula D3. [ka]

[0128] In some embodiments, the disassembled part has the structure of formula D1: [ka]

[0129] In some embodiments, the disassembled part is [ka] That is the case.

[0130] In some embodiments, the disassembled part is [ka] That is the case.

[0131] In some embodiments, the disassembled part is [ka] That is the case.

[0132] In some embodiments, the disassembled part has the structure of formula D2: [ka]

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

[0134] In some embodiments, R B9 It is bonded to the (S)-chiral center. In some embodiments, R B9 H is H.

[0135] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B3is 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.

[0136] In some embodiments, the disassembled part is [ka] That is the case.

[0137] In some embodiments, the disassembled part is [ka] That is the case.

[0138] In some embodiments, the disassembled part is [ka] In some embodiments, the disassembled part is [ka] That is the case.

[0139] In some embodiments, the disassembled part is [ka] That is the case.

[0140] In some embodiments, the disassembled part is [ka] That is the case.

[0141] In some embodiments, the disassembled part is [ka] That is the case.

[0142] In some embodiments, the disassembled part is [ka] That is the case.

[0143] In some embodiments, the disassembled part is [ka] That is the case.

[0144] In some embodiments, the disassembled part is [ka] That is the case.

[0145] In some embodiments, the disassembled part is [ka] That is the case.

[0146] In some embodiments, the disassembled part is [ka] That is the case.

[0147] In some embodiments, the disassembled part is [ka] That is the case.

[0148] In some embodiments, the disassembled part is [ka] That is the case.

[0149] In some embodiments, the disassembled part is [ka] That is the case.

[0150] In some embodiments, the disassembled part is [ka] That is the case.

[0151] In some embodiments, the disassembled part is [ka] That is the case.

[0152] In some embodiments, the disassembled part is [ka] That is the case.

[0153] In some embodiments, the disassembled part is [ka] That is the case.

[0154] In some embodiments, the disassembled part is [ka] That is the case.

[0155] In some embodiments, the disassembled part is [ka] That is the case.

[0156] In some embodiments, the disassembled part is [ka] That is the case.

[0157] In some embodiments, the disassembled part is [ka] That is the case.

[0158] In some embodiments, the disassembled part is [ka] That is the case.

[0159] In some embodiments, the disassembled part is [ka] That is the case.

[0160] In some embodiments, the decomposition part is the formula Da, [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ), [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, 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 10The 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 formula Da or having the structure of a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the disassembled portion has the structure of formula Da3. [ka]

[0162] In some embodiments, the disassembled part has the structure of formula Da1: [ka]

[0163] In some embodiments, the disassembled part has the structure of formula Da2: [ka]

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

[0165] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0166] 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 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.

[0167] In some embodiments, the disassembled part is [ka] That is the case.

[0168] In some embodiments, the disassembled part is given by formula E, [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ), [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-C10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4 However, H, 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, 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 Equation E is or having the structure of a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the disassembled part has the structure of formula E3. [ka]

[0170] In some embodiments, the disassembled part has the structure of formula E1: [ka]

[0171] In some embodiments, the disassembled part is [ka] That is the case.

[0172] In some embodiments, the disassembled part is [ka] That is the case.

[0173] In some embodiments, the disassembled part has the structure of formula E2: [ka]

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

[0175] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0176] In some embodiments, v2 is 0. In some embodiments, v2 is 1. 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. In some embodiments, RB9 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.

[0177] In some embodiments, the disassembled part is [ka] That is the case.

[0178] In some embodiments, the disassembled part is [ka] That is the case.

[0179] In some embodiments, the disassembled part is [ka] That is the case.

[0180] In some embodiments, the disassembled part is [ka] That is the case.

[0181] In some embodiments, the disassembled part is [ka] That is the case.

[0182] In some embodiments, the disassembled part is [ka] That is the case.

[0183] In some embodiments, the disassembled part is [ka] That is the case.

[0184] In some embodiments, the disassembled part is [ka] That is the case.

[0185] In some embodiments, the disassembled part is [ka] That is the case.

[0186] In some embodiments, the disassembled part is given by formula F, [ka] During the ceremony, L 4 However, -N(R B1 )(R B2 ), [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, 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. 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 Therefore, equation F or having the structure of a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the disassembled part has the structure of formula F3. [ka]

[0188] In some embodiments, the disassembled part has the structure of formula F1: [ka]

[0189] In some embodiments, the disassembled part is [ka] That is the case.

[0190] In some embodiments, the disassembled part is [ka] That is the case.

[0191] In some embodiments, the disassembled part is [ka] That is the case.

[0192] In some embodiments, the disassembled part has the structure of formula F2: [ka]

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

[0194] 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 B2H is H.

[0195] In some embodiments, the disassembled part is [ka] That is the case.

[0196] In some embodiments, the linker is given by 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 having a pharmaceutically acceptable salt structure 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 independently consists of optionally substituted C1-C4 alkyl groups and optionally substituted C6-C 10 Aryl, C6~C substituted by any choice 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 NThese are independently H and C, which are substituted by any 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 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.

[0197] 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, O, or NR N And 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 6~12 Arial, C2~C substituted by choice 10 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.

[0198] 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.

[0199] In some embodiments, B1 and B 4 Each of them is independent, O, [ka] [ka] That is the case.

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

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

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

[0203] In some embodiments, B 2 These are C1-C4 alkyl groups that have been optionally substituted.

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

[0205] In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0206] In some embodiments, D is absent, and the linker is A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -( B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 That is the case.

[0207] 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 heteroalkyl. 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 [ka] [ka] [ka] That is the case.

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

[0209] In some embodiments, the linker has the structure of formula III, A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -( B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 , Formula III During the ceremony, A 1 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 an optionally substituted ethynyl, and an optionally substituted 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 These are independently a halo, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted C2-C 10 It is a heterocycline, Each X is independently a halo.

[0210] 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.

[0211] 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 four-, five-, or six-membered monocyclic heterocyclyl is, [ka] That is the case.

[0212] In some embodiments, C2~C are optionally replaced. 10The heterocyclil is a spirocyclic heterocyclil. In some embodiments, the spirocyclic heterocyclil is [ka] That is the case.

[0213] In some embodiments, C2~C are optionally replaced. 10 The heterocyclil is a cross-linked heterocyclil. In some embodiments, the cross-linked heterocyclil is [ka] That is the case.

[0214] In some embodiments, C2~C 10 A heterocyclyl is a condensed bicyclic heterocyclyl. In some embodiments, a condensed bicyclic heterocyclyl is, [ka] That is the case.

[0215] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is -(L 1 ) q -(Optionally substituted C2~C9 heteroaryl)-(L 1 ) q 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 [ka] That is the case.

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

[0217] In some embodiments, at least one L 1 C6~C, which were replaced by optional selection. 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.

[0218] 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, [ka] That is the case.

[0219] In some embodiments, C3~C are optionally replaced. 10 The cycloalkyl is a crosslinked cycloalkyl. In some embodiments, the crosslinked cycloalkyl is [ka] That is the case.

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

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

[0222] 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.

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

[0224] In some embodiments, B 1 B 2 B 3 , and B 4 Each of these independently consists of O, ethynyl, an optionally substituted C2-C9 heteroaryl, and an optionally substituted C2-C 10 Heterocyclines, C3-C3 substituted by choice 10 Cycloalkyl or optionally substituted C6-C 10 It is an arrow. In some embodiments, B 1 B 2 B 3 , and B 4Each of these is independently a C2-C9 heteroaryl or C2-C9 heteroaryl by any choice. 10 It is a heterocycline. In some embodiments, B 1 and B 4 Each of them is independent, O, [ka] [ka] That is the case.

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

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

[0227] 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, [ka] That is the case.

[0228] In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

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

[0230] 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.

[0231] In some embodiments, the linker is one of the compounds 1 to 121 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 121 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 121 in Table 1 (e.g., BRM IC 50The 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).

[0232] In some embodiments, the present invention is characterized by compounds selected from the group consisting of 1 to 121 in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compounds are BRG1 IC 50 BRM IC 50 The compound is one of the compounds 1 to 121 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 15. 50 The compound is one of the compounds 1 to 121 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 15. 50 The value is ++ or higher (for example, +++ or ++++ (for example, ++++)) and the BRG1 IC 50 BRM IC 50 One of the compounds 1 to 121 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 .

[0233] In one embodiment, the present invention is characterized by compounds selected from the group consisting of 1 to 103 in Table 1, and pharmaceutically acceptable salts thereof.

[0234] [Table 1-1]

[0235] [Table 1-2]

[0236] Table 1-3

[0237] Table 1-4

[0238] Table 1-5

[0239] Table 1-6

[0240] Table 1-7

[0241] Table 1-8

[0242] Table 1-9

[0243] Table 1-10

[0244] Table 1-11

[0245] Table 1-12

[0246] Table 1-13

[0247] Table 1-14

[0248] Table 1-15

[0249] Table 1-16

[0250] Table 1-17

[0251] Table 1-18

[0252] Table 1-19

[0253] Table 1-20

[0254] Table 1-21

[0255] Table 1-22

[0256] [Table 1-23]

[0257] [Table 1-24]

[0258] [Table 1-25]

[0259] [Table 1-26]

[0260] [Table 1-27]

[0261] [Table 1-28]

[0262] In some embodiments, the compound contains at least 5 BRG1 IC 50 BRM IC 50 It has a ratio to 7. 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 IC50 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].

[0263] In one embodiment, the present invention is characterized by a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0264] In another embodiment, the present invention relates to 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 pharmaceutically acceptable composition thereof.

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

[0266] 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 pharmaceutically appropriate composition thereof to the subject.

[0267] In some embodiments, BAF complex-related disorders are cancer.

[0268] 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 pharmaceutically appropriate composition thereof.

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

[0270] In another embodiment, the present invention relates to a method for inhibiting BRG1, wherein the method comprises contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

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

[0272] In a further embodiment, the present invention relates to 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 pharmaceutically acceptable composition thereof.

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

[0274] 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 pharmaceutically appropriate composition thereof to the subject.

[0275] 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).

[0276] 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 pharmaceutically appropriate composition thereof.

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

[0278] 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 pharmaceutically appropriate composition thereof to the subject.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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, the obstruction is caused by Retroviridae viruses such as lentiviruses (e.g., human immunodeficiency virus, HIV) and delta-retroviruses (e.g., human T-cell leukemia virus I, HTLV-I), 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 adenovirus), Herpesviridae viruses (e.g., human cytomegalovirus, HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 2. HSV-2), Human Herpesvirus 6 (HHV-6), Herpesvirus K *The disorder is a viral infection 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), and 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.

[0284] In another embodiment, 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).

[0285] 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 50 IC 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.

[0286] 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, the method comprising administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof to the subject.

[0287] 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 pharmaceutically acceptable composition thereof to the subject.

[0288] 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, wherein the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0289] 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 pharmaceutically acceptable composition thereof.

[0290] 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 pharmaceutically acceptable composition thereof.

[0291] 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.

[0292] 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%).

[0293] 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).

[0294] 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%).

[0295] 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).

[0296] 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.

[0297] In some embodiments, the cancer harbors a mutation in GNAQ. In some embodiments, the cancer harbors a mutation in GNA11. In some embodiments, the cancer harbors a mutation in PLCB4. In some embodiments, the cancer harbors a mutation in CYSLTR2. In some embodiments, the cancer harbors a mutation in BAP1. In some embodiments, the cancer harbors a mutation in SF3B1. In some embodiments, the cancer harbors a mutation in EIF1AX. In some embodiments, the cancer harbors a TFE3 translocation. In some embodiments, the cancer harbors a TFEB translocation. In some embodiments, the cancer harbors a MITF translocation. In some embodiments, the cancer harbors an EZH2 mutation. In some embodiments, the cancer harbors a SUZ12 mutation. In some embodiments, the cancer harbors an EED mutation.

[0298] In some embodiments, the method further comprises administering to 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.

[0299] 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.

[0300] 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.

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

[0302] 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 or cytotoxic 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).

[0303] 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).

[0304] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in therapy.

[0305] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in reducing the activity of BAF complexes within cells.

[0306] In some embodiments, the BAF complex is located within cancer cells.

[0307] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in the treatment of BAF complex-related disorders.

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

[0309] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in the inhibition of intracellular BRM.

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

[0311] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in the treatment of disorders associated with loss-of-function mutations of BRG1.

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

[0313] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in inducing apoptosis in cells.

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

[0315] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in the treatment of cancer.

[0316] In some embodiments, 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.

[0317] In some embodiments, 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.

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

[0319] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in the treatment of cancers selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancers.

[0320] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in reducing tumor growth of cancers selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancers.

[0321] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in inhibiting the metastatic progression of cancers selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancers.

[0322] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in inhibiting metastatic colony formation of cancers selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancers.

[0323] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in reducing the level and / or activity of BRM in cancer cells selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancers.

[0324] In some embodiments, the cells are located within the object.

[0325] In some embodiments, cancer is metastatic.

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

[0327] In some embodiments, anticancer therapy includes chemotherapeutic agents or cytotoxic agents, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation.

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

[0329] In some embodiments, anticancer therapy is a chemotherapeutic agent or a cytotoxic agent.

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

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

[0332] In some embodiments, anticancer therapies and compounds or their pharmaceutical compositions are administered within 28 days of each other, in amounts that are effective in treating the target together.

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

[0334] In some embodiments, the cancer either did not respond to one or more chemotherapeutic agents or progressed after their administration.

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

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

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

[0338] In some embodiments, the present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, for use in the treatment of viral infections.

[0339] In some embodiments, the viral infection is caused by viruses belonging to the families Retroviridae, Hepadnaviridae, Flaviviridae, Adenoviridae, Herpesviridae, Papillomaviridae, Parvoviridae, Polyomaviridae, Paramyxoviridae, or Togaviridae.

[0340] 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.

[0341] chemical terms The terms used herein are for the purpose of describing specific embodiments and are not intended to be limiting.

[0342] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in 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.

[0343] As used herein, the term "acyl" refers to H or an alkyl group bonded to a parent molecular group via a carbonyl group, as defined herein, and is exemplified by formyl (i.e., carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0344] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0345] Alkylene is a divalent alkyl group. As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms), either alone or in combination with other groups.

[0346] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms), either alone or in combination with other groups.

[0347] As used herein, the term "amino" represents -N(R N1 )2, and each R N1 is independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these listed R N1Each of the groups may be optionally substituted or two Rs N1 combine to form an alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino group of the present invention may be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2).

[0348] 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 2 or 3 rings. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0349] As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain 7 to 30 carbons (e.g., C1-C6 alkyl C6-C 10 aryl, C1-C 10 alkyl C6-C 10 aryl, or C1-C 20 alkyl C6-C 10 aryl, etc., containing 7 to 16 or 7 to 20 carbons). In some embodiments, alkyl and aryl are each further substituted with 1, 2, 3, or 4 substituents as permitted by valence, as defined herein for each group.

[0350] As used herein, the term "azide" represents a -N3 group.

[0351] As used herein, the term "bridged polycycloalkyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges. The bridged polycycloalkyl group may be unsubstituted or substituted as defined herein for cycloalkyl.

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

[0353] 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.

[0354] 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 “CH2-cycloalkyl” refers to a cycloalkyl-CH2- group (e.g., cyclopropylmethyl and cyclobutylmethyl).

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

[0356] As used herein, the term “heteroalkyl” refers to an alkyl group as defined herein, in which one or more of 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. 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 one, two, three, or four substituents with acceptable valence, as described herein for alkenyl groups. An example of a heteroalkenyl group is “alkenoxy,” which, as used herein, refers to alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group. As used herein, the term “heteroalkynyl” refers to an alkynyl group, as defined herein, in which one or more of 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.

[0357] As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic, or tricyclic group of 5 to 12 atoms having at least one aromatic ring and containing one, two, or three ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by carbonyl groups. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0358] As used herein, the term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups consist of 7 to 30 carbon atoms (e.g., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 heteroaryl, or C1-C 20 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.

[0359] 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.

[0360] 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 10Alkyl 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.

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

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

[0363] 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).

[0364] As used herein, the term "nitro" refers to the -NO2 group.

[0365] 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).

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

[0367] 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.

[0368] 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.

[0369] 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.

[0370] 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 the invention pertains. 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.

[0371] 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.

[0372] 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.

[0373] 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.

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

[0375] 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.

[0376] 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.

[0377] 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).

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

[0379] As used herein, “combination therapy” or “administered in combination” means that two (or more) different 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.

[0380] "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.

[0381] "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.

[0382] 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).

[0383] 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).

[0384] "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.

[0385] "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.

[0386] "To reduce the levels of BRG1 and / or BRM" means to decrease the levels of BRG1 and / or BRM in cells or subjects. The levels of BRG1 and / or BRM can be measured using any method known in the art.

[0387] "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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, e.g., any compound of formula I or II. A pharmaceutically acceptable salt of any of the compounds described herein may include salts that are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, or allergic reactions, are within the bounds of sound medical judgment, and 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.

[0392] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts 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.

[0393] "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.

[0394] 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.

[0395] 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.

[0396] 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]

[0397] This disclosure features compounds useful for inhibiting BRG1 and, optionally, BRM. These compounds may be used, for example, 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. The exemplary compounds described herein include compounds having a structure according to formula I or II, [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl. m is 0, 1, 2, or 3, k is 0, 1, or 2, Each R 1 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, or optionally substituted CH2-C3-C8 cycloalkyl. Each X is independently a halo. L is the linker, B is the compound that is the decomposition part. Or it contains a pharmaceutically acceptable salt thereof.

[0398] The exemplary compounds described herein include compounds having a structure according to formula I or II, [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl. m is 0, 1, 2, or 3, k is 0, 1, or 2, L is the linker, B is the decomposition part, Each R 1However, independently, these are halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heterocycline. Each X is independently a halo in the compound. Or it contains a pharmaceutically acceptable salt thereof.

[0399] The exemplary compounds described herein include compounds having a structure according to formula I or II, [ka] During the ceremony, Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl. m is 0, 1, 2, or 3, k is 0, 1, or 2, L is the linker in Equation 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 10Cycloalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O)2, or NR N wherein each R N is independently H, optionally substituted C 1~4 alkyl, optionally substituted C 2~4 alkenyl, optionally substituted C 2~4 alkynyl, optionally substituted C 2~6 heterocyclyl, optionally substituted C 6~12 aryl, or optionally substituted C 1~7 heteroalkyl, C 1 and C 2 each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, B is a cleavage moiety, each R 1 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C~C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heterocyclyl, each X is independently halo, a compound, or a pharmaceutically acceptable salt thereof is included.

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

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

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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).

[0406] 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).

[0407] 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.

[0408] 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.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody 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).

[0416] 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.

[0417] 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.

[0418] 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 the 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.

[0419] 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.

[0420] 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.

[0421] 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.

[0422] 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]

[0423] The following abbreviations will be used throughout the following examples.

[0424] [Table 2-1]

[0425] [Table 2-2]

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

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

[0428] A solution of 3-buty-1-ol (552.89 g, 7888.26 mmol, 4 equivalents) and KHCO3 (592.30 g, 5916.197 mmol, 3 equivalents) in siRNA (2600 mL) and H2O (260 mL) was stirred at room temperature. To the above mixture, 1-bromo-N-hydroxymethanecarbonimidoyl bromide (400.00 g, 1972.066 mmol, 1.00 equivalent in EA (840 mL)) was added dropwise over 60 minutes at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction mixture was washed with water (500 mL x 2), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / SiO(30:1) to obtain the title compound (338.2 g, 88.98%), a grayish-white solid intermediate. LCMS(ESI)m / z[M+H] + = 192.

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

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

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

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

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

[0434] To a stirred solution of t-BuOK (244.51 g, 2179.031 mmol, 1.5 equivalents) and ethyl 2-(3-bromoisoxazole-5-yl) acetate (340.00 g, 1452.687 mmol, 1.00 equivalent) in THF (2000 mL), 2-iodopropane (321.03 g, 1888.493 mmol, 1.3 equivalents) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature and then diluted with water / ice at 0°C. The resulting mixture was extracted with siRNA (1000 mL x 2). The combined organic layers were washed with water (500 mL x 1) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (10:1) to obtain the title compound (284.1 g, 70.82%) as a colorless oil. (LCMS(ESI)m / z[M+H]) + =276.

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

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

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

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

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

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

[0441] Preparation of 2-(3-((2-chloropyrimidine-4-yl)oxy)isoxazole-5-yl)-3-methylbutanoate methyl (intermediate 2) [ka]

[0442] A solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (200 mg, 1.004 mmol, 1 equivalent), 4-bromo-2-chloropyrimidine (233.04 mg, 1.205 mmol, 1.2 equivalents), and Cs2CO3 (981.9 mg, 3.012 mmol, 3.0 equivalents) in DMF (5 mL) was stirred at 100°C for 1 hour under a nitrogen atmosphere. 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 10% to 100% over 20 minutes; Detector: UV 254 nm. The mixture was concentrated to obtain intermediate 2 (258 mg, crude). LCMS(ESI) m / z:[M+H] + =312.

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

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

[0445] 2-Chloropyrimidine-5-carbaldehyde (5g, 35.078 mmol, 1 equivalent) and NH2OH in EtOH (250 mL) .To a stirred solution of HCl (4.93 g, 70.945 mmol, 2.02 equivalents), NaOAc (14.48 g, 176.512 mmol, 5.03 equivalents) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in SiO (500 mL), washed with brine (500 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow solid (E)-N-[(2-chloropyrimidine-5-yl)methylidene]hydroxylamine (4.6 g, crude product), which was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 158.

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

[0447] A solution of (E)-N-[(2-chloropyrimidine-5-yl)methylidene]hydroxylamine (4.6 g, 29.195 mmol, 1 equivalent) and NCS (4.4 g, 32.951 mmol, 1.13 equivalents) in DMF (150 mL) was stirred at room temperature for 2 hours. The mixture was diluted with SiO (500 mL). The resulting mixture was washed with water (3 × 300 mL) and brine (1 × 300 mL), and the organic phase was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain yellow solid (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride (4.8 g, crude product). LCMS(ESI)m / z:[M+H] + = 192.

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

[0449] A solution of (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride (4.8 g, 25.00 mmol, 1 equivalent) in siRNA (80 mL) was treated with NaHCO3 (3 g, 35.712 mmol, 1.43 equivalents) at 0°C for 30 minutes under a dry nitrogen atmosphere. Methyl buto-3-isolate (2.02 g, 20.591 mmol, 0.82 equivalents) was then added in several portions at 0°C. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water (150 mL) and extracted with siRNA (2 × 400 mL). The combined organic layers were washed with brine (1 × 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (3:1) elution to obtain a pale yellow solid methyl 2-[3-(2-chloropyrimidine-5-yl)-1,2-oxazole-5-yl]acetate (2.5 g, 38.64%). LCMS(ESI)m / z:[M+H] + = 254.

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

[0451] A solution of 2-[3-(2-chloropyrimidine-5-yl)-1,2-oxazole-5-yl]methyl acetate (3 g, 11.828 mmol, 1 equivalent) and NaOMe (1.92 g, 35.484 mmol, 3.00 equivalent) in MeOH (50 mL) was stirred at room temperature for 1 hour under a dry nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (aqueous solution). The residue was dissolved in  (300 mL). The resulting mixture was washed with water (2 × 300 mL). The combined organic layer was washed with brine (1 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain pale yellow solid [3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]acetic acid (2.5 g, crude product), which was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 236.

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

[0453] A solution of [3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]acetic acid (2.4 g, 10.204 mmol, 1 equivalent) and (trimethylsilyl) diazomethane (2.33 g, 20.408 mmol, 2 equivalents) in DCM (20 mL) and MeOH (5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (3:1) elution to obtain a white solid 2-[3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]methyl acetate (1.2 g, 45.77%). LCMS(ESI)m / z:[M+H] + =250.

[0454] Step 6: Preparation of methyl 2-[3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate. [ka]

[0455] A solution of methyl 2-[3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]acetate (2.5 g, 10.031 mmol, 1 equivalent) in THF (20 mL) was treated with t-BuOK (1.2 g, 10.694 mmol, 1.07 equivalents) at 0°C for 30 minutes under a dry nitrogen atmosphere, and then 2-iodopropane (1.5 g, 8.824 mmol, 0.88 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 12 hours. The mixture was acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with siRNA (2 × 200 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. The residue was purified by silica gel column chromatography using PE / EA (3:1) elution to obtain a yellow oily methyl 2-[3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate (310 mg, 10.08%). LCMS(ESI)m / z:[M+H] + =292.

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

[0457] A solution of 2-[3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate methyl (200 mg, 0.687 mmol, 1 equivalent) and POCl3 (1.9 mL, 20.61 mmol, 30 equivalents) in DMF (1.5 mL) was stirred at 60°C for 3 hours under a dry nitrogen atmosphere. The residue was dissolved in  (100 mL). The resulting mixture was washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain brown oily 2-[3-(2-chloropyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate methyl (160 mg, crude composition), which was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =296.

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

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

[0460] To a stirred solution of 4-formylpiperidine-1-carboxylic acid (5 g, 23.444 mmol, 1.00 equivalent) in MeOH (10 mL) and H2O (10 mL), hydroxylamine hydrochloride (1.95 g, 28.133 mmol, 1.2 equivalents) and Na2CO3 (1.24 g, 11.722 mmol, 0.5 equivalents) were added at 0°C. The resulting mixture was stirred overnight at room temperature. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a colorless oily intermediate 2 (6 g, crude). LC-MS(ESI)m / z:[M+H] + = 229.

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

[0462] A mixture of intermediate 2 and NCS (3.5 g, 26.282 mmol, 1.0 equivalent) in DMF (20 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with water (50.00 mL) and extracted with SiO (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 3 (7.8 g, crude) as a colorless oil. LC-MS(ESI) m / z[M+H]+ =263.

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

[0464] A mixture of intermediate 3 (7.8 g, crude) and NaHCO3 (3.8 g, 45.675 mmol, 1.5 equivalents) in SiO2 (100 mL) was stirred at room temperature for 30 minutes. Methylbuta-3-inoate (2.99 g, 30.450 mmol, 1 equivalent) was added to the mixture at 0°C. The resulting mixture was stirred overnight at room temperature. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column, C18 silica gel; mobile phase, MeCN in water (0.05% FA), gradient from 0% to 100% over 30 minutes; detector, UV254 nm. The resulting mixture was concentrated under reduced pressure to obtain pale yellow oily intermediate 4 (4.1 g, 41.51%). LC-MS (ESI) m / z: [M+H] + = 325.

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

[0466] To a mixture of intermediate 4 (1.0 g, 3.083 mmol, 1.5 equivalents) and Na2SO4 (1.0 g) in THF (10 mL), t-BuOK (518.90 mg, 4.625 mmol, 1.5 equivalents) and 2-iodopropane (628.87 mg, 3.700 mmol, 1.2 equivalents) were added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 3 hours. The desired product was detected by LC-MS. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water MeCN (0.05% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to obtain intermediate 5 (330 mg, 29.21%) as a pale yellow oil. LCMS(ESI)m / z:[M+H] + =367.

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

[0468] To a stirred solution of intermediate 5 (320 mg, 0.873 mmol, 1.00 equivalent) in MeOH (5 mL), LiOH (62.74 mg, 2.619 mmol, 3 equivalents) in H2O (5 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. HCl aqueous solution (6 M) was added to the mixture to adjust the pH to approximately 5. The resulting mixture was extracted with HCl (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 6 (316 mg of crude material) as a grayish-white solid. LC-MS(ESI) m / z:[M+H] + =353.

[0469] Step 6: Preparation of tert-butyl 4-(5-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)piperidine-1-carboxylate (intermediate 7) [ka]

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

[0471] Step 7: Preparation of tert-butyl 4-{5-[(2R)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazole-3-yl}piperidine-1-carboxylate (intermediate 8) [ka]

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

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

[0474] To a stirred solution of intermediate 8 (200 mg, 0.300 mmol, 1.00 equivalent) in DCM (2 mL), 1 M HCl (2 mL) in 1,4-dioxane was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure to obtain intermediate 9 (247.5 mg) as a pale yellow solid. LC-MS(ESI) m / z:[M+H] + = 566.

[0475] Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-5) [ka]

[0476] Step 1: Preparation of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl]butanoate (intermediate 2). [ka]

[0477] To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazole-5-yl)-3-methylbutanoate (100.00 mg, 0.502 mmol, 1.00 equivalent) in MeCN (0.50 mL), perfluorobutanesulfonyl fluoride (303.29 mg, 1.004 mmol, 2.00 equivalent) and K2CO3 (208.13 mg, 1.506 mmol, 3.00 equivalent) were added at room temperature. The resulting mixture was stirred for 3 hours and then carefully quenched with water at 0°C. The resulting mixture was extracted with EA (2 × 50 mL), the combined organic layers were washed with brine (50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with PE / EA (2 / 1) to obtain a white solid intermediate 2 (217 mg, crude). LCMS(ESI)m / z:[M+H] + = 482.

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

[0479] To a stirred solution of intermediate 2 (217.00 mg, 0.451 mmol, 1.00 equivalent) in DMF (3.00 mL), tert-butylpiperazine-1-carboxylate (83.98 mg, 0.451 mmol, 1.00 equivalent) was added at room temperature. The resulting mixture was stirred at 130 °C for 1 hour. The mixture was cooled to room temperature. 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. This yielded intermediate 3 (54 mg, 32.59%) as a yellow oil. LCMS(ESI)m / z:[M+H] + = 368.

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

[0481] To a stirred solution of intermediate 3 (54.00 mg, 0.147 mmol, 1.00 equivalent) in MeOH (0.80 mL), THF (0.80 mL) and H2O (0.80 mL) were added at room temperature, followed by the addition of LiOH·H2O (18.50 mg, 0.441 mmol, 3.00 equivalent). The resulting mixture was stirred further at room temperature for 1 hour. The mixture was acidified to pH 6 with HCl (1 M, aqueous solution) and then extracted with EA (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. This yielded intermediate 4 (52 mg, crude), a yellow solid. LCMS(ESI)m / z:[M+H] + =354.

[0482] Step 4: Preparation of tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazole-3-yl)piperazine-1-carboxylate (intermediate 6). [ka]

[0483] To a stirred solution of intermediate 4 (52.00 mg, 0.119 mmol, 1.00 equivalent) in DMF (2.00 mL), HATU (135.56 mg, 0.357 mmol, 3.00 equivalent) and DIEA (76.80 mg, 0.595 mmol, 5.00 equivalent) were added at room temperature. (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (70.90 mg, 0.214 mmol, 1.80 equivalent) was added at room temperature to the above mixture. The resulting mixture was stirred for a further 1 hour. The mixture was directly purified by reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0 to 100% over 30 minutes. This yielded a white solid intermediate 6 (73 mg, 92.12%). LC-MS (ESI) m / z: [M+H] + = 667.

[0484] Step 5: Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (intermediate 7) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (intermediate 8). [ka]

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

[0486] Step 6: Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4). [ka]

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

[0488] Step 7: Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-5). [ka]

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

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

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

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

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

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

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

[0496] To a stirred mixture of tert-butyl 3-{3-chlorothieno[2,3-c]pyridazin-6-yl}azetidine-1-carboxylate (122 mg, 0.374 mmol, 1.00 equivalent) and 2-hydroxyphenylboronic acid (154.94 mg, 1.122 mmol, 3 equivalents) in dioxane (4 mL) and H2O (1 mL), Cs2CO3 (244.01 mg, 0.748 mmol, 2 equivalents) and XPhos Pd G3 (63.39 mg, 0.075 mmol, 0.2 equivalents) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80°C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions. Column, C18; mobile phase, MeCN in water (0.05% FA), 40%-60% gradient. This yielded the title compound as a white solid (85 mg, 53.28%). LC-MS (ESI) m / z: [M+H] + =384.

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

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

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

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

[0501] To a stirred mixture of tert-butyl 4-ethynylpiperidine-1-carboxylate (1.00 g, 4.778 mmol, 1.00 equivalent) and 4-bromo-3,6-dichloropyridazine (1.20 g, 5.256 mmol, 1.1 equivalent) in toluene (10.00 mL), Pd(PPh3)2Cl2 (0.50 g, 0.717 mmol, 0.15 equivalent), CuI (0.18 g, 0.956 mmol, 0.2 equivalent), and TEA (1.45 g, 14.334 mmol, 3 equivalents) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was dissolved in DMF (15.00 mL) and purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, water MeCN (0.05% FA), with a gradient from 0% to 100% for 25 minutes, to obtain a brown solid intermediate 2 (596 mg, 33.61%). LCMS(ESI) m / z: [M+H]+=356.25.

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

[0503] To a stirred solution of intermediate 2 (596.00 mg, 1.673 mmol, 1.00 equivalent) in NMP (10.00 mL), NaSH (93.79 mg, 1.673 mmol, 1.0 equivalent) was added at room temperature. The resulting mixture was stirred at 100 °C for 1 hour and then cooled to room temperature. The resulting mixture was extracted with SiO (3 × 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (10.00 mL) and purified by reversed-phase flash chromatography (column, C18; mobile phase, water MeCN (0.05% FA), gradient from 0% to 100% over 30 minutes) to obtain intermediate 3 (356 mg, 49.91%), a brown solid. LCMS(ESI)m / z:[M+H]+=353.87.

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

[0505] To a solution of intermediate 3 (350.00 mg, 0.989 mmol, 1.00 equivalent) and 2-hydroxyphenylboronic acid (204.63 mg, 1.484 mmol, 1.5 equivalents) in dioxane (5.00 mL) and H2O (1.00 mL), Cs2CO3 (644.51 mg, 1.978 mmol, 2.0 equivalents) and XPhos Pd G3 (83.72 mg, 0.099 mmol, 0.1 equivalent) were added. After stirring overnight at 90°C under a nitrogen atmosphere, the mixture was concentrated under reduced pressure. The residue was dissolved in DMF (10.00 mL) and purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, water MeCN (0.05% FA), with a gradient from 0% to 100% over 20 minutes, to obtain intermediate 4 (188 mg, 44.85%), a brown solid. LCMS(ESI) m / z: [M+H]+=411.52.

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

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

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

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

[0510] To a mixture of tert-butyl 4-ethynylpiperidine-1-carboxylate (8.00 g, 38.225 mmol, 1.00 equivalent) and 4-bromo-3,6-dichloropyridazine (10.45 g, 45.870 mmol, 1.20 equivalent) in toluene (80 mL), Pd(PPh3)2Cl2 (4.02 g, 5.734 mmol, 0.15 equivalent), CuI (14.56 g, 76.450 mmol, 2.00 equivalent), and TEA (11.60 g, 114.675 mmol, 3.00 equivalent) were added under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 0% to 50% ethyl acetate in petroleum ether to obtain a yellow solid intermediate 2 (5.00 g, 36.7%). LCMS(ESI) m / z:[M+H]+=356.

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

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

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

[0514] To a mixture of intermediate 3 (1.80 g, 5.087 mmol, 1.00 equivalent) in CHCl3 (20 mL), Br2 (8.13 g, 50.870 mmol, 10.00 equivalent) was added. The resulting mixture was stirred overnight at room temperature and then basicized with aqueous NaHCO3. Next, Boc2O (2.21 g, 10.174 mmol, 2.00 equivalent) was added, and the mixture was stirred for 2 hours. The mixture was extracted with RINKAN (3 × 100 mL), the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, water MeOH, with a gradient of 10% to 50% over 10 minutes, to obtain intermediate 4 (710.0 mg, 32.4%) as a yellow solid. LCMS(ESI)m / z:[M+H]+=432.

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

[0516] Intermediate 4 (710.0 mg, 1.641 mmol, 1.00 equivalent), K3PO4 (696.50 mg, 3.282 mmol, 2.00 equivalent), and Pd(AMPhos)Cl2 (174.25 mg, 0.246 mmol, 0.15 equivalent) were mixed in dioxane (10 mL) and H2O (2 mL). Trimethyl-1,3,5,2,4,6-trioxatrivolinane (411.90 mg, 3.282 mmol, 2.00 equivalent) was added to the mixture, and the resulting mixture was stirred at 60°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through a short Celite pad and eluted with ethyl acetate. The filtrate was concentrated under vacuum, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, water MeOH, with a gradient of 10% to 50% over 10 minutes to obtain intermediate 5 (450.0 mg, 74.5%), a yellow solid. LCMS(ESI) m / z: [M+H]+=368.

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

[0518] Intermediate 5 (450.0 mg, 1.223 mmol, 1.00 equivalent) and 2-hydroxyphenylboronic acid (337.43 mg, 2.446 mmol, 2.00 equivalent) were mixed in dioxane (10 mL) and H2O (2 mL). XPhos Pd G3 (155.31 mg, 0.183 mmol, 0.15 equivalent) and Cs2CO3 (1.2 g, 3.669 mmol, 3.00 equivalent) were added, and the resulting mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through a short pad of Celite and eluted with RINKAN. The filtrate was concentrated under vacuum, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, water MeOH, with a gradient of 10% to 50% over 10 minutes to obtain intermediate 6 (380.0 mg, 73.0%), a yellow solid. LCMS(ESI) m / z: [M+H]+=426.

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

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

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

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

[0523] A solution of 6-fluoro-5-methylpyridine-3-carbaldehyde (10 mg, 0.072 mmol, 1 equivalent), hydroxylamine hydrochloride (9.99 mg, 0.144 mmol, 2 equivalents), and Na2CO3 (22.85 mg, 0.216 mmol, 3 equivalents) in MeOH (0.5 mL) and H2O (0.5 mL) was stirred overnight at 25°C. The mixture was diluted with  (200 mL) and washed with water (200 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid intermediate 2 (2.2 mg, 99.29%). LCMS(ESI)m / z:[M+H] + = 155.

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

[0525] Intermediate 2 (2.2 g, 14.272 mmol, 1 equivalent) and NCS (2.86 g, 21.408 mmol, 1.5 equivalents) were dissolved in SiO2 (20 mL), and the resulting solution was stirred overnight at 25°C. The mixture was diluted with SiO2 (100 mL) and washed with water (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid intermediate 3 (3.6 g, crude). LCMS(ESI)m / z:[M+H] + = 189.

[0526] Step 3: Preparation of 2-[3-(6-fluoro-5-methylpyridine-3-yl)-1,2-oxazole-5-yl]methyl acetate (intermediate 4) [ka]

[0527] To a solution of intermediate 3 (3.6 g, 19.089 mmol, 1 equivalent) in SiO2 (14 mL), methyl buto-3-isoate (3.75 g, 38.178 mmol, 2 equivalents) and NaHCO3 (4.81 g, 57.267 mmol, 3 equivalents) were added at 0°C. The resulting solution was stirred overnight at 25°C. The mixture was diluted with SiO2 (100 mL) and washed with water (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, with a gradient from 0% to 100% over 30 minutes to obtain intermediate 4 (2.5 g, 52.34%) as a white solid. LCMS(ESI)m / z:[M+H] + =251.

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

[0529] Intermediate 4 (500 mg, 1.998 mmol, 1 equivalent), 2-iodopropane (679.35 mg, 3.996 mmol, 2 equivalents), and Cs2CO3 (1.3 g, 3.996 mmol, 2 equivalents) were dissolved in THF (5 mL). The resulting solution was stirred overnight at 60°C. The mixture was diluted with RINKAN (100 mL) and washed with water (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0-60% ACN in H2O to obtain the title compound (288 mg, 49.31%) as a white solid. LCMS(ESI)m / z:[M+H] + =293.

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

[0531] Step 1: Preparation of 2-cyano-2-cyclopropyl acetate tert-butyl (intermediate 2) [ka]

[0532] To a solution of 2-cyclopropylacetonitrile (10.00 g, 123.277 mmol, 1 equivalent) and Boc2O (53.81 g, 246.554 mmol, 2 equivalents) in THF (100 mL), LDA (26.41 g, 246.554 mmol, 2 equivalents) was added at -78 °C. After stirring at -78 °C for 2 hours, the reaction mixture was quenched with water (100 mL) at 0 °C. The resulting mixture was extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0% to 20% siRNA in PE to obtain a yellow solid intermediate 2 (20.00 g, 80.57%). No Ms signal was detected by 1H-NMR.

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

[0534] To a solution of intermediate 2 (15.00 g, 82.765 mmol, 1 equivalent) and 3,4,6-trichloropyridazine (15.18 g, 82.765 mmol, 1 equivalent) in DMSO (100 mL), DIEA (32.09 g, 248.295 mmol, 3 equivalents) was added. After stirring overnight at room temperature under a nitrogen atmosphere, the resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with RINKAN (500 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0% to 50% RINKAN in PE to obtain intermediate 3 (18.00 g, 59.64%), a pink solid. LCMS(ESI)m / z:[M+H] + = 328.

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

[0536] To a solution of intermediate 3 (10.00 g, 30.470 mmol, 1 equivalent) in DMSO (50 mL) and H2O (5 mL), NaCl (3.56 g, 60.940 mmol, 2 equivalents) was added. After stirring at 100°C for 3 hours, the resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with HCl (500 mL x 3). The combined organic layer was washed with brine (500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0% to 50% HCl in PE to obtain intermediate 4 (5.00 g, 64.7%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 228.

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

[0538] To a solution of intermediate 4 (3.00 g, 13.153 mmol, 1 equivalent) in NMP (50 mL), NaHS.2H2O (1.21 g, 13.153 mmol, 1 equivalent) was added. After stirring at 100°C for 20 minutes, the resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with HCl (200 mL x 3). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0% to 50% HCl in PE to obtain intermediate 5 (2.00 g, 60.6%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 226.

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

[0540] To a solution of intermediate 5 (2.00 g, 8.862 mmol, 1 equivalent) and CuCl2 (2.38 g, 17.724 mmol, 2 equivalents) in ACN (50 mL), t-BuNO2 (1.83 g, 17.724 mmol, 2 equivalents) was added. After stirring at 50°C for 3 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0% to 50% SiO2 in PE to obtain intermediate 6 (1.00 g, 41.4%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 245.

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

[0542] To a solution of intermediate 6 (1.00 g, 4.080 mmol, 1 equivalent) and 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (1.62 g, 8.160 mmol, 2 equivalents) in DMSO (20 mL), DIEA (1.58 g, 12.240 mmol, 3 equivalents) was added. After stirring at 100°C for 3 hours under a nitrogen atmosphere, the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with SiO2 (100 mL x 3). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0% to 50% SiO2 in PE to obtain intermediate 7 (900.0 mg, 48.7%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 407.

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

[0544] To a solution of intermediate 7 (900.0 mg, 2.212 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (610.11 mg, 4.424 mmol, 2 equivalents) in dioxane (20 mL) and H2O (4 mL), Cs2CO3 (2161.8 mg, 6.636 mmol, 3 equivalents) and XPhos Pd G3 (187.2 mg, 0.221 mmol, 0.1 equivalent) were added. After stirring at 80°C for 1 hour under a nitrogen atmosphere, the resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with RINKAN (50 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, ACN in water, 10% to 50% gradient over 10 minutes; detector; purified by reverse-phase flash chromatography at UV 254 nm to obtain a yellow solid intermediate 8 (800.0 mg, 70.0%). LCMS(ESI) m / z:[M+H] + = 465.

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

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

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

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

[0549] To a solution of 3,6-dichloro-5-methylthieno[2,3-c]pyridazine (639.12 mg, 2.916 mmol, 2.41 equivalents) in DMSO (8 mL), 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (240 mg, 1.210 mmol, 1.00 equivalent) and DIEA (469.36 mg, 3.630 mmol, 3 equivalents) were added. The resulting mixture was stirred at 60°C for 6 hours under a nitrogen atmosphere. The desired product could be detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water MeCN (0.1% FA), gradient from 10% to 80% over 30 minutes; detector, UV 254 nm. This yielded a yellow, oily intermediate 2 (280 mg, 42.51%). LCMS(ESI)m / z:[M+H] + =381.

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

[0551] A solution of 6-{3-chloro-5-methylthieno[2,3-c]pyridazin-6-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (300 mg, 0.788 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (217.28 mg, 1.576 mmol, 2 equivalents) in dioxane (6 mL) and H2O (1 mL) was prepared by adding Cs2CO3 (769.87 mg, 2.364 mmol, 3 equivalents) and XPhos Pd G3 (66.67 mg, 0.079 mmol, 0.1 equivalent). The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using PE / EA (1:1) elution to obtain intermediate 3 (160 mg, 46.32%), a yellow solid. LCMS(ESI)m / z[M+H]+ = 439.

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

[0553] A solution of intermediate 3 (150 mg, 0.342 mmol, 1 equivalent) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The resulting mixture was concentrated under vacuum. This yielded a yellow, oily I-12 (100 mg, 86.39%). LC-MS (ESI) m / z: [M + H] + =339.

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

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

[0556] To a stirred solution of 4-bromo-6-chloropyridazine-3-amine (43.00 g, 206.294 mmol, 1 equivalent) and CH2I2 (66.30 g, 247.553 mmol, 1.2 equivalents) in THF (300 mL), CuI (47.15 g, 247.553 mmol, 1.2 equivalents) and t-BuNO2 (25.53 g, 247.553 mmol, 1.2 equivalents) were added. The resulting mixture was stirred overnight at 60°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain a pale yellow solid intermediate 2 (25.00 g, 58.1%). LCMS(ESI)m / z:[M+H] + =319.

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

[0558] Intermediate 2 (25.00 g, 78.291 mmol, 1 equivalent) and 2-methyl-2-propantheol (7.77 g, 86.120 mmol, 1.1 equivalent) were stirred in DMF (300 mL) and Cs2CO3 (76.3 g, 234.873 mmol, 3 equivalents) was added. The resulting mixture was stirred at 100°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with SiO2 (3 × 500 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / SiO2 (10:1) to obtain intermediate 3 (16.00 g, 62.2%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 329.

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

[0560] A solution of intermediate 3 (16.00 g, 48.691 mmol, 1 equivalent) in 1,4-dioxane, tert-butyl cyanoacetate (13.75 g, 97.382 mmol, 2 equivalents), and Cs2CO3 (47.4 g, 146.073 mmol, 3 equivalents) was stirred at room temperature for 30 minutes. Picolinic acid (3.00 g, 24.346 mmol, 0.5 equivalents) was added to the mixture. The resulting mixture was stirred at 80°C for a further 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (10:1) elution to obtain intermediate 4 (5.30 g, 33.1%), a yellowish-brown solid. LCMS(ESI)m / z:[M+H] + =342.

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

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

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

[0564] To a solution of intermediate 5 (3.60 g, 19.393 mmol, 1 equivalent) and CuCl (3.84 g, 38.786 mmol, 2 equivalents) in MeCN (50 mL), tert-butyl nitrite (4.00 g, 38.789 mmol, 2 equivalents) was added in several portions at 0°C. The resulting mixture was stirred at 50°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / SiO(1:1) elution to obtain a light brown solid intermediate 6 (543.0 mg, 15.0%). LCMS(ESI)m / z:[M+H] + = 205.

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

[0566] To a stirred solution of intermediate 6 (543.0 mg, 2.648 mmol, 1 equivalent) and 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (525.01 mg, 2.648 mmol, 1 equivalent) in DMSO (8 mL), DIEA (1.03 g, 7.944 mmol, 3 equivalents) was added. The resulting mixture was stirred at 100°C for 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C 18 Silica gel; mobile phase: MeCN (0.1% FA) in water, gradient from 10% to 50% over 10 minutes; detector: UV 254 nm. This yielded a yellowish-brown solid intermediate 7 (253.0 mg, 46.5%). LC-MS (ESI) m / z: [M+H] + =367.

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

[0568] To a solution of intermediate 7 (253.0 mg, 0.690 mmol, 1 equivalent) and 2-(methoxymethoxy)phenylboronic acid (125.5 mg, 0.690 mmol, 1 equivalent) in 1,4-dioxane (4 mL) and H2O (1 mL), K3PO4 (292.7 mg, 1.380 mmol, 2 equivalents) and (DiMeIHeptCl)Pd(cinnamyl)Cl (80.5 mg, 0.069 mmol, 0.1 equivalent) were added. The resulting mixture was stirred for 2 hours and concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with  (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column, C 18 Silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. This yielded a yellowish-brown solid intermediate 8 (98.0 mg, 41.8%). LC-MS (ESI) m / z: [M+H] + = 469.

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

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

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

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

[0573] A solution of 5-bromo-2-methoxypyrimidine (9 g, 47.616 mmol, 1 equivalent), piperazine-1-carboxylate tert-butyl (13.30 g, 71.424 mmol, 1.5 equivalents), Pd2(dba)3 (2.18 g, 2.381 mmol, 0.05 equivalents), and BINAP (2.96 g, 4.762 mmol, 0.1 equivalents) in toluene (75 mL) was stirred at 80°C for 6 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, ACN in H2O, with a gradient from 0% to 25% over 30 minutes to obtain a white solid intermediate 2 (4.2 g, 29.97%). LC-MS(ESI) m / z:[M+H] + =295.

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

[0575] The solution of intermediate 2 (4.2 g, 14.268 mmol, 1 equivalent) in TFA (10 mL) and DCM (30 mL) was stirred at 25°C for 5 hours. The DCM in the reaction solution was removed by rotation under vacuum to obtain a yellow, oily crude intermediate 3 (10.0 g, crude substance). LCMS(ESI)m / z:[M+H] + = 195.

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

[0577] Intermediate 3 (10 g, 51.483 mmol, 1 equivalent) in DMSO (40 mL), methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl}butanoate (24.78 g, 51.483 mmol, 1 equivalent) and DIEA (19.96 g, 154.449 mmol, 3 equivalents) were mixed, and the resulting solution was stirred overnight at 100°C. 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, gradient from 0% to 30% over 30 minutes; detector, UV220 / 200 nm, to obtain intermediate 4 (3.7 g, 19.14%). LCMS(ESI)m / z:[M+H] + =376.

[0578] Step 4: Preparation of 2-{3-[4-(2-chloropyrimidine-5-yl)piperazin-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoate methyl (intermediate 5) [ka]

[0579] The solution of intermediate 4 (900 mg, 2.397 mmol, 1 equivalent) in POCl3 (6 mL) was stirred at 110°C for 18 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 (0.1% FA) in water, gradient from 0% to 58% over 30 minutes; detector, UV220 / 200 nm. This yielded intermediate 5 (360 mg, 39.53%), a yellow solid.

[0580] Step 5: Preparation of methyl 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidine-1-yl}pyrimidine-5-yl)piperazin-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoate methyl (intermediate 6) [ka]

[0581] Intermediate 5 (200 mg, 0.527 mmol, 1 equivalent) and 2-[5-methyl-6-(piperidine-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (342.69 mg, 1.054 mmol, 2 equivalents) are dissolved in dioxane (4 mL), and Cs2CO3 (343.10 mg, 1.054 mmol, 2 equivalents) and Pd-PEPPSI-IPentCl2-methylpyridine (o-pico Phosphorus (88.58 mg, 0.105 mmol, 0.2 equivalents) was added, and the resulting solution was stirred overnight at 90°C. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel; mobile phase, PE in EA, 0%~56% to obtain intermediate 6 (100 mg, 28.4%), a yellow solid. LC-MS(ESI)m / z:[M+H] + = 668.

[0582] Step 6: Preparation of 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidine-1-yl}pyrimidine-5-yl)piperazin-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoic acid (intermediate 7) [ka]

[0583] To a solution of methyl intermediate 6 (95 mg, 0.142 mmol, 1 equivalent) in MeOH (4 mL) and H2O (1 mL), LiOH (27.22 mg, 1.136 mmol, 8 equivalents) was added, and the resulting solution was stirred at room temperature for 16 hours. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). The mixture was diluted with SiO2 (50 mL) and washed with water (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid intermediate 7 (98 mg, crude), which was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 655.

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

[0585] Intermediate 7 (98 mg, 0.150 mmol, 1 equivalent) in DMF (2 mL), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (99.21 mg, 0.300 mmol, 2 equivalents) and PyBOP (155.77 mg, 0.300 mmol, 2 equivalents) were mixed and stirred at 25°C for 10 minutes. Then DIEA (96.72 mg, 0.750 mmol, 5 equivalents) was added to the mixture. The resulting solution was stirred at 25°C for 2 hours. The reaction product was purified by flash C18 chromatography with an elution gradient of 0-83% ACN in H2O to obtain intermediate 8 (87 mg, 59.28%), which was a yellow solid. LCMS(ESI)m / z:[M+H] + =968.

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

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

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

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

[0590] A stirred mixture of 2-(benzyloxy)acetaldehyde (10 g, 66.588 mmol, 1 equivalent) and Na2CO3 (3.53 g, 33.294 mmol, 0.5 equivalents) in EtOH (100 mL) was mixed with NH2OH.HCl (5.09 g, 73.247 mmol, 1.1 equivalents) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with SiO2 (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a colorless liquid intermediate 2 (13.196 g, crude). LC-MS (ESI) m / z: [M + H] + = 166.

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

[0592] A mixture of intermediate 2 (12 g, 72.643 mmol, 1 equivalent) and NCS (10.67 g, 79.907 mmol, 1.1 equivalents) in DMF (100 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with brine (200 mL). The resulting mixture was extracted with SiO (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 3 (18.1 g, crude) as a pale blue liquid. LC-MS(ESI) m / z[M+H] + = 200.

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

[0594] A mixture of intermediate 3 (12 g, 60.111 mmol, 1 equivalent) and NaHCO3 (7.57 g, 90.166 mmol, 1.5 equivalents) in EA (100 mL) was stirred at room temperature for 30 minutes. Methyl buto-3-isoate (5.90 g, 60.111 mmol, 1 equivalent) was added dropwise to the mixture at 0°C. The resulting mixture was stirred further at room temperature overnight. The desired product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 220 nm, to obtain a yellow liquid intermediate 4 (8.3 g, crude). LC-MS (ESI) m / z: [M+H] + = 262.

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

[0596] Intermediate 4 (8 g, 30.619 mmol, 1 equivalent) and MgSO4 (7.37 g, 61.238 mmol, 2 equivalents) were stirred in THF (80 mL), to which t-BuOK (15.31 mL, 15.309 mmol, 0.5 equivalents) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 30 minutes. 2-iodopropane (6.25 g, 36.743 mmol, 1.2 equivalents) was added to the above mixture at 0°C. The resulting mixture was further stirred at room temperature overnight. The desired product could be detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with DMF (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water MeCN (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 220 nm, to obtain intermediate 5 (4.18 g, 45.00%), a brown liquid. LCMS(ESI) m / z:[M+H] + =304.

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

[0598] A mixture of intermediate 5 and BBr3 (9.91 g, 39.558 mmol, 3 equivalents) in DCM (40 mL) was stirred under a nitrogen atmosphere at 0°C for 2 hours. The desired product was detected by LC-MS. The reaction mixture was quenched with water / ice at 0°C. The resulting mixture was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a yellow, oily intermediate 6 (1.5 g, pure). LC-MS(ESI) m / z:[M+H] + = 214.

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

[0600] A mixture of methyl intermediate 6 and Dess Martin (1193.46 mg, 2.814 mmol, 1.2 equivalents) in DCM (5 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The reaction was quenched by adding NaHCO3 (aqueous solution) and Na2S2O3 (aqueous solution) (200 mL) at room temperature. The resulting mixture was extracted with SiO2 (3 × 200 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow liquid intermediate 7 (530 mg, crude). LC-MS (ESI) m / z: [M + H] + = 212.

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

[0602] To a stirred mixture of intermediate 7 (500 mg, 2.367 mmol, 1 equivalent) and K2CO3 (981.49 mg, 7.101 mmol, 3 equivalents) in MeOH (5 mL), Seyfers-Gilbert homologation (682.16 mg, 3.550 mmol, 1.5 equivalents) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The desired product could be detected by LC-MS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water MeCN (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain pale yellow oily intermediate 8 (320 mg, 65.23%). LCMS(ESI) m / z:[M+H] + = 208.

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

[0604] A mixture of intermediate 8 (165.33 mg, 0.627 mmol, 1 equivalent), [1,3-bis[2,6-bis(propan-2-yl)phenyl]-2,3-dihydro-1H-imidazole-2-yl]dichloro(3-chloropyridine-1-ium-1-yl)palladium (42.62 mg, 0.063 mmol, 0.1 equivalent), CuI (11.95 mg, 0.063 mmol, 0.1 equivalent), and DIEA (405.40 mg, 3.135 mmol, 5 equivalents) in DMF (4 mL) was stirred at 80°C for 3 hours under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water MeCN (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain intermediate 9 (150 mg, 61.33%), a brown solid. LCMS(ESI)m / z:[M+H] + =389.

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

[0606] A mixture of intermediate 9 (159.21 mg, 1.155 mmol, 3 equivalents), XPhos Pd G3 (65.14 mg, 0.077 mmol, 0.2 equivalents), and Cs2CO3 (376.09 mg, 1.155 mmol, 3 equivalents) in dioxane (3 mL) and H2O (0.6 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 resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with RINKAN (3 × 200 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water MeCN (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain a reddish-brown solid intermediate 10 (109 mg, 63.30%). LCMS(ESI) m / z:[M+H] + = 448.

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

[0608] A mixture of intermediate 10 (100 mg, 0.223 mmol, 1 equivalent) and LiOH.H2O (26.76 mg, 1.115 mmol, 5 equivalents) in THF (3 mL) and H2O (3 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was concentrated under reduced pressure to obtain intermediate 11 (400 mg, crude), a brown solid. LC-MS(ESI)m / z:[M+H] + = 434.

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

[0610] A mixture of intermediate 11 (100 mg, 0.231 mmol, 1 equivalent), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (76.46 mg, 0.231 mmol, 1 equivalent), PyBOP (180.08 mg, 0.347 mmol, 1.5 equivalents), and DIEA (119.26 mg, 0.924 mmol, 4 equivalents) in DMF (2 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 (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes; Detector: Reverse-phase flash chromatography at UV 254 nm was used to obtain a yellow solid intermediate 12 (150 mg, 87.06%). LCMS(ESI) m / z:[M+H] + = 747.

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

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

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

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

[0615] Intermediate 2 (6.4 g, 21.816 mmol, 1.00 equivalent) was dissolved in DCM (60.0 mL) and TFA (20.0 mL). After stirring at room temperature for 1 hour, the desired product could be detected by LC-MS. The resulting mixture was concentrated under vacuum. This yielded a green, oily intermediate 3 (5.3 g, crude). LC-MS(ESI) m / z:[M+H] + = 194.

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

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

[0618] Step 4: Preparation of 2-{3-[4-(2-chloropyrimidine-5-yl)piperidine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoate methyl. Preparation of (intermediate 5). [ka]

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

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

[0621] To a solution of intermediate 5 (75.0 mg, 0.198 mmol, 1.00 equivalent) and 2-[5-methyl-6-(piperidine-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (77.3 mg, 0.238 mmol, 1.20 equivalents) in NMP (2 mL), K2CO3 (54.7 mg, 0.396 mmol, 2.00 equivalents) was added. After stirring at 100°C for 3 hours, the desired product could be detected by LC-MS. The crude product was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel, mobile phase: MeCN in water (0.05% FA), gradient from 0% to 100% over 30 minutes; detector: UV 254 nm) to obtain pale yellow solid intermediate 6 (58.0 mg, 43.87%). LCMS(ESI)m / z:[M+H] + = 668.

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

[0623] Intermediate 6 (58.0 mg, 0.087 mmol, 1.00 equivalent) and LiOH (6.3 mg, 0.261 mmol, 3.00 equivalent) were dissolved in MeOH (1.0 mL) and H2O (1.0 mL). After stirring at room temperature for 1 hour, the desired product could be detected by LC-MS. The resulting mixture was extracted with EA (3 × 3.0 mL). The combined organic layers were washed with water (1 × 3.0 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 7 (48.0 mg, crude), a white solid. LC-MS(ESI)m / z:[M+H] + = 654.

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

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

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

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

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

[0629] 2S,4R)-4-hydroxy-1-((R)-2-(3-((1s,4S)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)pyrimidine-5-yl)cyclohexyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide and (2S,4R)- Preparation of 4-hydroxy-1-((R)-2-(3-((1r,4R)-4-(2-(4-(3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)pyrimidine-5-yl)cyclohexyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compounds 64 and 65) [ka]

[0630] Step 1: Preparation of 4-(2-methoxypyrimidine-5-yl)cyclohexy-3-ene-1-carboxylate ethyl (intermediate 2). [ka]

[0631] A stirred solution of 5-bromo-2-methoxypyrimidine (3.37 g, 17.846 mmol, 1 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexy-3-ene-1-carboxylate ethyl (5 g, 17.846 mmol, 1.00 equivalent) in 1,4-dioxane (40 mL) and H2O (10 mL) is prepared by adding Pd(dppf)Cl 2.CH2Cl2 (1.45 g, 1.785 mmol, 0.1 equivalent) and K2CO3 (7.40 g, 53.538 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA(1 / 2) elution to obtain a yellow oily intermediate 2 (3.8, 81.4%). LCMS(ESI)m / z:[M+H] + =263.

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

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

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

[0635] To a stirred solution of intermediate 3 (4 g, 15.133 mmol, 1 equivalent) in THF (50 mL), LiAlH4 (0.57 g, 15.133 mmol, 1 equivalent) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 1 hour. The reaction product was quenched with water at 0°C. The resulting mixture was extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded a yellow, oily intermediate 4 (566 mg, 16.83%). LCMS(ESI)m / z:[M+H] + =223.

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

[0637] To a stirred solution of (COCl)2 (969.51 mg, 7.638 mmol, 3 equivalents) in DCM (10 mL), DMSO (795.75 mg, 10.184 mmol, 4 equivalents) was added under a nitrogen atmosphere at -78°C. The resulting mixture was stirred under a nitrogen atmosphere at -78°C for 30 minutes. Intermediate 4 (566 mg, 2.546 mmol, 1 equivalent) was added to the above mixture under a nitrogen atmosphere at -78°C. The resulting mixture was stirred under a nitrogen atmosphere at -78°C for a further 30 minutes. Et3N (1.29 g, 12.730 mmol, 5 equivalents) was added to the above mixture under a nitrogen atmosphere at -78°C. The resulting mixture was stirred under a nitrogen atmosphere from -78°C to room temperature for a further 1 hour. The reaction product was quenched with water at room temperature and extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 5 (450 mg, 79.5%), a yellowish oily substance. LC-MS(ESI) m / z:[M+H] + =221.

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

[0639] To a stirred solution of hydroxylamine hydrochloride (2.46 g, 35.412 mmol, 3 equivalents) in MeOH (8 mL) and H2O (8 mL), Na2CO3 (3.75 g, 35.412 mmol, 3 equivalents) was added at 0°C. Intermediate 5 (2.6 g, 11.804 mmol, 1 equivalent) was added to the above mixture at 0°C. The resulting mixture was stirred further at room temperature for 1 hour. The reaction products were quenched with water at 0°C. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded a yellow, oily intermediate 6 (2.8 g, crude). LCMS(ESI)m / z:[M+H] + = 236.

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

[0641] To a stirred solution of intermediate 6 (2.8 g, 11.900 mmol, 1 equivalent) in EA (30 mL), NCS (1.91 g, 14.280 mmol, 1.2 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The mixture was diluted with SiO2 (80 mL) and washed with water (80 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 7 (3.2 g, crude), a yellow solid crude product. LC-MS(ESI)m / z:[M+H] + =270.

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

[0643] To a stirred solution of intermediate 7 (3.2 g, 11.864 mmol, 1 equivalent) in EA (30 mL), NaHCO3 (2.99 g, 35.592 mmol, 3 equivalents) was added at 0°C. Methyl buto-3-isoate (4.66 g, 47.456 mmol, 4 equivalents) was added to the above mixture at 0°C. The resulting mixture was stirred at room temperature for a further 16 hours. The reaction product was quenched with water. The resulting mixture was extracted in EA (2 × 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: MeCN (0.1% FA) in water; Direct purification by reverse-phase flash chromatography with a gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded a brown, oily intermediate 8 (2.7 g, 68.68%). LC-MS (ESI) m / z: [M+H] + =332.

[0644] Step 8: Preparation of 2-(3-(4-(2-methoxypyrimidine-5-yl)cyclohexyl)isoxazole-5-yl)-3-methylbutanoate methyl (intermediate 9). [ka]

[0645] To a stirred solution of intermediate 8 (2.7 g, 8.148 mmol, 1 equivalent) in THF (15 mL), t-BuOK (2.74 g, 24.444 mmol, 3 equivalents) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 30 minutes. To the above mixture, 2-iodopropane (2.77 g, 16.296 mmol, 2 equivalents) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction products were quenched with water at 0°C. The resulting mixture was extracted with DCM (2 × 200 mL). The combined organic layers were concentrated under reduced pressure. This yielded brown, oily 2-{3-[4-(2-methoxypyrimidine-5-yl)cyclohexyl]-1,2-oxazole-5-yl}-3-methylbutanoic acid (2 g, crude). The product was dissolved in DCM (16 mL) and MeOH (4 mL), and TMSCHN2 (1.91 g, 16.692 mmol, 3 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water at 0°C. The resulting mixture was extracted with DCM (2 × 100 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: MeCN (0.1% FA) in water; Direct purification by reversed-phase flash chromatography with a gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded a brownish oily intermediate 9 (795 mg, 38.26%). LCMS(ESI)m / z:[M+H] + =374.

[0646] Step 9: Preparation of 2-(3-(4-(2-chloropyrimidine-5-yl)cyclohexyl)isoxazole-5-yl)-3-methylbutanoate methyl (intermediate 10). [ka]

[0647] To a stirred solution of intermediate 9 (795 mg, 2.129 mmol, 1 equivalent) in DMF (5 mL), POCl3 (979.15 mg, 6.387 mmol, 3 equivalents) was added at room temperature. The resulting mixture was stirred at 80°C for 16 hours. The mixture was cooled to room temperature. The residue was purified by reversed-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: MeCN in water (0.1% FA); Direct purification by reversed-phase flash chromatography with a gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded a brownish oily intermediate 10 (154 mg, 19.14%). LCMS(ESI)m / z:[M+H] + = 378.

[0648] Step 10: Preparation of 2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidine-1-yl}pyrimidine-5-yl)cyclohexyl]-1,2-oxazole-5-yl}-3-methylbutanoate methyl (intermediate 11). [ka]

[0649] To a stirred solution of intermediate 10 (100 mg, 0.265 mmol, 1 equivalent) and 2-[5-methyl-6-(piperidine-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (103.35 mg, 0.318 mmol, 1.2 equivalents) in DMSO (5 mL), DIEA (102.61 mg, 0.795 mmol, 3.0 equivalents) was added at room temperature under a nitrogen atmosphere. The resulting mixture 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, MeOH in water (0.1% FA), gradient from 0% to 100% over 25 minutes; detector, UV 254 nm. This yielded intermediate 11 (105 mg, 59.50%), a pale yellow solid. LCMS(ESI)m / z:[M+H] + = 667.

[0650] Step 11: Preparation of 2-(3-(4-(2-chloropyrimidine-5-yl)cyclohexyl)isoxazole-5-yl)-3-methylbutanoate methyl (intermediate 12). [ka]

[0651] To a stirred solution of intermediate 11 (100 mg, 0.150 mmol, 1 equivalent) in MeOH (5 mL), LiOH (17.96 mg, 0.750 mmol, 5.0 equivalents) in H2O (2 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with HCl (aqueous solution). The resulting mixture was extracted with HCl (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 12 (85 mg, 86.83%), a pale yellow solid. LCMS(ESI)m / z:[M+H] + = 653.

[0652] Step 12: Preparation of (2S,4R)-4-hydroxy-1-(2-{3-[4-(2-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidine-1-yl}pyrimidine-5-yl)cyclohexyl]-1,2-oxazole-5-yl}-3-methylbutanoyl)-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 13). [ka]

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

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

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

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

[0657] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1) [ka]

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

[0659] To a solution of 3,6-dichloro-4-iodopyridazine (1 g, 3.638 mmol, 1 equivalent) and 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl (0.81 g, 3.638 mmol, 1 equivalent) in toluene (10 mL), Pd(PPh3)2Cl2 (0.26 g, 0.364 mmol, 0.1 equivalent) and TEA (1.10 g, 10.914 mmol, 3 equivalents) were added, and the resulting solution was stirred at 60°C for 6 hours. The mixture was diluted with HCl (400 mL) and washed with water (400 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography with an elution gradient of 0-43% PE in EA to obtain intermediate 2 (1.11 g, 82.85%), a brown solid. LCMS(ESI)m / z:[M+H] + = 368.

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

[0661] To a solution of intermediate 2 (1.1 g, 2.987 mmol, 1 equivalent) in NMP (10 mL), NaSH (0.17 g, 2.987 mmol, 1 equivalent) was added, and the resulting solution was stirred at 100°C for 6 hours. Without further workup, the crude reaction solution was purified by flash C18 chromatography with an elution gradient of 0% to 46% ACN in H2O to obtain intermediate 3 (422 mg, 38.61%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 366.

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

[0663] To a solution of tert-butyl intermediate 3 (400 mg, 1.093 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (226.19 mg, 1.639 mmol, 1.5 equivalents) in 1,4-dioxane (4 mL) and H2O (1 mL), XPhos Pd G3 (92.54 mg, 0.109 mmol, 0.1 equivalent) and Cs2CO3 (712.41 mg, 2.186 mmol, 2 equivalents) were added, and the resulting solution was stirred at 80°C for 3 hours. The mixture was diluted with RINKAN (300 mL) and washed with water (300 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0-41% ACN in H2O to obtain intermediate 4 (347 mg, 74.94%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 424.

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

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

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

[0667] Intermediate 5 (250 mg, 0.773 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 (372.04 mg, 0.773 mmol, 1 equivalent) were dissolved in DMSO (3 mL), to which DIEA (299.73 mg, 2.319 mmol, 3 equivalents) was added, and the resulting solution was stirred at 100 °C for 5 hours. The crude reaction solution was purified by flash C18 chromatography with an elution gradient of 0-45% ACN in H2O to obtain intermediate 6 (203 mg, 52.04%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 505.

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

[0669] To a solution of intermediate 6 (200 mg, 0.396 mmol, 1 equivalent) in MeOH (2 mL) and H2O (0.5 mL), LiOH (47.46 mg, 1.980 mmol, 5 equivalents) was added, and the resulting solution was stirred at 25°C for 2 hours. The mixture was acidified to pH 5-6 with HCl (1 M in H2O). The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 7 (297 mg, crude), a brown solid. LCMS(ESI)m / z:[M+H] + =491.

[0670] Step 7: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 8) [ka]

[0671] To a solution of intermediate 7 (200 mg, 0.408 mmol, 1 equivalent) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (270.24 mg, 0.816 mmol, 2 equivalents) in DMF (3 mL), PyBOP (424.31 mg, 0.816 mmol, 2 equivalents) and DIEA (263.46 mg, 2.040 mmol, 5 equivalents) were added, and the resulting solution was stirred at 25°C for 2 hours. Without further workup, the crude reaction solution was purified by flash C18 chromatography with an elution gradient of 0% to 52% ACN in H2O to obtain intermediate 8 (184 mg, 56.2%). LCMS(ESI)m / z:[M+H] + = 804.

[0672] Step 7: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3,3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka]

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

[0674] The compounds in Table 2 were prepared using the same procedure as used above to prepare (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 1).

[0675] [Table 3-1]

[0676] [Table 3-2]

[0677] [Table 3-3]

[0678] [Table 3-4]

[0679] [Table 3-5]

[0680] [Table 3-6]

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

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

[0683] The resulting solution was stirred at 25°C for 0.5 hours. Then, t-BuNO2 (2.47 g, 23.988 mmol, 1 equivalent) was added to a solution of 4-bromo-6-chloropyridazine-3-amine (5 g, 23.988 mmol, 1 equivalent) and CuI (5.48 g, 28.786 mmol, 1.2 equivalents) in THF (60 mL) and CH2I2 (7.71 g, 28.786 mmol, 1.2 equivalents). The crude product was purified by silica column chromatography with an elution gradient of 0-80% EA in PE to obtain intermediate 2 (2.9 g, 37.86%), a yellow solid. LCMS(ESI)m / z:[M+H] + =319.

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

[0685] Intermediate 2 (2 g, 6.263 mmol, 1 equivalent) in methylbenzene (15 mL, 0.011 mmol) and TEA (1.90 g, 18.789 mmol, 3 equivalents), and 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.56 g, 6.263 mmol, 1 equivalent), Pd(PPh3)2Cl2 (0.88 g, 1.253 mmol, 0.2 equivalents), and CuI (0.24 g, 1.253 mmol, 0.2 equivalents) were mixed and stirred at 25°C for 2 hours. The crude product was purified by silica column chromatography with an elution gradient of 0-17% EA in PE to obtain yellow oily intermediate 3 (1.6 g, 57.96%). LCMS(ESI)m / z:[M+H] + = 441.

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

[0687] Intermediate 3 (1.6 g, 3.630 mmol, 1 equivalent) and NaSH (203.50 mg, 3.630 mmol, 1 equivalent) were dissolved in NMP (10 mL, 51.850 mmol), and the resulting solution was stirred at 100°C for 2 hours. The resulting mixture was diluted with EA (400 mL) and washed with water (3 × 400 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 column chromatography with an elution gradient of 0-34% EA in PE to obtain an orange solid intermediate 4 (890 mg, 62.24%). LCMS(ESI) m / z: [M+H]+=394.

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

[0689] Intermediate 4 (890 mg, 2.259 mmol, 1 equivalent) and a solution of 2-hydroxyphenylboronic acid (467.43 mg, 3.388 mmol, 1.5 equivalents), Cs2CO3 (1.47 g, 4.518 mmol, 2 equivalents), and XPhos Pd G3 (191.24 mg, 0.226 mmol, 0.1 equivalent) in 1,4-dioxane (4 mL) and H2O (1 mL) were stirred at 80°C for 2 hours. The resulting mixture was diluted with EA (400 mL) and washed with water (3 × 400 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 column chromatography with an elution gradient of 0-15% EA in PE to obtain brown oily intermediate 5 (571 mg, 55.97%). LCMS(ESI)m / z:[M+H] + = 452.

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

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

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

[0693] Intermediate 6 (300 mg, 0.854 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 (410.81 mg, 0.854 mmol, 1.0 equivalent) were dissolved in DMSO (5 mL), to which DIEA (330.96 mg, 2.562 mmol, 3.0 equivalents) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography under the following conditions: Column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 100% over 10 minutes; detector, UV 254 nm. This yielded a yellowish-brown solid intermediate 7a (181 mg, 26.03%). LC-MS (ESI) m / z: [M+H] + = 815.

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

[0695] Intermediate 7 (170 mg, 0.209 mmol, 1 equivalent) and NaOH (83.46 mg, 2.090 mmol, 10 equivalents) were dissolved in MeOH (4 mL) and H2O (1 mL), and the resulting solution was stirred at 25°C for 4 hours. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with SiO (3 × 200 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 (155 mg, crude), a brown solid. LCMS(ESI)m / z:[M+H] + = 519.

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

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

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

Chem.

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

Chem.

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

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

[0702] A solution of 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)-5-methylpyridine-3-yl)isoxazole-5-yl)-3-methylbutanoate methyl (50 mg, 0.086 mmol, 1 equivalent) in MeOH (2 mL) was treated with LiOH.H2O (20.52 mg, 0.860 mmol, 10 equivalents) at room temperature, followed by the dropwise addition of H2O (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 5 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with H2O (3 × 10 mL). This yielded 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)-5-methylpyridine-3-yl)isoxazole-5-yl)-3-methylbutanoic acid (47 mg) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 570.

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

[0704] 2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)-5-methylpyridine-3-yl)isoxazole-5-yl)-3-methylbutanoic acid (40 mg, 0.070 mmol, 1 equivalent) and intermediate 8 (27.93 mg, 0.084 mmol, 1.2 equivalents) were stirred in DMF (0.5 mL), to which PyBOP (73.08 mg, 0.140 mmol, 2 equivalents) and DIEA (27.23 mg, 0.210 mmol, 3 equivalents) were added in several portions at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The desired product could be detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient from 0% to 100% over 30 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This yielded a pale yellow solid (2S,4R)-4-hydroxy-1-(2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)-5-methylpyridine-3-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (35 mg). LCMS(ESI) m / z:[M+H] + = 883.

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

[0706] The above product was purified by chiral preparative HPLC under the following conditions: Column, CHIRALPAK ID, 2 * 25 cm, 5 μm; mobile phase, MtBE:DCM = 2:1 (10 mM / L) and MeOH- (hold 50% MeOH- for 12 minutes); detector, UV254. This yielded the title compound (second peak) (14.3 mg) as a grayish-white solid. 1H NMR(300MHz,DMSO-d6)δ12.38(s,1H),8.99(s,1H),8.74(s,1H),8.60(d,J=2.3Hz,1H),8.46(t,J=8.1Hz,1H),8.07-7.96(m,2H) ),7.48-7.34(m,6H),7.09-6.97(m,2H),6.87(d,J=39.5Hz,1H),5.13(s,1H),5.02-4.88(m,1H),4.40(t,J=7.9Hz,1H),4.31(s, 1H),3.86(d,J=9.6Hz,1H),3.78-3.68(m,3H),3.53(d,J=7.6Hz,2H),3.00(t,J=12.1Hz,2H),2.47(s,3H),2.37-2.33(m,3H),2. 22(d,J=12.5Hz,3H),2.11-1.89(m,3H),1.82(d,J=8.7Hz,1H),1.54-1.36(m,3H),1.02(d,J=6.4Hz,3H),0.84(d,J=6.8Hz,3H). LCMS(ESI)m / z:[M+H] + = 883.25.

[0707] The compounds in Table 3 were prepared using appropriate fluoropyridine and 2-(5-methyl-6-(piperidine-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol, using the same procedure as used above to prepare (2S,4R)-4-hydroxy-1-((R)-2-(3-(6-(4-(3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl)piperidine-1-yl)-5-methylpyridine-3-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 2).

[0708] [Table 4-1]

[0709] [Table 4-2]

[0710] [Table 4-3]

[0711] [Table 4-4]

[0712] [Table 4-5]

[0713] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidine-1-yl}-3-methylphenyl)-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) [ka]

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

[0715] A solution of 4-bromo-3-methylbenzaldehyde (4 g, 20.096 mmol, 1 equivalent) and hydroxylamine hydrochloride (2.79 g, 40.192 mmol, 2.0 equivalents) in MeOH (20 mL) and H2O (20 mL) was stirred at room temperature for 4 hours. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. A white solid intermediate 2 (4.5 g, 104.61%) was obtained. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + = 214.

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

[0717] The solutions of intermediate 2 (4.4 g, 20.555 mmol, 1 equivalent) and NCS (4.12 g, 30.832 mmol, 1.5 equivalents) in SiO2 (40 mL) were stirred at room temperature for 12 hours. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with SiO2 (2 × 300 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 3 (3.0 g, 58.73%), a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + = 248.

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

[0719] The solutions of intermediate 3 (3.0 g, 12.072 mmol, 1 equivalent) and methyl buto-3-isoate (1.18 g, 12.072 mmol, 1.0 equivalent) in SiO2 (2 mL) were stirred at room temperature for 12 hours. The residue was purified by silica gel column chromatography using PE / EA (1:1) elution to obtain intermediate 4 (3.0 g, 80.12%), a yellow solid. LCMS(ESI)m / z[M+H] + =310.

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

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

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

[0723] To a solution of intermediate 5 (200 mg, 0.568 mmol, 1 equivalent) and 2-[5-methyl-6-(piperidine-4-yl)thieno[2,3-c]pyridazin-3-yl]phenol (221.74 mg, 0.682 mmol, 1.2 equivalents) in dioxane (1 mL), Cs2CO3 (555.01 mg, 1.704 mmol, 3.0 equivalents), Pd2(dba)3 (311.98 mg, 0.341 mmol, 0.6 equivalents) and BINAP (106.07 mg, 0.170 mmol, 0.3 equivalents) were added. After stirring at 100°C for 6 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (7:3) elution to obtain intermediate 6 (80 mg, 23.61%), a yellow solid. LCMS(ESI)m / z[M+H] + = 597.

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

[0725] The solutions of intermediate 6 (80 mg, 0.134 mmol, 1 equivalent) and LiOH (64.21 mg, 2.680 mmol, 20 equivalents) in MeOH (4 mL) were stirred at 60°C for 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: MeCN (0.1% FA) in water, gradient from 0% to 60% over 40 minutes; Detector: UV 254 nm. This yielded intermediate 7 (45 mg, 57.60%) as a white solid. LC-MS (ESI) m / z [M+H] + = 583.

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

[0727] The solutions of intermediate 7 (45 mg, 0.077 mmol, 1 equivalent) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (30.71 mg, 0.092 mmol, 1.2 equivalents), PyBOP (80.37 mg, 0.154 mmol, 2.0 equivalents), and DIEA (29.94 mg, 0.231 mmol, 3.0 equivalents) in DMF (1 mL) were stirred at room temperature for 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: Column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 80% over 40 minutes; detector, UV 254 nm. This yielded a white solid intermediate 8 (34 mg, 49.13%). LC-MS(ESI)m / z[M+H] + = 896.

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

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

[0730] The compounds in Table 4 were prepared using appropriate aryl bromides and 2-(5-methyl-6-(piperidine-4-yl)thieno[2,3-c]pyridazin-3-yl)phenol, using the same procedure as used above to prepare (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{4-[3-(2-hydroxyphenyl)-5-methylthieno[2,3-c]pyridazin-6-yl]piperidine-1-yl}-3-methylphenyl)-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).

[0731] [Table 5-1]

[0732] [Table 5-2]

[0733] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidine-1-yl]pyrimidine-5-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 5) [ka]

[0734] Step 1: Preparation of 2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidine-1-yl]pyrimidine-5-yl}-1,2-oxazole-5-yl)-3-methylbutanoate methyl (intermediate 2) [ka]

[0735] A mixture of 2-{6-[(3S)-pyrrolidine-3-yl]thieno[2,3-c]pyridazin-3-yl}phenol (400 mg, 1.345 mmol, 1 equivalent), 2-[3-(2-chloropyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate methyl (397.77 mg, 1.345 mmol, 1 equivalent), and DIEA (869.24 mg, 6.725 mmol, 5 equivalents) in DMSO (4 mL) was stirred at 100°C for 3 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, MeOH (0.1% FA) in water, gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain a yellow solid intermediate 2 (130 mg, 17.36%). LCMS(ESI) m / z:[M+H] + = 557.

[0736] Step 2: Preparation of 2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidine-1-yl]pyrimidine-5-yl}-1,2-oxazole-5-yl)-3-methylbutanoic acid (intermediate 3) [ka]

[0737] A mixture of intermediate 2 (130 mg, 0.234 mmol, 1 equivalent) and LiOH (16.78 mg, 0.702 mmol, 3 equivalents) in MeOH (2 mL), THF (2 mL), and H2O (1 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was concentrated under reduced pressure to obtain intermediate 3 (142 mg, crude), a yellow solid. LC-MS(ESI)m / z[M+H] + = 543.

[0738] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidine-1-yl]pyrimidine-5-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 4) [ka]

[0739] The mixture of intermediate 3 (142 mg, 0.262 mmol, 1 equivalent), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (86.73 mg, 0.262 mmol, 1 equivalent), PyBOP (204.28 mg, 0.393 mmol, 1.5 equivalents), and DIEA (169.12 mg, 1.310 mmol, 5 equivalents) in DMF (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, water MeCN (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain a yellow solid intermediate 4 (100 mg, 44.64%). LCMS(ESI)m / z:[M+H] + = 856.

[0740] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidine-1-yl]pyrimidine-5-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka]

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

[0742] The compounds in Table 5 were prepared using appropriate aryl chlorides and amines, using the same procedure as used above to prepare (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(3R)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidine-1-yl]pyrimidine-5-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 5).

[0743] [Table 6-1]

[0744] [Table 6-2]

[0745] [Table 6-3]

[0746] [Table 6-4]

[0747] [Table 6-5]

[0748] [Table 6-6]

[0749] [Table 6-7]

[0750] [Table 6-8]

[0751] Table 6-9

[0752] Table 6-10

[0753] Table 6-11

[0754] Table 6-12

[0755] Table 6-13

[0756] Table 6-14

[0757] Table 6-15

[0758] Table 6-16

[0759] Table 6-17

[0760] Table 6-18

[0761] [Table 6-19]

[0762] Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{4-[3-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidine-5-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 9) [ka]

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

[0764] To a solution of 4-bromo-6-chloropyridazine-3-amine (20.00 g, 95.951 mmol, 1.00 equivalent) in THF (200.00 mL), CuI (21.93 g, 115.141 mmol, 1.20 equivalent) and CH2I2 (30.84 g, 115.141 mmol, 1.20 equivalent) were added at room temperature. To the above mixture, t-BuNO2 (11.87 g, 115.141 mmol, 1.20 equivalent) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred further at 60°C under a nitrogen atmosphere for 6 hours. The mixture was cooled to room temperature. The reaction product was quenched with water at 0°C. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were washed with saturated brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (1:1) elution to obtain intermediate 2 (15 g, 48.96%), a yellow solid. LCMS(ESI)m / z:[M+H] + =319.

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

[0766] To a solution of intermediate 2 (15.00 g, 46.975 mmol, 1.00 equivalent) in THF (100.00 mL), 2-methyl-2-propantheol (5.08 g, 56.370 mmol, 1.20 equivalent) and NaH (2.25 g, 93.950 mmol, 2.00 equivalent, 60%) were added at 0°C. The resulting mixture was stirred at 60°C for 1 hour. The reaction product was quenched with water at 0°C. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were washed with saturated brine (1 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to obtain intermediate 4 (6.4 g, 41.46%), a yellow solid. LCMS(ESI)m / z:[M+H] + = 329.

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

[0768] To a stirred solution of intermediate 4 (6.40 g, 19.477 mmol, 1.00 equivalent) and tert-butyl cyanoacetate (5.50 g, 38.954 mmol, 2.00 equivalent) in 1,4-dioxane (60.00 mL), CuI (0.74 g, 3.895 mmol, 0.20 equivalent), picolinic acid (1.20 g, 9.739 mmol, 0.50 equivalent), and Cs2CO3 (19.04 g, 58.431 mmol, 3.00 equivalent) were added at room temperature. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography under the following conditions. Column: C18 silica gel; Mobile phase: H2O in ACN (0.1% FA), gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220nm. This yielded brown oily intermediate 6 (5g, 75.10%). LC-MS (ESI) m / z: [M+H] + =342.

[0769] Step 4: Preparation of 2-[4-(tert-butylsulfanil)-6-chloropyridazine-3-yl]acetonitrile (intermediate 7). [ka]

[0770] Intermediate 6 (5.00 g, 14.626 mmol, 1.00 equivalent) was added to HFIP (50.00 mL) at room temperature. The resulting mixture was stirred at 60°C for 16 hours. The residue was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: H2O in ACN (0.1% FA), gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded a brownish oily intermediate 7 (1.2 g, 33.94%). LCMS(ESI) m / z:[M+H] + = 242.

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

[0772] Intermediate 7 (1.20 g, 4.964 mmol, 1.00 equivalent) was added to trifluoroacetaldehyde (10.00 mL) at room temperature. The resulting mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: H2O in ACN (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded intermediate 8 (283 mg, 30.71%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 186.

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

[0774] To a stirred solution of intermediate 8 (283.00 mg, 1.525 mmol, 1.00 equivalent) in ACN (10.00 mL), CuCl (301.86 mg, 3.050 mmol, 2.00 equivalent) was added at 0°C. To the above mixture, t-BuNO2 (314.42 mg, 3.050 mmol, 2.00 equivalent) was added at 0°C. The resulting mixture was stirred further at room temperature for 1 hour. The reaction product was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: H2O in ACN (0.1% FA), gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded intermediate 9 (153 mg, 48.94%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 205.

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

[0776] To a stirred solution of intermediate 9 (153.00 mg, 0.746 mmol, 1.00 equivalent) in DMSO (5.00 mL), piperazine (192.81 mg, 2.238 mmol, 3.00 equivalent) and DIEA (482.17 mg, 3.730 mmol, 5.00 equivalent) were added at room temperature. The resulting mixture was stirred at 100°C for 1 hour. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18 silica gel; Mobile phase: H2O in ACN (0.1% FA), gradient from 0% to 100% over 30 minutes; Detector: UV254 / 220 nm. This yielded intermediate 11 (114 mg, 59.98%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 255.

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

[0778] Intermediate 11 (114.00 mg, 0.448 mmol, 1.00 equivalent) and 2-hydroxyphenylboronic acid (185.18 mg, 1.344 mmol, 3.00 equivalent) were stirred in 1,4-dioxane (8.00 mL) and H2O (2.00 mL)....

Claims

1. A compound having the structure of formula I or II, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 The compound of formula I or II has the structure of formula I-A or II-A, 【Chemistry 2】 During the ceremony, The dashed lines indicate single or double bonds. m is 0, 1, or 2, k is 0, 1, or 2, Each R １ is, independently, halo, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ２ to C ９ heterocyclyl, optionally substituted C ３ to C ８ cycloalkyl, or optionally substituted CH ２ -C ３ to C ８ cycloalkyl, and Each X is independently a halo. L is the linker in 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 linker L and ring system A. A ２ However, this is a bond between the decomposition part B and the linker L. 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 ２ ~C ９ 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 ２～６ 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, and the decomposition part is formula C, 【Transformation 3】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Chemistry 4】 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, C was replaced by an arbitrary choice. 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 is H, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ 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, independently, halogen, and 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, the bond between the decomposition part B and the linker L is A compound having the structure of formula C, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-H or II-H. 【Transformation 5】

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

4. When m is 1, R １ However, C was replaced by a randomly selected option. １ ~C ６ Alkyl or optionally substituted C ３ ~C ８ A compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein k is 1 and X is Cl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein k is 0.

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

8. B １ , B ２ , B ３ , and B ４ Each of these can be independently replaced by O, ethynyl, or C of any choice. ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ９ Heterocycline, C by optional substitution ３ ~C １０ Cycloalkyl or optionally substituted C ６ ~C １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an aryl compound.

9. B １ and B ４ Each of them, independently, O, 【Transformation 6】 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. B １ but, 【Transformation 8】 The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. B ４ but, O, 【Chemistry 9】 The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

12. B ２ However, NH, 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. The aforementioned disassembled part 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein linker L has the following structure. 【Chemistry 12】 【Chemistry 13】

15. Linker L is the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein linker L has the following structure. 【Chemistry 14】

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A therapeutic agent for BAF complex-related disorders comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

18. A therapeutic agent for disorders associated with loss-of-function mutations of BRG1, comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

19. A cancer treatment agent comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

20. The therapeutic agent according to claim 19, 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 carcinoma, appendiceal cancer, small intestine cancer, or penile cancer.

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