BENZOYPARAZINE: Pyrazines and their Use

Abstract

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

Description

[Technical Field]

[0001] 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.

[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 Initiative]

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

[0004] In one embodiment, the present invention relates to a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, m is 0, 1, 2, or 3. k is 0, 1, or 2. Each R 1 These are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano. Each X is independently a halo or optionally substituted C1-C6 heteroalkyl. L is a linker, B is characterized by a decomposition portion, which is the compound of formula I or a pharmaceutically acceptable salt thereof.

[0005] In another embodiment, the present invention relates to a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, m is 0, 1, 2, or 3. k is 0, 1, or 2. Each R 1 These are independently a halo, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C9 heterocyclyl, or an optionally substituted C3-C8 cycloalkyl. Each X is independently a halo. L is a linker, B is characterized by a decomposition portion, which is the compound of formula I or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the compound has the structure of Formula I-A.

Chem.

[0007] In some embodiments, the compound has the structure of Formula I-B.

Chem.

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

[0009] In some embodiments, R 1 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R 1 is alkoxy. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is halo. In some embodiments, R 1 is F or Cl. In some embodiments, R 1 is optionally substituted C1-C6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is difluoromethoxy. In some embodiments, R 1 is difluoromethyl. In some embodiments, R 1 is optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is methine. In some embodiments, R 1 is optionally substituted C3-C8 cycloalkyl. In some embodiments, R 1 is cyclopropane. In some embodiments, R 1is cyclopropoxy. In some embodiments, R 1 is an optionally substituted C2-C9 heterocycline. In some embodiments, R 1 is an optionally substituted amino acid. In some embodiments, R 1 It is cyano.

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

[0011] In some embodiments, m is 0.

[0012] In some embodiments, m is 1.

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

[0014] In some embodiments, k is 1.

[0015] In some embodiments, k is 0.

[0016] In one embodiment, the present invention relates to a compound having the structure of formula IV, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, k is 0, 1, or 2. Each X is independently a halo. L is a linker, B is characterized by a decomposition part, which is the compound of formula IV or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the disassembled part B has the structure of formula A-1 [ka] During the ceremony, Y 1 teeth, [ka] And, R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R A6 is H, or optionally substituted C1-C6 alkyl, and R A7 is H, or optionally substituted C1-C6 alkyl, or R A6 and R A7 These combine with the carbon atoms to which they are bonded to form optionally substituted C3-C6 carbocyrills or optionally substituted C2-C5 heterocyclines, 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 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R A1 , R A2 , R A3 , and R A4 Each of these is independently H, A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 The aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 carbocyrill, hydroxyl, thiol, or optionally substituted amino, or R A1 and R A2 , R A2 and R A3 , and / or R A3 and R A4 Each of them combines with the carbon atoms to which it is bonded, [ka] Forming, [ka] However, C6~C was optionally substituted. 10 Aryl, optionally substituted C3-C 10 A carbocyclyl, an optionally substituted C2-C9 heteroaryl, or a C2-C9 heterocyclyl, any of which is A 2 It is optionally replaced by 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, A 2 This is the connection between the decomposition part and the linker.

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

[0019] 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.

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

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

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

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

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

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

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

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

[0028] In some embodiments, the disassembled part includes the structure of formula A2. [ka]

[0029] In some embodiments, the disassembled part is [ka] That is the case.

[0030] In some embodiments, the disassembled part includes the structure of formula A4. [ka]

[0031] In some embodiments, the disassembled part is [ka] That is the case.

[0032] In some embodiments, the disassembled part has the structure of formula A5. [ka]

[0033] In some embodiments, the disassembled part has the structure of formula A6. [ka]

[0034] In some embodiments, the degradation moiety has the structure of Formula A8.

Chemical formula

[0035] In some embodiments, the degradation moiety has the structure of Formula A10.

Chemical formula

[0036] In some embodiments, the degradation moiety

Chemical formula

[0037] In some embodiments, the degradation moiety

Chemical formula

[0038] In some embodiments, the degradation moiety has the structure of Formula C

Chemical formula

Chemical formula

[0039] In some embodiments, the disassembled part has the structure of formula C. [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] And, R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B3 is, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. v2 is 0, 1, 2, 3, or 4. Each R B6 A is independent of A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 The 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 is H or optionally substituted C1-C6 alkyl, R B10 is either H or F, A 2 This is the connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 And, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the disassembled part has the structure of formula C3. [ka]

[0041] In some embodiments, the disassembled portion has the structure of formula C4. [ka]

[0042] In some embodiments, the disassembled part has the structure of formula C1. [ka]

[0043] In some embodiments, the disassembled part is [ka] That is the case.

[0044] In some embodiments, the disassembled part is [ka] That is the case.

[0045] In some embodiments, the disassembled part is [ka] That is the case.

[0046] In some embodiments, the disassembled part is [ka] That is the case.

[0047] In some embodiments, the disassembled part is [ka] That is the case.

[0048] In some embodiments, the disassembled part is [ka] That is the case.

[0049] In some embodiments, the disassembled part has the structure of formula C2. [ka]

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

[0051] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0052] 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.

[0053] In some embodiments, the disassembled part is [ka] That is the case.

[0054] In some embodiments, the decomposition portion has the structure of formula Ca2. [ka]

[0055] In some embodiments, the disassembled portion has the structure of formula Cb2. [ka]

[0056] In some embodiments, the disassembled portion has the structure of formula Cc2. [ka]

[0057] In some embodiments, the decomposed part has the structure of formula Cd2. [ka]

[0058] In some embodiments, the decomposed portion has the structure of formula Ce2. [ka]

[0059] In some embodiments, the disassembled portion has the structure of formula Cf2. [ka]

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

[0061] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0062] 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 are optionally substituted. 10 It is carbocyclyl. In some embodiments, R B3 is cyclopropane. In some embodiments, R B3 R is cyclobutane. In some embodiments, R B3 R is fluoro-2-methylpropane. In some embodiments, R B8 H is H. In some embodiments, R B2 H is H.

[0063] In some embodiments, the disassembled part is [ka] That is the case.

[0064] In some embodiments, the disassembled part is [ka] That is the case.

[0065] In some embodiments, the disassembled part is [ka] That is the case.

[0066] In some embodiments, the disassembled part is [ka] That is the case.

[0067] In some embodiments, the disassembled part is [ka] That is the case.

[0068] In some embodiments, the disassembled part is [ka] That is the case.

[0069] In some embodiments, the disassembled part is [ka] That is the case.

[0070] In some embodiments, the disassembled part is [ka] That is the case.

[0071] In some embodiments, the disassembled part is [ka] That is the case.

[0072] In some embodiments, the disassembled part has the structure of formula C5. [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] And, R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B3 is, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted 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 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. v2 is 0, 1, 2, 3, or 4. Each R B6 A is independent of A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 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 B8Each 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 is H or optionally substituted C1-C6 alkyl, R B11 This includes H, alcohol, boronic acid, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 alkyl. 10 Carbocyclyl, optionally substituted 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. and 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 That is, or a pharmaceutically acceptable salt thereof.

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

[0074] In some embodiments, the disassembled part has the structure of formula C6. [ka]

[0075] In some embodiments, the disassembled part has the structure of formula C1. [ka]

[0076] In some embodiments, the disassembled part has the structure of formula C8. [ka]

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

[0078] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0079] 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, R B8 H is H. In some embodiments, R B2 H is H.

[0080] In some embodiments, the disassembled part is [ka] That is the case.

[0081] In some embodiments, the disassembled part has the structure of formula D. [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] And, R B1H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B3 is, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. v2 is 0, 1, 2, 3, or 4. Each R B6 A is independent of A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C2-C6 alkynyls, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 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 is H or optionally substituted C1-C6 alkyl, A 2 This is the connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 That is, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the disassembled part has the structure of formula D3. [ka]

[0083] In some embodiments, the disassembled part has the structure of formula D1. [ka]

[0084] In some embodiments, the disassembled part is [ka] That is the case.

[0085] In some embodiments, the disassembled part is [ka] That is the case.

[0086] In some embodiments, the disassembled part is [ka] That is the case.

[0087] In some embodiments, the disassembled part has the structure of formula D2. [ka]

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

[0089] In some embodiments, R B9 It is bonded to the (S)-chiral center. In some embodiments, R B9 H is H.

[0090] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B3 is isopropyl. In some embodiments, R B6 H is H. In some embodiments, R B6 is a halogen. In some embodiments, R B6 is fluorine. In some embodiments, R B6 is bromine. In some embodiments, R B6 is chlorine. In some embodiments, R B6 is cyano. In some embodiments, R B6 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R B6 is an optionally substituted C3-C6 alkynyl. In some embodiments, R B6 is methoxy. In some embodiments, RB6 It is 3-methoxy-1-propanoxy.

[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 is [ka] That is the case.

[0095] In some embodiments, the disassembled part is [ka] That is the case.

[0096] In some embodiments, the disassembled part is [ka] That is the case.

[0097] In some embodiments, the disassembled part is [ka] That is the case.

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

[0099] In some embodiments, the disassembled part is [ka] That is the case.

[0100] In some embodiments, the disassembled part is [ka] That is the case.

[0101] In some embodiments, the disassembled part is [ka] That is the case.

[0102] In some embodiments, the disassembled part is [ka] That is the case.

[0103] In some embodiments, the disassembled part is [ka] That is the case.

[0104] In some embodiments, the disassembled part is [ka] That is the case.

[0105] In some embodiments, the disassembled part is [ka] That is the case.

[0106] In some embodiments, the disassembled part is [ka] That is the case.

[0107] In some embodiments, the disassembled part is [ka] That is the case.

[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 has the structure of formula Da [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] And, R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B3 is, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted 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 B4H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. Each of X1 and X2 is independently C, N, or O. v2 is 0, 1, 2, 3, or 4. Each R B6 A is independent of A 2 , halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 heteroalkyls, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 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 is H or optionally substituted C1-C6 alkyl, A 2 This is the connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 That is, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the disassembled portion has the structure of formula Da3. [ka]

[0118] In some embodiments, the disassembled portion has the structure of formula Da1. [ka]

[0119] In some embodiments, the disassembled portion has the structure of formula Da2. [ka]

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

[0121] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0122] 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.

[0123] In some embodiments, the disassembled part is [ka] That is the case.

[0124] In some embodiments, the disassembled part has the structure of formula E. [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] And, R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B3 is, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B9This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally substituted C2-C 10 It is a heterocycline, B 10 This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, and optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C 10 Heterocyclines, optionally substituted aminos, or cyanos, and A 2 This is the connection between the decomposition part and the linker. R B1 , R B3 , and R B6 Only one of them is A 2 That is, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the disassembled part has the structure of formula E3. [ka]

[0126] In some embodiments, the disassembled portion has the structure of formula E1. [ka]

[0127] In some embodiments, the disassembled part is [ka] That is the case.

[0128] In some embodiments, the disassembled part is [ka] That is the case.

[0129] In some embodiments, the disassembled part has the structure of formula E2. [ka]

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

[0131] In some embodiments, R B9 It is bonded to the (S)-chiral center.

[0132] 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, R B9 is an optionally substituted C1-C6 alkyl group. In some embodiments, R B9 is methyl. In some embodiments, R B9 H is H. In some embodiments, R B9 is an optionally substituted C3-C6 alkynyl. In some embodiments, R B10 is absent. 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, RB10 H is H. In some embodiments, R B10 is cyano. In some embodiments, R B10 C3~C are optionally substituted. 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.

[0133] In some embodiments, the disassembled part is [ka] That is the case.

[0134] In some embodiments, the disassembled part is [ka] That is the case.

[0135] In some embodiments, the disassembled part is [ka] That is the case.

[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] 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 has the structure of formula F. [ka] During the ceremony, L 4 is -N(R B1 )(R B2 ), [ka] And, R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. R B3 is, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B4 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl C6-C 10 It is Ariel, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. A 2 This is the connection between the decomposition part and the linker. R B1 or R B3 Only one of them is A 2 That is, or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the disassembled part has the structure of formula F3. [ka]

[0144] In some embodiments, the disassembled part has the structure of formula F1. [ka]

[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 has the structure of formula F2. [ka]

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

[0150] 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.

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

[0152] In some embodiments, the linker has the structure of formula II, A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h-(D)-(B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 , Formula II or a pharmaceutically acceptable salt thereof, During the ceremony, A 1 This is a bond between the linker and ring system A, A 2 This is the connection between the decomposition part and the linker. B 1 B 2 B 3 , and B 4 Each of these independently consists of an optionally substituted C1-C4 alkyl group and an optionally substituted C6-C4 alkyl group. 10 Aryl, optionally substituted C6~C 10 Aryl C 1~4 Alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C 6~12 Aryl, O, S, S(O)2, or NR N And, Each R N These are H, which is independently and optionally replaced by C. 1~4 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkinyl, optionally substituted C 2~10 Heterocyclines, optionally substituted C 2~6 Heteroaryl or optionally substituted C 1~7 It is heteroalkyl, C 1 and C 2 Each of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. D is C, which is optionally substituted. 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkinyl, optionally substituted C 2~10 Heterocyclines, optionally substituted C 2~6 Heteroaryl, optionally substituted C 6~12 Aryl, optionally substituted C2-C 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.

[0153] In some embodiments, B 1 B 2 B 3 , and B 4 Each of these independently consists of an optionally substituted C1-C2 alkyl group, an optionally substituted C1-C3 heteroalkyl group, and an optionally substituted C2-C3 group. 10 Heterocyclines, optionally substituted C 2~6 Heteroaryl, O, or NR N And D is C which is optionally substituted. 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkinyl, optionally substituted C 2~10Heterocyclines, optionally substituted C 6~12 Aryl, optionally substituted C2-C 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 to something.

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

[0155] In some embodiments, B 1 and B 4 Each of them is independent, [ka] [ka] That is the case.

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

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

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

[0159] In some embodiments, B 2 These are C1-C4 alkyl groups that have been optionally substituted.

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

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

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

[0163] In some embodiments, the linker is D. In some embodiments, D is optionally replaced by C. 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkinyl, optionally substituted C 2~10 Heterocyclines, optionally substituted C 2~6 Heteroaryl, optionally substituted C 6~12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1~10 It is a heteroalkyl group. In some embodiments, D is optionally substituted with C3-C 10 It is a cycloalkyl group, where f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is optionally substituted with C3-C 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 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 substituted with C3~C 10It 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 substituted with 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 substituted with 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] That is the case.

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

[0165] In some embodiments, the linker has the structure of formula III, A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -( B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 , Formula III During the ceremony, A 1 This is a bond between the linker and ring system A, A 2 This is the connection between the decomposition part and the linker. B 1 B 2 B 3 , and B 4 Each of them independently has an optionally substituted ethynyl and an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O)2, or NR N And, Each R N These are H, which is independently and optionally replaced by C. 1~4 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkinyl, optionally substituted C 2~10 Heterocyclines, optionally substituted C 6~12 aryl, 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.

[0166] In some embodiments, the linker is structure-(L 1 ) n In the formula, n is 1, 2, or 3, and each L 1 O, NR are independent of each other. N , ethynyl, optionally substituted C2-C 10 Heterocyclines, C2-C9 heteroaryls with optional substitution, C6-C9 heteroaryls with optional substitution 10 Aryl or optionally substituted C3-C 10 It is a cycloalkyl group.

[0167] In some embodiments, at least one L1 C2~C is an arbitrarily substituted C2~C 10 It is a heterocycline. In some embodiments, 2-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.

[0168] In some embodiments, C2~C are optionally substituted. 10 A heterocyclil is a spirocyclic heterocyclil. In some embodiments, the heterocyclil is, [ka] That is the case.

[0169] In some embodiments, C2~C are optionally substituted. 10 The heterocyclil is a cross-linked heterocyclil. In some embodiments, the cross-linked heterocyclil is [ka] That is the case.

[0170] In some embodiments, C2~C are optionally substituted. 10 A heterocyclyl is a condensed bicyclic heterocyclyl. In some embodiments, a condensed bicyclic heterocyclyl is, [ka] That is the case.

[0171] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is -(L 1 ) q-(C2~C9 heteroaryls that are optionally substituted)-(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.

[0172] 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.

[0173] In some embodiments, at least one L 1 C6~C is an arbitrarily substituted C6~C 10 It is an aryl group. In some embodiments, C6~C is optionally substituted. 10 The aryl is a six-membered monocyclic aryl. In some embodiments, the six-membered monocyclic aryl is optionally substituted with a phenyl compound.

[0174] In some embodiments, at least one L 1 C3~C are optionally substituted. 10 It is a cycloalkyl group. In some embodiments, it is optionally substituted with C3-C 10 Carbocyclyl is a monocyclic cycloalkyl. In some embodiments, a 6-membered monocyclic cycloalkyl is [ka] That is the case.

[0175] In some embodiments, C3~C are optionally substituted. 10The cycloalkyl is a crosslinked cycloalkyl. In some embodiments, the crosslinked cycloalkyl is [ka] That is the case.

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

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

[0178] 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 , Here, B 1 B 2 B 3 , and B 4 Each of them independently has an optionally substituted ethynyl and an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N That is the case.

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

[0180] In some embodiments, B 1 B 2 B 3 , and B 4 Each of these is independently O, ethynyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C 10 Heterocyclines, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C6-C 10 It is an arrow. In some embodiments, B 1 B 2 B 3 , and B 4 Each of these is independently an optionally substituted C2-C9 heteroaryl, or an optionally substituted C2-C 10 It is a heterocycline. In some embodiments, B 1 and B 4 Each of them is independent, [ka] [ka] That is the case.

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

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

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

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

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

[0186] 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.

[0187] In some embodiments, the linker is one of the compounds 1 to 291 in Table 1 (e.g., BRG1 IC 50and 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 291 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 291 in Table 1 (e.g., BRM IC 50 The value is ++ or greater (for example, +++ or ++++ (for example, ++++)) and the BRG1 IC 50 and 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).

[0188] In one embodiment, the present invention is characterized by a compound selected from the group consisting of 1 to 291 in Table 1, and a pharmaceutically acceptable salt thereof. In some embodiments, the compound is BRG1 IC 50 and BRM IC 50 The compound is one of the compounds 1 to 291 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 21. 50 The compound is one of the compounds 1 to 291 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 21. 50 The value is ++ or greater (for example, +++ or ++++ (for example, ++++)) and the BRG1 IC 50 and BRM IC 50 The compound is one of the compounds 1 to 291 in Table 1 or a pharmaceutically acceptable salt thereof, having a ratio of at least 5 (for example, at least 7, 10, 15, 20, 25, or 30).

[0189] Table 1-1

[0190] Table 1-2

[0191] Table 1-3

[0192] Table 1-4

[0193] Table 1-5

[0194] Table 1-6

[0195] Table 1-7

[0196] Table 1-8

[0197] Table 1-9

[0198] Table 1-10

[0199] Table 1-11

[0200] Table 1-12

[0201] Table 1-13

[0202] Table 1-14

[0203] Table 1-15

[0204] Table 1-16

[0205] Table 1-17

[0206] Table 1-18

[0207] Table 1-19

[0208] Table 1-20

[0209] Table 1-21

[0210] Table 1-22

[0211] Table 1-23

[0212] Table 1-24

[0213] Table 1-25

[0214] Table 1-26

[0215] Table 1-27

[0216] Table 1-28

[0217] Table 1-29

[0218] Table 1-30

[0219] Table 1-31

[0220] Table 1-32

[0221] Table 1-33

[0222] Table 1-34

[0223] Table 1-35

[0224] Table 1-36

[0225] Table 1-37

[0226] Table 1-38

[0227] Table 1-39

[0228] Table 1-40

[0229] Table 1-41

[0230] Table 1-42

[0231] Table 1-43

[0232] Table 1-44

[0233] Table 1-45

[0234] Table 1-46

[0235] Table 1-47

[0236] Table 1-48

[0237] Table 1-49

[0238] Table 1-50

[0239] Table 1-51

[0240] Table 1-52

[0241] Table 1-53

[0242] Table 1-54

[0243] Table 1-55

[0244] Table 1-56

[0245] Table 1-57

[0246] Table 1-58

[0247] Table 1-59

[0248] Table 1-60

[0249] Table 1-61

[0250] Table 1-62

[0251] Table 1-63

[0252] Table 1-64

[0253] Table 1-65

[0254] Table 1-66

[0255] Table 1-67

[0256] Table 1-68

[0257]

Table 1-69

[0258] Table 1-70

[0259] Table 1-71

[0260] [Table 1-72]

[0261] [Table 1-73]

[0262] [Table 1-74]

[0263] [Table 1-75]

[0264] [Table 1-76]

[0265] [Table 1-77]

[0266] [Table 1-78]

[0267] [Table 1-79]

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

[0269] In one embodiment, the present invention is characterized by a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0270] In another embodiment, the present invention relates to a method for reducing the activity of intracellular BAF complexes, the method comprising contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

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

[0272] In 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 to the subject an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof.

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

[0274] In a further embodiment, the present invention relates to a method for inhibiting BRM, characterized in that the method involves contacting cells with an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof.

[0275] In some embodiments, the cells are cancer cells.

[0276] In another aspect, the present invention provides a method for inhibiting BRG1, characterized in that the method involves contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

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

[0278] 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 pharmaceutical composition thereof.

[0279] In some embodiments, the cells are cancer cells.

[0280] 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 to the subject an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof.

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

[0282] In another embodiment, the present invention relates to a method for inducing apoptosis in cells, the method comprising contacting cells with an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof.

[0283] In some embodiments, the cells are cancer cells.

[0284] In a further embodiment, the present invention relates to a method for treating cancer in a subject in need thereof, the method comprising administering an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds) or a pharmaceutical composition thereof to the subject.

[0285] 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.

[0286] 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.

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

[0288] In some embodiments of the methods described above, 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, carboplatin, or other platinum-based drugs). The patient did not respond to taxanes such as taxel and docetaxel, ALK inhibitors, MET inhibitors, Alimta®, Abraxane®, Adriamycin®, gemcitabine, Avastin®, Halaven®, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, Gemzar®, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbletabrin, or PDL1 inhibitors.

[0289] In some embodiments of the methods described above, the cancer is determined to have or does not 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 is determined to have or does not have an Epidermal Growth Factor Receptor (EGFR) mutation. In some embodiments of the methods described above, the cancer is determined to have or does not have an Anaplastic Lymphoma Kinase (ALK) driver mutation. In some embodiments of the methods described above, the cancer is determined to have or does not 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.

[0290] In another aspect, the Disclosure provides a method for treating a BAF-related disorder (e.g., cancer or viral infection) in a subject requiring treatment. 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 acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, viral infections include Retroviridae viruses such as lentiviruses (e.g., human immunodeficiency virus (HIV) and delta-retroviruses (e.g., human T-cell leukemia virus I (HTLV-I) and human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae viruses (e.g., hepatitis B virus (HBV)), Flaviviridae viruses (e.g., hepatitis C virus (HCV)), Adenoviridae viruses (e.g., human adenoviruses), Herpesviridae viruses (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), and herpesvirus K * The disorders are infections caused by viruses of the following families: CMV (varicella-zoster virus), Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1)), Parvoviridae (e.g., parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., measles virus), or Togaviridae (e.g., rubella virus). In some embodiments, the disorder is coffin sillis, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0291] In another aspect, the Disclosure provides a method for treating a viral infection in a subject in need of treatment. This method involves administering to a subject an effective amount of any of the aforementioned compounds (e.g., BRM / BRG1 biinhibitor compounds or BRM-selective compounds), a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, viral infections include Retroviridae viruses such as lentiviruses (e.g., human immunodeficiency virus (HIV) and delta-retroviruses (e.g., human T-cell leukemia virus I (HTLV-I) and human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae viruses (e.g., hepatitis B virus (HBV)), Flaviviridae viruses (e.g., hepatitis C virus (HCV)), Adenoviridae viruses (e.g., human adenoviruses), Herpesviridae viruses (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), and herpesvirus K * 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).

[0292] In some embodiments of the aforementioned models, the compound is a BRM-selective compound. In some embodiments, the BRM-selective compound inhibits the level and / or activity of BRM at least 10 times more than the compound inhibits the level and / or activity of BRG1, and / or the compound binds to BRM at least 10 times more than the compound binds to BRG1. For example, in some embodiments, the BRM-selective compound is IC for BRG1. 50 or IP 50IC is at least 10 times lower 50 or IP 50 It has. In some embodiments of the above-described aspects, the compound is a BRM / BRG1 biinhibitor compound. In some embodiments, the BRM / BRG1 biinhibitor compound has similar activity against both BRM and BRG1 (e.g., activity of the compound against BRM and BRG1 of up to 10 times (e.g., less than 5 times, less than 2 times)). In some embodiments, the activity of the BRM / BRG1 biinhibitor compound is greater against BRM. In some embodiments, the activity of the BRM / BRG1 biinhibitor compound is greater against BRG1. For example, in some embodiments, the BRM / BRG1 biinhibitor compound has IC against BRM 50 or IP 50 However, IC for BRG1 50 or IP 50 It is within 10 times that amount.

[0293] 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.

[0294] 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 in need thereof, the method comprising administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof to the subject.

[0295] In another embodiment, the present invention relates to a method for suppressing the metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, characterized in that the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0296] In another embodiment, the present invention relates to a method for suppressing metastatic colony formation of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, wherein the method comprises administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0297] In another embodiment, the present invention relates to a method for reducing the levels and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer cells, wherein the method comprises contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

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

[0299] 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%).

[0300] 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).

[0301] 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%).

[0302] 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).

[0303] 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 other embodiments, cell-migrating cancer is non-metastatic cell-migrating cancer. Metastatic cancer may spread by disseminating on the surface of the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, metastatic cancer may spread 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 metastatic colony formation of cancer in the liver.

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

[0305] In some embodiments, the method further comprises administering to 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.

[0306] 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.

[0307] In some embodiments, the anticancer therapy and the compound of the present invention are administered within 28 days of each other, in amounts effective to treat the subject together.

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

[0309] In some embodiments, the cancer is resistant to one or more chemotherapeutic agents or cytotoxic agents (for example, the cancer is determined to be resistant to chemotherapeutic agents or cytotoxic agents (e.g., by genetic markers), or is determined to be highly likely to be resistant to chemotherapeutic agents or cytotoxic agents (e.g., cancer that did not respond to chemotherapeutic agents or cytotoxic agents)). In some embodiments, the cancer did not respond to one or more chemotherapeutic agents. In some embodiments, the cancer was resistant to or unresponsive to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0310] 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).

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

[0312] chemical terms The terms used herein are for the purpose of describing specific embodiments and are not intended to be limiting.

[0313] In 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.

[0314] As used herein, the term “acyl” refers to a hydrogen or alkyl group bonded to a parent group via a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbon atoms.

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

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

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

[0318] As used herein, the term "amino" means -N(R N1 ) represents 2, and each R N1 These are independently H, OH, NO2, N(R) N2 )2, SO2OR N2 SO2R N2 SOR N2, N protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others as described herein), and these listed R N1 Each of the bases can be optionally substituted, or two Rs N1 These combine to form alkylenes or heteroalkylenes, and each R N2 The group is independently H, alkyl, or aryl. The amino group of the present invention is an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R) N1 )2) This could be the case.

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

[0320] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Unsubstituted arylalkyls include benzyl and phenethyl, which have 7 to 30 carbon atoms (e.g., C1-C6 alkyl, C6-C6 alkyl). 10 Aryl, C1~C 10 Alkyl C6~C 10 Aryl, or C1-C 20 Alkyl C6~C 10 It contains aryl groups (with 7 to 16 or 7 to 20 carbon atoms). In some embodiments, the alkyl and aryl groups are further substituted with 1, 2, 3, or 4 substituents, regardless of valency, as defined herein for each group.

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

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

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

[0324] As used herein, the term "carbocyclyl" refers to a non-aromatic C3-C3 ring formed by carbon atoms. 12 This refers to monocyclic, bicyclic, or tricyclic structures. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl groups.

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

[0326] As used herein, the term "halo" means a fluorine, chlorine, bromine, or iodine group.

[0327] 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.

[0328] 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, regardless of valency, as described herein for an alkenyl group. An example of a heteroalkenyl group is “alkenoxy,” which, as used herein, refers to an alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.

[0329] 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 one, two, three, or four substituents, regardless of valency, as described herein for an alkynyl group. An example of a heteroalkynyl group is “alkynoxy,” which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0330] As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic, or tripolycyclic 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 include pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0331] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups 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, regardless of valency, as defined herein for each group.

[0332] 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.

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

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

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

[0336] 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).Examples of N protecting groups include, but are not limited to, acyl, allyroyl, 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, alanine, leucine, and phenylalanine, a sulfonyl-containing group, for example, benzenesulfonyl and p-toluenesulfonyl, and a carbamate-forming group, for example, 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).

[0337] As used herein, the term "nitro" refers to the -NO2 group.

[0338] The term "oxo" as used herein represents a divalent oxygen atom (for example, the structure of oxo may be shown as =O). For example, a carbonyl group is a carbon substituted with an oxo (e.g., 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).

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

[0340] 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 may be 1, 2, 3, 4, or 5 substituents, regardless of valency. 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.

[0341] 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 diastereomer forms. Diastereomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of diastereomers whose mirror images cannot be superimposed because they contain asymmetrically substituted carbon atoms that function as chiral centers. Enantiomer means one of a pair of molecules that are mirror images of each other and cannot be superimposed. Diastereomers are most commonly diastereomers that are unrelated as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the stereochemistry of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomer from a racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods thereunder. Suitable 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. "Racemate" or "racemic mixture" means a compound containing two enantiomers, and 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 atoms 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 an E configuration (substituents are on the opposite side 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 diastereomers arising from hindered rotations around a single bond where the steric strain barrier against rotation is sufficiently high 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 separation methods include forming salts of the free bases of each isomer of an isomer pair using optically active acids (followed by fractional crystallization and regeneration of the free bases), forming salts of the acidic form of each isomer of an isomer pair using optically active amines (followed by fractional crystallization and regeneration of the free acids), forming esters or amides of each isomer of an isomer pair using optically pure acids, amines, or alcohols (followed by chromatographic separation and removal of chiral auxiliaries), or separating an isomer mixture of either the starting material or the final product using various well-known chromatographic methods. If the stereochemistry of a disclosed compound is named or shown by structure, the named or shown diastereomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight relative to other diastereomers. If a single enantiomer is named or shown by structure, the shown or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight optically pure. If a single diastereomer is named or shown by structure, the shown or named diastereomer is 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 isomer. Diastereomer purity by weight is expressed as the weight of a single diastereomer or as a ratio to the total weight of all diastereomers.If the stereochemistry of a disclosed compound is named or shown by structure, the named or shown diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction relative to other diastereomers. If a single enantiomer is named or shown by structure, the shown 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 shown by structure, the shown 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 moles of the enantiomer, or the ratio of the moles of the enantiomer to the moles of its optical isomer. Similarly, the purity percentage by mole fraction is the moles of the diastereomer, or the ratio of the moles of the diastereomer to the moles of its isomer. If a disclosed compound is named or indicated by structure without showing 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 without 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 structure without showing stereochemistry, and has two or more chiral centers, the name or structure should be understood to encompass a diastereomer without other diastereomers, several diastereomers without other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is concentrated relative to other diastereomers, or a mixture of diastereomers in which one or more diastereomers are concentrated relative to other diastereomers. The present invention encompasses all of these forms.

[0342] The compounds of this disclosure also include all isotopes of atoms present in the intermediate or final compounds. An "isotope" refers to an atom that has the same atomic number but a different mass number, resulting from a different number of neutrons in its nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0343] 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. 15O, 13 N, 11 C, and 18 Positron-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 well known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by substituting an isotope-labeled reagent with an unisotope-labeled reagent, following a procedure similar to that disclosed for the compounds of the present invention described herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials are described herein for use in this disclosure. Other suitable methods and materials known in the art may also be used. Those materials, methods, and examples are illustrative and not intended to limit. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated in their entirety by reference. In case of any conflict, this specification, including definitions, shall prevail.

[0344] 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 processes, may be understood to encompass the components or processes of the list.

[0345] 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.

[0346] 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, intranasal, intraperitoneal, subarachnoid, intratumoral, intravenous, intraventricular, mucosa, nasal cavity, oral, rectal, subcutaneous, sublingual, topical, trachea (including by intratracheal infusion), percutaneous, vaginal, and vitreous humor.

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

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

[0349] As used herein, the term “BRG1 loss of function mutation” refers to a mutation in BRG1 that results in a protein with reduced activity (e.g., 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 BRG1 loss of function mutations include, but are not limited to, mutations and deletions of homozygous BRG1 at the C-terminus of BRG1.

[0350] As used herein, the term “BRG1 loss of function disorder” refers to a disorder (e.g., cancer) that presents with a reduction in 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).

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

[0352] As used herein, “combination therapy” or “administered in combination” means that two (or more) different 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 can occur by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by 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.

[0353] "Determining the level" of a protein or RNA means detecting the protein or RNA by a method known in the art, either directly or indirectly. "Directly determining" means performing a process to obtain a physical entity or value (e.g., performing an assay or test on a sample, or "analyzing a sample" as the term is defined herein). "Indirectly determining" 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 well known in the art and are not limited to those described above, but include quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

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

[0355] As used herein, the term “degrader” refers to a small molecule compound 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).

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

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

[0358] "Reducing the activity of BRG1 and / or BRM" means reducing the level of activity or associated downstream effects related to BRG1 and / or BRM. A non-limiting example of inhibiting BRG1 and / or BRM activity 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 reducing the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrading agent.

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

[0360] "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, of about 10%, 15%, 2 This means a decrease or increase of 0%, approximately 50%, approximately 75%, approximately 100%, or more than approximately 200%, a decrease or increase of less than approximately 0.01 times, approximately 0.02 times, approximately 0.1 times, approximately 0.3 times, approximately 0.5 times, or less than approximately 0.8 times, or an increase of approximately 1.2 times, approximately 1.4 times, approximately 1.5 times, approximately 1.8 times, approximately 2.0 times, approximately 3.0 times, approximately 3.5 times, approximately 4.5 times, approximately 5.0 times, approximately 10 times, approximately 15 times, approximately 20 times, approximately 30 times, approximately 40 times, approximately 50 times, approximately 100 times, approximately 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.

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

[0362] 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 a mammal, such as a human. 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 a disease in a mammal. 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 a sterile solution without particulate stumps and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0363] As used herein, “pharmaceutically acceptable excipient” 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.

[0364] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, e.g., any compound of formula I. Any pharmaceutically acceptable salt of any of the compounds described herein may be suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reactions, within the bounds of sound medical judgment, and may include salts that are balanced by a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PHStahl and CGWermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting free base groups with suitable organic acids.

[0365] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts containing inorganic or organic acids, or the salts may be prepared from inorganic or organic bases in the acidic form of the compounds of the present invention. 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.

[0366] "Reference" 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, such as a predetermined negative control value such as a "normal control," or a previous sample taken from the same subject, a sample from a normal healthy subject such as normal cells or tissue, a sample from a subject without disease (e.g., cells or tissue), a sample from a subject diagnosed with a 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 at a well-known normal concentration (e.g., any of those described herein). "Reference standard or level" means a value or numerical value derived from the reference sample. "Normal control value" is a predetermined value indicating a non-disease state, for example, a value expected in a healthy control subject. Typically, normal control values ​​are expressed as a range ("between X and Y"), a high threshold ("no higher than X"), or a low threshold ("no lower than X"). Subjects with measurements within the normal control range for a particular biomarker are typically referred to as being "within normal limits" for that biomarker. Normal reference standards or levels may be values ​​or numbers derived from normal subjects without disease or disorder (e.g., cancer) or subjects treated with the compounds of the present invention. In preferred embodiments, reference samples, standards, or levels are matched to the sample subject by at least one of the following criteria: age, weight, sex, disease stage, and overall health. Standard curves of levels of purified proteins or RNA within the normal reference range, e.g., any of those described herein, may also be used as references.

[0367] As used herein, the term “subject” refers to 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.

[0368] As used herein, the terms “treat,” “treated,” or “treating” mean a therapeutic procedure or any means aimed at slowing (reducing) an undesirable physiological condition, disorder, or disease, or obtaining 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 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 "prophylactically treat" or "prevent" a disorder in subjects with an increased risk of developing the disorder.

[0369] 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]

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

[0371] In one embodiment, the present invention relates to a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, m is 0, 1, 2, or 3. k is 0, 1, or 2. Each R 1 These are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano. Each X is independently a halo or optionally substituted C1-C6 heteroalkyl. L is a linker, B is characterized by the decomposition portion, which is the compound of formula IV, or a pharmaceutically acceptable salt thereof.

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

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

[0374] 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.

[0375] One aspect of the present invention relates to a method for treating disorders associated with loss-of-function mutations of BRG1, 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 a subject in need. In some embodiments, the compound is administered in a dose and time that is effective in producing one or more of the following (e.g., two or more, three or more, four or more) results from (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.

[0376] 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 measurement method. For example, tumor size may be measured as the diameter of the tumor.

[0377] 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 measurement method, 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).

[0378] 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).

[0379] Treating cancer may result in an increase in the mean survival time of a population of subjects treated according to the present invention compared to a population of untreated subjects. 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 start 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 the pharmaceutically acceptable salt of the present invention.

[0380] 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.

[0381] 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 tumors, adrenocortical carcinoma, appendiceal cancer, small intestine cancer, and penile cancer.

[0382] Combined 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.

[0383] 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 dose of one or more therapeutic compounds may be reduced from the standard dose when administered alone. For example, the dose 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 dose of the combined compounds should provide a therapeutic effect.

[0384] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful 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 biposulfan, aziridines such as benzodopa, carbocone, metadopa and uredopa, ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine, acetogenins (especially bratacin and bratacinone), camptothecin (including its synthetic analog topotecan), bryostatin, calistatin, and CC-1065 (its adzeresin, karzeresin and bi). (including zelesin 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, trophosphamide, uracil mustard, and nitrosourea.For example, carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine, and antibiotics, for example, engine antibiotics (for example, calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)), dynemicins including dynemicin A, bisphosphonates, for example, clodronate, esperamicin, and neocartinostatin chromophores and related pigment protein engine antibiotic chromophores), aclasinomycin, actinomycin, autramycin, azacerin, bleomycin, kakuchi Cactinomycin, Carabicin, Caminomycin, Cardinophilin, Chromomycinis, Dactinomycin, Daunorubicin, Detorubicin, 6-Diazo-5-Oxo-L-Norleucine, Adriamycin (registered trademark) (Doxorubicin including Morpholino-Doxorubicin, Cyanomorpholino-Doxorubicin, 2-Pyrrolidino-Doxorubicin and Deoxydoxorubicin), E Pyrubicin, esorubicin, idarubicin, marcelomycin, mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potfiromycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin, and Antimetabolites, such as methotrexate and 5-fluorouracil (5-FU), folic acid analogs, such as denopterin, methotrexate, pteropterin, and trimethrexate, purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine, and pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and enocitabine.Floxuridine, androgens, such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as floric acid, acegraton, aldofamide glycoside, aminolevulinic acid, enyluracil, amsacrin, bestrabusil, bisanthren, edatraxate, defofamine, demecolsin, diaziquan, and elfomitin. hine), erliptinium acetate, epotilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansinoids, such as maytansine and anthamitosine, mitogwazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, fenamet, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazine, procarbazine, and PSK (registered trademark) polysaccharide complex (JHS Natural Products (Eugene, Oreg.), lazoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triadicone, 2,2',2''-trichlorotriethylamine, trichothecenes (especially T-2 toxin, verlaculin A, loridine A, and angidin), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitractol, pipobromane, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, and taxoids, such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane®, and albumin-modified nanoparticle formulations of paclitaxel (American Pharmaceuticals). Partners, Schaumberg, Ill., and Taxotere® doxetaxel (Rhone-Poulenc 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), and topoisomerase inhibitor RFS Examples include difluoromethylornithine (DMFO), retinoids such as retinoic acid, capecitabine, and any pharmaceutically acceptable salt, acid, or derivative thereof. 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 well known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

[0385] In some embodiments, the second therapeutic agent is a 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. Such drugs include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab), Synagis (palivizumab), Remicade (infliximab), Herceptin (trastuzumab), Mylotarg (gemtuzumab ozogamicin), Campus (alemtuzumab), Zevalin (ibritumomab tiuxetan), Humira (adalimumab), Xolair (omalizumab), Bexal (tositumomab-I-131), Laptiva (efalizumab), Erbitux (cetuximab), Avastin (bevacizumab), Tysabri (natalizumab), and Actemra (tocilizumab) Examples include Vectibix (panitumumab), Lucentis (ranibizumab), Soliris (eculizumab), Cimzia (certolizumab pegol), Simponi (golimumab), Ilaris (canakinumab), Stelara (ustekinumab), Arzera (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.

[0386] 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.

[0387] The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, a humanized antibody or a fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with 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).

[0388] In any of the combination embodiments described herein, the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially, 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 days prior, 1 to 14 days prior, 1 to 21 days prior, or 1 to 30 days prior or after the administration of the second therapeutic agent.

[0389] 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.

[0390] The compounds of the present invention may be in the form of free bases, salts, solvates, and prodrugs. All forms are within the scope of the present invention. As can be understood by those skilled in the art, according to the methods of the present invention, the compounds described, or their salts, solvates, or prodrugs, may be administered to a patient in various forms depending on the selected route of administration. The compounds of the present invention may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and pharmaceutical compositions may be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, subarachnoid, rectal, and topical administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0391] 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, equipped 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.

[0392] 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.

[0393] 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 recipient's age, health, and weight, the nature and severity of symptoms, the frequency of treatment, and the type of concurrent treatment, if any, and the clearance rate of the compound in the treated animal. Those skilled in the art 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.

[0394] 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]

[0395] The following abbreviations will be used throughout the following examples.

[0396] [Table 2-1]

[0397] [Table 2-2]

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

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

[0400] To a stirred solution of 2-(3-bromo-1,2-oxazol-5-yl)ethane-1-ol (30 g, 156 mmol) in acetone (389 mL), Jones' reagent (2 M in acetone, 156 mL, 312 mmol) was added dropwise at 0°C. The resulting solution was stirred overnight at 25°C. The mixture was diluted with water and extracted with Â. The organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain a brown solid of 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 86.5%). LCMS(ESI)m / z:[M+H] + = 206.08 and 208.08.

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

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

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

[0404] 2-(3-bromoisoxazole-5-yl)methyl acetate (23.4 g, 106 mmol) and KO in THF (210 mL) t To a stirred solution of Bu (17.8 g, 159 mmol), 2-iodopropane (13.8 mL, 137 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 hours, then quenched with water / ice. The resulting solution was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate / petroleum ether) to obtain a clear oily methyl 2-(3-bromoisoxazole-5-yl)-3-methylbutanoate (16.7 g, 60%).

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

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

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

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

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

[0410] To a solution of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (8.16 g, 44.0 mmol) in methanol (30 mL), SOCl2 (14.2 mL, 197 mmol) was slowly added. The mixture was stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. The residue was diluted with water and extracted with siRNA. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (MeOH / DCM) to obtain a clear oily methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (7.79 g, 89%). LCMS(ESI)m / z:[M+H] + = 200.15.

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

[0412] To a solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (7.79 g, 39.1 mmol) in DMF (90 mL), 2-bromo-1,1-diethoxyethane (8.77 mL, 58.6 mmol) and potassium carbonate (10.8 g, 78.2 mmol) were added. The reaction mixture was stirred overnight at 70°C. After cooling the reaction mixture, it was added to the mixture. The resulting mixture was extracted several times with RINKAN. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel flash chromatography (RINKAN: heptane) to obtain a colorless oily methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate (7.8 g, 63%). LCMS(ESI)m / z:[M-C2H5O] + = 270.30.

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

[0414] To a solution of methyl 2-[3-(2,2-diethoxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate (7.8 g, 24.7 mmol) in methanol (50 mL) and water (25 mL), lithium hydroxide monohydrate (4.14 g, 98.8 mmol) was added. The reaction mixture was stirred at 40°C for 2 hours. The pH was adjusted to 4-5 with 1 N HCl. The mixture was extracted several times with ethyl acetate, and the combined organic layer was dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (DCM: MeOH) to obtain a colorless oily 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid (6.1 g, 89%). LCMS(ESI)m / z:[MH] - = 300.21.

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

[0416] To a solution of (S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in 70 mL of DCM at 0°C, HATU (8.98 g, 23.5 mmol) was added, followed by the dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring at room temperature for 16 hours, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layer was washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (MeOH:DCM) to obtain tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylic acid (8.33 g, 98%). LCMS(ESI)m / z:[M+H] + = 432.38.

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

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

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

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

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

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

[0423] (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-3) and 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). [ka]

[0424] 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. [ka]

[0425] To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (100.00 mg, 0.502 mmol, 1.00 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. The residue was purified by silica gel column chromatography using PE / EA(2 / 1) elution to obtain methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl]butanoate (217 mg) as a white solid. LCMS(ESI)m / z:[M+H] + = 482.

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

[0427] To a stirred solution of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl]butanoate (217.00 mg, 0.451 mmol, 1.00 equivalent) in DMF (3.00 mL), tert-butylpiperazine-1-carboxylic acid (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 (0.1% FA) in water, and purification was performed over 30 minutes with a gradient from 0 to 100%. This yielded a yellow, oily tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]piperazine-1-carboxylic acid (54 mg, 32.59%). LCMS(ESI)m / z:[M+H] + = 368.

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

[0429] To a stirred solution of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]piperazine-1-carboxylic acid (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 LiOH .H2O (18.50 mg, 0.441 mmol, 3.00 equivalents) was added. The resulting mixture was stirred 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 brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. This yielded a yellow solid 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazole-5-yl]-3-methylbutanoic acid (52 mg, crude product). LCMS(ESI)m / z:[M+H] + =354.

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

[0431] To a stirred solution of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazole-5-yl]-3-methylbutanoic acid (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. To the above mixture, (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. The resulting mixture was stirred for 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, direct purification over 30 minutes with a gradient from 0 to 100%. This yielded 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-carboxylic acid as a white solid (73 mg, 92.12%). LCMS(ESI)m / z:[M+H] + = 667.

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

[0433] tert-butyl4-(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-carboxylic acid (73 mg) was analyzed by SFC under the following conditions: column, CHIRAL ART Amylose-C NEO, 3 *A 25 cm, 5 mm, mobile phase, and MeOH were prepared. This provided the following:

[0434] tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)piperazine-1-carboxylate (37 mg, second peak). LCMS(ESI)m / z:[M+H] + = 667.

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

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

[0437] 37.00 mg, 0.055 mmol, 1.00 equivalent) of tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)piperazine-1-carboxylate was dissolved in 1.50 mL of DCM, and 1.50 mL, 26.276 mmol, 473.57 equivalents of HCl in 1,4-dioxane were added at 0°C. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This yielded a yellow, oily I-3 (45 mg, crude product). LCMS(ESI)m / z:[M+H] + = 567.

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

[0439] The following intermediates in Table 2 were prepared by starting with methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl]butanoate and a suitable amine, in the same manner as described in the preparation of intermediate I-3.

[0440] [Table 3]

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

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

[0443] 2-chloropyrimidine-5-carbaldehyde (5g, 35.078 mmol, 1 equivalent) and NH2OH in EtOH (250mL) . 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 with siRNA (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.

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

[0445] 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.

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

[0447] 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) under a dry nitrogen atmosphere at 0°C for 30 minutes, and then methyl buto-3-inoate (2.02 g, 20.591 mmol, 0.82 equivalents) was gradually added 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.

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

[0449] 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 layers were 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.

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

[0451] 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) 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.

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

[0453] 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 equivalent) under a dry nitrogen atmosphere at 0°C for 30 minutes, and then 2-iodopropane (1.5 g, 8.824 mmol, 0.88 equivalent) 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 ELISA (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.

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

[0455] 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 product), which was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =296.

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

[0457] (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(2-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (30.00 mg, 0.055 mmol, 1.00 equivalent) and 2-methyl-2-butene (0.78 mg, 0.011 mmol, 0.20 equivalents) were stirred in tert-butanol (2 mL) and then added dropwise at 0°C to a solution of NaClO2 (50.19 mg, 0.550 mmol, 10.00 equivalent) and NaH2PO4 (78.77 mg, 0.550 mmol, 10.00 equivalent) in water (2.00 mL). The mixture was stirred at 0°C for 0.5 hours, then heated to room temperature and stirred for 1.5 hours. The reactants were quenched by adding a mixture of saturated Na2S2O3 solution and brine, and CHCl3 was added. 3( Extraction was performed using 20 mL x 3 solutions. The combined organic extracts were dried with Na2SO4, filtered, concentrated under vacuum, and purified by silica gel chromatography (PE / SiO7 = 1:1 to 1:3). This yielded intermediate I-8 (15.80 mg, 49.93%) as a colorless oil. LCMS(ESI)m / z:[M+H] + = 557.

[0458] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-6-yl]-5-methylthieno[2,3-c]pyridazin-6-yl]azetidine-1-yl}ethoxy)-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). Preparation of 2-[6-(azetidine-3-yl)sinnolin-3-yl]phenol (intermediate I-9). [ka]

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

[0460] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (10.33 g, 36.488 mmol, 2.00 equivalents) in DMF (10.00 mL), I2 (2.32 g, 9.122 mmol, 0.50 equivalents) and Zn (3.58 g, 54.732 mmol, 3.00 equivalents) were added at 0°C (Solution A). The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. To a stirred solution of methyl 2-(5-bromo-2-nitrophenyl)acetate (5.00 g, 18.244 mmol, 1.00 equivalent) in DMF (10.00 mL), Pd2(dba)3-CHCl3 (1.89 g, 1.824 mmol, 0.10 equivalent), t-BuXPhos (0.77 g, 1.824 mmol, 0.10 equivalent), and CuI (0.35 g, 1.824 mmol, 0.10 equivalent) were added at room temperature (=Solution B). Solution B was added to Solution A at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction products were quenched with water at 0°C. The resulting mixture was extracted with RINKAN (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / SiO(2:1) to obtain intermediate 3 (4.1g, 64.14%) as a brown oily substance. LCMS(ESI)m / z:[M+H] + =351.

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

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

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

[0464] To a stirred solution of intermediate 4 (3.00 g, 11.988 mmol, 1.00 equivalent) in DCM (30.00 mL), Ac2O (3.67 g, 35.964 mmol, 3.00 equivalent) and Et3N (3.64 g, 35.964 mmol, 3.00 equivalent) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10 / 1) to obtain intermediate 5 (4.5 g, >100%) as a yellow oily substance. LCMS(ESI)m / z:[M+H] + =293.

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

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

[0467] Step 5: Preparation of 5-(1-acetylazetidine-3-yl)-1-amino-3H-indole-2-one (intermediate 7). [ka]

[0468] To a stirred solution of intermediate 6 (2.10 g, 8.006 mmol, 1.00 equivalent) in DCM (34.00 mL), NOBF4 (1.87 g, 16.012 mmol, 2.00 equivalent) was added at 0°C. The resulting mixture was stirred at 0°C for 1 hour. SnCl2·2H2O (18.23 g, 80.060 mmol, 10.00 equivalent) and concentrated HCl were added to the mixture. HCl (68.00 mL) 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 purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water-based MeCN, gradient from 0% to 100% over 30 minutes, detector, UV254 / 220 nm. Intermediate 7 (1.6 g, 81.48%) was obtained as a brown oily substance. LCMS(ESI)m / z:[M+H] + = 246.

[0469] Step 6: Preparation of 1-[3-(3-hydroxysinnolin-6-yl)azetidine-1-yl]ethanone (intermediate 8). [ka]

[0470] To a stirred solution of intermediate 7 (1.60 g, 5.708 mmol, 1.00 equivalent) in DCM (10.00 mL), Pb(OAc)4 (3.80 g, 8.562 mmol, 1.50 equivalent) was added at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The reaction product was quenched with MeOH 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, water-based MeCN, gradient from 0% to 100% over 30 minutes, detector, UV254 / 220 nm. This yielded intermediate 8 (880 mg, 63.38%) as a green oily substance. LCMS(ESI) m / z:[M+H] + = 244.

[0471] Step 7: Preparation of 6-(1-acetylazetidine-3-yl)sinnoline-3-yltrifluoromethanesulfonate (intermediate 9). [ka]

[0472] To a stirred solution of intermediate 8 (880.00 mg, 3.617 mmol, 1.00 equivalent) in DCM (20.00 mL), Tf2O (10.21 g, 36.170 mmol, 10.00 equivalent) and pyridine (2.86 g, 36.170 mmol, 10.00 equivalent) were 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 purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water with MeCN (0.1% FA), direct purification by reverse-phase flash chromatography with a gradient from 0% to 100% over 30 minutes, detector, UV254 / 220 nm. This yielded a brownish oily intermediate 9 (415 mg, 30.57%). LCMS(ESI)m / z:[M+H] + =376.

[0473] Step 8: Preparation of 1-{3-[3-(2-hydroxyphenyl)sinnolin-6-yl]azetidine-1-yl}ethanone (intermediate 11). [ka]

[0474] To a stirred solution of intermediate 9 (415.00 mg, 1.106 mmol, 1.00 equivalent) and 2-hydroxyphenylboronic acid (458.16 mg, 3.320 mmol, 3.00 equivalent) in 1,4-dioxane (8.00 mL) and H2O (2.00 mL), XPhos Pd G3 (187.13 mg, 0.221 mmol, 0.20 equivalent) and Cs2CO3 (1.082 g, 3.320 mmol, 3.00 equivalent) were added at room temperature. The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the mixture to room temperature, it 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), direct purification by reverse-phase flash chromatography with a gradient from 0% to 100% over 30 minutes, detector, UV254 / 220nm. This yielded intermediate 11 (254 mg, 71.95%) as a yellow oily substance. LCMS(ESI)m / z:[M+H] + =320.

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

[0476] To a stirred solution of intermediate 11 (254.00 mg, 0.794 mmol, 1.00 equivalent) in MeOH (5.00 mL) and H2O (5.00 mL), KOH (133.39 mg, 2.382 mmol, 3.00 equivalent) was added at room temperature. The resulting mixture was stirred at 70°C for 1 hour. After cooling the mixture to room temperature, it 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-based MeCN (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV254 / 220 nm. This yielded I-9 (134 mg, 60.91%) as a white solid. LCMS(ESI)m / z:[M+H] + = 278.

[0477] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-6-yl]azetidine-1-yl}ethoxy)-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]

[0478] To a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (29.24 mg, 0.054 mmol, 1.00 equivalent) in DMSO (1.00 mL), IO-9 (15.00 mg, 0.054 mmol, 1.00 equivalent) was added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture, NaBH(OAc)3 (34.39 mg, 0.162 mmol, 3.00 equivalent) and AcOH (catalyst) were added at room temperature. The resulting mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature. The reaction was quenched with water at 0°C and then purified by Chiral-Prep-HPLC under the following conditions: column, Xselect CSH F-phenyl OBD column, 19 * 250 mm, 5 μm, mobile phase: water (0.05% FA) and MeOH (43% MeOH, up to 67% in 7 mins), detector: UV254 / 220 nm. This yielded compound 1 (6.8 mg, 15.50%) as a white solid. 11H NMR (400 MHz, DMSO-d6)δ 12.16-11.87(m, 1H), 8.98(d, J=2.1Hz, 1H), 8.87(d, J=8.2Hz, 1H), 8.4 7-8.39(m, 2H), 8.30-8.15(m, 1H, FA), 8.14-8.06(m, 1H), 8.04-7.94(m, 2H), 7.47-7.41(m, 2H), 7.41-7.31(m, 3H), 7.09-7.00(m, 2H), 6.10(s, 1 H), 5.25-4.97(m, 1H), 4.97-4.85(m, 1H), 4.37(t, J=7.9Hz, 1H), 4.31-4 .23(m, 1H), 4.18(t, J=5.4Hz, 2H), 3.97-3.86(m, 1H), 3.79(t, J=7.3Hz , 2H), 3.73-3.62(m, 2H), 3.59-3.42(m, 3H), 2.86(t, J=5.4Hz, 2H), 2.45 (d, J=6.6Hz, 3H), 2.30-2.13(m, 1H), 2.08-1.98(m, 1H), 1.82-1.72(m, 1H), 1.37(d, J=7.0Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.81(d, J=6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + = 802.40.

[0479] The compounds in Table 3 were prepared using appropriate amines and aldehydes (or ketones) with the same procedure as that used above for the preparation of compound 1.

[0480] [Table 4]

[0481] (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-6-yl]azetidine-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 4) and (2 Preparation of S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-6]-yl]azetidine-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]

[0482] Step 1: Preparation of methyl 2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-6-yl]azetidine-1-yl}pyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate (intermediate 3). [ka]

[0483] To a stirred solution of I-(50.00 mg, 0.180 mmol, 1.00 equivalent) in DMSO (2.00 mL) at room temperature, methyl 2-[3-(2-chloropyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate (53.32 mg, 0.180 mmol, 1.00 equivalent) and DIEA (69.91 mg, 0.540 mmol, 3.00 equivalent) were added. The resulting mixture was stirred at 100 °C for 6 hours. The mixture was cooled to room temperature and 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, UV254 / 220 nm. This yielded intermediate 3 (20 mg, 20.67%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 537.

[0484] Step 2: Preparation of 2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-6-yl]azetidine-1-yl}pyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoic acid (intermediate 4). [ka]

[0485] To a stirred solution of intermediate 3 (20.00 mg, 0.037 mmol, 1.00 equivalent) in MeOH (1.00 mL) and H2O (1.00 mL), LiOH·H2O (4.69 mg, 0.111 mmol, 3.00 equivalent) was added at room temperature. The resulting mixture was stirred at room temperature for 6 hours. The mixture was acidified to pH 3 with HCl aqueous solution (1 M). The resulting mixture was concentrated under reduced pressure. This yielded intermediate 4 (20 mg, crude) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 523.

[0486] Step 3: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-6-yl]azetidine-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 6). [ka]

[0487] To a stirred solution of intermediate 4 (20.00 mg, 0.038 mmol, 1.00 equivalent) in DMF (1.00 mL), PyBOP (59.28 mg, 0.114 mmol, 3 equivalents) and DIEA (24.51 mg, 0.190 mmol, 5 equivalents) 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 (12.62 mg, 0.038 mmol, 1 equivalent) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (10 mmol / L NH4HCO3) in H2O, gradient from 0% to 100% over 30 minutes, detector, UV254 / 220nm. This yielded intermediate 6 (5 mg, 15.62%) as an off-white oily substance. LCMS(ESI)m / z:[M+H] + = 836.

[0488] Step 4: (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-6-yl]azetidine-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 4) and Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-6]-yl]azetidine-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]

[0489] Intermediate 6 (5.00 mg) was purified by Chiral-Prep-HPLC under the following conditions: Column, CHIRALPAK ID, 2 * 25cm, 5mm, mobile phase: MtBE (10mM NH3-MeOH) and MeOH (50% MeOH retained for 29 minutes), detector: UV254 / 220nm. The following results were obtained.

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

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

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

change

[0493] ({5-[(2R)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl}oxy)acetic acid (30.11 mg, 0.054 mmol, 1.00 equivalent) was dissolved in DMF (1.00 mL) and PyBOP (84.44 mg, 0.162 mmol, 3.00 equivalent) and DIEA (34.95 mg, 0.270 mmol, 5.00 equivalent) were added at room temperature. I-9 (15.00 mg, 0.054 mmol, 1.00 equivalent) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by Prep-HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 19 * Chiral Prep-HPLC was performed at 150 mm, 5 μm, with water (10 mmol / L NH4HCO3) and CH3CN (up to 55% from 42% CH3CN after 7 mins) using a UV254 / 220 nm detector. Compound 6 (15.5 mg, 33.86%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d6)δ 11.93-11.69(m, 1H), 8.98(s, 1H), 8.88(s, 1H), 8.50(d, J=8.8Hz, 1H), 8.43(d, J=7.7Hz, 1H), 8.15-8.07(m, 2H), 8.02-7.97(m, 1H), 7.47-7.41(m, 2H), 7.41-7.33(m, 3H), 7.10-7.01(m, 2H), 6.19(d, J=1.6Hz, 1H), 5.11(d, J=3.7Hz, 1H), 4.97-4.86(m, 1H), 4.80(s, 2) H), 4.77-4.65(m, 1H), 4.48-4.34(m, 3H), 4.32-4.18(m, 2H), 4.15-4.05(m, 1H), 3.74-3.65(m, 2H), 3.51-3.42(m, 1H), 2.47-2.43(m , 3H), 2.31-2.15(m, 1H), 2.07-1.96(m, 1H), 1.83-1.69(m, 1H), 1.37(d, J=6.9Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.80(d, J=6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + = 816.70.

[0494] The compounds in Table 4 were prepared using appropriate amines and carboxylic acids, employing the same procedure as that used above for the preparation of compound 6.

[0495] [Table 5]

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

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

[0498] A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (12.40 g, 43.784 mmol, 1.2 equivalents) and I2 (4.63 g, 18.244 mmol, 0.5 equivalents) in DMF (100 mL) was cooled to 0°C. Zn (7.16 g, 109.461 mmol, 3 equivalents) was added gradually at this temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Next, CuI (1.39 g, 7.297 mmol, 0.2 equivalents), Pd(dba)2 (4.20 g, 7.297 mmol, 0.2 equivalents), XPhos (3.478 g, 7.297 mmol, 0.2 equivalents), and methyl 2-(4-bromo-2-nitrophenyl) acetate (10 g, 36.487 mmol, 1 equivalent) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The resulting mixture was filtered through a Celite pad, and the filtrate was washed with SiO2 (3 × 200 mL). The filtrate was washed with water (3 × 300 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 and eluted with PE / EA (3:1) to obtain intermediate 2 (5 g, 35.20%) as a yellow oily substance. LCMS(ESI)m / z:[M+H] + =351.

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

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

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

[0502] To a stirred mixture of intermediate 3 (5 g, 13.726 mmol, 1.00 equivalent) and Et3N (6.94 g, 68.630 mmol, 5 equivalents) in DCM (20 mL), Ac2O (2.10 g, 20.589 mmol, 1.5 equivalents) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (14:1) to obtain intermediate 4 (3.5 g, 78.52%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =293.

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

[0504] A mixture of intermediate 4 (3.5 g, 11.974 mmol, 1 equivalent) and NH4Cl (12.81 g, 239.480 mmol, 20 equivalents) in MeOH (50 mL) was cooled to 0°C, and then Zn (7.83 g, 119.740 mmol, 10 equivalents) was gradually added. The resulting mixture was stirred at 0°C for 1 hour. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with SiO2 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 5 (2 g, 57.31%) as a yellow oily substance. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =263.

[0505] Step 5: Preparation of 6-(1-acetylazetidine-3-yl)-1-amino-3H-indole-2-one (intermediate 6). [ka]

[0506] A mixture of intermediate 5 (2 g, 7.625 mmol, 1 equivalent) in DCM (40 mL) was cooled to 0°C. NOBF4 (1.34 g, 11.438 mmol, 1.5 equivalents) was then added all at once. The resulting mixture was stirred at 0°C for 1 hour. SnCl2 (11.69 g, 61.000 mmol, 8 equivalents) in HCl (60 mL) was added dropwise to the mixture at 0°C. The resulting mixture was then stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water-based MeCN, gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 6 (600 mg, 28.87%) as a green solid. LCMS(ESI) m / z:[M+H] + = 246.

[0507] Step 6: Preparation of 1-[3-(3-hydroxysinnolin-7-yl)azetidine-1-yl]ethanone (intermediate 7). [ka]

[0508] A mixture of intermediate 6 (600 mg, 2.446 mmol, 1 equivalent) in DCM (10 mL) was cooled to 0°C. Next, Pb(OAc)4 (1301.55 mg, 2.935 mmol, 1.2 equivalents) was added gradually. The resulting mixture was stirred at 0°C for 1 hour, and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water-based MeCN, gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 7 (400 mg, 60.50%) as a yellow solid. LCMS(ESI) m / z:[M+H] + = 244.

[0509] Step 7: Preparation of 7-(1-acetylazetidine-3-yl)sinnoline-3-yltrifluoromethanesulfonate (intermediate 8). [ka]

[0510] To a stirred mixture of intermediate 7 (400 mg, 1.644 mmol, 1 equivalent) and DMAP (40.18 mg, 0.329 mmol, 0.2 equivalents) in DCM (10 mL), TEA (499.17 mg, 4.932 mmol, 3 equivalents) was added. The mixture was cooled to 0°C. Tf2O (695.86 mg, 2.466 mmol, 1.5 equivalents) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 0°C for a further 1 hour. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 8 (400 mg, 58.33%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =376.

[0511] Step 8: Preparation of 1-{3-[3-(2-hydroxyphenyl)sinnolin-7-yl]azetidine-1-yl}ethanone (intermediate 9). [ka]

[0512] To a solution of intermediate 3 (310 mg, 0.826 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (341.77 mg, 2.478 mmol, 3 equivalents) in dioxane (5 mL) and H2O (1 mL), Cs2CO3 (807.34 mg, 2.478 mmol, 3 equivalents) and XPhos Pd G3 (139.83 mg, 0.165 mmol, 0.2 equivalents) were added. After stirring at 80°C for 1 hour under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and extracted with RINKAN (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography 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. This yielded intermediate 9 (100 mg, 34.12%) as a yellow solid. LCMS(ESI) m / z:[M+H] + =320.

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

[0514] To a stirred mixture of intermediate 9 (100 mg, 0.313 mmol, 1 equivalent) in MeOH (3 mL) and H2O (3 mL), KOH (175.68 mg, 3.130 mmol, 10 equivalents) was gradually added at room temperature. The resulting mixture was stirred at 70°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water-based MeCN (0.1% FA), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded I-10 (92 mg, 95.35%) as a yellow solid. LC-MS (ESI) m / z: [M+H] + = 278.

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

[0516] I-10 (16 mg, 0.058 mmol, 1 equivalent) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (31.19 mg, 0.058 mmol, 1 equivalent) were dissolved in DCM (1 mL) and MeOH (1 mL), and AcOH (3.46 mg, 0.058 mmol, 1 equivalent) and NaBH3CN (10.88 mg, 0.174 mmol, 3 equivalents) were added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions: the column was a Kinetex EVO C18 Column, 21.2 *150 mm, 5 mm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN, flow rate: 25 mL / min, gradient: 35% B to 62% B over 7 minutes, then 62% B, detector: UV254 / 220 nm. Compound 8 (18.1 mg, 38.77%) was obtained as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6)δ 12.03(d, J=6.3Hz, 1H), 8.96(d, J=22.1Hz, 2H), 8.48-8.32(m, 2H), 8.13(d, J=8.5Hz, 2H), 7.99(d, J=8.7Hz, 1H), 7.50-7.30(m, 5H), 7 .13-6.99(m, 2H), 6.03(d, J=50.8Hz, 1H), 5.11(d, J=3.7Hz, 1H), 4.92(t, J=7.1Hz, 1H), 4.38(t, J=7.8Hz, 1H), 4.29(s, 1H), 4.19(t, J =5.4Hz, 2H), 3.98(t, J=7.1Hz, 1H), 3.83(d, J=7.2Hz, 2H), 3.75-3.62(m, 2H), 3.46(d, J=11.2Hz, 3H), 2.89(s, 2H), 2.46(d, J=2.7Hz, 3H), 2.24(s, 1H), 2.04(t, J=10.3Hz, 1H), 1.86-1.69(m, 1H), 1.42(dd, J=22.1, 7.0Hz, 3H), 0.96(d, J=6.5Hz, 3H), 0.89-0.73(m, 3H). LCMS(ESI)m / z:[M+H] + = 802.30.

[0517] The compounds in Table 5 were prepared using appropriate amines and aldehydes (or ketones) with the same procedure as that used above for the preparation of compound 8.

[0518] [Table 6]

[0519] (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-7-yl]azetidine-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 11) and (2 Preparation of S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-7]-yl]azetidine-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 12). [ka]

[0520] Step 1: Preparation of methyl 2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-7-yl]azetidine-1-yl}pyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate (intermediate 2). [ka]

[0521] DIEA (111.85 mg, 0.864 mmol, 3 equivalents) was added to a stirred solution of I-10 (80 mg, 0.288 mmol, 1 equivalent) and methyl 2-[3-(2-chloropyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoate (106.63 mg, 0.288 mmol, 1 equivalent) in DMSO (3.00 mL). The resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase A: water (0.1% FA), mobile phase B: CH3CN, flow rate: 35 mL / min, gradient: 0% B to 100% B over 40 minutes, detector, UV254 / 220 nm. This yielded intermediate 2 (110 mg, 67.51%) as a pale yellow solid. LC-MS(ESI) m / z:[M+H] + = 537.

[0522] Step 2: Preparation of 2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-7-yl]azetidine-1-yl}pyrimidine-5-yl)-1,2-oxazole-5-yl]-3-methylbutanoic acid (intermediate 3). [ka]

[0523] A solution of LiOH (49.10 mg, 2.050 mmol, 10 equivalents) in THF (3.00 mL) and H2O (0.60 mL) was stirred at room temperature under a nitrogen atmosphere for 10 minutes. Intermediate 2 (110 mg, 0.205 mmol, 1 equivalent) was added to the above mixture. The resulting mixture was then stirred overnight at room temperature and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase A: water (0.1% FA), mobile phase B: CH3CN, flow rate: 35 mL / min, gradient: 0% B to 100% B over 40 minutes, detector, UV254 / 220 nm. This yielded intermediate 3 (98 mg, 86.91%) as a pale yellow solid. LCMS(ESI) m / z: [M+H] + = 523.

[0524] Step 3: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-7-yl]azetidine-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]

[0525] Intermediate 3 (98 mg, 0.188 mmol, 1 equivalent) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (62.16 mg, 0.188 mmol, 1 equivalent) were dissolved in DMF (3.00 mL), and PyBOP (195.19 mg, 0.376 mmol, 2 equivalents) and DIEA (72.72 mg, 0.564 mmol, 3 equivalents) were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase A: water (0.1% FA), mobile phase B: CH3CN, flow rate: 35 mL / min, gradient: 0% B to 100% B over 40 minutes, detector: UV254 / 220 nm. This yielded intermediate 4 (90 mg, 54.54%) as a pale yellow solid. LCMS(ESI) m / z: [M+H] + = 836.

[0526] Step 4: (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnolin-7-yl]azetidine-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 11) and Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)sinnoline-7]-yl]azetidine-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 12). [ka]

[0527] Intermediate 4 (90 mg) was purified by Chiral-Prep-HPLC under the following conditions: column, CHIRALPAK ID, 2 * 25 cm, 5 μm, mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH, flow rate: 20 mL / min, gradient: 10% B to 50% B over 65 minutes, detector: UV254 / 220 nm. The following results were obtained.

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

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

[0530] The compounds listed in Table 6 were prepared using appropriate amines and heteroaryl halides, following the same procedure as that used to prepare compound 11.

[0531] [Table 7-1]

[0532] [Table 7-2]

[0533] [Table 7-3]

[0534] [Table 7-4]

[0535] [Table 7-5]

[0536] [Table 7-6]

[0537] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 13) and ( Preparation of 2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 14). [ka]

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

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

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

[0541] To a mixture of intermediate 2 (8.00 g, 32.921 mmol, 1.00 equivalent) in DCM (80 mL), NOBF4 (5.72 g, 49.381 mmol, 1.50 equivalent) was added at 0°C. The mixture was stirred for 1 hour, and then a 50 mL HCl solution of SnCl2·2H2O (44.4 g, 197.526 mmol, 6.00 equivalent) was added at 0°C. The resulting mixture was then stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water, gradient from 0% to 30% over 10 minutes, detector, UV 254 nm. This yielded intermediate 3 (3.71 g, 50.0%) as a yellow solid. LCMS(ESI) m / z:[M+H] + = 227.

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

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

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

[0545] A mixture of intermediate 4 (800.0 mg, 3.571 mmol, 1.00 equivalent), tert-butylpiperazine-1-carboxylic acid (2.65 g, 14.284 mmol, 4.00 equivalent), Xantphos (412.6 mg, 0.714 mmol, 0.20 equivalent), and t-BuONa (1.028 g, 10.713 mmol, 3.00 equivalent) in dioxane (20 mL) was mixed with Pd2(dba)3 (654 mg, 0.714 mmol, 0.20 equivalent) under a nitrogen atmosphere. The mixture was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water, gradient from 10% to 50% over 10 minutes, detector, UV 254 nm. This yielded intermediate 5 (205.0 mg, 17.4%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =331.

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

[0547] A mixture of intermediate 5 (205.0 mg, 0.621 mmol, 1.00 equivalent) and pyridine (496.8 mg, 6.210 mmol, 10.00 equivalent) in DCM (5 mL) was mixed with Tf2O (350.2 mg, 1.242 mmol, 2.00 equivalent) at 0°C. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 6 (210.0 mg, crude product). LCMS(ESI)m / z:[M+H] + = 463.

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

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

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

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

[0552] Step 8: Preparation of methyl 2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoate (intermediate 9). [ka]

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

[0554] Step 9: Preparation of 2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoic acid (intermediate 10). [ka]

[0555] To a stirred mixture of intermediate 9 (130.0 mg, 0.229 mmol, 1.00 equivalent) in MeOH (2 mL) and H2O (1 mL), LiOH.H2O (93.8 mg, 2.290 mmol, 10 equivalents) was added. After stirring at 60°C for 2 hours, the mixture was cooled to room temperature. The mixture was acidified to pH 6 with 4 M HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). This yielded intermediate 10 (150.0 mg, crude product) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 552.

[0556] Step 10: Preparation of (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (intermediate 11). [ka]

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

[0558] Step 11: (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 13) Preparation of (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)sinnolin-6-yl)piperazine-1-yl)pyrimidine-5-yl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 14). [ka]

[0559] Intermediate 11 (130 mg) was separated by chiral HPLC using the following conditions: Column: CHIRALPAK IA, 2 * The parameters used were 25 cm, 20 μm, mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH, flow rate: 20 mL / min, gradient: 10%B to 50%B over 30 minutes, detector: UV254 / 220 nm. The following results were obtained.

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

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

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

Chem.

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

Chem.

[0564] 4-chloro-1-fluoro-2-nitrobenzene (11 g, 63 mmol), dimethyl malonate (12.5 g, 95 mmol), Cs2CO3 (41.1 g, 126 mmol), and DMF (63 mL) were stirred at room temperature for 6 hours. The reaction mixture was partitioned between 1 M aqueous HCl and toluene. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain intermediate 2 (18 g, 99%) as a yellow oil. The crude product was used directly in the next step without further purification.

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

[0566] Intermediate 2 was combined with AcOH (30 mL) and concentrated. The reaction mixture was quenched with saturated HCl (30 mL) and heated at 95°C for 16 hours. The mixture was diluted with H2O to form a precipitate. The solid was collected by vacuum filtration, washed with H2O and hexane / ether (1:1), and dried to obtain intermediate 3 as a white solid (11.2 g, 83%).

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

[0568] Intermediate 3 (11.2 g, 52 mmol) was suspended in CH2Cl2 (250 mL). Oxalyl chloride (7 mL, 79 mmol) was added to the mixture, followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room temperature for 1 hour, and then added dropwise to MeOH at 0°C. The solvent was removed under vacuum, and intermediate 4 (12 g, 98%) was obtained as a white solid. The crude product was used directly in the next step without further purification.

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

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

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

[0572] Intermediate 5 (9.5g, 48 mmol) o The mixture was suspended in CH2Cl2 (150 mL) at °C. Nitrosonium tetrafluoroborate (8.4 g, 72 mmol) was added to the mixture all at once. The mixture was then heated to 0°C. o The mixture was stirred at °C for 1 hour. The mixture was directly added to a vigorously stirred mixture of concentrated SnCl2 dihydrate (43.8 g, 194 mmol). HCl (200 mL) was added at 0°C. The mixture was slowly warmed to room temperature while stirring. After 24 hours, the mixture was filtered. The solid was washed with H2O and ether, and then dried to obtain intermediate 6 as a yellow solid (6.6 g, 76%). LCMS(ESI)m / z:[M+H] + = 183.

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

[0574] Intermediate 6 (6.6 g, 37 mmol) was suspended in toluene (500 mL) at 0°C. Tert-butyl hypochlorous acid (4 g, 37 mmol) was added to the mixture all at once. The mixture was stirred at 0°C for 20 minutes. The solid was collected by vacuum filtration, washed with H2O and hexane / ether (1:1), and dried to obtain intermediate 7 (3 g, 45%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 181.

[0575] Step 7: Preparation of 7-chlorosinnoline-3-yltrifluoromethanesulfonate (intermediate 8). [ka]

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

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

[0578] A mixture of intermediate 8 (4.2 g, 13.4 mmol), Pd(dppf)Cl2 (1 g, 1.3 mmol), K3PO4 (5.6 g, 26.8 mmol), and (2-(methoxymethoxy)phenyl)boronic acid (3 g, 16 mmol) in dioxane (20 mL) / H2O (2 mL) was stirred at 40°C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was washed with SiO2 (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (8:1) to obtain I-12 (2.8 g, 70%) as a yellow solid. LCMS(ESI) m / z:[M+H] + =301.

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

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

[0581] 4-Chloro-2-fluoro-1-nitrobenzene (16.5 g, 94.5 mmol), dimethyl malonate (18.8 g, 143 mmol), Cs2CO3 (61.6 g, 189 mmol), and DMF (100 mL) were stirred at room temperature for 6 hours. The reaction mixture was partitioned between 1 M aqueous HCl and SiO2. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain intermediate 2 (28 g, 99%) as a yellow oil. The crude product was used directly in the next step without further purification.

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

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

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

[0585] Intermediate 3 (17 g, 78 mmol) was suspended in CH2Cl2 (300 mL). Oxalyl chloride (10.5 mL, 119 mmol) was added to the mixture, followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room temperature for 1 hour, and then added dropwise to MeOH at 0°C. The solvent was removed under vacuum, and intermediate 4 (18 g, 98%) was obtained as a white solid. The crude product was used directly in the next step without further purification.

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

[0587] Intermediate 4 (18 g, 77 mmol) was suspended at 0°C in a mixture of MeOH (300 mL) and NH4Cl (83 g, 1.53 mol). Zinc powder (25 g, 386 mmol) was added in one batch. The mixture was stirred at room temperature for 1 hour and then filtered through Celite. The filtrate was concentrated and then partitioned between SiO2 and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain intermediate 5 (14.3 g, 94%) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 200.

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

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

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

[0591] Intermediate 6 (10 g, 56 mmol) was suspended in toluene (500 mL) at 0°C. Tert-butyl hypochlorous acid (6 g, 56 mmol) was added to the mixture all at once. The mixture was stirred at 0°C for 20 minutes. The solid was collected by vacuum filtration, washed with H2O and hexane / ether (1:1), and dried to obtain intermediate 7 (4.5 g, 45%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 181.

[0592] Step 7: Preparation of 6-chlorosinnoline-3-yltrifluoromethanesulfonate (intermediate 8). [ka]

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

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

[0595] A mixture of intermediate 8 (6.3 g, 20.1 mmol), Pd(dppf)Cl2 (1.5 g, 1.95 mmol), K3PO4 (8.4 g, 40.2 mmol), and (2-(methoxymethoxy)phenyl)boronic acid (4.5 g, 24 mmol) in dioxane (40 mL) / H2O (6 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filtrate was washed with SiO2 (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (8:1) to obtain I-13 (4.1 g, 69%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =301.

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

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

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

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

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

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

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

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

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

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

[0606] A solution of intermediate 5 (16 g, 57.444 mmol, 1 equivalent) and NOBF4 (10.07 g, 86.166 mmol, 1.5 equivalents) in DCM (300 mL) was stirred at 0°C for 2 hours. SnCl2 (88.06 g, 459.552 mmol, 8.0 equivalents) in HCl (300 mL) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature for a further 24 hours. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The resulting mixture was concentrated under reduced pressure. This yielded intermediate 6 (10.4 g, crude) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =261.

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

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

[0609] Step 7: Preparation of 7-bromo-6-chlorosinnoline-3-yltrifluoromethanesulfonate (intermediate 8). [ka]

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

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

[0612] To a solution of intermediate 8 (3.00 g, 7.662 mmol, 1 equivalent) and 2-(methoxymethoxy)phenylboronic acid (1.39 g, 7.662 mmol, 1.0 equivalent) in dioxane (100 mL) and H2O (25 mL), K3PO4 (4.88 g, 22.986 mmol, 3.0 equivalents) and Pd(dppf)Cl2 (1.12 g, 1.532 mmol, 0.2 equivalents) were added. After stirring at room temperature under a nitrogen atmosphere for 1 hour, the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography. Elution with PE / siRNA (10:1) yielded I-14 (960 mg, 32.83%) as a yellow solid. LCMS(ESI)m / z[M+H] + = 827.

[0613] The following intermediates in Table 7 were prepared using the same method as described for the preparation of intermediate I-14.

[0614] [Table 8]

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

[0616] To a solution of I-14 (1 g, 2.634 mmol, 1 equivalent) and cyclopropylboronic acid (678.80 mg, 7.902 mmol, 3.0 equivalents) in dioxane (10 mL) and H2O (2.5 mL), K3PO4 (1677.37 mg, 7.902 mmol, 3.0 equivalents) and Pd(dppf)Cl2 (385.4 mg, 0.527 mmol, 0.2 equivalents) were added. After stirring at 60°C for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (8:1) to obtain I-20 (380.0 mg, 42.3%) as a yellow solid. LCMS(ESI)m / z[M+H] + =341.

[0617] Preparation of tert-butyl6-{6-chloro-3-[2-(methoxymethoxy)phenyl]sinnoline-7-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid (I-21). [ka]

[0618] A solution of Zn (413.32 mg, 6.324 mmol, 6 equivalents), I2 (133.71 mg, 0.527 mmol, 0.5 equivalents), and tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (681.01 mg, 2.108 mmol, 2 equivalents) in DMF was stirred at 30°C for 2 hours under a nitrogen atmosphere. To the above mixture, I-14 (400 mg, 1.054 mmol, 1 equivalent), XPhos Pd G3 (178.37 mg, 0.211 mmol, 0.2 equivalents), and XPhos (100.46 mg, 0.211 mmol, 0.2 equivalents) were gradually added over 5 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60°C under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with Depositphotos (30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to obtain I-21 (190 mg, 36.36%) as a yellow solid. LC-MS (ESI) m / z: [M + H] + = 496.

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

[0620] To a stirred solution of I-21 (220 mg, 0.444 mmol, 1 equivalent) and Zn(CN)2 (208.33 mg, 1.776 mmol, 4 equivalents) in DMF (3 mL), XPhos Pd G3 (75.09 mg, 0.089 mmol, 0.2 equivalents) was gradually added at room temperature. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with RINKAN (50 mL). The combined organic layers were washed with brine (2 × 25 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 (5:1) to obtain I-22 (117 mg, 54.21%) as a yellow oily substance. LCMS(ESI) m / z:[M+H]+=487.

[0621] Preparation of tert-butyl6-(6-chloro-3-(2-(methoxymethoxy)phenyl)sinnoline-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (I-23). [ka]

[0622] To a solution of I-14 (340.0 mg, 0.90 mmol, 1.00 equivalent) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (435.8 mg, 0.90 mmol, 1.00 equivalent) in toluene (10 mL), BINAP (111.5 mg, 0.18 mmol, 0.20 equivalent), Pd2(dba)3 (164.0 mg, 0.18 mmol, 0.20 equivalent), and t-BuONa (172.1 mg, 1.79 mmol, 2.00 equivalent) were added. The mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and eluted with PE:Â = 10:1 to 2:1 to obtain I-23 (350.0 mg, 78.6%) as an orange solid. LCMS(ESI)m / z:[M+H] + = 497. [ka]

[0623] tert-butyl6-(6-cyano-3-(2-(methoxymethoxy)phenyl)sinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-24) was prepared using I-23 in the same procedure as for I-22.

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

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

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

[0627] To a solution of I-23 (200 mg, 0.402 mmol, 1 equivalent) and Pd2(dba)3 (36.85 mg, 0.040 mmol, 0.1 equivalent) in dioxane (1.2 mL, 14.165 mmol), cyclopropanol (1.2 mL), CH3COONa (99.03 mg, 1.206 mmol, 3 equivalents) and t-BuXPhos (34.18 mg, 0.080 mmol, 0.2 equivalents) was added. The resulting solution was prepared in an N2 atmosphere. The mixture was stirred at 80°C for 16 hours under gaseous conditions. The mixture was diluted with toluene (150 mL) and washed with water (150 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 and eluted with 0-50% toluene in petroleum ether to obtain I-26 (61 mg, 29.23%) as a yellow solid. LC-MS (ESI) m / z: [M+H] + = 519.

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

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

[0630] Preparation of tert-butyl6-(6-cyano-3-(2-(methoxymethoxy)phenyl)quinoline-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (I-28). [ka]

[0631] To a solution of I-23 (350.0 mg, 0.70 mmol, 1.00 equivalent) in DMF (7 mL), XPhos (67.1 mg, 0.14 mmol, 0.20 equivalent), XPhos Pd G3 (119.2 mg, 0.14 mmol, 0.20 equivalent), and Zn(CN)2 (248.1 mg, 2.11 mmol, 3.00 equivalent) were added at room temperature. The mixture was stirred at 100 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with siRNA (3 x 20 mL). The combined organic layer was washed with H2O (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and eluted with PE:siRNA = 10:1 to 1:1 to obtain I-28 (150.0 mg, 43.7%) as an orange solid. LCMS(ESI)m / z:[M+H] + = 488.

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

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

[0634] To a stirred solution of I-23 (923.0 mg, 1.857 mmol, 1 equivalent) and KOH (0.31 g, 5.571 mmol, 3 equivalents) in 1,4-dioxane (5 mL) and H2O (5 mL), Pd2(dba)3 (0.34 g, 0.371 mmol, 0.2 equivalents) and di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (0.16 g, 0.371 mmol, 0.2 equivalents) were added. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography. Elution with CH2Cl2 / MeOH (12:1) yielded I-29 (780.0 mg, 87.7%) as a brown solid. LCMS(ESI)m / z:[M+H] + = 479.

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

[0636] Sodium 2-chloro-2,2-difluoroacetate (286.7 mg, 1.881 mmol, 3 equivalents) was added to a stirred mixture of I-29 (300.0 mg, 0.627 mmol, 1 equivalent) and Cs2CO3 (612.76 mg, 1.881 mmol, 3 equivalents) in DMF (6 mL). The resulting mixture was stirred at 60°C for 2 hours. The resulting mixture was extracted with RINKAN (2 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / RINKAN (6:1) to obtain I-30 (140.0 mg, 42.2%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 529.

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

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

[0639] To a solution of I-17 (1.00 g, 2.634 mmol, 1 equivalent), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.52 g, 2.634 mmol, 1 equivalent), and BINAP (0.33 g, 0.527 mmol, 0.2 equivalents) in toluene (12 mL), Pd2(dba)3 (0.48 g, 0.527 mmol, 0.2 equivalents) and t-BuONa (0.51 g, 5.268 mmol, 2 equivalents) were added, and the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (5:1) to obtain I-35 (1.00 g, 76.9%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 497.

[0640] Step 2: Preparation of tert-butyl6-{5-ethenyl-3-[2-(methoxymethoxy)phenyl]sinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (I-36). [ka]

[0641] To a solution of I-35 (1.00 g, 2.012 mmol, 1 equivalent) and ethenyldifluoro-lambda4-boranyl)-lambda2-fluoranide (0.19 g, 2.012 mmol, 1 equivalent) in H2O (2 mL) and dioxane (10 mL), XPhos Pd G3 (0.34 g, 0.402 mmol, 0.2 equivalents) and Cs2Co3 (1.97 g, 6.036 mmol, 3 equivalents) were added, and the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with MeOH / H2O (5:1) to obtain I-36 (900.0 mg, 91.8%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 489.

[0642] Step 3: Preparation of tert-butyl6-{6-formyl-3-[2-(methoxymethoxy)phenyl]sinnoline-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (I-37). [ka]

[0643] To a solution of I-36 (840.0 mg, 1.719 mmol, 1 equivalent) and 2,6-lutidine (368.5 mg, 3.438 mmol, 2 equivalents) in dioxane (60 mL) and H2O (30 mL), NaIO4 (1470.9 mg, 6.876 mmol, 4 equivalents) and K2OsO4.2H2O (50.9 mg, 0.138 mmol, 0.08 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL) and extracted with siRNA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (5:1) to obtain I-37 (400.0 mg, 47.4%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =491.

[0644] Step 4: Preparation of tert-butyl6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]sinnoline-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (I-31). [ka]

[0645] To a solution of intermediate 4 (400.0 mg, 0.815 mmol, 1 equivalent) and dimethyl (1-diazo-2-oxopropyl)phosphonate (234.9 mg, 1.222 mmol, 1.5 equivalents) in MeOH (6 mL), K2CO3 (338.1 mg, 2.445 mmol, 3 equivalents) was added, and the mixture was stirred at room temperature for 3 hours. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (5:1) to obtain I-31 (220.0 mg, 55.4%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 487. [ka]

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

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

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

[0649] To a stirred solution of J-21 (500.0 mg, 1.317 mmol, 1 equivalent) and potassium vinyltrifluoroborate (352.9 mg, 2.634 mmol, 2 equivalents) in dioxane (7.5 mL) and H2O (1.5 mL), XPhos Pd G3 (222.9 mg, 0.263 mmol, 0.2 equivalents) and Cs2CO3 (1287.3 mg, 3.951 mmol, 3 equivalents) were added. The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / EA (9:1) to obtain intermediate 2 (350.0 mg, 81.2%) as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =327.

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

[0651] Intermediate 2 (350 mg, 1.070 mmol, 1 equivalent) and NaIO4 (924.6 mg, 4.281 mmol, 4 equivalents) were stirred in dioxane (3 mL) and H2O (3 mL). K2OsO4,2H2O (18.1 mg, 0.053 mmol, 0.05 equivalents) and 2,6-lutidine (228.9 mg, 2.140 mmol, 2 equivalents) were added at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated sodium hyposulfite (aqueous solution) at 0°C. The resulting mixture was extracted with RINKAN (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / Â 1:1) to obtain intermediate 3 (300 mg, 85.2%) as a pale yellow solid. LC-MS (ESI) m / z:[M+H] + = 329.

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

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

[0654] Using the same procedure as described above, 6-chloro-7-(difluoromethyl)-3-(2-(methoxymethoxy)phenyl)sinnoline (I-34) was prepared from I-33.

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

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

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

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

[0659] A solution of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (20 g, 78.604 mmol, 1 equivalent), dimethyl malonate (11.42 g, 86.464 mmol, 1.1 equivalents), and Cs2CO3 (51.22 g, 157.208 mmol, 2.0 equivalents) in DMF (50 mL) was stirred at room temperature for 12 hours. The mixture was acidified to pH 6 with 1 N HCl (aqueous solution). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with siRNA (3 × 200 mL). The combined organic layers were washed with brine (3 × 300 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 2 (20 g, 69.4%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + = 366.

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

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

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

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

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

[0665] To a solution of intermediate 4 (3.0 g, 9.724 mmol, 1 equivalent) and cyclopropylboronic acid (1.67 g, 19.448 mmol, 2.0 equivalents) in dioxane (20 mL), H2O (5 mL) was mixed with K3PO4 (6.19 g, 29.172 mmol, 3.0 equivalents) and Pd(dppf)Cl2 (1.42 g, 1.945 mmol, 0.2 equivalents). After stirring at 60°C for 2 hours under a nitrogen atmosphere, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / SiO(5:1) to obtain intermediate 5 (1.8 g, 68.6%) as a yellow solid. LCMS(ESI)m / z[M+H] + =270.

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

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

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

[0669] A mixture of intermediate 6 (1.8 g, 7.509 mmol, 1 equivalent) and NOBF4 (1.32 g, 11.264 mmol, 1.5 equivalents) in DCM (25 mL) was stirred at 0°C for 1 hour. SnCl2 (8.63 g, 45.054 mmol, 6.0 equivalents) in HCl (30 mL) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature for a further 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C 18 Silica gel, mobile phase, water-based MeCN (0.1% FA), gradient from 0% to 50% over 50 minutes, detector, UV 254 nm. This yielded intermediate 7 (700.0 mg, 41.8%) as a yellow solid. LC-MS (ESI) m / z [M+H] + =223.

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

[0671] Intermediate 7 (300.0 mg, 1.360 mmol, 1 equivalent) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (539.1 mg, 2.720 mmol, 2.0 equivalents) were dissolved in dioxane (5 mL), to which Cs2CO3 (1328.9 mg, 4.080 mmol, 3.0 equivalents) and Pd-PEPPSI-IPentCl 2-methylpyridine (215.5 mg, 0.272 mmol, 0.2 equivalents) were added. After stirring at 100°C for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C 18 Silica gel, mobile phase, water-based MeCN (0.1% FA), gradient from 0% to 50% over 50 minutes, detector, UV 254 nm. This yielded intermediate 8 (250.0 mg, 48.0%) as a yellow solid. LC-MS (ESI) m / z [M+H] + =221.

[0672] Step 8: Preparation of tert-butyl 6-(6-cyclopropyl-3-hydroxysinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (intermediate 9) [ka]

[0673] Intermediate 8 (300.0 mg, 1.360 mmol, 1 equivalent) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (539.1 mg, 2.720 mmol, 2.0 equivalents) were dissolved in dioxane (5 mL), to which Cs2CO3 (1328.9 mg, 4.080 mmol, 3.0 equivalents) and Pd-PEPPSI-IPentCl 2-methylpyridine (215.5 mg, 0.272 mmol, 0.2 equivalents) were added. After stirring at 100°C for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C 18Silica gel, mobile phase, water-based MeCN (0.1% FA), gradient from 0% to 50% over 50 minutes, detector, UV 254 nm. This yielded intermediate 9 (250.0 mg, 48.0%) as a yellow solid. LC-MS (ESI) m / z [M+H] + =383.

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

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

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

[0677] To a solution of intermediate 10 (210.0 mg, 0.408 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (168.8 mg, 1.224 mmol, 3.0 equivalents) in dioxane (4 mL) and H2O (1 mL), Cs2PO3 (259.4 mg, 1.224 mmol, 3.0 equivalents) and XPhos Pd G3 (59.4 mg, 0.082 mmol, 0.2 equivalents) were added. After stirring at 60°C for 1 hour under a nitrogen atmosphere, 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, water-based MeCN (0.1% FA), gradient from 0% to 60% over 40 minutes, detector, UV 254 nm. This yielded intermediate 11 (100.0 mg, 53.4%) as a yellow oily substance. LC-MS (ESI) m / z [M+H] + = 503.

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

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

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

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

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

[0683] A solution of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (30.00 g, 128.192 mmol, 1.00 equivalent) and dimethyl malonate (16.94 g, 128.192 mmol, 1.00 equivalent) in DMF (300 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water (2 L). The resulting mixture was extracted with SiO (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 2 (44.00 g, 96.1%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 246.

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

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

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

[0687] To a stirred solution of intermediate 3 (33.00 g, 120.407 mmol, 1.00 equivalent) in DCM (300 mL), (COCl)2 (30.56 g, 240.814 mmol, 2.00 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. MeOH (165 mL) was added dropwise to the mixture over 10 minutes at 0°C. The resulting mixture was stirred for a further 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with SiO2 (3 × 700 mL). The combined organic layers were washed with sodium bicarbonate solution (3 × 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 4 (35.00 g, 98.88%) as a pale yellow oily substance. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 288.

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

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

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

[0691] To a stirred solution of intermediate 5 (32.00 g, 123.976 mmol, 1.00 equivalent) in DCM (320 mL), NOBF4 (21.72 g, 185.964 mmol, 1.50 equivalent) was added at 0°C. The resulting mixture was stirred at 0°C for 2 hours. SnCl2 (118.79 g, 619.880 mmol, 5.00 equivalent) and HCl (320 mL) were gradually added to the mixture over 10 minutes at 0°C. The resulting mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with water (3 × 300 mL). This yielded intermediate 6 (13.00 g, 43.06%) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =241.

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

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

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

[0695] To a solution of intermediate 7 (2.00 g, 8.366 mmol, 1.00 equivalent), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.32 g, 16.732 mmol, 2.00 equivalent), and Cs2CO3 (8.18 g, 25.098 mmol, 3.00 equivalent) in dioxane (25 mL), {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazole-2-yl}dichloro(2-methyl-1λ4-pyridine-1-yl)palladium (351.8 mg, 0.418 mmol, 0.05 equivalent) was added, and the mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with RINKAN (3 × 300 mL). The combined organic layers were washed with brine (3 × 400 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (12:1) to obtain intermediate 8 (3.40 g, 62.71%) as a black solid. LCMS(ESI)m / z:[M+H] + =257.

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

[0697] In 40 mL of DCM, a solution of intermediate 8 (3.40 g, 9.539 mmol, 1.00 equivalent) and TEA (2.90 g, 28.617 mmol, 3.00 equivalent) was added to 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (5.11 g, 14.308 mmol, 1.50 equivalent) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (1 L). The resulting mixture was extracted with RINKAN (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (7:3) to obtain an orange solid intermediate 9 (1.9 g, 36.7%). LCMS(ESI)m / z:[M+H] + = 489.

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

[0699] To a stirred solution of intermediate 9 (1.90 g, 3.890 mmol, 1.00 equivalent) and 2-(methoxymethoxy)phenylboronic acid (707.8 mg, 3.890 mmol, 1.00 equivalent) in dioxane (20 mL) and H2O (4 mL), Pd(dppf)Cl2 (569.2 mg, 0.778 mmol, 0.20 equivalent) and K3PO4 (2.48 g, 11.670 mmol, 3.00 equivalent) were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with water (500 mL). The aqueous layer was extracted with SiO2 (3 × 400 mL). The combined organic layers were washed with brine (3 × 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 and eluted with PE / EA (2:8) to obtain a yellow solid intermediate 10 (780.0 mg, 42.1%). LCMS(ESI)m / z:[M+H] + = 477.

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

[0701] Intermediate 10 (770.0 mg, 1.616 mmol, 1.00 equivalent) was mixed in DCM (8 mL) and TFA (2 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C 18 Silica gel, mobile phase, water with MeOH (0.05% TFA), gradient from 0% to 100% over 30 minutes, detector, UV254 / 220nm. The resulting mixture was concentrated under vacuum. This yielded I-41 (374.0 mg, 62.6%) as a red solid. LC-MS (ESI) m / z: [M+H] + =333. [ka]

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

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

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

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

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

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

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

[0709] A mixture of intermediate 3 (1.37 g, 4.719 mmol, 1 equivalent) and acetic anhydride (0.96 g, 9.438 mmol, 2 equivalents) in DCM (13 mL) was stirred at room temperature for 50 minutes. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (9:1) to obtain intermediate 4 (1.44 g, 91.82%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =332.

[0710] Step 4: Preparation of methyl 2-(4-(2-acetyl-2-azaspiro[3,3]heptan-6-yl)-2-aminophenyl)acetate (intermediate 5) [ka]

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

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

[0713] A stirred mixture of intermediate 5 (1.127 g, 3.727 mmol, 1 equivalent) was suspended in DCM (12 mL) at 0°C. NOBF4 (0.65 g, 5.590 mmol, 1.5 equivalents) was added to the mixture. The mixture was stirred at 0°C for 1 hour. This mixture was directly added at 0°C to a vigorously stirred mixture of SnCl2 (5.71 g, 29.816 mmol, 8 equivalents) in HCl (6 mL, 197.477 mmol, 181.49 equivalents). The resulting mixture was stirred overnight at 30°C. 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, gradient from 0% to 40% over 30 minutes, detector, UV 254 nm. This yielded intermediate 6 (520 mg, 48.89%) as a pale yellow solid. LC-MS (ESI) m / z: [M+H] + = 285.

[0714] Step 6: Preparation of 1-[6-(3-hydroxysinnolin-7-yl)-2-azaspiro[3,3]heptan-2-yl]etanone intermediate 7) [ka]

[0715] A solution of intermediate 6 (500 mg, 1.752 mmol, 1 equivalent) and Pb(OAc)4 (932.34 mg, 2.102 mmol, 1.2 equivalents) in DCM (6 mL) was stirred at room temperature for 20 minutes. The desired product was 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, ACN in water, gradient from 0% to 40% over 20 minutes, detector, UV 254 nm. This yielded intermediate 7 (232 mg, 46.73%) as a yellow solid. LC-MS(ESI) m / z: [M+H] + =283.

[0716] Step 7: Preparation of 7-(2-acetyl-2-azaspiro[3,3]heptan-6-yl)sinnoline-3-yltrifluoromethanesulfonate (intermediate 8) [ka]

[0717] A solution of intermediate 7 (250 mg, 0.882 mmol, 1 equivalent) and Tf2O (1249.68 mg, 4.429 mmol, 5.02 equivalents) in pyridine (6 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The residue was dissolved in SiO2 (50 mL). The combined organic layer was washed with water (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS(ESI)m / z:[M+H] + = 415.

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

[0719] To a stirred solution of dioxane (2.5 mL) and H2O (0.5 mL) containing intermediate 8 (60 mg, 0.072 mmol, 1 equivalent, 50%) and 2-hydroxyphenylboronic acid (19.92 mg, 0.144 mmol, 2 equivalents), XPhos Pd G3 (12.23 mg, 0.014 mmol, 0.2 equivalents) and Cs2CO3 (70.59 mg, 0.216 mmol, 3 equivalents) were added. The resulting mixture was stirred under a nitrogen atmosphere at 60°C for 2 hours. The desired product was detected by LC-MS. The crude product (60 mg purified by Chiral-Prep-HPLC) was subjected to the following conditions (NB-Prep-HPLC-01): Column, Xselect CSH C18 OBD column 30 * The intermediate 9 was purified using a 150 mm 5 μm mobile phase, water (0.1% FA), and ACN (from 35% ACN to 58% in 7 minutes) to obtain 8.9 mg, 34.08%, as a bright yellow solid. 1H NMR (400MHz, DMSO-d6)δ 12.05(s, 1H), 8.90(s, 1H), 8.24(s, 1H), 8.15-8.06(m, 2H), 7.86-7.78(m, 1H), 7.41-7.33(m, 1H), 7.09-7.00(m, 2H), 4.31(s, 1 H), 4.09(s, 1H), 4.03(s, 1H), 3.81(s, 1H), 3.72(p, J=8.7Hz, 1H), 2.75-2.64(m, 2H), 2.50-2.42(m, 2H), 1.76(d, J=13.2Hz, 3H). LCMS(ESI)m / z:[M+H] + = 359.16.

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

[0721] A solution of intermediate 9 (122 mg, 0.339 mmol, 1 equivalent) and KOH (190.44 mg, 3.390 mmol, 10 equivalents) in MeOH (1.5 mL) and H2O (1.5 mL) was stirred overnight at -70°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, water with MeCN (0.1% FA), gradient from 10% to 60% over 40 minutes, detector, UV 254 nm. This yielded I-43 (102 mg, 94.68%) as a grayish-white solid. LC-MS (ESI) m / z [M+H] + =317.

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

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

[0724] A solution of tert-butyl 3-iodoazetidine-1-carboxylate (22.94 g, 81.035 mmol, 1 equivalent), I2 (10.28 g, 40.517 mmol, 0.5 equivalents), and Zn (15.89 g, 243.105 mmol, 3 equivalents) in DMF (250 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. To the above mixture, CuI (3.09 g, 16.207 mmol, 0.2 equivalents), Pd(dppf)Cl2 (11.86 g, 16.207 mmol, 0.2 equivalents), and intermediate 4 (25 g, 81.035 mmol, 1 equivalent) were added at room temperature. The resulting mixture was stirred for a further 3 hours at room temperature. The resulting mixture was filtered, and the filter cake was washed with SiO2 (3 × 50 mL). The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (2:1) to obtain intermediate 5 (32 g, 97.4%) as a pale yellow oily substance. LCMS(ESI)m / z:[M+H] + =385.

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

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

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

[0728] To a stirred solution of intermediate 6 (40 g, crude) and Et3N (21.33 g, 210.747 mmol, 3 equivalents) in DCM (250 mL), Ac2O (7.17 g, 70.249 mmol, 1 equivalent) was added dropwise at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, and then concentrated under reduced pressure. The crude product was purified by reverse-phase flash under the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 0% B to 100% B in 40 minutes, 254 / 220 nm), and intermediate 7 (21 g, 86.9%) was obtained as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =327.

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

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

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

[0732] A solution of intermediate 8 (9.5 g, crude) and NOBF4 (5.61 g, 48.019 mmol, 1.5 equivalents) in DCM (100 mL) was stirred at 0°C for 1 hour. SnCl2 (36.81 g, 192.078 mmol, 6 equivalents) in HCl (100 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure. The crude product was purified by reverse-phase flash under the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 45 mL / min, gradient: 0%B to 50%B in 40 minutes, 254 / 220 nm), and intermediate 9 (5.2 g, 34.8%) was obtained as a yellow solid. LCMS(ESI) m / z:[M+H] + =280.

[0733] Step 9: Preparation of 1-[3-(7-chloro-3-hydroxysinnolin-6-yl)azetidine-1-yl]ethanone (intermediate 10). [ka]

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

[0735] Step 10: Preparation of 6-(1-acetylazetidine-3-yl)-7-chlorosinnoline-3-yltrifluoromethanesulfonate (intermediate 11). [ka]

[0736] To a stirred solution of intermediate 10 (1.5 g, 4.321 mmol, 1 equivalent, 80%) and Et3N (1.31 g, 12.963 mmol, 3 equivalents) in DCM (2 mL), DMAP (0.26 g, 2.160 mmol, 0.5 equivalents) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.54 g, 4.321 mmol, 1 equivalent) were added at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by silica gel column chromatography and eluted with PE / SiO(1:1) to obtain intermediate 11 (1.5 g, 72.0%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =410.

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

[0738] To a stirred solution of intermediate 11 (700.0 mg, 1.708 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (353.44 mg, 2.562 mmol, 1.5 equivalents) in dioxane (70 mL) and H2O (14 mL), PPd(dppf)Cl2 (250.00 mg, 0.342 mmol, 0.2 equivalents) and K3PO4 (1087.85 mg, 5.124 mmol, 3 equivalents) were added. The resulting mixture was stirred at 60°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with HCl (3 × 100 mL). The combined organic layers were washed with brine (1 × 300 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash under the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 0% B to 100% B over 40 minutes, 254 / 220 nm), and intermediate 12 (436.0 mg, 68.5%) was obtained as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =354.

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

[0740] To a stirred solution of intermediate 12 (25.0 mg, 0.071 mmol, 1 equivalent) and cyclopropyltrifluoro-lambda-4-borane potassium (52.28 mg, 0.355 mmol, 5 equivalents) in toluene (2 mL) and H2O (0.4 mL), Pd(dppf)Cl2 (10.34 mg, 0.014 mmol, 0.2 equivalents) and K2CO3 (29.30 mg, 0.213 mmol, 3 equivalents) were added. The resulting mixture was stirred at 60°C for 1 hour under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions (column: XBridge Shield RP). 18 OBD, 30 * Intermediate 13 (2.8 mg, 11.0%) was obtained as a pale yellow solid using LCMS (ESI) m / z: [M+H]. Measurement parameters: 150 mm, 5 μm, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 35%B to 50%B, 50%B over 8 minutes, wavelength: 254 / 220 nm, RT1 (min): 8.86, number of runs: 0). LCMS (ESI) m / z: [M+H] + = 741.30. 1 H NMR (400MHz, methanol-d4)δ 8.80(s, 1H), 8.17-7.95(m, 3H), 7.40-7.32(m, 1H), 7.10-6.96(m, 2H), 4.79(t, J=8.5Hz, 1H), 4.68-4.48( m, 3H), 4.30(dd, J=9.4, 6.3Hz, 1H), 2.08-2.00(m, 1H), 1.96(s, 3H), 1.23-1.13(m, 2H), 0.97-0.89(m, 2H).

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

[0742] A solution of intermediate 13 (150.0 mg, 0.417 mmol, 1 equivalent) and KOH (234.1 mg, 4.170 mmol, 10 equivalents) in MeOH (2 mL) and H2O (2 mL) was stirred overnight at 60°C. The residue was purified by reverse-phase flash under the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 35 mL / min, gradient: 0% B to 100% B in 40 minutes, 254 / 220 nm), and I-44 (61.0 mg, 44.2%) was obtained as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =318.

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

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

[0745] In 150 mL of DMF, 3-methoxy-1,2-oxazole-5-carboxylic acid (15 g, 104.823 mmol, 1 equivalent), N,O-dimethylhydroxylamine (7.68 g, 125.788 mmol, 1.2 equivalents), and HATU (47.83 g, 125.788 mmol, 1.2 equivalents) were added to DIEA (67.74 g, 524.115 mmol, 5 equivalents). The solution was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with SiO2 (800 mL) and washed with H2O (800 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in petroleum ether with a 0% to 39% gradient to obtain intermediate 2 (17.6 g, 90.19%) as a yellow oily substance. LCMS(ESI)m / z:[M+H] + = 187.

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

[0747] To a solution of intermediate 2 (16 g, 85.944 mmol, 1 equivalent) in THF (150 mL), bromo(isopropyl)magnesium (25.32 g, 171.888 mmol, 2 equivalents) was added under an N2 atmosphere at -78°C. The resulting solution was stirred at -78°C for 2 hours. The reaction solution was diluted with MeOH (30 mL) and concentrated. The residue was diluted with SiO2 (600 mL) and washed with water (3 × 600 mL). 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 0-15% ethyl acetate in petroleum ether to obtain intermediate 3 (9.8 g, 67.40%) as a colorless oil. LCMS(ESI)m / z:[M+H] + =170.

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

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

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

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

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

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

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

[0755] To a solution of Intermediate 6 (200 mg, 1.009 mmol, 1 equiv) in MeOH (3 mL) and H2O (3 mL) was added NaOH (403.61 mg, 10.090 mmol, 10 equiv). The resulting solution was stirred at 80 °C for 1 hour. The mixture was acidified to pH 2 with 1 M HCl (aqueous solution). The solution was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 7 (220 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + = 218.

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

Chemical Structure

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

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

Chemical Structure

[0759] Step 1: Preparation of tert-butyl6-{3-[2-(methoxymethoxy)phenyl]sinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (intermediate 2). [ka]

[0760] To a stirred mixture of 7-chloro-3-[2-(methoxymethoxy)phenyl]sinnoline (6 g, 19.951 mmol, 1 equivalent) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.58 g, 7.980 mmol, 1.2 equivalents) in 50 mL of dioxane, Cs2CO3 (19.50 g, 59.853 mmol, 3 equivalents) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (1.68 g, 1.995 mmol, 0.1 equivalent) were gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was further stirred at 100°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain intermediate 2 (8 g, 86.69%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 463.

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

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

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

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

[0765] Step 4: Preparation of [3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl]acetic acid (intermediate 5). [ka]

[0766] A mixture of intermediate 4 (700 mg, 1.401 mmol, 1 equivalent) and LiOH·H2O (587.94 mg, 14.010 mmol, 10 equivalents) in MeOH (8 mL) and H2O (2 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product was detected by LC-MS. The mixture was acidified to pH 5 with HCl (aqueous solution). The resulting mixture was diluted with CH2Cl2 / MeOH (9:1) (100 mL). The resulting mixture was washed with 3 × 100 mL of brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 5 (500 mg, 73.49%) as a red solid. LC-MS(ESI)m / z:[M+H] + = 486.

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

[0768] To a stirred mixture of Intermediate 5 (210 mg, 0.433 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (186.35 mg, 0.563 mmol, 1.3 eq) in DMF (2 mL), PyBOP (450.15 mg, 0.866 mmol, 2 eq) and DIEA (226.01 μL, 1.299 mmol, 3 eq) were added dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. 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 of 10% - 90% in 30 minutes, detector, UV254 nm. Thereby, Intermediate 6 (102 mg, 29.52%) was obtained as a yellow solid. LCMS (ESI) m / z: [M+H] + = 799.

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

Chemical Structure

[0770] Intermediate 6 was purified under the following conditions (column: CHIRALPAK ID, 2 * 25 cm, 5 μm, mobile phase, MtBE (10 mM NH3-MeOH) and EtOH (held at 50% EtOH in for 30 minutes), detector, UV254 nm. Thereby, 51 (the second peak) (47.8 mg, 45.74%) was obtained as a red solid. 11H NMR (400 MHz, DMSO-d6)δ 12.82(d, J=4.8Hz, 1H), 9.00(d, J=6.4Hz, 1H), 8.76(s, 1H), 8.42(d, J=7. 7Hz, 1H), 8.07-8.01(m, 1H), 7.96(d, J=9.0Hz, 1H), 7.50-7.42(m, 2H), 7.3 7(d, J=8.1Hz, 2H), 7.35-7.25(m, 2H), 7.01(d, J=8.0Hz, 3H), 5.87(d, J=42 .8Hz, 1H), 5.12(d, J=3.6Hz, 1H), 5.05-4.85(m, 1H), 4.37(t, J=7.7Hz, 1H) , 4.29(s, 5H), 4.13(s, 4H), 3.71(dd, J=10.6, 4.4Hz, 1H), 3.60(t, J=10.6H z, 1H), 3.45(dd, J=14.0, 10.8Hz, 1H), 2.47(d, J=4.9Hz, 3H), 2.34-2.13(m , 1H), 2.03(t, J=10.0Hz, 1H), 1.79(ddd, J=12.8, 8.2, 4.9Hz, 1H), 1.43(dd , J=32.8, 7.0Hz, 3H), 0.96(d, J=6.5Hz, 3H), 0.82(dd, J=14.9, 6.7Hz, 3H). LCMS(ESI)m / z:[M+H] + = 799.15.

[0771] The compounds listed in Table 8 were prepared using appropriate Boc-diamines and chloro-sinnoline, following the same procedure as that used for the preparation of compound 51.

[0772] [Table 9-1]

[0773] [Table 9-2]

[0774] [Table 9-3]

[0775] Table 9-4

[0776] Table 9-5

[0777] Table 9-6

[0778] Table 9-7

[0779] Table 9-8

[0780] Table 9-9

[0781] Table 9-10

[0782] Table 9-11

[0783] Table 9-12

[0784] Table 9-13

[0785] Table 9-14

[0786] Table 9-15

[0787] Table 9-16

[0788] Table 9-17

[0789] Table 9-18

[0790] Table 9-19

[0791] Table 9-20

[0792] Table 9-21

[0793] Table 9-22

[0794] Table 9-23

[0795] Table 9-24

[0796] [Table 9-25]

[0797] [Table 9-26]

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

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

[0800] 4-bromo-1H-1,2,3-triazole (1 g, 6.758 mmol, 1 equivalent) and 2-bromo-2-cyclopropyl ethyl acetate (2.80 g, 13.516 mmol, 2 equivalents) were added to DMF (5 mL) with K2CO3 (1.87 g, 13.516 mmol, 2 equivalents). The resulting solution was stirred at 60°C for 4 hours. The resulting mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water with MeCN (0.1% TFA), gradient from 0% to 100% over 30 minutes, detector, UV254 / 220 nm, yielding I-46 (611 mg, 32.98%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 274. [ka]

[0801] Ethyl 2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclobutyl acetate (I-47) and ethyl 2-(4-bromo-1H-1,2,3-triazol-1-yl)-3-methylbutanoate (I-48) were prepared from 4-bromo-1H-1,2,3-triazole using the same procedure as for I-46.

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

[0803] A solution of intermediate 2 (489 mg, 1.784 mmol, 1 equivalent) and LiOH (213.62 mg, 8.920 mmol, 5 equivalents) in MeOH (4 mL) and H2O (1 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 3 (481 mg, crude) as a yellow solid. LCMS(ESI) m / z: [M+H]+=245.

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

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

[0806] Step 4: Preparation of tert-butyl6-(1-{1-cyclopropyl-2-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl))phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-2-oxoethyl}-1,2,3-triazole-4-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate (intermediate 5). [ka]

[0807] Intermediate 4 (281 mg, 0.502 mmol, 1 equivalent) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (199.16 mg, 1.004 mmol, 2 equivalents), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (42.25 mg, 0.050 mmol, 0.1 equivalent), and Cs2CO3 (327.29 mg, 1.004 mmol, 2 equivalents) were stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water MeCN (0.1% NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV254 / 220nm. Intermediate 5 (116 mg, 34.12%) was obtained as a yellow solid. LCMS(ESI)m / z:[M+H] + = 677.

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

[0809] To a solution of intermediate 5 (106 mg, 0.157 mmol, 1 equivalent) in DCM (1.5 mL), TFA (0.5 mL) was added and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water with MeCN (0.1% NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV254 / 220 nm. Intermediate 6 (61 mg, 67.54%) was obtained as a yellow solid. LCMS(ESI) m / z:[M+H] + = 577.

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

[0811] A 1,4-dioxane (1 mL) solution containing intermediate 6 (51 mg, 0.088 mmol, 1 equivalent), I-12 (22.70 mg, 0.088 mmol, 1 equivalent), Pd-PEPPSI-IPentCl 2-methylpyridine (9 mg, 0.009 mmol, 0.1 equivalent), and Cs2CO3 (57.63 mg, 0.176 mmol, 2 equivalents) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and 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% NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV 254 / 220 nm. Intermediate 7 (43 mg, 61.01%) was obtained as a red solid. LCMS(ESI)m / z:[M+H] + = 797.

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

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

[0814] The compounds listed in Table 9 were prepared using the same procedure as that used for the preparation of compound 210-001.

[0815] [Table 10-1]

[0816] [Table 10-2]

[0817] [Table 10-3]

[0818] [Table 10-4]

[0819] [Table 10-5]

[0820] [Table 10-6]

[0821] [Table 10-7]

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

[0823] Step 1: Preparation of tert-butyl6-(1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazole-4-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylic acid (intermediate 2) [ka]

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

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

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

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

[0828] To a stirred solution of intermediate 3 (1 g, 3.409 mmol, 1 equivalent) and I-12 (1.31 g, 5.114 mmol, 1.5 equivalents) in dioxane (10 mL), Cs2Co3 (3.34 g, 10.227 mmol, 3 equivalents) and Pd-PEPPSI-IPentCl 2-methylpyridine (2.87 mg, 0.003 mmol, 0.1 equivalent) were gradually 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 could be detected by LC-MS. The resulting mixture was diluted with SiO2 (100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 4 (985 mg, 56.26%) as a yellow solid. LC-MS (ESI) m / z [M+H] + = 514.

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

[0830] A mixture of intermediate 4 (985 mg, 1.918 mmol, 1 equivalent) and LiOH·H2O (459.32 mg, 19.180 mmol, 10 equivalents) in MeOH (4 mL) and H2O (2 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 HCl (aqueous solution). The resulting mixture was diluted with CH2Cl2 (3 × 50 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. This yielded I-49 (498 mg, 53.48%) as a red solid. LC-MS(ESI)m / z[M+H] + = 486.

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

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

[0833] A mixture of tert-butyl N-[(4-bromo-2-chlorophenyl)methyl]carbamate (1 g, 3.119 mmol, 1 equivalent), trimethylsilylacetylene (919.06 mg, 9.357 mmol, 3 equivalents), Pd(dppf)Cl2.CH2Cl2 (127.04 mg, 0.156 mmol, 0.05 equivalents), and CuI (59.40 mg, 0.312 mmol, 0.1 equivalents) in TEA (10 mL) was stirred at 80°C for 4 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with  (2 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (4:1) to obtain intermediate 2 (1.15 g, crude) as a pale yellow solid. LCMS(ESI)m / z:[M+H] + = 338.

[0834] Step 2: Preparation of tert-buty...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, m is 0, 1, 2, or 3, k is 0, 1, or 2, Each R １ is, independently, halo, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ２ -C ９ heterocyclyl, optionally substituted C ３ -C ８ cycloalkyl, optionally substituted C ３ -C ８ cycloalkoxy, optionally substituted C ２ -C ６ alkynyl, optionally substituted amino, or cyano, Each X is independently replaced by a halo or optionally substituted with C. １ ~C ６ It is heteroalkyl, L is in equation 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 A linker or a pharmaceutically acceptable salt thereof, During the ceremony, A １ However, this is a bond between the linker and ring system A, A ２ However, this is a connection between the disassembled part B and the linker. B １ , B ２ , B ３ , and B ４ Each of these is independently and arbitrarily substituted C １ ~C ４ Alkyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ６ ~C １０ Aryl C １～４ Alkyl, optionally substituted C １ ~C ４ Heteroalkyl, optionally substituted C ３ ~C １０ Cycloalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally substituted C ２ ~C １０ Heterocyclyl, optionally substituted C ２ ~C ６ Heteroaryl, optionally substituted C ６～１２ Ariel, O, S, S(O) ２ , or NR Ｎ And, Each R Ｎ However, independently, H and C are optionally substituted. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, optionally substituted C ２～４ Alkinyl, optionally substituted C ２～１０ Heterocyclyl, optionally substituted C ２～６ Heteroaryl or optionally substituted C １～７ It is heteroalkyl, C １ and C ２ Each of these is independently a carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. Each of f, g, h, i, j, and k is independently either 0 or 1. D is optionally substituted C １～１０ alkyl, optionally substituted C ２～１０ alkenyl, optionally substituted C ２～１０ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ２～６ heteroaryl, optionally substituted C ６～１２ aryl, optionally substituted C ２ ~C １０ polyethylene glycol, optionally substituted C ３ ~C １０ cycloalkyl, optionally substituted C ３ ~C １０ carbocyclyl, or optionally substituted C １～１０ heteroalkyl, or D is absent, and the linker is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ and is B is the disassembled part, and the disassembled part has the structure of formula C. 【Chemistry 2】 During the ceremony, L ４ However, -N(R Ｂ１ ) (Caution Ｂ２ ), 【Transformation 3】 And, R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ However, H is optionally replaced by C. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C which is optionally substituted １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ４ However, H is optionally replaced by C. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C １ ~C ６ Alkyl C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl C ６ ~C １０ It is Ariel, R Ｂ５ However, H is optionally replaced by C. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, A ２ , halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkinyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally substituted C ２ ~C ９ Heterocyclyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ Each of these can be independently replaced by H, a halogen, or a C which is optionally substituted. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ９ However, H or C which is optionally substituted. １ ~C ６ It is alkyl, R Ｂ１０ However, it is H or F, A ２ However, this is a connection between the disassembled part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one of them is A ２ The structure is A compound of formula I, or a pharmaceutically acceptable salt thereof, having either the compound of formula I or a pharmaceutically acceptable salt thereof.

2. Each R １ However, independently, halo, and C are optionally substituted. １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ２ ~C ９ Heterocyclines, or optionally substituted C ３ ~C ８ It is a cycloalkyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each X is independently a halo.

3. The compound having the structure of formula I-A, or a pharmaceutically acceptable salt thereof, according to claim 1: 【Chemistry 4】

4. The compound having the structure of formula I-B, the compound according to claim 1, or a pharmaceutically acceptable salt thereof: 【Transformation 5】

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

6. R １ However, C is optionally substituted. １ ~C ６ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, which is an alkoxy or a halo.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the decomposition portion has the structure of formula Ca2, formula Cb2, formula Cc2, formula Cd2, formula Ce2, or formula Cf2: 【Transformation 6】

8. R Ｂ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

9. R Ｂ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein H is present.

10. R Ｂ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein H is present.

11. R Ｂ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

12. R Ｂ３ However, C is optionally substituted. １ ~C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

13. The aforementioned disassembled part 【Transformation 7】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. The aforementioned disassembled part 【Transformation 8】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. The aforementioned linker, 【Chemistry 9】 【Chemistry 10】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure of the compound described in claim 1.

16. The aforementioned linker, 【Chemistry 11】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure of the compound described in claim 1.

17. The aforementioned linker, 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure of the compound described in claim 1.

18. A compound selected from the group consisting of compounds 1 to 291 in Table 1 below, or a pharmaceutically acceptable salt thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 【Table 1-67】 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A cancer treatment agent comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

21. The therapeutic agent according to claim 20, 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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