Compound and its use

Abstract

The present disclosure features a compound of formula I, or a pharmaceutically acceptable salt thereof, and a formulation containing the same. Also disclosed is a method for treating BAF complex-related disorders such as cancer. [Chemical 1] JPEG2025516584000576.jpg39128

Description

Technical Field

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

Background Art

[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, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is required for the growth of cancer cells. BRM, also known as the potential global transcriptional activator SNF2L2 and / or the ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for the growth of tumor cells in cells characterized by loss-of-function mutations of BRG1. Deactivation of BRG and / or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.

Summary of the Invention

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

[0004] In one aspect, the present invention is a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0005] In some embodiments, the compound has the structure of Formula I-A,

Chemical formula

[0006] In some embodiments, the compound has the structure of formula I-B

Chemical formula

[0007] In some embodiments, the compound has the structure of formula I-C

Chemical formula

[0008] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, X is Cl or F.

[0009] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, R1 is optionally substituted C 1 ~C 6 Is alkyl. In some embodiments, R 1 Is methyl. In some embodiments, R 1 Is difluoromethyl.

[0010] In some embodiments, R 2 Is H. In some embodiments, R 2 Is optionally substituted C 1 ~C 6 Is alkyl. In some embodiments, R 2 Is optionally substituted C 3 ~C 8 Is cycloalkyl (e.g., monocyclic, spiro, bridged). In some embodiments, R2 is optionally substituted C 2 ~C 9 is a heterocycle. In some embodiments, R 2 is H, CH 3 ,

Chemical formula

[0011] In some embodiments, the compound has the structure of Formula I-D:

Chemical formula

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

[0013] In some embodiments, R 1 is methyl or difluoromethyl. In some embodiments, k is 0.

[0014] In some embodiments, the compound has the structure of Formula I-E:

Chemical formula

[0015] In some embodiments, the compound has the structure of Formula I-F:

Chemical formula

[0016] In some embodiments, the compound has the structure of Formula I-G:

Chemical formula

[0017] In some embodiments, the compound has the structure of Formula I-H:

Chem.

[0018] In some embodiments, the compound has the structure of Formula I-I:

Chem.

[0019] In some embodiments, the compound has the structure of Formula I-J:

Chem.

[0020] In some embodiments, the compound has the structure of Formula I-K:

Chem.

[0021] In some embodiments, the compound has the structure of Formula I-L:

Chem.

[0022] In some embodiments, the compound has the structure of Formula I-M:

Chem.

[0023] In some embodiments, the compound has the structure of Formula I-N:

Chem.

[0024] In some embodiments, the compound has the structure of Formula I-O:

Chem.

[0025] In some embodiments, the compound has the structure of Formula I-P:

Chem.

[0026] In some embodiments, the compound has the structure of Formula I-Q:

Chem.

[0027] In some embodiments, the compound has the structure of Formula I-R:

Chem.

[0028] In some embodiments, the compound has the structure of Formula I-S:

Chem.

[0029] In some embodiments, the compound has the structure of Formula I-T:

Chem.

[0030] In some embodiments, the compound has the structure of Formula I-U:

Chem.

[0031] In some embodiments, the compound has the structure of Formula I-V:

Chem.

[0032] In some embodiments, the compound has the structure of Formula I-W: [Chemical formula]

[0033] In some embodiments, the cleavage moiety B has the structure of Formula A-1, [Chemical formula] wherein, Y 1 is [Chemical formula] and R A5 is H, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 heteroalkyl, R A6 is H or optionally substituted C 1 ~C 6 alkyl, R A7 is H or optionally substituted C 1 ~C 6 alkyl, or R A6 and R A7 together with the carbon atom to which each is attached, combine to form an optionally substituted C 3 ~C 6 carbocyclic or an optionally substituted C 2 ~C 5 heterocyclic, or R A6 and R A7 together with the carbon atom to which each is attached, combine to form an optionally substituted C 3 ~C 6 carbocyclic or an optionally substituted C 2 ~C 5 heterocyclic, R A8 is H, optionally substituted C1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 is heteroalkyl, R A1 , R A2 , R A3 , and R A4 each independently is H, A 2 , halogen, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 2 ~C 9 heterocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 2 ~C 9 heteroaryl, optionally substituted C 2 ~C 6 alkenyl, optionally substituted C 2 ~C 6 heteroalkenyl, optionally substituted -O-C 3 ~C 6 carbocyclic, hydroxyl, thiol, or optionally substituted amino, or R A1 and R A2 , R A2 and R A3 , and / or R A3 and R A4 together with the carbon atom to which each is attached combine to form

Chemical formula

Chemical formula

Chemical formula

[0034] In some embodiments, R A5 is H or methyl. In some embodiments, R A5 is H.

[0035] In some embodiments, each of R A1 、R A2 、R A3 、and R A4 is independently H or A 2 。

[0036] In some embodiments, R A1 is A 2 and each of R A2 、R A3 、and R A4 is H.

[0037] In some embodiments, R A2 is A 2 and each of R A1 、R A3 、and R A4 is H.

[0038] In some embodiments, R A3 is A 2and R A1 、R A2 、and R A4 are each H.

[0039] In some embodiments, R A4 is A 2 and R A1 、R A2 、and R A3 are each H.

[0040] In some embodiments, Y 1 is

Chemical formula

[0041] In some embodiments, R A6 is H. In some embodiments, R A7 is H.

[0042] In some embodiments, Y 1 is

Chemical formula

[0043] In some embodiments, R A8 is H or optionally substituted C 1 ~C 6 alkyl. In some embodiments, R A8 is H or methyl. In some embodiments, R A8 is methyl.

[0044] In some embodiments, the degradation moiety comprises the structure of formula A2:

Chemical formula

[0045] In some embodiments, the degradation moiety is

Chemical formula

[0046] In some embodiments, the degradation moiety comprises the structure of Formula A4: [Chemical Formula]

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

[0048] In some embodiments, the degradation moiety has the structure of Formula A5: [Chemical Formula]

[0049] In some embodiments, the degradation moiety has the structure of Formula A6: [Chemical Formula]

[0050] In some embodiments, the degradation moiety has the structure of Formula A8: [Chemical Formula]

[0051] In some embodiments, the degradation moiety has the structure of Formula A10: [Chemical Formula]

[0052] In some embodiments, the degradation moiety has the following structure [Chemical Formula]

[0053] In some embodiments, the decomposition part has the following structure [Chemical formula]

[0054] In some embodiments, the decomposition part is formula C, where [Chemical formula] wherein L 4 is -N(R B1 )(R B2 ), [Chemical formula] and R B1 is H, A 2 , optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 heteroalkyl,[ R B2 is H, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 heteroalkyl,[ R B3 is A 2 , optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 1 ~C 6 alkyl C 3 ~C 10 carbocyclic, or optionally substituted C 1 ~C6 alkyl C 6 ~C 10 is aryl, R B4 is H, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 1 ~C 6 alkyl C 3 ~C 10 carbocyclic, or optionally substituted C 1 ~C 6 alkyl C 6 ~C 10 is aryl, R B5 is H, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 is heteroalkyl, v2 is 0, 1, 2, 3, or 4, each R B6 is independently A 2 , halogen, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 2 ~C 6 alkynyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 2 ~C 9 heterocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 2 ~C 9 heteroaryl, optionally substituted C 2 ~C 6 alkenyl, optionally substituted C 2 ~C 6heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R B7 and R B8 each independently is H, halogen, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 6 ~C 10 aryl, R B9 is H or optionally substituted C 1 ~C 6 alkyl, A 2 is a bond between the cleavage moiety and the linker, R B1 、R B3 、and R B6 only one and only one of them is A 2 , having the structure of formula C or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the cleavage moiety is of formula C,

Chemical formula

Chemical formula

[0056] In some embodiments, the cleavage moiety has the structure of formula C3.

Chemical formula

[0057] In some embodiments, the cleavage moiety has the structure of formula C4. [Chemistry]

[0058] In some embodiments, the degradation moiety has the structure of Formula C1: [Chemistry]

[0059] In some embodiments, the degradation moiety is [Chemistry] as follows.

[0060] In some embodiments, the degradation moiety is [Chemistry] as follows.

[0061] In some embodiments, the degradation moiety is [Chemistry] as follows.

[0062] In some embodiments, the degradation moiety is [Chemistry] as follows.

[0063] In some embodiments, the degradation moiety is [Chemistry] as follows.

[0064] In some embodiments, the degradation moiety is [Chemistry] as follows.

[0065] In some embodiments, the cleavage moiety has the structure of Formula C2:

Chemical formula

[0066] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0067] In some embodiments, R B9 is attached to the (S)-asymmetric center.

[0068] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B7 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B3 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B8 is H. In some embodiments, R B2 is H.

[0069] In some embodiments, the cleavage moiety is

Chemical formula

[0070] In some embodiments, the cleavage moiety has the structure of Formula Ca2:

Chemical formula

[0071] In some embodiments, the degradation moiety has the structure of formula Cb2:

Chemical formula

[0072] In some embodiments, the degradation moiety has the structure of formula Cc2:

Chemical formula

[0073] In some embodiments, the degradation moiety has the structure of formula Cd2:

Chemical formula

[0074] In some embodiments, the degradation moiety has the structure of formula Ce2:

Chemical formula

[0075] In some embodiments, the degradation moiety has the structure of formula Cf2:

Chemical formula

[0076] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0077] In some embodiments, R B9 is attached to the (S)-asymmetric center.

[0078] In some embodiments, v2 is 0. In some embodiments, RB4 is H. In some embodiments, R B5 is H. In some embodiments, R B7 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B3 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B3 is optionally substituted C 3 ~C 10 carbocyclic. In some embodiments, R B3 is cyclopropane. In some embodiments, R B3 is cyclobutane. In some embodiments, R B3 is fluoro-2-methylpropane. In some embodiments, R B8 is H. In some embodiments, R B2 is H.

[0079] In some embodiments, the degradation moiety is

Chemical formula

[0080] In some embodiments, the degradation moiety is

Chemical formula

[0081] In some embodiments, the degradation moiety is

Chemical formula

[0082] In some embodiments, the degradation moiety is [Chemical formula] is as follows.

[0083] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0084] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0085] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0086] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0087] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0088] In some embodiments, the decomposition part is Formula C5, where [Chemical formula] in the formula, L 4 is -N(R B1 )(R B2 ), [Chemical formula] is as follows, R B1is H, A 2 C optionally substituted 1 ~C 6 alkyl, or C optionally substituted 1 ~C 6 heteroalkyl, R B2 is H, C optionally substituted 1 ~C 6 alkyl, or C optionally substituted 1 ~C 6 heteroalkyl, R B3 is A 2 C optionally substituted 1 ~C 6 alkyl, C optionally substituted 1 ~C 6 heteroalkyl, C optionally substituted 3 ~C 10 carbocyclic, C optionally substituted 6 ~C 10 aryl, C optionally substituted 1 ~C 6 alkyl C 3 ~C 10 carbocyclic, or C optionally substituted 1 ~C 6 alkyl C 6 ~C 10 aryl, R B5 is H, C optionally substituted 1 ~C 6 alkyl, or C optionally substituted 1 ~C 6 heteroalkyl, v2 is 0, 1, 2, 3, or 4, each R B6 is independently A 2 halogen, C optionally substituted 1 ~C 6 alkyl, C optionally substituted 2 ~C 6 alkynyl, C optionally substituted 1 ~C 6 heteroalkyl, C optionally substituted3 ~C 10 Carbocyclic, optionally substituted C 2 ~C 9 Heterocyclic, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2 ~C 9 Heteroaryl, optionally substituted C 2 ~C 6 Alkenyl, optionally substituted C 2 ~C 6 Heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R B7 and R B8 each independently is H, halogen, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 6 ~C 10 aryl, R B9 is H or optionally substituted C 1 ~C 6 alkyl, R B11 is H, alcohol, boronic acid, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 1 ~C 6 alkyl C 3 ~C 10 carbocyclic, or optionally substituted C 1 ~C 6 alkyl C 6 ~C 10 aryl, A 2 is a bond between the cleavage moiety and the linker, R B1 , R B3 , and R B6 only one and only one of which is A2 is of formula C5 or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, R B11 is boric acid.

[0090] In some embodiments, the cleavage moiety has the structure of formula C6.

Chemical formula

[0091] In some embodiments, the cleavage moiety has the structure of formula C1:

Chemical formula

[0092] In some embodiments, the cleavage moiety has the structure of formula C8:

Chemical formula

[0093] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0094] In some embodiments, R B9 is attached to the (S)-asymmetric center.

[0095] In some embodiments, v2 is 0. In some embodiments, R B5 is H. In some embodiments, R B7 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B3is optionally substituted C 1 ~C 6 is alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B8 is H. In some embodiments, R B2 is H.

[0096] In some embodiments, the cleavage moiety is

Chemical formula

[0097] In some embodiments, the cleavage moiety is of formula D,

Chemical formula

Chemical formula

[0098] In some embodiments, the cleavage moiety has the structure of formula D3.

Chemical formula

[0099] In some embodiments, the cleavage moiety has the structure of formula D1:

Chemical formula

[0100] In some embodiments, the cleavage moiety is,

Chemical formula

[0101] In some embodiments, the cleavage moiety is,

Chemical formula

[0102] In some embodiments, the degradation moiety is

Chem.

[0103] In some embodiments, the degradation moiety has the structure of formula D2:

Chem.

[0104] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0105] In some embodiments, R B9 is attached to an (S)-asymmetric center. In some embodiments, R B9 is H.

[0106] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B6 is H. In some embodiments, R B6 is halogen. In some embodiments, R B6 is fluorine. In some embodiments, R B6 is bromine. In some embodiments, R B6 is chlorine. In some embodiments, R B6is cyano. In some embodiments, R B6 is optionally substituted C 1 ~C 6 heteroalkyl. In some embodiments, R B6 is optionally substituted C 3 ~C 6 alkynyl. In some embodiments, R B6 is methoxy. In some embodiments, R B6 is 3-methoxy-1-propoxy.

[0107] In some embodiments, the cleavage moiety is

Chemical formula

[0108] In some embodiments, the cleavage moiety is

Chemical formula

[0109] In some embodiments, the cleavage moiety is

Chemical formula

[0110] In some embodiments, the cleavage moiety is

Chemical formula

[0111] In some embodiments, the cleavage moiety is

Chemical formula

[0112] In some embodiments, the cleavage moiety is

Chemical formula

[0113] In some embodiments, the decomposition part is

Chemical formula

[0114] In some embodiments, the decomposition part is

Chemical formula

[0115] In some embodiments, the decomposition part is

Chemical formula

[0116] In some embodiments, the decomposition part is

Chemical formula

[0117] In some embodiments, the decomposition part is

Chemical formula

[0118] In some embodiments, the decomposition part is

Chemical formula

[0119] In some embodiments, the decomposition part is

Chemical formula

[0120] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0121] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0122] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0123] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0124] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0125] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0126] In some embodiments, the decomposition part is [Chemical formula] is as follows.

[0127] In some embodiments, the decomposition part is [Chemical formula] is as follows.

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

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

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

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

[0132] In some embodiments, the degradation moiety is Formula Da, wherein [Chemical formula] wherein L 4 is -N(R B1 )(R B2 ), [Chemical formula] and R B1 is H, A 2 , optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 heteroalkyl, and R B2 is H, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C6 is heteroalkyl, R B3 is A 2 , optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 1 ~C 6 alkyl C 3 ~C 10 carbocyclic, or optionally substituted C 1 ~C 6 alkyl C 6 ~C 10 aryl, R B4 is H, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 1 ~C 6 alkyl C 3 ~C 10 carbocyclic, or optionally substituted C 1 ~C 6 alkyl C 6 ~C 10 aryl, R B5 is H, optionally substituted C 1 ~C 6 alkyl, or optionally substituted C 1 ~C 6 is heteroalkyl, X 1 and each X 2 is independently C, N, or O, v2 is 0, 1, 2, 3, or 4, each R B6 is independently A2 , halogen, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 2 ~C 6 alkynyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 2 ~C 9 heterocyclic, optionally substituted C 6 ~C 10 aryl, optionally substituted C 2 ~C 9 heteroaryl, optionally substituted C 2 ~C 6 alkenyl, optionally substituted C 2 ~C 6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, and R B9 is H or optionally substituted C 1 ~C 6 alkyl, and A 2 is a bond between the cleavable moiety and the linker, and R B1 , R B3 , and R B6 only one and only one of is A 2 in the formula Da or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the cleavable moiety has the structure of formula Da3.

Chemical formula

[0134] In some embodiments, the cleavable moiety has the structure of formula Da1:

Chemical formula

[0135] In some embodiments, the cleavage moiety has the structure of formula Da2:

Chemical formula

[0136] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0137] In some embodiments, R B9 is attached to the (S)-asymmetric center.

[0138] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 is H. In some embodiments, X 1 is C. In some embodiments, X 2 is N.

[0139] In some embodiments, the cleavage moiety is

Chemical formula

[0140] In some embodiments, the cleavage moiety has the formula E,

Chemical formula

Chem.

[0141] In some embodiments, the cleavage moiety has the structure of formula E3.

Chemical Formula

[0142] In some embodiments, the cleavage moiety has the structure of Formula E1:

Chemical formula

[0143] In some embodiments, the cleavage moiety is

Chemical formula

[0144] In some embodiments, the cleavage moiety is

Chemical formula

[0145] In some embodiments, the cleavage moiety has the structure of Formula E2:

Chemical formula

[0146] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0147] In some embodiments, R B9 is attached to the (S)-asymmetric center.

[0148] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, RB3 is isopropyl. In some embodiments, R B2 is H. In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl. In some embodiments, R B9 is H. In some embodiments, R B9 is optionally substituted C 3 ~C 6 alkynyl. In some embodiments, R B10 is absent. In some embodiments, R B9 is [1.1.1]pentane. In some embodiments, R B9 is cyclopropane. In some embodiments, R B9 is cyclobutane. In some embodiments, R B9 is cyclopentane. In some embodiments, R B10 is H. In some embodiments, R B10 is cyano. In some embodiments, R B10 is optionally substituted C 3 ~C 10 carbocyclyl. In some embodiments, R B10 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B10 is methyl.

[0149] In some embodiments, the cleavage moiety is

Chemical formula

[0150] In some embodiments, the cleavage moiety is

Chemical formula

[0151] In some embodiments, the decomposed part is

Chemical formula

[0152] In some embodiments, the decomposed part is

Chemical formula

[0153] In some embodiments, the decomposed part is

Chemical formula

[0154] In some embodiments, the decomposed part is

Chemical formula

[0155] In some embodiments, the decomposed part is

Chemical formula

[0156] In some embodiments, the decomposed part is

Chemical formula

[0157] In some embodiments, the decomposed part is

Chemical formula

[0158] In some embodiments, the decomposed part is Formula F, where

Chemical formula

Chemical

[0159] In some embodiments, the cleavage moiety has the structure of formula F3.

Chemical Structure

[0160] In some embodiments, the cleavage moiety has the structure of formula F1:

Chemical Structure

[0161] In some embodiments, the cleavage moiety is

Chemical Structure

[0162] In some embodiments, the cleavage moiety is

Chemical Structure

[0163] In some embodiments, the cleavage moiety has the structure of Formula F2:

Chemical formula

[0164] In some embodiments, R B9 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B9 is methyl.

[0165] In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is optionally substituted C 1 ~C 6 alkyl. In some embodiments, R B3 is isopropyl. In some embodiments, R B2 is H.

[0166] In some embodiments, the cleavage moiety is

Chemical formula

[0167] In some embodiments, the linker has Formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 or a pharmaceutically acceptable salt thereof, and Formula II has the structure of Formula II or a pharmaceutically acceptable salt thereof, and wherein, A 1 is a bond between the linker and ring system A, A 2 is a bond between the cleavage moiety and the linker, B 1 B, 2 B, 3 and B 4 each independently is optionally substituted C 1 ~C 4 alkyl, optionally substituted C 6 ~C 10 aryl, optionally substituted C 6 ~C 10 arylC 1~4 alkyl, optionally substituted C 1 ~C 4 heteroalkyl, optionally substituted C 3 ~C 10 cycloalkyl, optionally substituted C 3 ~C 10 carbocyclic, optionally substituted C 2 ~C 8 heterocyclic, optionally substituted C 2 ~C 6 heteroaryl, optionally substituted C 6~12 aryl, O, S, S(O) 2 or NR N and, each R N independently is H, optionally substituted C 1~4 alkyl, optionally substituted C 2~4 alkenyl, optionally substituted C 2~4 alkynyl, optionally substituted C 2~10 heterocyclic, optionally substituted C 2~6 heteroaryl, or optionally substituted C 1~7 heteroalkyl, C 1 and C 2 each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k independently is 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 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 is as follows.

[0168] In some embodiments, each of B 1 , B 2 , B 3 , and B 4 is independently optionally substituted C 1 ~C 2 alkyl, optionally substituted C 1 ~C 3 heteroalkyl, optionally substituted C 2 ~C 10 heterocyclyl, optionally substituted C 2~6 heteroaryl, O, or NR N is as follows, and D is optionally substituted C 1~10 alkyl, optionally substituted C 2~10 alkenyl, optionally substituted C 2~10Alkynyl, optionally substituted C 2~10 Heterocyclyl, optionally substituted C 6~12 Aryl, optionally substituted C 2 ~C 10 Polyethylene glycol, or optionally substituted C 1~10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is a chemical bond connecting to -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond connecting to.

[0169] In some embodiments, each of B 1 , B 2 , B 3 , and B 4 is independently optionally substituted C 1 ~C 2 alkyl, optionally substituted C 1 ~C 3 heteroalkyl, optionally substituted C 2 ~C 10 heterocyclyl, optionally substituted C 2~6 heteroaryl, optionally substituted C 3 ~C 10 cycloalkyl, optionally substituted C 3 ~C 10 carbocyclyl, O, or NR N is.

[0170] In some embodiments, each of B 1 and B 4 is independently

Chemical formula

Chemical formula

[0171] In some embodiments, B 1 is

Chemical formula

Chemical formula

[0172] In some embodiments, B 4 is

Chemical formula

Chemical formula

[0173] In some embodiments, C 1 is

Chemical formula

[0174] In some embodiments, B 2 is optionally substituted C 1 ~C 4 alkyl.

[0175] In some embodiments, D is optionally substituted C 1 ~C 10 alkyl.

[0176] 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.

[0177] In some embodiments, D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is.

[0178] In some embodiments, the linker is D. In some embodiments, D is optionally substituted C 1~10 alkyl, optionally substituted C 2~10 alkenyl, optionally substituted C 2~10 alkynyl, optionally substituted C 2~10 heterocyclyl, optionally substituted C 2~6 heteroaryl, optionally substituted C 6~12 aryl, optionally substituted C 2 ~C 10 polyethylene glycol, or optionally substituted C 1~10 heteroalkyl. In some embodiments, D is optionally substituted C 3 ~C 10 cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is optionally substituted C 3 ~C10 is a cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is optionally substituted C 3 ~C 10 is a cycloalkyl, 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 C 3 ~C 10 is a cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is optionally substituted C 3 ~C 10 is a carbocyclic ring, 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 C 3 ~C 10 is a carbocyclic ring, 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 C 3 ~C 10 is a carbocyclic ring, 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 C 3 ~C 10 is a carbocyclic ring, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is

Chemical formula

Chemical formula

[0179] In some embodiments, the linker has the following structure:

Chemical formula

Chemical formula

[0180] 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 wherein, A 1 is the bond between the linker and Ring System A, A 2 is the bond between the cleavage moiety and the linker, B 1 , B 2 , B 3 , and B 4 each independently is optionally substituted ethynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 3 -C 10 carbocyclic, optionally substituted C 2 -C 10 heterocyclic, optionally substituted C 2 -C 9 heteroaryl, O, S, S(O) 2 , or NR N , and each R N is independently H, optionally substituted C 1~4 alkyl, optionally substituted C 2~4 alkenyl, optionally substituted C 2~4 alkynyl, optionally substituted C 2~10 heterocyclic, optionally substituted C6~12 Aryl, or optionally substituted C 1~7 is heteroalkyl, C 1 and C 2 each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k independently is 0 or 1.

[0181] In some embodiments, the linker has the structure -(L 1 ) n - where n is 1, 2, or 3 and each L 1 is independently O, NR N , ethynyl, optionally substituted C 2 ~C 10 heterocyclyl, optionally substituted C 2 ~C 9 heteroaryl, optionally substituted C 6 ~C 10 aryl, or optionally substituted C 3 ~C 10 cycloalkyl.

[0182] In some embodiments, at least one L 1 is optionally substituted C 2 ~C 10 heterocyclyl. In some embodiments, the optionally substituted C 2 ~C 10 heterocyclyl is a 4-, 5-, or 6-membered monocyclic heterocyclyl. In some embodiments, the 4-, 5-, or 6-membered monocyclic heterocyclyl is

Chemical formula

[0183] In some embodiments, the optionally substituted C 2 ~C 10 heterocyclyl is a spirocyclic heterocyclyl. In some embodiments, the spirocyclic heterocyclyl is [Chem.] is.

[0184] In some embodiments, the optionally substituted C 2 ~C 10 heterocyclyl is a bridged heterocyclyl. In some embodiments, the bridged heterocyclyl is [Chem.] is.

[0185] In some embodiments, the optionally C 2 ~C 10 heterocyclyl is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic heterocyclyl is [Chem.] is.

[0186] In some embodiments, at least one L 1 is an optionally substituted C 2 ~C 9 heteroaryl. In some embodiments, the linker is -(L 1 ) q -(optionally substituted C 2 ~C 9 heteroaryl)-(L 1 ) q wherein each q is independently 0 or 1. In some embodiments, the optionally substituted C 2 ~C 9 heteroaryl is a 6-membered monocyclic heteroaryl. In some embodiments, the 6-membered monocyclic heteroaryl is [Chem.] is.

[0187] In some embodiments, at least one L 1is optionally substituted C 2 ~C 9 is a heteroaryl. In some embodiments, the linker is

Chemical formula

[0188] In some embodiments, at least one L 1 is optionally substituted C 6 ~C 10 is aryl. In some embodiments, the optionally substituted C 6 ~C 10 aryl is a 6-membered monocyclic aryl. In some embodiments, the 6-membered monocyclic aryl is optionally substituted phenyl.

[0189] In some embodiments, at least one L 1 is optionally substituted C 3 ~C 10 is cycloalkyl. In some embodiments, the optionally substituted C 3 ~C 10 cycloalkyl is a monocyclic cycloalkyl. In some embodiments, the 6-membered monocyclic cycloalkyl is

Chemical formula

[0190] In some embodiments, the optionally substituted C 3 ~C 10 cycloalkyl is a bridged cycloalkyl. In some embodiments, the bridged cycloalkyl is

Chemical formula

[0191] In some embodiments, at least one L 1 is ethynyl.

[0192] In some embodiments, only one L 1 is O. In some embodiments, only one L 1 is NR N . In some embodiments, R N is optionally substituted C 1 ~C 4 alkyl. In some embodiments, R N is H.

[0193] 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 , wherein each of B 1 , B 2 , B 3 , and B 4 is independently optionally substituted ethynyl, optionally substituted C 6 ~C 10 aryl, optionally substituted C 3 ~C 10 cycloalkyl, optionally substituted C 2 ~C 10 heterocyclyl, optionally substituted C 2 ~C 9 heteroaryl, O, or NR N .

[0194] In some embodiments, at least one of f, h, i, and k is 1.

[0195] In some embodiments, each of B 1 , B 2 , B 3 , and B 4 is independently O, ethynyl, optionally substituted C 2 ~C 9Heteroaryl, optionally substituted C 2 ~C 10 Heterocyclyl, optionally substituted C 3 ~C 10 Cycloalkyl, or optionally substituted C 6 ~C 10 is aryl. In some embodiments, B 1 、B 2 、B 3 、and B 4 each independently is optionally substituted C 2 ~C 9 heteroaryl or optionally substituted C 2 ~C 10 heterocyclyl. In some embodiments, B 1 and B 4 each independently is

Chemical Structure

Chemical Structure

[0196] In some embodiments, B 1 is

Chemical Structure

Chemical Structure

[0197] In some embodiments, B 4 is

Chemical Structure

Chemical Structure

[0198] In some embodiments, B 2 is NR N is. In some embodiments, B2 is NH. In some embodiments, B 2 is optionally substituted C 2 ~C 9 is a heteroaryl. In some embodiments, B 2 is

Chemical formula

[0199] 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.

[0200] In some embodiments, the linker has the following structure:

Chemical formula

Chemical formula

Chemical formula

[0201] In some embodiments, the shortest chain of atoms connecting two valences of the linker is 2 to 10 atoms in length. In some embodiments, the shortest chain of atoms connecting two valences of the linker is 6 atoms in length.

[0202] In some embodiments, the linker is any one of Compounds 1 to 121 in Table 1 (e.g., BRG1 IC 50 of BRM IC 50has the structure of the linker in any of the compounds having a ratio to [compound name] of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30). In some embodiments, the linker has the structure of the linker in any one of Compounds 1-121 in Table 1 (e.g., BRM IC 50 has a value of ++ or more (e.g., +++ or ++++(e.g., ++++)) in any of the compounds) and has the structure of the linker in any one of Compounds 1-121 in Table 1 (e.g., BRM IC 50 has a value of ++ or more (e.g., +++ or ++++(e.g., ++++)), and BRG1 IC 50 of BRM IC 50 has a ratio to [compound name] of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) in any of the compounds) and has the structure of the linker in any one of the compounds.

[0203] In one aspect, the present invention features a compound selected from the group consisting of 1-121 in Table 1, and a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof, having a ratio to the BRM IC of BRG1 IC 50 of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30). In some embodiments, the compound is any one of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof, having a BRM IC 50 of ++ or more (e.g., +++ or ++++(e.g., ++++)) as shown in Table 15. In some embodiments, the compound is any one of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof, having a BRM IC 50 of ++ or more (e.g., +++ or ++++(e.g., ++++)) as shown in Table 15, and a ratio to the BRM IC of BRG1 IC 50 of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) as shown in Table 15. 50 of BRM IC 50 In some embodiments, the compound is any one of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof.

[0204]

Table 1-1

[0205]

Table 1-2

[0206]

Table 1-3

[0207]

Table 1-4

[0208]

Table 1-5

[0209]

Table 1-6

[0210]

Table 1-7

[0211]

Table 1-8

[0212]

Table 1-9

[0213]

Table 1-10

[0214]

Table 1-11

[0215]

Table 1-12

[0216]

Table 1-13

[0217]

Table 1-14

[0218]

Table 1-15

[0219]

Table 1-16

[0220]

Table 1-17

[0221]

Table 1-18

[0222]

Table 1-19

[0223]

Table 1-20

[0224]

Table 1-21

[0225]

Table 1-22

[0226]

Table 1-23

[0227]

Table 1-24

[0228]

Table 1-25

[0229]

Table 1-26

[0230]

Table 1-27

[0231]

Table 1-28

[0232]

Table 1-29

[0233]

Table 1-30

[0234]

Table 1-31

[0235]

Table 1-32

[0236]

Table 1-33

[0237]

Table 1-34

[0238] In some embodiments, the compound has a ratio to BRM IC of at least 5 BRG1 IC. 50 of BRM IC 50 In some embodiments, the compound has a ratio to BRM IC of at least 7 BRG1 IC. 50 of BRM IC 50 In some embodiments, the compound has a ratio to BRM IC of at least 10 BRG1 IC. 50 of BRM IC 50 In some embodiments, the compound has a ratio to BRM IC of at least 15 BRG1 IC. 50 of BRM IC 50 In some embodiments, the compound has a ratio to BRM IC of at least 20 BRG1 IC. 50 of BRM IC 50 In some embodiments, the compound has a ratio to BRM IC of at least 25 BRG1 IC. 50 of BRM IC 50 In some embodiments, the compound has a ratio to BRM IC of at least 30 BRG1 IC. 50 of BRM IC 50 In one aspect, the invention features a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient.

[0239] In one aspect, the invention features a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient.

[0240] In another aspect, the present invention is a method for reducing the activity of the BAF complex in a cell, the method comprising contacting the cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0241] In some embodiments, the cell is a cancer cell.

[0242] In another aspect, the present invention is a method for treating a BAF complex-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0243] In some embodiments, the BAF complex-related disorder is cancer or a viral infection.

[0244] In a further aspect, the present invention is a method for inhibiting BRM, the method comprising contacting a cell with an effective amount of any one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0245] In some embodiments, the cell is a cancer cell.

[0246] In another aspect, the present invention is a method for inhibiting BRG1, the method comprising contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0247] In some embodiments, the cell is a cancer cell.

[0248] In a further aspect, the present invention is a method for inhibiting BRM and BRG1, the method comprising contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0249] In some embodiments, the cell is a cancer cell.

[0250] In another aspect, the present invention is a method of 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 one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0251] In some embodiments, the disorder associated with a loss-of-function mutation of BRG1 is cancer. In other embodiments, the subject is determined to have a loss-of-function disorder of BRG1, e.g., is determined to have a cancer with a loss of function of BRG1 (e.g., the cancer is determined to contain cancer cells with a loss of BRG1 function).

[0252] In another aspect, the present invention is a method of inducing apoptosis in a cell, the method comprising contacting the cell with an effective amount of any one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0253] In some embodiments, the cell is a cancer cell.

[0254] In a further aspect, the present invention is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0255] In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, or penile cancer.

[0256] In some embodiments of any of the foregoing methods, 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.

[0257] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0258] In some embodiments of any of the foregoing methods, the cancer is a drug-resistant cancer or has not responded to previous therapies (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolomide, irinotecan, CAR-T therapy, Herceptin®, Perjeta®, tamoxifen, Xeloda®, docetaxel, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, Alimta®, Abraxane®, Adriamycin®, gemcitabine, Avastin®, Halaven®, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, Gemzar®, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabulin, or PDL1 inhibitors).

[0259] In some embodiments of any of the foregoing methods, the cancer has or is determined to have a BRG1 mutation. In some embodiments of any of the foregoing methods, the BRG1 mutation is homozygous. In some embodiments of any of the foregoing methods, the cancer does not have or is determined not to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have or is determined not to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has or is determined to have a KRAS mutation. In some embodiments of any of the foregoing methods, the BRG1 mutation is in the ATPase catalytic domain of the protein. In some embodiments of any of the foregoing methods, the BRG1 mutation is a deletion at the C-terminus of BRG1.

[0260] In another aspect, the present disclosure provides a method of treating a disorder associated with BAF (e.g., cancer or viral infection) in a subject in need thereof. The method comprises contacting the cells with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a viral infection, and the retrovirus (e.g., Human immunodeficiency virus (HIV) and deltaretrovirus (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), etc. of the family Retroviridae, the family Hepadnaviridae (e.g., hepatitis B virus (HBV)), the family Flaviviridae (e.g., hepatitis C virus (HCV)), the family Adenoviridae (e.g., human adenovirus), the family Herpesviridae (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K *, CMV, varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV), HPV E1), Parvoviridae family (e.g., parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., measles virus), Togaviridae family (e.g., rubella virus). In some embodiments, the disorder is Coffin-Siris, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0261] In another aspect, the present disclosure provides a method for treating a viral infection in a subject in need thereof. The method comprises administering to the subject an effective amount of any of the foregoing compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound), or a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is caused by a virus of the Retroviridae family (e.g., human immunodeficiency virus (HIV) and deltaretrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., human adenovirus), Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K *, an infection caused by a virus of the family Herpesviridae (e.g., herpes simplex virus (HSV), cytomegalovirus, varicella-zoster virus), the family Papillomaviridae (e.g., human papillomavirus (HPV), HPV E1), the family Parvoviridae (e.g., parvovirus B19), the family Polyomaviridae (e.g., JC virus and BK virus), the family Paramyxoviridae (e.g., measles virus), or the family Togaviridae (e.g., rubella virus).

[0262] In some embodiments of any of the foregoing aspects, the compound is a BRM-selective compound. In some embodiments, a BRM-selective compound inhibits the level and / or activity of BRM by at least 10-fold more than it inhibits the level and / or activity of BRG1, and / or the compound binds to BRM by at least 10-fold more than it binds to BRG1. For example, in some embodiments, a BRM-selective compound has an IC 50 or IP 50 that is at least 10-fold lower than the IC 50 or IP 50 for BRG1. In some embodiments of any of the foregoing aspects, the compound is a BRM / BRG1 dual inhibitor compound. In some embodiments, a BRM / BRG1 dual inhibitor compound has similar activity against both BRM and BRG1 (e.g., the activity of the compound against BRM and BRG1 is within 10-fold (e.g., less than 5-fold, less than 2-fold)). In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRM. In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRG1. For example, in some embodiments, a BRM / BRG1 dual inhibitor compound has an IC 50 or IP 50 that is within 10-fold of the IC 50 or IP 50 for BRG1.

[0263] In another aspect, the present invention is a method for treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0264] In another aspect, the present invention is a method for reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0265] In another aspect, the present invention is a method for suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer in a subject, the method comprising administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0266] In another aspect, the present invention is a method for suppressing metastatic colony formation of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer in a subject, the method comprising administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0267] In another aspect, the present invention is a method for reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer cells, the method comprising contacting the cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0268] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cells are within the subject.

[0269] In some embodiments of any of the above aspects, the 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%).

[0270] In some embodiments, the 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 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of 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 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0271] In some embodiments of any 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%).

[0272] 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 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of 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 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0273] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein, and / or the cell or subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein, and / or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein, and / or the cell or subject has been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a blood cancer, such as multiple myeloma, large cell lymphoma, acute T cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda 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 sarcoma). In some embodiments, the cancer is renal cell cancer (e.g., Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). Metastatic cancer may include cells that exhibit migration and / or invasion of migratory cells and / or may include cells that exhibit endothelial mobilization and / or angiogenesis. In other embodiments, the migratory cancer is a cell migratory cancer. In still other embodiments, the cell migratory cancer is a non-metastatic cell migratory cancer. Metastatic cancer can be a cancer that spreads through seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid space.Alternatively, metastatic cancer can be cancer that spreads via the lymphatic system or hematogenously. In some embodiments, an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colony formation of cancer in the liver.

[0274] 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.

[0275] In some embodiments, the method further comprises administering to a subject or contacting the cells with an anti-cancer therapy, such as a chemotherapeutic agent or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation. In some embodiments, the anti-cancer therapy is a chemotherapeutic agent or cytotoxic agent, such as an antimetabolite, antimitotic, antitumor antibiotic, asparagine-specific enzyme, bisphosphonate, antineoplastic agent, alkylating agent, DNA repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory agent, Janus-related kinase inhibitor, phosphoinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor.

[0276] In some embodiments, the compounds of the invention are used in combination with another anti-cancer therapy, a MEK inhibitor, and / or a PKC inhibitor used in the treatment of choroidal melanoma, such as surgery. For example, in some embodiments, the method further comprises performing surgery before, after, or simultaneously with the administration of the compounds of the invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or simultaneously with the administration of the compounds of the invention.

[0277] In some embodiments, the anti-cancer therapy and the compounds of the invention are each administered within 28 days of each other and in an amount effective to treat the subject together.

[0278] In some embodiments, the subject or cancer has and / or is identified as having a loss-of-function mutation in BRG1.

[0279] In some embodiments, the cancer is resistant to one or more chemotherapeutic agents or cytotoxic agents (e.g., the cancer is determined to be resistant to a chemotherapeutic agent or cytotoxic agent (such as by a genetic marker), or is determined to be likely to be resistant to a chemotherapeutic agent or cytotoxic agent (such as a cancer that did not respond to a chemotherapeutic agent or cytotoxic agent)). In some embodiments, the cancer did not respond to one or more chemotherapeutic agents. In some embodiments, the cancer is resistant to or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or trametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0280] In some embodiments, the cancer is resistant to or unresponsive to a previously administered therapeutic agent used in the treatment of melanoma, such as a MEK inhibitor or a PKC inhibitor. For example, in some embodiments, the cancer is resistant to or unresponsive to a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or trametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0281] In one aspect, the present invention provides the use of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions, in the manufacture of a medicament. In some embodiments, the use is as described for the methods described herein.

[0282] Chemical terms The terms used herein are for the purpose of describing particular embodiments and are not intended to be limiting.

[0283] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in the particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituents described herein may be present as necessary to satisfy the valency of the atoms. For example, unsubstituted C 2 An alkyl group has the formula -CH 2 CH 3 and is used. When referred to in connection with a group defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups, but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group includes only those atoms that form part of the heterocyclic ring.

[0284] As used herein, the term "acyl" refers to an H or alkyl group attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain from 1 to 6, 1 to 11, or 1 to 21 carbons.

[0285] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group having from 1 to 20 carbon atoms (e.g., from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 6 carbon atoms, or from 1 to 3 carbon atoms).

[0286] Alkylene is a divalent alkyl group. As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon residue having a carbon-carbon double bond and having from 2 to 20 carbon atoms (e.g., from 2 to 16 carbon atoms, from 2 to 10 carbon atoms, from 2 to 6 carbon atoms, or 2 carbon atoms), either alone or in combination with other groups.

[0287] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon residue having a carbon-carbon triple bond and having from 2 to 20 carbon atoms (e.g., from 2 to 16 carbon atoms, from 2 to 10 carbon atoms, from 2 to 6 carbon atoms, or 2 carbon atoms), either alone or in combination with other groups.

[0288] As used herein, the term "amino" represents -N(R N1 ) 2 where each R N1 is independently H, OH, NO 2 , N(R N2 ) 2 , SO 2 OR N2 , SO 2 R N2 , SOR N2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and each of these listed R N1 groups may optionally be substituted, or two R N1 s combine to form alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino group of the present invention may be an unsubstituted amino (i.e., -NH 2 ) or a substituted amino (i.e., -N(R N1 ) 2 ).

[0289] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. When polycyclic, the aryl group contains 2 or 3 rings. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0290] As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups include those having 7 to 30 carbons (e.g., C 1 ~C 6 alkyl C 6 ~C 10 aryl, C 1 ~C 10 alkyl C 6 ~C 10 aryl, or C 1 ~C 20 alkyl C 6 ~C 10 aryl, etc., containing 7 to 16 or 7 to 20 carbons). In some embodiments, alkyl and aryl are each further substituted with 1, 2, 3, or 4 substituents as permitted by valency, as defined herein for each group.

[0291] As used herein, the term "azido" refers to -N 3 group.

[0292] As used herein, the term "bridged polycycloalkyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges. The bridged polycycloalkyl group may be unsubstituted or substituted as defined herein for cycloalkyl.

[0293] As used herein, the term "cyano" refers to -CN group.

[0294] As used herein, the term "carbocyclic" refers to a non-aromatic C where the ring is formed by carbon atoms 3 ~C 12 monocyclic, bicyclic or tricyclic structure. The carbocyclic structure includes cycloalkyl groups and unsaturated carbocyclic groups.

[0295] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent monocyclic, bicyclic, or tricyclic group of 3 to 10, preferably 3 to 6 carbon atoms. The cycloalkyl group may be fully saturated or contain one or more double or triple bonds provided that the ring is not aromatic. This term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. As used herein, the term "CH 2 -cycloalkyl" refers to a cycloalkyl-CH 2 - group (e.g., cyclopropylmethyl and cyclobutylmethyl).

[0296] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0297] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, wherein one or more of the constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy", which, as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkylene is a divalent heteroalkyl group. As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more of the constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group is further substituted with 1, 2, 3, or 4 substituents, as permitted by valence, as described herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy", which, as used herein, refers to alkenyl-O-. Heteroalkenylene is a divalent heteroalkenyl group. As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein, wherein one or more of the constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group is further substituted with 1, 2, 3, or 4 substituents, as permitted by valence, as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy", which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0298] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic group of 5 to 12 atoms having at least one aromatic ring and containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0299] As used herein, the term "heteroarylalkyl" represents an alkyl group substituted with a heteroaryl group. An unsubstituted heteroarylalkyl group contains 7 to 30 carbons (e.g., C 1 ~C 6 alkyl C 2 ~C 9 heteroaryl, C 1 ~C 10 alkyl C 2 ~C 9 heteroaryl, or C 1 ~C 20 alkyl C 2 ~C 9 heteroaryl, etc., containing 7 to 16 or 7 to 20 carbons). In some embodiments, the alkyl and heteroaryl are each further substituted with 1, 2, 3, or 4 substituents as permitted by the valency for each group as defined herein.

[0300] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or tricyclic group of 3 to 12 atoms having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and the ring is not aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0301] As used herein, the term "heterocyclylalkyl" represents an alkyl group substituted with a heterocyclyl group. An unsubstituted heterocyclylalkyl group contains 7 to 30 carbons (e.g., C 1 ~C 6 alkyl C 2 ~C 9 heterocyclyl, C 1 ~C 10 alkyl C 2 ~C 9 heterocyclyl, or C 1 ~C 20 alkyl C 2 ~C 9 heterocyclyl, etc., containing 7 to 16 or 7 to 20 carbons). In some embodiments, the alkyl and heterocyclyl are each further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0302] As used herein, the term "hydroxyalkyl" represents an alkyl group substituted with an -OH group.

[0303] As used herein, the term "hydroxyl" represents an -OH group.

[0304] As used herein, the term "N-protecting group" represents a group intended to protect an amino group from unwanted reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).The N-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D,L, or D,L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-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, 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).

[0305] As used herein, the term "nitro" refers to the -NO 2 group.

[0306] As used herein, the term "oxo" refers to a divalent oxygen atom (e.g., the structure of oxo can be shown as =O). For example, a carbonyl group is a carbon substituted with oxo (e.g., alkyl carbon, alkenyl carbon, alkynyl carbon, heteroalkyl carbon, heteroalkenyl carbon, heteroalkynyl carbon, carbocyclic carbon, etc.). Alternatively, sulfur may be substituted with one or two oxo groups (e.g., -SO- or -SO 2 -) in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclic group.

[0307] As used herein, the term "thiol" refers to the -SH group.

[0308] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclic groups may be substituted or unsubstituted. When substituted, unless otherwise specified, there are 1, 2, 3, 4, or 5 substituents where the valence allows. The 1 to 5 substituents are each independently acyl, alkyl (e.g., unsubstituted and substituted, the substituents including any groups described herein, e.g., aryl, halo, hydroxy), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyclic (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., unsubstituted and substituted methoxy, ethoxy, or thioalkoxy), heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclic, amino (e.g., NH 2 or monoalkylamino or dialkylamino), azide, cyano, nitro, thiol, and oxo. Each of the substituents is unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl (e.g., substituted and unsubstituted phenyl), carbocyclic (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroaryl, heterocyclic, amino (e.g., NH 2 or mono- or dialkylamino), azide, cyano, nitro, thiol, and oxo. Each of the substituents is unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, the substituents are themselves unsubstituted.

[0309] The compounds of the present invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, for example, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or by asymmetric chromatography (chromatography using a chiral adsorbent or eluent). That is, the specific disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly a pair of stereoisomers that cannot be superimposed on their mirror images because they contain an asymmetrically substituted carbon atom that functions as a chiral center. An enantiomer means one of a pair of molecules that are mirror images of each other and cannot be superimposed. Diastereomers are most commonly stereoisomers that are not related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomers from a racemate using one or more well-known techniques and methods such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating 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 does not exhibit optical activity. That is, they do not rotate the plane of polarization. "Geometric isomers" means isomers in which the orientation of the substituted atoms is different in relation to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of a carbon-carbon double bond can be in the E (substituents are on the opposite side of the carbon-carbon double bond) configuration or in the Z (substituents are oriented on the same side) configuration. "R", "S", "S * ", "R *", "E", "Z", "cis", and "trans" indicate the configuration with respect to the core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from restricted rotation around a single bond where the steric strain barrier to rotation is high enough to allow isolation of conformational isomers. The compounds of the present invention can be prepared as individual isomers by enantioselective synthesis or by separation from a mixture of isomers. Conventional separation techniques include forming salts of the free bases of each isomer of an isomer pair using an optically active acid (subsequently followed by fractional crystallization and regeneration of the free base), forming salts of the acid forms of each isomer of an isomer pair using an optically active amine (subsequently followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each of the isomers of an isomer pair using an optically pure acid, amine, or alcohol (subsequently followed by chromatographic separation and removal of the chiral auxiliary), or separating a mixture of isomers of either the starting material or the final product using various well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or indicated by the structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to other stereoisomers. When a single enantiomer is named or indicated by the structure, the indicated or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure. When a single diastereomer is named or indicated by the structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure. The percent optical purity is the ratio of the weight of the enantiomer or the weight of the enantiomer and the weight of its optical isomer. The diastereomeric purity by weight is the ratio of the weight of one diastereomer or the weight of all diastereomers. When the stereochemistry of a disclosed compound is named or indicated by the structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to other stereoisomers.If a single enantiomer is named or indicated by structure, the indicated or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction. If a single diastereomer is named or indicated by structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction. The purity percentage by mole fraction is the ratio of the mole of the enantiomer, or the mole of the enantiomer and the mole of its optical isomer. Similarly, the purity percentage by mole fraction is the ratio of the mole of the diastereomer, or the mole of the diastereomer and the mole of its isomer. If the 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 the enantiomer of the compound without the corresponding optical isomer, the racemic mixture of the compound, the mixture of the compound, or the mixture in which one enantiomer is enriched relative to the corresponding optical isomer. If the 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 the diastereomer without other diastereomers, some diastereomers without other diastereomer pairs, the mixture of diastereomers, the mixture of diastereomer pairs, the mixture of diastereomers in which one diastereomer is enriched relative to the other diastereomer, or the mixture of diastereomers in which one or more diastereomers are enriched relative to the other diastereomers. The present invention encompasses all of these forms.

[0310] The compounds of the present disclosure also include all isotopes of atoms present in the intermediate or final compounds. "Isotope" refers to atoms having the same atomic number but different mass numbers, which result from different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0311] Unless otherwise specified, the structures shown in this specification also mean that they include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the 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 I and other hydrogen isotopes, 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 C-labeled ones) may be useful in compound or substrate tissue distribution assays. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes may be useful due to the ease of their preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2 H) may result in certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced required dose). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C or 14 C enriched carbon. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. The preparation of isotope-labeled compounds is known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by substituting an isotope-labeled reagent for a non-isotope-labeled reagent according to procedures similar to those disclosed for the compounds of the invention described herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure. Other suitable methods and materials known in the art can also be used. Those materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0312] Definition In this application, unless the context clearly indicates otherwise: (i) the term "a" can be understood to mean "at least one"; (ii) the term "or" can be understood to mean "and / or"; (iii) the terms "comprising" and "including" can be understood to include the listed elements or steps, whether presented alone or together with one or more additional elements or steps.

[0313] As used herein, the terms "about" and "approximately" refer to values within 10% of the value being described. For example, the term "about 5 nM" refers to the range of 4.5 to 5.5 nM.

[0314] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route. For example, in some embodiments, administration is by bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by tracheal instillation), transdermal, vaginal, and intravitreal.

[0315] As used herein, the term "BAF complex" refers to a BRG1- or hBRM-associated factor complex in human cells.

[0316] As used herein, the term "BAF complex-related disorder" refers to a disorder caused or affected by the level of activity of the BAF complex.

[0317] As used herein, the term "loss-of-function mutation of BRG1" refers to a mutation in BRG1 that results in a protein having a reduced activity (e.g., a reduction of at least 1% of BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction of BRG1 activity). Exemplary loss-of-function mutations of BRG1 include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0318] As used herein, the term "loss-of-function disorder of BRG1" refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., a reduction of at least 1% of BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction of BRG1 activity).

[0319] The term "cancer" refers to a condition caused by the proliferation of malignant tumor cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0320] As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dosage and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of two or more agents may be simultaneous or parallel, and the agents may be co-formulated. In some embodiments, two or more agents are not co-formulated and are administered in a sequential manner as part of the prescribed regimen. In some embodiments, the administration of two or more agents or combined treatments is such that the reduction of symptoms, or other parameters associated with the disorder, is greater than that observed with one agent or treatment delivered alone or in the absence of the other. The effects of the two treatments can be partially additive, fully additive, or supra-additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent can be effected by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the combination may be administered by intravenous injection, while the second therapeutic agent of the combination may be administered orally.

[0321] To "determine the level of" a protein or RNA means to detect the protein or RNA by a method known in the art, either directly or indirectly. "Determining directly" 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). "Determining indirectly" refers to receiving a physical entity or value from another entity or source (e.g., a third-party laboratory that has 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, immunohistochemical analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC) mass spectrometry, microsite cytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on the properties of the protein, including, but not limited to, enzyme activity or interaction with other protein partners. Methods for measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0322] As used herein, "reducing the activity of the BAF complex" means reducing the level of activity associated with the BAF complex or associated downstream effects. Non-limiting examples of reducing the activity of the BAF complex include activation of Sox2. The activity level of the BAF complex can be measured using any method known in the art, such as the method described in Kadoch et al, Cell 2013:153-85(71), which is incorporated herein by reference.

[0323] As used herein, the term "degrader" refers to a small molecule compound that includes a degrading moiety, and the compound interacts with a protein (e.g., BRG1 and / or BRM) in a manner that results in degradation of the protein (e.g., binding of the compound results in at least a 5% reduction in the level of the protein in a cell or subject).

[0324] As used herein, the term "degrading moiety" refers to a moiety that, when bound, results in degradation of a protein (e.g., BRG1 and / or BRM). In one example, this moiety binds to a protease or ubiquitin ligase that metabolizes the protein (e.g., BRG1 and / or BRM).

[0325] "Modulating the activity of the BAF complex" as used herein means changing the level of activity associated with the BAF complex (e.g., GBAF) or associated downstream effects. The activity level of the BAF complex can be measured using any method known in the art, such as the method described in Kadoch et al, Cell 153:71-85(2013), which is incorporated herein by reference.

[0326] "Reducing the activity of BRG1 and / or BRM" means decreasing the level of the activity associated with BRG1 and / or BRM or the associated downstream effects. Non-limiting examples of inhibiting the activity of BRG1 and / or BRM include decreasing the level of the BAF complex in cells. The activity level of BRG1 and / or BRM can be measured using any method known in the art. In some embodiments, the agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrader.

[0327] "Reducing the level of BRG1 and / or BRM" means decreasing the level of BRG1 and / or BRM in a cell or subject. The level of BRG1 and / or BRM can be measured using any method known in the art.

[0328] "Level" means the level of a protein or mRNA encoding a protein, compared to a reference substance. The reference substance can be any useful reference substance, as defined herein. A "decreased level" or "increased level" of a protein means a decrease or increase in the protein level compared to the reference substance (e.g., a decrease or increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more), a decrease or increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200% compared to the reference substance, a decrease or increase of less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less, or an increase of about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more. The level of a protein may be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein or mRNA in a sample.

[0329] As used herein, the term "inhibiting BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition can be determined using methods known in the art, such as a BRM ATPase assay, a Nano DSF assay, or a BRM luciferase cell assay.

[0330] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein, formulated with pharmaceutically acceptable excipients and suitable for administration to mammals, such as humans. Typically, pharmaceutical compositions are manufactured or sold under the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of mammalian diseases. Pharmaceutical compositions can be formulated, for example, in unit dosage forms (such as tablets, capsules, caplets, gelcaps, or syrups) for oral administration, topically (such as as creams, gels, lotions, or ointments), intravenously (such as as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0331] As used herein, "pharmaceutically acceptable excipient" refers to any component other than the compounds described herein that has the property of being substantially non-toxic and non-inflammatory in a patient (such as a vehicle capable of suspending or dissolving an active compound). Excipients can include, for example, anti-adhesion agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavoring agents, fragrances, lubricants (flow promoters), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration.

[0332] As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of a compound, e.g., any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, and may include salts with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base moiety with a suitable organic acid.

[0333] The compounds of the present invention may have ionizable groups so as to be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts containing an inorganic or organic acid, or the salts may be prepared from inorganic or organic bases in the case of the acidic form of the compounds of the present invention. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as appropriate methods for preparing the salts, are well known in the art. The salts can be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0334] "Reference substance" means any useful reference substance used to compare protein or RNA levels. A reference substance can be any sample, standard, standard curve, or level used for comparison purposes. A reference substance can be a normal reference sample or reference standard or level. A "reference sample" can be, for example, a control, a predetermined negative control value such as a "normal control", or a previous sample taken from the same subject, a sample from a normal healthy subject such as normal cells or normal tissue, a sample from a subject without a 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 a purified protein or RNA of a known normal concentration (e.g., any of those described herein). "Reference standard or level" means a value or numerical value derived from a reference sample. A "normal control value" is a predetermined value indicating a non-diseased state, for example, a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("X or less"), or a low threshold ("X or more"). A subject having a measurement within the normal control value of a particular biomarker is typically said to be "within the normal range" of that biomarker. A normal reference standard or level can be a value or number derived from a normal subject without a disease or disorder (e.g., cancer), a subject treated with the compound of the present invention. In a preferred embodiment, the reference sample, standard, or level matches the sample subject sample according to at least one of the following criteria: age, weight, gender, disease stage, and overall health. A standard curve of the level of a purified protein or RNA within the normal reference range, for example, any of those described herein, can also be used as a reference.

[0335] As used herein, the term "subject" refers to any organism to which a composition according to the invention can be administered for, e.g., experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal, such as mammals like mice, rats, rabbits, non-human primates, and humans. A subject can be a human or an animal seeking, requiring, receiving, or likely to receive treatment in the future, or being treated by a professional trained in treating a particular disease or condition.

[0336] As used herein, the terms "treat", "treated", or "treatment" mean a therapeutic intervention or any means, the purpose of which is to slow down (reduce) an undesirable physiological state, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the degree of a state, disorder, or disease, stabilization (i.e., not worsening) of a state, disorder, or disease, delay or slowing in the onset of progression of a state, disorder, or disease, improvement or remission (partial or total) of a state, disorder, or disease state, improvement of at least one measurable physical parameter not necessarily distinguishable by the patient, or enhancement or improvement of a state, disorder, or disease. Treatment includes inducing a clinically significant response without undue levels of side effects. Treatment also includes extending the survival period compared to the predicted survival period in the absence of treatment. The compounds of the invention may also be used, for example, to "prophylactically treat" or "prevent" a disorder in a subject at increased risk of developing the disorder.

[0337] Details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will be apparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0338] The present disclosure features compounds useful for inhibiting BRG1 and optionally BRM. These compounds may be used, for example, to modulate the activity of the BAF complex for the treatment of BAF-related disorders such as cancer (e.g., loss-of-function disorders of BRG1). Exemplary compounds described herein include compounds having a structure according to Formula I, or a pharmaceutically acceptable salt thereof.

[0339] The compound of Formula I is as follows,

Chemical formula

[0340] In some embodiments, the compound has the structure of any one of Compounds 1 to 121 in Table 1, or a pharmaceutically acceptable salt thereof.

[0341] Other embodiments, and exemplary methods for the synthesis of these compounds, are described herein.

[0342] Pharmaceutical use The compounds described herein are useful in the methods of the present invention and, without being bound by theory, 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, disorders associated with loss-of-function mutations of BRG1.

[0343] One aspect of the present invention relates to a method of treating a disorder associated with a loss-of-function mutation 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 thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of (a) 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) decrease in tumor recurrence, (h) increase in the survival rate of the subject, and (i) increase in the progression-free survival period of the subject.

[0344] Treatment of cancer can result in a reduction in the size or volume of the tumor. For example, after treatment, the tumor size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) relative to its size prior to treatment. The tumor size may be measured by any reproducible means of measurement. For example, the tumor size may be measured as the diameter of the tumor.

[0345] Cancer treatment can further result in a decrease in the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) relative to the number before treatment. The number of tumors may be measured by any reproducible measurement means. For example, the number of tumors may be measured by counting tumors that are visible to the naked eye or visible at a specific magnification (e.g., 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold).

[0346] Cancer treatment can result in a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) relative to the number before treatment. The number of metastatic nodules may be measured by any reproducible measurement means. For example, the number of metastatic nodules may be measured by counting metastatic nodules that are visible to the naked eye or visible at a specific magnification (e.g., 2-fold, 10-fold, or 50-fold).

[0347] Treating cancer can result in an increase in the average survival time of a population of subjects treated according to the present invention compared to an untreated population of subjects. For example, the average survival time increases by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of the population may be measured by any reproducible means. The increase in the average survival time of the population may be measured, for example, by calculating the length of the average survival period after the start of treatment with the compound of the present invention for the population. The increase in the average survival time of the population may also be measured, for example, by calculating the length of the average survival period after the completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention for the population.

[0348] Furthermore, treating cancer can result in a decrease in the mortality rate of the treated population compared to the untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). The decrease in the mortality rate of the treated population can be measured by any reproducible means, such as calculating the average number of disease-related deaths per unit time after the start of treatment with a pharmaceutically acceptable salt of the present invention for the population. The decrease in the mortality rate of the population can 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 a pharmaceutically acceptable salt of the present invention for the population.

[0349] 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, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, and penile cancer.

[0350] Combination formulations and their use The compounds of the present invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any cancer described herein.

[0351] Combination therapy The compounds of the present invention can be used alone, or in combination with additional therapeutic agents, such as other agents for treating cancer or related conditions, or in combination with other types of treatment for treating cancer. In combination therapies, the dosage of one or more therapeutic compounds may be reduced from the standard dosage when administered alone. For example, the dosage may be determined empirically from drug combinations and permutations, or may be estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds when combined should be one that provides a therapeutic effect.

[0352] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful for the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthraquinone-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, metadopa, ureidopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (especially, bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; calicheamicin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide, uracil mustard;Nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994))); dynemicin including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore and related pigment protein enediyne antibiotic chromophore), aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine;Pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demeclocycline; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichlorotriethylamine; trichothecenes (especially, T-2 toxin, verrucarin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa;Taxoids, such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), Abraxane® albumin-engineered nanoparticle formulation of paclitaxel without Cremophor® (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinol; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; Novantrone®; teniposide; edatrexate; daunomycin; aminopterin; Xeloda®; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. In the cocktails administered in combination with the first therapeutic agent described herein, two or more chemotherapeutic agents can be used. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.;

[0353] In some embodiments, the second therapeutic agent is a therapeutic agent that 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 like bevacizumab (Avastin®). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof). Such agents include rituxan (rituximab), zenapax (daclizumab), simulect (basiliximab); synagis (palivizumab); remicade (infliximab); herceptin (trastuzumab); mylotarg (gemtuzumab ozogamicin); campath (alemtuzumab); zevalin (ibritumomab tiuxetan); humira (adalimumab); xolair (omalizumab); bexxar (tositumomab-I-131); raptiva (efalizumab); erbitux (cetuximab); avastin (bevacizumab); tysabri (natalizumab); actemra (tocilizumab); victibix (panitumumab); lucentis (ranibizumab); soliris (eculizumab); simdria (certolizumab pegol); simponi (golimumab); ilaris (canakinumab); stelara (ustekinumab); arzerra (ofatumumab); prolia (denosumab); numax (motavizumab); ABThrax (raxibacumab); benlysta (belimumab); yervoy (ipilimumab); adcetris (brentuximab vedotin); perjeta (pertuzumab); kadcyla (ado-trastuzumab emtansine); and gaziva (obinutuzumab). Antibody-drug conjugates are also included.

[0354] The second agent may be a therapeutic agent that is a non-drug treatment. For example, the second therapeutic agent is radiotherapy, cryotherapy, thermotherapy, and / or surgical resection of tumor tissue.

[0355] The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®; pembrolizumab / Keytruda®; pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.

[0356] In any of the embodiments of the combinations described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either 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 - 7, 1 - 14, 1 - 21, or 1 - 30 days before or after the second therapeutic agent.

[0357] Pharmaceutical composition The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biologically compatible form suitable for in vivo administration. Thus, in one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention mixed with a suitable diluent, carrier, or excipient.

[0358] The compounds of the present invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the present invention. According to the methods of the present invention, as will be understood by those skilled in the art, the described compounds, or salts, solvates, or prodrugs thereof, may be administered to a patient in various forms depending on the selected route of administration. The compounds of the present invention may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, trans-epithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period.

[0359] The compounds of the present invention can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or encapsulated in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the compounds of the present invention may be incorporated with excipients and used in the form of digestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, and in oils. These preparations may contain a preservative to prevent the growth of microorganisms under normal storage and use conditions. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003, 20th ed.) and The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it can be easily administered via a 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 usually provided in a sterile form in a sealed container, in the form of a cartridge or refill, for use with a nebulizer, in single or multiple dose amounts. Alternatively, the sealed container may be a single dispensing device such as a single-dose nasal inhaler or aerosol dispenser fitted with a metering valve, which is intended for disposal after use.When the dosage form includes an aerosol dispenser, it contains a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage form can 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, for example, into a tumor as an intratumoral injection. Intratumoral injection is a direct injection into the tumor blood vessels and is particularly contemplated for individual solid accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein can be advantageously contacted, for example, by administering an injection or multiple injections into the tumor at approximately 1 cm intervals. In the case of surgical intervention, the present invention can be used preoperatively, such as to subject inoperable tumors to resection. Continuous administration can also be applied, where appropriate, for example, by implanting a catheter into the tumor or tumor blood vessels.

[0360] The compounds of the present invention can be administered to animals, such as humans, alone or in combination with a pharmaceutically acceptable carrier, as described herein, and the ratio is determined by the solubility and chemical nature of the compound, the selected route of administration, and standard pharmaceutical practice.

[0361] Dosage The dosage of the compound of the present invention and / or the composition containing the compound of the present invention can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration; the age, health, and weight of the recipient, the nature and degree of the symptoms, the frequency of treatment, and if any, the type of co-treatment, and the clearance rate of the compound in the animal being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention may first be administered at a suitable dosage, and this amount may be adjusted as necessary according to the clinical response. Generally, satisfactory results can be obtained when the compound of the present invention is administered to humans at a daily dosage of, for example, 0.05 mg to 3000 mg (measured in solid form). The dosage range includes, for example, 10 to 1000 mg (for example, 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.

[0362] Alternatively, the dosage can be calculated using the patient's weight. For example, the dosage of the compound or its pharmaceutical composition administered to the patient may range from 0.1 to 100 mg / kg (for example, 0.25 to 25 mg / kg). In exemplary and non-limiting embodiments, the dosage may range from 0.5 to 5.0 mg / kg (for example, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg) or from 5.0 to 20 mg / kg (for example, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg).

Example

[0363] The following abbreviations are used throughout the following examples.

[0364]

Table 2-1

[0365] [Table 2-2]

[0366] Example 1. Preparation of compounds Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1). [Chem.]

[0367] Step 1: Preparation of 2-(3-bromoisoxazol-5-yl)acetic acid. [Chem.] To a stirred solution of 2-(3-bromo-1,2-oxazol-5-yl)ethan-1-ol (30 g, 156 mmol) in acetone (389 mL) was added dropwise Jones reagent (2 M in acetone, 156 mL, 312 mmol) at 0 °C. The resulting solution was stirred at 25 °C overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 2-(3-bromoisoxazol-5-yl)acetic acid as a brown solid (28 g, 86.5%). LCMS (ESI) m / z: [M+H] + = 206.08 and 208.08.

[0368] Step 2: Preparation of methyl 2-(3-bromoisoxazol-5-yl)acetate. [Chem.] A solution of 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 135 mmol) and concentrated H 2 SO 4 (3 mL, 72 mmol) in methanol (250 mL) was stirred at 70 °C for 2 h. The resulting solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO 4It was dried and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc / petroleum ether) to obtain methyl 2-(3-bromoisoxazol-5-yl)acetate (23.4 g, 79%) as a white solid. LCMS (ESI) m / z: + = 219.90 and 221.86.

[0369] Step 3: Preparation of methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate.

Chemical formula

[0370] Step 4: Preparation of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid.

Chemical formula

[0371] Step 5: Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid.

Chem.

[0372] Step 6: Preparation of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate.

Chem.

[0373] Step 7: Preparation of methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate.

Chem.

[0374] Step 8: Preparation of 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid.

Chemical Structure

[0375] Step 9: Preparation of (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl. [Chemistry] To a solution of (S)-1-(4-(4-methylthiazol-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 DCM (70 mL) at 0 °C, HATU (8.98 g, 23.5 mmol) was added, and then DIEA (16.4 mL, 98.0 mmol) was added dropwise. After stirring at room temperature for 16 h, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (MeOH:DCM) to give tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.33 g, 98%). LCMS (ESI) m / z: [M+H] + = 432.38.

[0376] Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride. [Chemistry] To (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl (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. 15 mL of MeOH was added to the mixture, and the mixture was stirred at room temperature for 2 h. 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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride, which was used in the next step without further purification.

[0377] Step 11: Preparation of (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2).

Chem.

[0378] Step 12: Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1).

Chem.

[0379] The following intermediates in Table 2 were prepared in a manner similar to the manner described in the preparation of Intermediate I-1, starting from methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate and the appropriate alkyl bromide.

[0380] [Table 3]

[0381] (2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-5) and (2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4) Preparation. [Chemical formula]

[0382] Step 1: Preparation of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate. [Chemical formula] To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (100.00 mg, 0.502 mmol, 1.00 equiv) in MeCN (0.50 mL) was added perfluorobutanesulfonyl fluoride (303.29 mg, 1.004 mmol, 2.00 equiv) and K 2 CO 3 (208.13 mg, 1.506 mmol, 3.00 equiv) 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 anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to obtain 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoic acid methyl ester (217 mg) as a white solid. LCMS (ESI) m / z: [M+H] + =482.

[0383] Step 2: Preparation of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate.

Chemical Structure

[0384] Step 3: Preparation of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid.

Chemical Structure

[0385] Step 4: Preparation of tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate.

Chemical formula

[0386] Step 5: Preparation of tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate. [Chemical formula] tert-Butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate (73 mg) was purified by SFC using the following conditions: column, CHIRAL ART Amylose-C NEO, 3 * 25 cm, 5 μm; mobile phase, MeOH. Thereby, the following were obtained: tert-Butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (37 mg, second peak). LCMS (ESI) m / z: [M+H] + = 667. tert-Butyl 4-(5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (34 mg, first peak). LCMS (ESI) m / z: [M+H] + = 667.

[0387] Step 6: Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-5) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4). [Chemical formula] HCl in 1,4-dioxane (1.50 mL, 26.276 mmol, 473.57 equivalents) was added to a stirred solution of tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (37.00 mg, 0.055 mmol, 1.00 equivalent) in DCM (1.50 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This gave I-5 (45 mg, crude product) as a yellow oil. LCMS (ESI) m / z: [M+H] + = 567.

[0388] I-4 was prepared according to the same protocol as I-5 and obtained as a yellow oil. LCMS (ESI) m / z: [M+H] + = 567.

[0389] The following intermediates in Table 3 were prepared in a manner similar to the manner described in the preparation of Intermediate I-5, starting from methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate and the appropriate amine.

[0390] [Table 4]

[0391] Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. [Chemical Structure]

[0392] Step 1: (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine. [Chemical Structure] To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (5 g, 35.078 mmol, 1 eq) and NH 2 OH . HCl (4.93 g, 70.945 mmol, 2.02 eq) in EtOH (250 mL) was added NaOAc (14.48 g, 176.512 mmol, 5.03 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with brine (500 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine (4.6 g, crude product) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + = 158.

[0393] Step 2: Preparation of (Z)-2-chloro-N-hydroxypyrimidine-5-carboximidoyl chloride. [Chemical Structure] A solution of (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine (4.6 g, 29.195 mmol, 1 equiv) and NCS (4.4 g, 32.951 mmol, 1.13 equiv) in DMF (150 mL) was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with water (3 × 300 mL), brine (1 × 300 mL), and the organic phase was dried over anhydrous Na 2 SO 4 4. The filtrate was concentrated under reduced pressure to afford (Z)-2-chloro-N-hydroxypyrimidine-5-carboximidoyl chloride (4.8 g, crude product) as a yellow solid. LCMS (ESI) m / z: [M+H] + = 192.

[0394] Step 3: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate.

Chemical Structure

[0395] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid. [Chem.] A solution of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (3 g, 11.828 mmol, 1 equiv) and NaOMe (1.92 g, 35.484 mmol, 3.00 equiv) in MeOH (50 mL) was stirred at room temperature for 1 hour under a dry nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (aqueous solution). The residue was dissolved in EtOAc (300 mL). The resulting mixture was washed with water (2 × 300 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.5 g, crude product) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + = 236.

[0396] Step 5: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate [Chem.] A solution of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.4 g, 10.204 mmol, 1 equiv) and (trimethylsilyl)diazomethane (2.33 g, 20.408 mmol, 2 equiv) in DCM (20 mL) and MeOH (5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (1.2 g, 45.77%) as a white solid. LCMS (ESI) m / z: [M+H] + = 250.

[0397] Step 6: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate. [Chem.] A solution of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (2.5 g, 10.031 mmol, 1 equiv) in THF (20 mL) was treated with t-BuOK (1.2 g, 10.694 mmol, 1.07 equiv) at 0 °C for 30 min under a dry nitrogen atmosphere, and then 2-iodopropane (1.5 g, 8.824 mmol, 0.88 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The mixture was acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate as a yellow oil (310 mg, 10.08%). LCMS (ESI) m / z: [M+H] + = 292.

[0398] Step 7: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate.

Chemical formula

[0399] Preparation of 2-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(2-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)acetic acid (I-10)

Chem.

[0400] (2S,4R)-4-Hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-Hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1) Preparation. 2-(6-(Azetidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5) Preparation

Chem.

[0401] Step 1: tert-Butyl 3-[2-(4-amino-6-chloropyridazin-3-yl)ethynyl]azetidine-1-carboxylate (Intermediate 2) Preparation [Chemical formula] 3,6-Dichloropyridazin-4-amine (2.87 g, 17.501 mmol, 1.00 equivalent) in ACN (45 mL), Et 3 N (8.85 g, 87.505 mmol, 5 equivalents) and tert-butyl 3-ethynylazetidine-1-carboxylate (3.49 g, 19.251 mmol, 1.1 equivalents) were added to a stirred solution of Pd(PPh 3 ) 2 Cl 2 (2.46 g, 3.500 mmol, 0.2 equivalent) and CuI (0.67 g, 3.500 mmol, 0.2 equivalent). The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. After concentration under reduced pressure, the residue was purified by flash chromatography under the following conditions. Column, silica gel; Mobile phase, EA in PE, 10% - 50% gradient in 25 minutes; Detector, UV254 nm. Thereby, Intermediate 2 (2.87 g, 53.11%) in the form of a yellowish-brown solid was obtained as a result. LCMS (ESI) m / z [M+H] + = 309.

[0402] Step 2: tert-Butyl 3-[3-chloro-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carboxylate (Intermediate 3) Preparation [Chemical formula] A solution of Intermediate 2 (2.82 g, 9.133 mmol, 1.00 equivalent) and K 2 CO 3 (3.79 g, 27.399 mmol, 3.00 equivalents) in DMF (20 mL) was stirred at 60 °C for 2 hours. The mixture was purified by reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; Mobile phase, CH 3 CN in water, 0% - 100% gradient in 25 minutes; Detector, UV254 nm. Thereby, Intermediate 3 (1.27 g, 45.10%) in the form of a yellow solid was obtained as a result. LCMS (ESI) m / z: [M+H] + = 309.

[0403] Step 3: tert-Butyl 3-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carboxylate (Intermediate 4) Preparation

Chem.

[0404] Step 4: 2-(6-(Azetidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5) Preparation

Chem.

[0405] (2S,4R)-4-Hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-Hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1) Preparation.

Chem.

[0406] The compounds in Table 4 were prepared using appropriate amines and aldehydes (or ketones) using a procedure similar to the procedure used above for the preparation of Compound 1.

[0407]

Table 5

[0408] (2S,4R)-4-Hydroxy-1-[(2R)-2-[3-(4-{3-[3-(2-Hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carbonyl}piperidin-1-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 6) Preparation.

Chem.

[0409] The compounds in Table 5 were prepared using appropriate amines and carboxylic acids using a procedure similar to the procedure used above for the preparation of Compound 6.

[0410]

Table 6

[0411] (2S,4R)-4-Hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8) Preparation.

[0412] (2-(6-(Azetidin-3-yl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenyl)phenol (Intermediate 7) Preparation

Chemical Structure

[0413] Step 1: 4-Bromo-6-chloro-3-iodopyridazine (Intermediate 2) Preparation

Chemical Structure

[0414] Step 2: tert-Butyl 3-((4-bromo-6-chloropyridazin-3-ylethynyl)azetidine-1-carboxylate (Intermediate 3) Preparation

Chemical formula

[0415] Step 3: tert-Butyl 3-((6-chloro-4-(methylamino)pyridazin-3-ylethynyl)azetidine-1-carboxylate (Intermediate 4) Preparation

Chemical formula

[0416] Step 4: tert-Butyl 3-(3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 5) Preparation

Chemical Structure

[0417] Step 5: tert-Butyl 3-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 6) Preparation

Chemical Structure

[0418] Step 6: 2-(6-(Azetidin-3-yl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenyl)phenol (Intermediate 7) Preparation

Chemical Structure

[0419] (2S,4R)-4-Hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8) Preparation.

Chemical Structure

[0420] The compounds in Table 6 were prepared using the appropriate amines and aldehydes (or ketones) using a procedure similar to the procedure used above for the preparation of compound 8.

[0421]

Table 7

[0422] (2S,4R)-4-Hydroxy-1-[(2R)-2-[3-(4-{3-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carbonyl}piperidin-1-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 13) Preparation. [Chem.] 1-{5-[(2R)-1-[(2S,4R)-4-Hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl}piperidine-4-carboxylic acid (20 mg, 0.033 mmol, 1 equiv) and Intermediate 7 (11.95 mg, 0.043 mmol, 1.3 equiv) in DMF (1 mL) were added to a stirred mixture of PyBOP (34.14 mg, 0.066 mmol, 2 equiv) and DIEA (12.72 mg, 0.099 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 1.5 h. The mixture was purified by preparative HPLC under the following conditions: column: SunFire Prep C18 8 OBD column, 19 * × 150 mm, 5 μm; mobile phase, water (0.1% NH 4 4HCO 3 ) and CH 3 3CN (from 13% CH 3 3CN to 47% maximum in 7 min). Thereby, Compound 13 as a white solid (15.3 mg, 52.04%) was obtained as a result. 11H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.21 - 8.14 (m, 1H), 7.50 - 7.41 (m, 2H), 7.40 - 7.29 (m, 3H), 7.14 (s, 1H), 7.03 - 6.95 (m, 2H), 6.16 (s, 1H), 5.11 (d, J = 3.8 Hz, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.74 (t, J = 8.6 Hz, 1H), 4.52 (t, J = 7.4 Hz, 1H), 4.43 - 4.33 (m, 2H), 4.31 - 4.26 (m, 2H), 4.15 - 4.07 (m, 1H), 3.77 (s, 3H), 3.75 - 3.63 (m, 3H), 3.58 (d, J = 9.9 Hz, 1H), 3.44 (d, J = 10.9 Hz, 1H), 2.82 (q, J = 11.0 Hz, 2H), 2.46 (d, J = 1.7 Hz, 3H), 2.24 - 2.20 (m, 2H), 2.04 - 1.97 (m, 1H), 1.86 - 1.64 (m, 3H), 1.56 (t, J = 12.8 Hz, 2H), 1.38 (d, J = 7.0 Hz, 3H), 1.00 - 0.92 (m, 3H), 0.82 (dd, J = 15.2, 6.7 Hz, 3H). LCMS (ESI) m / z: [[M+H]] + = 872.38。

[0423] The compounds in Table 7 were prepared using the appropriate amines and carboxylic acids using a procedure similar to the procedure used above for the preparation of Compound 13.

[0424]

Table 8

[0425] (2S,4R)-1-((R)-2-(3-(2-(3-(5-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14) Preparation.

Chem.

[0426] Step 1: Preparation of tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 2).

Chem.

[0427] Step 2: Preparation of tert-butyl 3-(5-(difluoromethyl)-3-(2-(methoxymethoxy)phenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 3).

Chemical Structure

[0428] Step 3: Preparation of 2-(6-(azetidin-3-yl)-5-(difluoromethyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 4). [Chem.] To a stirred solution of Intermediate 3 (24.00 mg, 0.052 mmol, 1 equiv) in DCM (1.00 mL) was added TFA (1.00 mL) 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 reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; mobile phase, MeOH in water, 0% - 100% gradient over 20 minutes; detector, UV 254 nm. As a result, yellow-green oily Intermediate 4 (12 mg, 71.33%) was obtained. LCMS (ESI) m / z: [M+H]+ = 317.3.

[0429] Step 4: Preparation of (2S,4R)-1-((R)-2-(3-(2-(3-(5-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14). [Chem.] To a stirred mixture of Intermediate 4 (10.00 mg, 0.032 mmol, 1 equiv) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (17.09 mg, 0.032 mmol, 1.0 equiv) in MeOH (1.00 mL) and DCM (1.00 mL) were added AcOH (catalyst) and NaBH 3 CN (5.96 mg, 0.096 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1.00 mL) and purified by preparative HPLC under the following conditions. Column: XBridge Shield RP18 OBD, 19 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3CN; Flow rate: 25 mL / min; Gradient: 38%B - 60%B in 7 minutes; Detector, UV254 / 220 nm. As a result, white solid compound 14 (6.9 mg, 23.72%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 8.98 (d, J = 1.7 Hz, 1H), 8.69 (s, 1H), 8.41 (d, J = 7.7 Hz, 1H), 8.19 - 8.00 (m, 2H), 7.47 - 7.42 (m, 2H), 7.40 - 7.31 (m, 3H), 7.24 (s, 1H), 7.06 - 6.97 (m, 2H), 6.08 (d, J = 10.5 Hz, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.91 (t, J = 7.1 Hz, 1H), 4.37 (t, J = 7.9 Hz, 1H), 4.28 (s, 1H), 4.22 - 4.11 (m, 2H), 4.05 (t, J = 7.4 Hz, 1H), 3.80 (t, J = 7.2 Hz, 2H), 3.74 - 3.60 (m, 2H), 3.49 - 3.37 (m, 3H), 2.84 (t, J = 5.3 Hz, 2H), 2.45 (d, J = 3.0 Hz, 3H), 2.26 - 2.19 (m, 1H), 2.03 (t, J = 9.9 Hz, 1H), 1.78 (ddd, J = 12.7, 7.9, 4.7 Hz, 1H), 1.45 - 1.36 (m, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.81 (dd, J = 13.8, 6.6 Hz, 3H). LCMS (ESI) m / z: [M + H]+ = 841.3.

[0430] (2S,4R)-4-Hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, formic acid (Compound 16) preparation.

Chemical Structure

[0431] Step 1: Preparation of tert-butyl 3-((6-chloro-4-(oxetan-3-ylamino)pyridazin-3-yl)ethynyl)azetidine-1-carboxylate (Intermediate 2)

Chemical Structure

[0432] Step 2: Preparation of tert-butyl 3-(3-chloro-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 3)

Chemical Structure

[0433] Step 3: Preparation of tert-butyl 3-(3-(2-hydroxyphenyl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 4)

Chemical Structure

[0434] Step 4: Preparation of 2-(6-(azetidin-3-yl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5)

Chemical formula

[0435] Step 5: (2S,4R)-4-Hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, formic acid (Compound 16) preparation.

Chemical formula

[0436] (2S,4R)-4-Hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 17) preparation. Preparation of 2-[6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 5)

Chem.

[0437] Step 1: Preparation of tert-butyl 4-[(4-amino-6-chloropyridazin-3-yl)ethynyl]piperidine-1-carboxylate (Intermediate 2)

Chem.

[0438] Step 2: Preparation of tert-butyl 4-{3-chloro-5H-pyrrolo[3,2-c]pyridazin-6-yl}piperidine-1-carboxylate (Intermediate 3) [Chemical formula] Intermediate 2 (1 g, 2.969 mmol, 1 equiv) and K 2 CO 3(2.05 g, 14.845 mmol, 5.0 equiv) of the mixture in DMF (5 mL) was stirred at 60 °C for 24 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and then 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 in water, gradient of 10% - 50% in 10 min; detector, UV 254 nm. As a result, intermediate 3 as a yellow solid (433 mg, 43.30%) was obtained. LCMS (ESI) m / z: [M + H]+ = 337.

[0439] Step 3: Preparation of tert-butyl 4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 4)

Chemical formula

[0440] Step 4: Preparation of 2-[6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 5)

Chem.

[0441] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 17).

Chem.

[0442] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 18) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 19).

Chem.

[0443] Step 1: Preparation of methyl 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 6)

Chem.

[0444] Step 2: Preparation of 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 7)

Chemical Structure

[0445] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 18) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 19).

Chemical Structure

[0446] Compound 18 in the form of an off-white solid (27.3 mg, 24.79%). 1H NMR (400 MHz, DMSO-d6) δ 14.49 (s, 1H), 12.07 (s, 1H), 8.92 (d, J = 56.8 Hz, 3H), 8.44 (d, J = 7.7 Hz, 1H), 8.23 (s, 1H), 8.05 (dd, J = 8.5, 1.7 Hz, 1H), 7.49 - 7.34 (m, 4H), 7.30 (td, J = 7.6, 1.6 Hz, 1H), 7.00 - 6.91 (m, 3H), 6.75 (d, J = 2.4 Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.91 (t, J = 9.7 Hz, 3H), 4.39 (t, J = 7.9 Hz, 1H), 4.30 (s, 1H), 3.85 (d, J = 9.8 Hz, 1H), 3.76 (dd, J = 10.4, 4.4 Hz, 1H), 3.51 (d, J = 10.6 Hz, 1H), 3.17 (t, J = 12.5 Hz, 3H), 2.45 (d, J = 6.6 Hz, 3H), 2.36 - 2.30 (m, 1H), 2.17 (d, J = 12.7 Hz, 2H), 2.04 (t, J = 10.6 Hz, 1H), 1.85 - 1.70 (m, 3H), 1.45 - 1.36 (m, 3H), 1.02 (dd, J = 6.7, 4.2 Hz, 3H), 0.85 (dd, J = 8.8, 5.9 Hz, 3H). LCMS (ESI) m / z: [M+H]+ = 853.35.

[0447] Compound 19 in the form of an off-white solid (13.5 mg, 12.52%). 1H NMR (400 MHz, DMSO-d6) δ 14.49 (d, J = 3.8 Hz, 1H), 12.06 (s, 1H), 8.98 (d, J = 18.7 Hz, 1H), 8.83 (d, J = 18.0 Hz, 2H), 8.29 (d, J = 7.9 Hz, 1H), 8.23 (s, 1H), 8.09 - 8.02 (m, 1H), 7.53 - 7.41 (m, 1H), 7.40 - 7.26 (m, 4H), 7.00 - 6.91 (m, 3H), 6.75 (s, 1H), 5.14 (d, J = 3.6 Hz, 1H), 5.05 - 4.81 (m, 3H), 4.45 (t, J = 7.7 Hz, 1H), 4.29 (s, 1H), 3.95 (d, J = 9.0 Hz, 1H), 3.64 - 3.58 (m, 2H), 3.17 (t, J = 12.4 Hz, 3H), 2.41 (s, 3H), 2.36 - 2.29 (m, 1H), 2.16 (d, J = 12.5 Hz, 2H), 2.11 - 2.02 (m, 1H), 1.78 (dd, J = 16.5, 8.9 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 6.6 Hz, 2H), 0.87 (t, J = 6.4 Hz, 4H). LCMS (ESI) m / z: [M+H] + = 853.35.

[0448] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 20). Preparation of 2-(5-methyl-6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 4).

Chem.

[0449] Step 1: Preparation of tert-butyl 4-(3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 2).

Chem.

[0450] Step 2: Preparation of tert-butyl 4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 3).

Chemical Structure

[0451] Step 3: Preparation of 2-(5-methyl-6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 4).

Chemical Structure

[0452] (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 20).

Chem.

[0453] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 21) and (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 22).

Chem.

[0454] Step 1: Preparation of methyl 2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 5).

Chem.

[0455] Step 2: Preparation of 2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 6).

Chemical Structure

[0456] Step 3: Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 21) and (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 22).

Chemical Structure

[0457] Compound 21 as a white solid (10.3 mg, 6.07%). 11H NMR (300 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.06 (s, 1H), 8.92 (d, J = 2.3 Hz, 2H), 8.68 (s, 1H), 8.51 - 8.41 (m, 1H), 8.23 - 8.07 (m, 1H), 7.55 - 7.32 (m, 5H), 6.92 (s, 2H), 6.85 (s, 1H), 5.19 (d, J = 3.6 Hz, 1H), 5.02 - 4.82 (m, 3H), 4.52 - 4.21 (m, 2H), 4.99 (s, 3H), 3.88 - 3.85 (m, 1H), 3.80 - 3.70 (m, 1H), 3.58 - 3.45 (m, 1H), 3.23 (d, J = 12.4 Hz, 2H), 2.53 (d, J = 5.0 Hz, 3H), 2.41 - 2.23 (m, 1H), 2.22 - 2.09 (m, 2H), 2.11 (t, J = 10.6 Hz, 1H), 1.93 - 1.65 (m, 3H), 1.56 - 1.53 (m, 1H), 1.41 - 1.35 (m, 3H), 1.15 (s, 1H), 1.09 (d, J = 6.4 Hz, 3H). LCMS (ESI) m / z: [M+H] + = 867.3。

[0458] Compound 22 in the form of a white solid (7.9 mg, 4.66%). 1 1H NMR (300 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.06 - 8.91 (m, 1H), 8.90 (d, J = 14.5 Hz, 2H), 8.69 (s, 1H), 8.38 - 8.06 (m, 2H), 7.59 - 7.45 (m, 1H), 7.43 - 7.28 (m, 4H), 7.06 - 6.95 (m, 2H), 6.85 (s, 1H), 5.21 (s, 1H), 5.03 - 4.80 (m, 3H), 4.7 - 3.48 (m, 1H), 4.37 (s, 1H), 4.03 (s, 4H), 3.70 - 3.60 (s, 1H), 3.57 - 3.50 (m, 1H) 3.23 - 3.15 (m, 2H), 2.42 - 2.39 (m, 3H), 2.23 - 2.01 (m, 3H), 1.91 - 1.65 (m, 3H), 1.52 - 1.48 (m, 1H), 1.45 - 1.41 (m, 1H), 1.41 - 1.31 (m, 2H), 1.28 - 1.21 (m, 1H), 1.09 (d, J = 6.6 Hz, 3H), 0.91 - 0.81 (m, 4H). LCMS (ESI) m / z: [M+H] + = 867.3。

[0459] (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 23) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 24).

Chem.

[0460] Step 1: Preparation of 3,6-dichloro-N-ethylpyridazin-4-amine (Intermediate 2).

Chem.

[0461] Step 2: Preparation of tert-butyl 4-([6-chloro-4-(ethylamino)pyridazin-3-yl]ethynyl)piperidine-1-carboxylate (Intermediate 3).

Chem.

[0462] Step 3: Preparation of tert-butyl 4-{3-chloro-5-ethylpyrrolo[3,2-c]pyridazin-6-yl}piperidine-1-carboxylate (Intermediate 4).

Chem.

[0463] Step 4: Preparation of tert-butyl 4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 5).

Chem.

[0464] Step 5: Preparation of 2-[5-ethyl-6-(piperidin-4-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 6).

Chem.

[0465] Step 6: Preparation of methyl 2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 7).

Chem.

[0466] Step 7: Preparation of 2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 8).

Chem.

[0467] Step 8: Preparation of (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 23) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 24).

Chem.

[0468] Compound 23 as a white solid (36.7 mg, 15.21%). 11H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 8.99 (s, 1H), 8.84 (s, 2H), 8.61 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.23 - 8.16 (m, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.32 (td, J = 7.6, 1.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 2H), 6.93 (s, 1H), 6.87 - 6.80 (m, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.99 - 4.90 (m, 3H), 4.50 - 4.35 (m, 3H), 4.31 (s, 1H), 3.85 (d, J = 9.7 Hz, 1H), 3.80 - 3.58 (m, 1H), 3.51 (d, J = 10.7 Hz, 1H), 3.31 - 3.27 (m, 1H), 3.20 (t, J = 12.7 Hz, 2H), 2.48 - 2.42 (m, 3H), 2.39 - 2.27 (m, 1H), 2.17 - 1.97 (m, 3H), 1.86 - 1.71 (m, 3H), 1.52 - 1.33 (m, 6H), 1.06 - 0.99 (m, 3H), 0.89 - 0.81 (m, 3H). LCMS (ESI) m / z: [M + H] + = 881.35。

[0469] White solid compound 24 (20.4 mg, 8.53%). 11H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.02 - 8.94 (m, 1H), 8.86 - 8.78 (m, 2H), 8.61 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.23 - 8.16 (m, 1H), 7.53 - 7.41 (m, 1H), 7.40 - 7.27 (m, 4H), 6.98 (t, J = 7.7 Hz, 2H), 6.93 (s, 1H), 6.86 - 6.81 (m, 1H), 5.14 (s, 1H), 4.96 - 4.82 (m, 3H), 4.49 - 4.41 (m, 3H), 4.30 (s, 1H), 3.95 (d, J = 9.0 Hz, 1H), 3.67 - 3.40 (m, 2H), 3.31 - 3.26 (m, 1H), 3.19 (t, J = 12.7 Hz, 2H), 2.47 (s, 1H), 2.41 (s, 2H), 2.40 - 2.32 (m, 1H), 2.14 - 2.02 (m, 3H), 2.00 - 1.71 (m, 3H), 1.52 - 1.29 (m, 6H), 1.02 (d, J = 6.6 Hz, 3H), 0.91 - 0.79 (m, 3H). LCMS (ESI) m / z: [[M+H]] + = 881.45.

[0470] (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-Cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 25) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-Cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 26) Preparation.

Chem.

[0471] Step 1: Preparation of 3,6-dichloro-N-cyclopropylpyridazin-4-amine (Intermediate 2).

Chem.

[0472] Step 2: Preparation of tert-butyl 4-([6-chloro-4-(cyclopropylamino)pyridazin-3-yl]ethynyl)piperidine-1-carboxylate (Intermediate 3).

Chemical formula

[0473] Step 3: Preparation of tert-butyl 4-{3-chloro-5-cyclopropylpyrrolo[3,2-c]pyridazin-6-yl}piperidine-1-carboxylate (Intermediate 4).

Chemical formula

[0474] Step 4: Preparation of tert-butyl 4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 5).

Chemical Structure

[0475] Step 5: Preparation of 2-[5-cyclopropyl-6-(piperidin-4-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 6).

Chemical Structure

[0476] Step 6: Preparation of methyl 2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 7).

Chem.

[0477] Step 7: Preparation of 2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 8).

Chem.

[0478] Step 8: Preparation of (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 25) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 26).

Chem.

[0479] Compound 25 as a white solid (52 mg, 40.69%). 11H NMR (400 MHz, DMSO-d6) δ 14.31 (s, 1H), 8.99 (s, 1H), 8.85 (d, J = 2.9 Hz, 2H), 8.44 (d, J = 7.7 Hz, 1H), 8.35 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.32 (td, J = 7.6, 1.5 Hz, 1H), 6.99 (t, J = 8.2 Hz, 2H), 6.93 (s, 1H), 6.82 (d, J = 3.3 Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H), 5.02 - 4.87 (m, 3H), 4.39 (t, J = 7.9 Hz, 1H), 4.31 (s, 1H), 3.85 (d, J = 9.7 Hz, 1H), 3.76 (dd, J = 10.3, 4.2 Hz, 1H), 3.59 - 3.42 (m, 3H), 3.18 (t, J = 12.7 Hz, 2H), 2.45 (d, J = 6.6 Hz, 3H), 2.40 - 2.29 (m, 1H), 2.21 (d, J = 12.7 Hz, 2H), 2.11 - 1.87 (m, 1H), 1.85 - 1.64 (m, 3H), 1.49 (d, J = 6.9 Hz, 5H), 1.17 (d, J = 3.6 Hz, 2H), 1.02 (t, J = 5.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). LCMS (ESI) m / z: [[M + H]] + = 893.30.

[0480] Compound 26 as a white solid (35.6 mg, 29.10%). 11H NMR (400 MHz, DMSO-d6) δ 14.31 (d, J = 4.1 Hz, 1H), 8.98 (d, J = 15.0 Hz, 1H), 8.83 (d, J = 19.3 Hz, 2H), 8.35 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.14 (dd, J = 8.1, 1.6 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.40 - 7.26 (m, 4H), 7.04 - 6.91 (m, 3H), 6.82 (d, J = 3.2 Hz, 1H), 5.15 (dd, J = 3.6, 1.4 Hz, 1H), 5.08 - 4.83 (m, 3H), 4.51 (dt, J = 51.6, 7.4 Hz, 1H), 4.29 (d, J = 7.5 Hz, 1H), 3.95 (d, J = 9.0 Hz, 1H), 3.67 - 3.41 (m, 4H), 3.17 (t, J = 12.7 Hz, 2H), 2.44 (d, J = 24.0 Hz, 3H), 2.39 - 2.31 (m, 1H), 2.21 (d, J = 12.7 Hz, 2H), 2.12 - 1.90 (m, 1H), 1.75 (ddt, J = 35.8, 14.3, 8.3 Hz, 3H), 1.49 (d, J = 6.9 Hz, 1H), 1.35 (dd, J = 6.9, 3.5 Hz, 4H), 1.18 (q, J = 3.7 Hz, 2H), 1.02 (d, J = 6.5 Hz, 2H), 0.92 - 0.77 (m, 4H). LCMS (ESI) m / z: [M+H] + = 893.30。

[0481] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 27). Preparation of 2-(5-methyl-6-(piperazin-1-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 8)

Chem.

[0482] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (Intermediate 2)

Chem.

[0483] Step 2: Preparation of 6-chloro-3-iodo-N-methylpyridazin-4-amine (Intermediate 3)

Chem.

[0484] Step 3: Preparation of tert-butyl 6-amino-3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazine-7-carboxylate (Intermediate 4)

Chem.

[0485] Step 4: Preparation of tert-butyl 6-bromo-3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazine-7-carboxylate (Intermediate 5)

Chem.

[0486] Step 5: Preparation of tert-butyl 3-chloro-5-methyl-6-(piperazin-1-yl)pyrrolo[3,2-c]pyridazine-7-carboxylate (Intermediate 6)

Chem.

[0487] Step 6: Preparation of 1-{3-chloro-5-methylpyrrolo[3,2-c]pyridazin-6-yl}piperazine (Intermediate 7)

Chemical Structure

[0488] Step 7: Preparation of 2-[5-methyl-6-(piperazin-1-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 8)

Chemical Structure

[0489] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 27).

Chem.

[0490] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 28) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 29).

Chem.

[0491] Step 1: Preparation of methyl 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 9)

Chem.

[0492] Step 2: Preparation of 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 10).

Chemical Structure

[0493] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 12).

Chemical Structure

[0494] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 28) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 29). [Chemical formula] Intermediate 12 (120 mg) was purified by chiral HPLC under the following conditions. Column: CHIRAL ART Amylose-SA, 2 * 25 cm, 5 μm; mobile phase A: MtBE (10 mM NH 3 -MeOH), mobile phase B: MeOH, flow rate: 20 mL / min; gradient: 20%B to 50%B in 16 minutes; detector, UV254 / 220 nm. As a result, the following were obtained.

[0495] Compound 28 as a white solid (35.40 mg, 29.50%). 11H NMR (400 MHz, DMSO-d6) δ 14.82 (s, 1H), 8.99 (s, 1H), 8.89 (d, J = 3.9 Hz, 2H), 8.44 (d, J = 10.4 Hz, 2H), 8.15 (dd, J = 8.9, 1.6 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.41 - 7.35 (m, 2H), 7.34 - 7.26 (m, 1H), 7.02 - 6.92 (m, 3H), 6.33 (s, 1H), 5.23 - 5.01 (m, 1H), 5.01 - 4.69 (m, 1H), 4.39 (t, J = 7.9 Hz, 1H), 3.35 - 3.25 (m, 1H), 4.08 (t, J = 5.1 Hz, 4H), 3.86 (d, J = 9.7 Hz, 1H), 3.80 (s, 3H), 3.79 - 3.72 (m, 1H), 3.69 - 3.47 (m, 1H), 3.32 - 3.26 (m, 4H), 2.45 (d, J = 6.6 Hz, 3H), 2.39 - 2.18 (m, 1H), 2.09 - 1.99 (m, 1H), 1.86 - 1.75 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H). LCMS (ESI) m / z: [M+H] + = 868.25。

[0496] Compound 29 in the form of a white solid (18.00 mg, 15.00%). 11H NMR (400 MHz, DMSO-d6) δ 14.83 (s, 1H), 9.01 - 8.94 (m, 1H), 8.89 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.18 - 8.12 (m, 1H), 7.52 - 7.41 (m, 1H), 7.40 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 7.01 - 6.93 (m, 3H), 6.33 (d, J = 0.8 Hz, 1H), 5.14 (d, J = 3.7 Hz, 1H), 4.98 - 4.83 (m, 1H), 4.45 (t, J = 7.7 Hz, 1H), 4.35 - 4.22 (m, 1H), 4.12 - 4.03 (m, 4H), 3.96 (d, J = 8.9 Hz, 1H), 3.80 (d, J = 1.7 Hz, 3H), 3.68 - 3.57 (m, 2H), 3.31 - 3.26 (m, 4H), 2.41 (s, 3H), 2.23 - 1.87 (m, 2H), 1.84 - 1.75 (m, 1H), 1.34 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.86 (t, J = 6.6 Hz, 3H). LCMS (ESI) m / z: [[M + H]] + = 868.25。

[0497] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-hydroxy-4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 30).

Chem.

[0498] Step 1: Preparation of tert-butyl 4-([6-chloro-4-(methylamino)pyridazin-3-yl]ethynyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 2)

Chem.

[0499] Step 2: Preparation of tert-butyl 4-{3-chloro-5-methylpyrrolo[3,2-c]pyridazin-6-yl}-4-hydroxypiperidine-1-carboxylate (Intermediate 3)

Chemical Structure

[0500] Step 3: Preparation of tert-butyl 4-hydroxy-4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 4)

Chemical Structure

[0501] Step 4: Preparation of 4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-4-ol (Intermediate 5)

Chem.

[0502] Step 5: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-hydroxy-4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 30)

Chem.

[0503] (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 31)

Chem.

[0504] Step 1: Preparation of tert-butyl 3-{3-chloropyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 2)

Chem.

[0505] Step 2: Preparation of tert-butyl 3-[3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidine-1-carboxylate (Intermediate 3)

Chemical formula

[0506] Step 3: Preparation of 2-[5-(azetidin-3-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 4). [ka] A solution of intermediate 3 (40 mg, 0.109 mmol, 1.00 equiv) and TFA (1 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: Column: Kinetex EVO C18, 21.2 * 150, 5 μm; Mobile phase A: Water (10 mmol / L NH 4 HCO 3 ), mobile phase B:CH 3 CN; flow rate: 25 mL / min; gradient: 14% B to 32% B in 6 min, then 32% B; detector, UV 254 / 220 nm. This resulted in intermediate 4 (16.5 mg, 56.36%) as a white solid. LCMS (ESI) m / z: [M+H] + =267.

[0507] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 31) [ka] (2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (40.60 mg, 0.075 mmol, 1.0 equiv.) and Intermediate 4 (20 mg, 0.075 mmol, 1 equiv.) in CH 3 A solution of OH (1 mL) and DCM (1 mL) was stirred at room temperature for 10 min. To the above mixture was added AcOH (catalyst) and NaBH 3 CN (14.16 mg, 0.225 mmol, 3.0 equiv.) was added. The resulting mixture was stirred at room temperature for an additional 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep C18 OBD, 19 * 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH 4 HCO 3 ), mobile phase B:CH3 CN; Flow rate: 25 mL / min; Gradient: 28%B - 57%B in 7 minutes; Detector, UV254 / 220nm. As a result, white solid compound 31 (19.6 mg, 31.84%) was obtained. 1 H NMR (300 MHz, DMSO-d6) δ 14.43 (s, 1H), 9.06 (s, 1H), 8.84 (s, 1H), 8.53 - 8.43 (m, 2H), 8.20 (d, J = 8.3 Hz, 1H), 7.56 - 7.35 (m, 5H), 7.14 (t, J = 3.9 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.17 (s, 1H), 5.51 (t, J = 6.6 Hz, 1H), 5.18 (d, J = 3.6 Hz, 1H), 4.98 (t, J = 7.2 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.36 (brs, 1H), 4.29 (t, J = 5.3 Hz, 2H), 3.95 (t, J = 7.4 Hz, 2H), 3.82 - 3.69 (m, 2H), 3.63 (t, J = 6.9 Hz, 2H), 3.57 - 3.48 (m, 1H), 3.04 (t, J = 5.4 Hz, 2H), 2.53 (d, J = 2.8 Hz, 3H), 2.37 - 2.24 (m, 1H), 2.17 - 2.04 (m, 1H), 1.92 - 1.78 (m, 1H), 1.48 (dd, J = 21.3, 7.0 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H). LCMS (ESI) m / z: + = 791.00.

[0508] (2S,4R)-1-((R)-2-(3-(2-(3-(7-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 32) Preparation

Chem.

[0509] Step 1: Preparation of tert-butyl 3-{7-bromo-3-chloropyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 2)

Chem.

[0510] Step 2: Preparation of tert-butyl 3-{3-chloro-7-ethenylpyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 3)

Chemical Structure

[0511] Step 3: Preparation of tert-butyl 3-{3-chloro-7-formylpyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 4)

Chemical Structure

[0512] Step 4: Preparation of tert-butyl 3-[3-chloro-7-(difluoromethyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidine-1-carboxylate (Intermediate 5) [Chemical Structure Diagram] A solution of intermediate 4 (142.0 mg, 0.422 mmol, 1.00 equiv) and DAST (1 mL, 15.22 equiv) in DCM (5 mL) was stirred at 0 °C for 3 h under a nitrogen atmosphere. The reaction was quenched with NH 4 Cl at 0 °C. The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (3 × 4 mL) and then dried over anhydrous Na 2 SO 4 . 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, 0% - 100% gradient in 10 min; detector, UV 254 nm. Thereby, intermediate 5 as a pale yellow solid (15.0 mg, 9.9%) was obtained as a result. LCMS (ESI) m / z: [M + H] + = 359.

[0513] Step 5: Preparation of tert-butyl 3-[7-(difluoromethyl)-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidine-1-carboxylate (Intermediate 6)

Chem.

[0514] Step 6: Preparation of 2-[5-(azetidin-3-yl)-7-(difluoromethyl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 7)

Chem.

[0515] Step 7: Preparation of (2S,4R)-1-((R)-2-(3-(2-(3-(7-(Difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 32)

Chem.

[0516] (2S,4R)-4-Hydroxy-1-[(2R)-2-(3-{2-[(1R,5S,6S)-6-[3-(2-hydroxyphenyl)-6-methylpyrrolo[3,2-c]pyridazin-5-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethoxy}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 33) Preparation

Chemical Structure

[0517] Step 1: Preparation of 4-bromo-6-chloro-3-[3-(trimethylsilyl)prop-1-yn-1-yl]pyridazine (Intermediate 2)

Chem.

[0518] Step 2: Preparation of tert-butyl (1R,5S,6S)-6-{3-chloro-6-methylpyrrolo[3,2-c]pyridazin-5-yl}-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3)

Chem.

[0519] Step 3: Preparation of tert-butyl (1R,5S,6S)-6-[3-(2-hydroxyphenyl)-6-methylpyrrolo[3,2-c]pyridazin-5-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 4)

Chem.

[0520] Step 4: Preparation of 2-{5-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-6-methylpyrrolo[3,2-c]pyridazin-3-yl}phenol (Intermediate 5)

Chem.

[0521] Step 5: Preparation of (2S,4R)-4-Hydroxy-1-[(2R)-2-(3-{2-[(1R,5S,6S)-6-[3-(2-hydroxyphenyl)-6-methylpyrrolo[3,2-c]pyridazin-5-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethoxy}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 33)

Chem.

[0522] (2S,4R)-1-((R)-2-(3-(2-((S)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34) and (2S,4R)-1-((S)-2-(3-(2-((S)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35) Preparation. [Chemical]

[0523] Step 1: Preparation of tert-butyl 3-(3-chloro-5-cyclopropyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 2) [Chemical] To a solution of Intermediate 1 (3 g, 14.702 mmol, 1 equiv) in toluene (20 mL), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (3.44 g, 17.642 mmol, 1.2 equiv), CuI (0.56 g, 2.940 mmol, 0.2 equiv), Pd(PPh3)2Cl2 (2.06 g, 2.940 mmol, 0.2 equiv), and TEA (4.46 g, 44.106 mmol, 3 equiv) were added under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL) and then washed with brine (2 × 200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash C18 chromatography with an elution gradient of 0% - 35% CH3CN (0.05% FA) in water to give Intermediate 2 as a yellow oil (2.18 g, 40.86%). LCMS (ESI) m / z: [M+H]+ = 363.

[0524] Step 2: Preparation of tert-butyl 3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 3) [Chemical] A solution of Intermediate 2 (2.5 g, 6.890 mmol, 1 equiv) and 2-hydroxyphenylboronic acid (1.43 g, 10.335 mmol, 1.5 equiv) in dioxane (16 mL) and H2O (4 mL) was added with XPhos Pd G3 (583.19 mg, 0.689 mmol, 0.1 equiv) and Cs2CO3 (4.49 g, 13.780 mmol, 2 equiv) under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL) and then washed with brine (2 × 200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash C18 chromatography with an elution gradient of 0% - 65% CH3CN (0.05% FA) in water to give Intermediate 3 as a yellow oil (1.5 g, 51.77%). LCMS (ESI) m / z: [M+H]+ = 421.

[0525] Step 3: Preparation of (S)-tert-butyl 3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 4a) and (R)-tert-butyl 3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 4b)

Chemical formula

[0526] Step 4: Preparation of (S)-2-(5-cyclopropyl-6-(pyrrolidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5)

Chemical formula

[0527] Step 5: Preparation of methyl 2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 6)

Chemical formula

[0528] Step 6: Preparation of 2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 7)

Chemical formula

[0529] Step 7: Preparation of (2S,4R)-1-(2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 8)

Chem.

[0530] Step 8: Preparation of (2S,4R)-1-((R)-2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34) and (2S,4R)-1-((S)-2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35)

Chem.

[0531] White solid compound 34 (57.9 mg, 17.36%). 1H NMR (400 MHz, DMSO-d6) δ 14.23 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.86 (s, 2H), 8.44 (d, J = 7.7 Hz, 1H), 8.37 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.41 - 7.29 (m, 3H), 7.00 (t, J = 7.9 Hz, 2H), 6.92 (d, J = 10.4 Hz, 2H), 5.12 (s, 1H), 4.94 (h, J = 6.9 Hz, 1H), 4.39 (t, J = 7.9 Hz, 1H), 4.29 (dd, J = 10.9, 6.9 Hz, 2H), 4.13 (p, J = 7.8 Hz, 1H), 3.94 - 3.81 (m, 2H), 3.74 (td, J = 11.8, 5.4 Hz, 2H), 3.54 - 3.44 (m, 2H), 2.69 - 2.58 (m, 2H), 2.52 (d, J = 6.9 Hz, 3H), 2.45 (d, J = 7.0 Hz, 2H), 2.10 - 1.99 (m, 1H), 1.80 (ddd, J = 12.8, 8.0, 4.7 Hz, 1H), 1.50 - 1.28 (m, 5H), 1.21 (p, J = 6.8, 6.2 Hz, 2H), 1.01 (d, J = 6.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z: [M + H]+ = 879.25.

[0532] White solid compound 35 (43.9 mg, 13.11%). 1H NMR (400 MHz, DMSO-d6) δ 14.23 (d, J = 6.2 Hz, 1H), 8.95 (s, 1H), 8.81 (s, 2H), 8.37 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.52 - 7.41 (m, 1H), 7.38 - 7.29 (m, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.04 - 6.96 (m, 2H), 6.92 - 6.86 (m, 2H), 5.14 (d, J = 3.6 Hz, 1H), 4.88 (t, J = 7.3 Hz, 1H), 4.64 (t, J = 7.7 Hz, 1H), 4.28 (t, J = 9.2 Hz, 3H), 3.94 (t, J = 7.8 Hz, 2H), 3.82 (d, J = 9.0 Hz, 2H), 3.75 (s, 2H), 2.65 (s, 2H), 2.52 (dt, J = 19.2, 10.3 Hz, 3H), 2.50 - 2.28 (m, 1H), 1.80 (dt, J = 12.7, 6.2 Hz, 1H), 1.49 (d, J = 6.9 Hz, 1H), 1.34 (dd, J = 7.3, 3.6 Hz, 4H), 1.21 (s, 2H), 1.12 (d, J = 6.6 Hz, 2H), 0.87 (t, J = 6.4 Hz, 4H). LCMS (ESI) m / z: [M + H]+ = 879.25.

[0533] (2S,4R)-1-((R)-2-(3-(2-((R)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36) and (2S,4R)-1-((R)-2-(3-(2-((S)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37) Preparation.

Chem.

[0534] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

Chem.

[0535] Step 2: Preparation of 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

Chemical Structure

[0536] Step 3: Preparation of (2S,4R)-1-(2-(3-(2-((R)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 4)

Chemical Structure

[0537] Step 4: Preparation of (2S,4R)-1-((R)-2-(3-(2-((R)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36) and (2S,4R)-1-((S)-2-(3-(2-((R)-3-(5-Cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37) [Chemical formula] Intermediate 4 (200 mg) was purified by chiral preparative HPLC under the following conditions. Column: CHIRAL ART Amylose-SA, 3 * 25 cm, 5 μm; mobile phase, MtBE (0.5% 2M NH3-MeOH) / EtOH (50% EtOH held for 52 min). As a result, the following were obtained.

[0538] White solid compound 36 (82.8 mg). 1H NMR (400 MHz, DMSO-d6) δ 14.24 (d, J = 3.7 Hz, 1H), 8.99 (d, J = 1.5 Hz, 1H), 8.86 (s, 2H), 8.44 (d, J = 7.7 Hz, 1H), 8.37 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.41 - 7.29 (m, 3H), 7.02 (t, J = 7.7 Hz, 2H), 7.00 - 6.89 (m, 2H), 5.12 (d, J = 3.6 Hz, 1H), 4.94 (q, J = 6.8 Hz, 1H), 4.39 (t, J = 7.9 Hz, 1H), 4.29 (t, J = 9.3 Hz, 2H), 4.13 (p, J = 7.8 Hz, 1H), 3.94 - 3.83 (m, 2H), 3.81 - 3.58 (m, 3H), 3.54 - 3.44 (m, 2H), 2.62 (s, 1H), 2.45 (d, J = 6.5 Hz, 3H), 2.38 - 2.26 (m, 2H), 2.10 - 1.99 (m, 1H), 1.80 (dd, J = 12.6, 4.7 Hz, 1H), 1.49 (d, J = 7.0 Hz, 3H), 1.36 (dd, J = 19.3, 7.2 Hz, 2H), 1.19 (d, J = 6.5 Hz, 2H), 1.02 (dd, J = 6.6, 4.0 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z: [M+H]+ = 879.25.

[0539] White compound 37 (47.3 mg). 1H NMR (400 MHz, DMSO-d6) δ 14.24 (d, J = 6.1 Hz, 1H), 8.98 (d, J = 16.9 Hz, 1H), 8.86 (s, 2H), 8.37 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.52 - 7.41 (m, 2H), 7.38 - 7.25 (m, 2H), 7.04 - 6.95 (m, 2H), 6.88 - 6.75 (m, 2H), 5.14 (d, J = 3.6 Hz, 2H), 5.08 - 4.93 (m, 1H), 4.88 (p, J = 7.0 Hz, 2H), 4.44 (t, J = 7.8 Hz, 1H), 4.32 - 4.23 (m, 1H), 4.14 (p, J = 7.5 Hz, 1H), 3.81 - 3.69 (m, 2H), 3.63 (s, 1H), 3.57 - 3.44 (m, 2H), 2.63 (s, 1H), 2.47 (s, 1H), 2.40 (s, 2H), 2.35 (d, J = 6.6 Hz, 2H), 2.12 - 2.02 (m, 1H), 1.85 - 1.73 (m, 1H), 1.49 (d, J = 7.0 Hz, 1H), 1.34 (d, J = 7.1 Hz, 4H), 1.20 (d, J = 9.0 Hz, 2H), 1.01 (d, J = 6.6 Hz, 2H), 0.91 - 0.78 (m, 4H). LCMS (ESI) m / z: [M + H]+ = 879.25.

[0540] The compounds in Table 8 were prepared using an appropriate amine using a procedure similar to the procedure used above for the preparation of compound 37.

[0541] [Table 9-1]

[0542] [Table 9-2]

[0543] [Table 9-3]

[0544]

Table 9-4

[0545]

Table 9-5

[0546]

Table 9-6

[0547] Preparation of Methyl 2-(3-(6-fluoro-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoate (I-11)

Chem.

[0548] Step 1: Preparation of (Z)-N-[(6-Fluoro-5-methylpyridin-3-yl)methylene]hydroxylamine (Intermediate 2)

Chem.

[0549] Step 2: Preparation of (E)-6-Fluoro-N-hydroxy-2-methylpyridine-3-carboximidoyl chloride (Intermediate 3)

Chem.

[0550] Step 3: Preparation of Methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]acetate (Intermediate 4)

Chemical Structure

[0551] Step 4: Preparation of Methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (I-11)

Chemical Structure

[0552] The following intermediates in Table 9 were prepared starting from the appropriate aldehyde in a manner similar to that described in the preparation of Intermediate I-11.

[0553]

Table 10

[0554] Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[(3S)-3-[5-Cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 110)

Chem.

[0555] Step 1: Preparation of methyl 2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2).

Chem.

[0556] Step 2: Preparation of 2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3). [Chem.] To a solution of Intermediate 2 (100 mg, 0.169 mmol, 1 equiv) in methanol (4 mL) were added LiOH (20.20 mg, 0.845 mmol, 5 equiv) and water (1 mL). The resulting solution was stirred at 25 °C for 2 h. The mixture was acidified to pH 6 with HCl (aqueous solution, 1 mol / L). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford Intermediate 3 as a yellow solid (140 mg, crude). LCMS (ESI) m / z: [M+H] + = 579.

[0557] Step 3: Preparation of (2S,4R)-1-[2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4). [Chem.] To a solution of Intermediate 3 (130 mg, 0.225 mmol, 1 equiv) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (74.46 mg, 0.225 mmol, 1 equiv) in DMF (2 mL) were added DIEA (145.18 mg, 1.125 mmol, 5 equiv) and PyBOP (233.82 mg, 0.450 mmol, 2 equiv). The resulting solution was stirred at 25 °C for 2 h. Without further work-up, the crude reaction solution was subjected to HPLC (column: XBridge Shield RP18 OBD column, 30 * × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2O), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 2% B - 2% B in 1 minute, 2% B - 44% B in 1.5 minutes, 44% B - 61% B in 8.5 minutes, 61% B; Wavelength: 254 / 220 nm; RT1 (min): 9.75, Number of Runs: 0, and purified to obtain Intermediate 4 as a yellow solid (65 mg, 32.43%). LCMS (ESI) m / z: + = 892.

[0558] Step 4: Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 110). [Chemical Structure] Intermediate 4 (65 mg) was purified by chiral HPLC under the following conditions (Column: XBridge Shield RP18 OBD column, 30 * × 150 mm, 5 μm; Mobile Phase A: water (10 mmol / L NH 4 4HCO 3 3 + 0.1% NH 3 4.H2O), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 2% B - 2% B in 1 minute, 2% B - 44% B in 1.5 minutes, 44% B - 61% B in 8.5 minutes, 61% B; Wavelength: 254 / 220 nm; RT1 (min): 9.75, Number of Runs: 0). Compound 110 - 001 as a white solid (the second peak) (21.8 mg, 10.10%) was obtained. 11H NMR (400 MHz, DMSO-d6) δ 14.24 (s, 1H), 8.98 (d, J = 2.0 Hz, 1H), 8.48 - 8.38 (m, 1H), 8.35 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.78 - 7.65 (m, 1H), 7.48 - 7.45 (m, 2H), 7.41 - 7.28 (m, 2H), 7.25 - 7.05 (m, 1H), 6.99 (t, J = 7.6 Hz, 2H), 6.91 (d, J = 5.8 Hz, 1H), 6.85 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.92 (q, J = 7.1 Hz, 1H), 4.39 (t, J = 7.9 Hz, 1H), 4.30 (s, 1H), 4.20 (dd, J = 10.2, 7.1 Hz, 1H), 4.02 (p, J = 7.6 Hz, 1H), 3.89 - 3.79 (m, 4H), 3.76 (dd, J = 10.6, 4.4 Hz, 1H), 3.53 - 3.43 (m, 2H), 2.59 - 2.52 (m, 1H), 2.48 - 2.41 (m, 6H), 2.39 - 2.21 (m, 2H), 2.09 - 1.99 (m, 1H), 1.95 - 1.80 (m, 1H), 1.44 (dd, J = 39.2, 7.0 Hz, 3H), 1.36 - 1.30 (m, 2H), 1.26 - 1.16 (m, 2H), 1.01 (dd, J = 6.6, 3.9 Hz, 3H), 0.85 (dd, J = 9.9, 6.7 Hz, 3H). LCMS (ESI) m / z: [M + H] + = 892.20。

[0559] The compounds in Table 10 were prepared using an appropriate amine using a procedure similar to the procedure used above for the preparation of Compound 110.

[0560]

Table 11

[0561] Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 116).

Chem.

[0562] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2). [Chemistry] To a stirred solution of Intermediate 1 (240 mg, 0.749 mmol, 1 equiv) in DMSO (1 mL), I-12 (443.03 mg, 1.498 mmol, 2 equiv) and DIEA (484.08 mg, 3.745 mmol, 5 equiv) were added at room temperature. The resulting mixture was stirred at 120 °C for 2 h. The desired product could be detected by LCMS. The crude product was purified by flash C18 chromatography, elution gradient H 2 O from 0 to 60% ACN to give Intermediate 2 as a yellow solid (133 mg, 30.63%). LCMS (ESI) m / z: [M+H] + = 580.

[0563] Step 2: Preparation of 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3). [Chemistry] To a solution of Methyl Intermediate 2 (128 mg, 0.221 mmol, 1 equiv) in MeOH (4 mL), H 2 O (1 mL) and LiOH (26.44 mg, 1.105 mmol, 5 equiv) were added and the resulting solution was stirred at 25 °C for 2 h. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with H 2 O (150 mL × 3), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 3 as a yellow solid (126 mg, crude). LCMS (ESI) m / z: [M+H] + = 566.

[0564] Step 3: Preparation of (2S,4R)-1-[2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4). [Chemistry] Intermediate 3 (126 mg, 0.223 mmol, 1 equiv) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (147.66 mg, 0.446 mmol, 2 equiv) in a stirred solution of DMF (2.8 mL) were added with PyBOP (231.85 mg, 0.446 mmol, 2 equiv) and DIEA (143.95 mg, 1.115 mmol, 5 equiv). The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The mixture was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 * × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B - 65% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 9.15) to give Intermediate 4 (66 mg, 33.71%) as a white solid. LCMS (ESI) m / z: [M+H] + = 879.

[0565] Step 4: Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 116).

Chemical Structure

[0566] Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 82).

Chem.

[0567] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

Chem.

[0568] Step 2: Preparation of 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

Chemical formula

[0569] Step 3: Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 4)

Chemical formula

[0570] Step 4: Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 82). [Chemical formula] Intermediate 4 (57 mg) was purified using chiral preparative HPLC under the following conditions. Column: CHIRAL ART Cellulose-SB, 2 *25 cm, 5 μm; Mobile phase A: MtBE (10 mM NH3-MeOH), Mobile phase B: MeOH--HPLC, Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 16 min; Wavelength: 264 / 244 nm; RT1 (min): 6.25, RT2 (min): 10.5, Sample solvent: MeOH:DCM = 2:1, Injection volume: 1 mL; As a result, white solid compound 82 (17.1 mg, 19.73%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 14.26 (s, 1H), 8.98 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.37 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 8.16 (dd, J = 8.0, 1.7 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.40 - 7.29 (m, 3H), 7.12 - 6.94 (m, 5H), 6.91 (d, J = 4.2 Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H), 5.06 - 4.86 (m, 1H), 4.39 (t, J = 7.9 Hz, 1H), 4.30 (s, 1H), 4.21 - 4.05 (m, 2H), 3.89 (d, J = 9.7 Hz, 1H), 3.85 - 3.71 (m, 2H), 3.73 - 3.58 (m, 2H), 3.55 - 3.44 (m, 2H), 2.70 - 2.57 (m, 1H), 2.45 (d, J = 8.4 Hz, 3H), 2.40 - 2.29 (m, 2H), 2.04 (t, J = 10.5 Hz, 1H), 1.86 - 1.70 (m, 1H), 1.57 - 1.28 (m, 5H), 1.27 - 1.15 (m, 2H), 1.02 (dd, J = 6.6, 2.7 Hz, 3H), 0.85 (t, J = 7.6 Hz, 3H). LCMS (ESI) m / z: [M + H]+ = 878.07.

[0571] The compounds in Table 11 were prepared using the appropriate amine using a procedure similar to the procedure used above for the preparation of compound 82.

[0572]

Table 12

[0573] Preparation of (2S,4R)-1-((R)-2-(3-(4-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyridin-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 91)

Chem.

[0574] Step 1: Preparation of methyl 2-(3-{4-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2) [Chemistry] To a stirred solution of I-14 (200.0 mg, 0.590 mmol, 1 equiv) and 2-{5-cyclopropyl-6-[(3R)-pyrrolidin-3-yl]pyrrolo[3,2-c]pyridazin-3-yl}phenol (188.9 mg, 0.590 mmol, 1 equiv) in 1,4-dioxane (5 mL), Cs 2 CO 3 (576.3 mg, 1.770 mmol, 3 equiv) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (24.0 mg, 0.029 mmol, 0.05 equiv) were added. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by reverse-phase flash chromatography under the following conditions. Column, C 18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient of 30% - 70% in 30 min; detector, UV 254 nm. Thereby, intermediate 2 as a yellow solid (210.0 mg, 61.5%) was obtained as a result. LCMS (ESI) m / z: [M+H] + = 579.

[0575] Step 2: Preparation of 2-(3-{4-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3) [Chemistry] To a stirred solution of intermediate 2 (210.0 mg, 0.363 mmol, 1 equiv) in THF (5 mL) and H 2 O (5 mL), LiOH (86.9 mg, 3.630 mmol, 10 equiv) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized to pH 7 with 1 N HCl and the precipitated solid was collected by filtration and washed with water (3 × 1 mL). Thereby, intermediate 3 as a yellow solid (180.0 mg, 10.54%) was obtained as a result. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H]+ = 565。

[0576] Step 3: Preparation of (2S,4R)-1-((R)-2-(3-(4-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyridin-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 4)

Chem.

[0577] Step 4: Preparation of (2S,4R)-1-((R)-2-(3-(4-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyridin-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 91)

Chem.

[0578] Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 105)

Chem.

[0579] Step 1: 3,6-Dichloro-N-cyclobutylpyridazin-4-amine (Intermediate 2)

Chem.

[0580] Step 2: Preparation of tert-butyl 6-{2-[6-chloro-4-(cyclobutylamino)pyridazin-3-yl]ethynyl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 3)

Chem.

[0581] Step 3: Preparation of tert-butyl 6-{3-chloro-5-cyclobutylpyrrolo[3,2-c]pyridazin-6-yl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 4)

Chem.

[0582] Step 4: Preparation of tert-butyl 6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 5)

Chemical formula

[0583] Step 5: Preparation of 2-(6-{2-azaspiro[3.3]heptan-6-yl}-5-cyclobutylpyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 6)

Chemical formula

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 In the formula,[[]]END]] ring system A is a 5- to 9-membered heterocyclyl or heteroaryl containing at least one N,[[]]END]] m is 0, 1, 2, or 3,[[]]END]] k is 0, 1, or 2,[[]]END]] Each R １ is, independently, halo, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ２ to C ９ heterocyclyl, optionally substituted C ３ to C ８ cycloalkyl, or optionally substituted CH ２ -C ３ to C ８ cycloalkyl, and each X is independently halo,[[]]END]] L is a linker,[[]]END]] B is a cleavable moiety, a compound, or a pharmaceutically acceptable salt thereof.[[]]END]]

2. The compound has the structure of formula I-A,[[]]END]] 【Chemical Formula 2】 wherein R ２ is H, C １ to C ６ alkyl optionally substituted, C ３ to C ８ cycloalkyl optionally substituted, C ２ to C ９ heterocyclyl, or a bond to -L-B, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

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

5. R ２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is H.

6. R ２ is C optionally substituted with １ -C ６ alkyl, a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. R ２ is optionally substituted C ３ to C ８ cycloalkyl, a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

8. R ２ is optionally substituted C ２ -C ９ heterocyclyl, a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

9. R ２ is H, CH ３ , 【Chemical Formula 5】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.[[]]END]]

10. R ２ is H, CH ３ , [Chemical Formula 6] The compound according to claim 9, or a pharmaceutically acceptable salt thereof.[[]]END]]

11. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-D:[[]]END]] 【Chemical Formula 7】

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein m is 1.[[]]END]]

13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein m is 2.[[]]END]]

14. R １ is optionally substituted C １ to C ６ alkyl, a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

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

16. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein m is 0.[[]]END]]

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein k is 0.[[]]END]]

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein k is 1.[[]]END]]

19. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein k is 2.[[]]END]]

20. The compound according to any one of claims 1 to 16 and 18 to 19, or a pharmaceutically acceptable salt thereof, wherein X is Cl or F.[[]]END]]

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-E, formula I-F, formula I-G, formula I-H, or formula I-I:[[]]END]] 【Chemical Formula 8】

22. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-J, formula I-K, formula I-L, formula I-M, or formula I-N:[[]]END]] 【Chemical Formula 9】

23. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula I-O, Formula I-P, Formula I-Q, Formula I-R, or Formula I-S: 【Chemical Formula 10】

24. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula I-T, Formula I-U, Formula I-V, or Formula I-W: 【Chemical 11】

25. The degradation moiety B has a structure of Formula A-1, 【Chemical 12】 wherein, Y １ is 【Chemical 13】 it is, R Ａ５ is H, optionally substituted C １ to C ６ alkyl, or optionally substituted C １ to C ６ heteroalkyl, and R Ａ６ is H or C optionally substituted with １ -C ６ -C alkyl, R Ａ７ is H or C optionally substituted with １ -C ６ -C alkyl, or R Ａ６ and R Ａ７ together with the carbon atom to which each is attached combine to form an optionally substituted C ３ -C ６ -C carbocyclic or an optionally substituted C ２ -C ５ -C heterocyclic, or R Ａ６ and R Ａ７ together with the said carbon atom to which each is attached combine to form an optionally substituted C ３ -C ６ -C carbocyclic or an optionally substituted C ２ -C ５ -C heterocyclic, and R Ａ８ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ａ１ 、R Ａ２ 、R Ａ３ 、and R Ａ４ each independently is H, A ２ 、halogen, optionally substituted C １ ~C ６ alkyl, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ２ ~C ９ heterocyclic, optionally substituted C ６ ~C １０ aryl, optionally substituted C ２ ~C ９ heteroaryl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ heteroalkenyl, optionally substituted --O--C ３ ~C ６ carbocyclic, hydroxyl, thiol, or optionally substituted amino, or R Ａ１ and R Ａ２ 、R Ａ２ and R Ａ３ 、and / or R Ａ３ and R Ａ４ combine together with the carbon atom to which each is attached, 【Chemical Formula 14】 forms, 【Chemical Formula 15】 is optionally substituted C ６ - C １０ aryl, optionally substituted C ３ - C １０ carbocyclic, optionally substituted C ２ - C ９ heteroaryl, or C ２ - C ９ heterocyclic, and any of them is optionally substituted with A ２ and, R Ａ１ , R Ａ２ , R Ａ３ , and R Ａ４ One of them is A ２ or 【Chemical 16】 is A ２ is replaced by, and A ２ is a bond between the cleavage moiety and the linker, the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has the following structure 【Chemical 17】

27. The degradation moiety is Formula C, 【Chemical Formula 18】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 19】 it is, R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, C optionally substituted １ ~C ６ alkyl, or C optionally substituted １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ ~C ６ alkyl, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ６ ~C １０ aryl, optionally substituted C １ ~C ６ alkyl C ３ ~C １０ carbocyclic, or optionally substituted C １ ~C ６ alkyl C ６ ~C １０ aryl, and R Ｂ４ is H, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is, independently, A ２ , halogen, optionally substituted C １ -C ６ -alkyl, optionally substituted C ２ -C ６ -alkynyl, optionally substituted C １ -C ６ -heteroalkyl, optionally substituted C ３ -C １０ -carbocyclyl, optionally substituted C ２ -C ９ -heterocyclyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C ２ -C ９ -heteroaryl, optionally substituted C ２ -C ６ -alkenyl, optionally substituted C ２ -C ６ -heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ each independently is H, halogen, optionally substituted C １ to C ６ alkyl, or optionally substituted C ６ to C １０ aryl, and R Ｂ９ is H or optionally substituted C １ to C ６ alkyl, R Ｂ１０ is H or F, A ２ is the bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one and only one of is A ２ A compound according to any one of claims 1 to 24, having the structure of formula C or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

28. The degradation moiety is Formula C, 【Chemical 20】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 21】 it is, R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, C optionally substituted with １ ~C ６ alkyl, or C optionally substituted with １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, C optionally substituted １ -C ６ alkyl, or C optionally substituted １ -C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is, independently, A ２ , halogen, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ２ -C ９ heterocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ heteroalkenyl, hydroxy, thiol, or optionally substituted amino, R Ｂ７ and R Ｂ８ each independently is H, halogen, optionally substituted C １ ~C ６ alkyl, or optionally substituted C ６ ~C １０ aryl, and R Ｂ９ is H or optionally substituted C １ -C ６ -alkyl, A ２ is a bond between the decomposition part and the linker, R Ｂ１ 、R Ｂ３ 、and R Ｂ６ Only one and only one of ２ is A, a compound according to any one of claims 1 to 24 having the structure of formula C or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.

29. The degradation moiety is [Chemical 22] The compound according to claim 27 or 28, or a pharmaceutically acceptable salt thereof.

30. The degradation moiety is 【Chemical 23】 The compound according to claim 27, or a pharmaceutically acceptable salt thereof.

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

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

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

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

35. The degradation moiety is Formula C5, 【Chemical Formula 28】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 29】 it is, R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, C optionally substituted with １ ~C ６ alkyl, or C optionally substituted with １ ~C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is independently A ２ , halogen, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclyl, optionally substituted C ２ to C ９ heterocyclyl, optionally substituted C ６ to C １０ aryl, optionally substituted C ２ to C ９ heteroaryl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ７ and R Ｂ８ each independently is H, halogen, optionally substituted C １ to C ６ alkyl, or optionally substituted C ６ to C １０ aryl, and R Ｂ９ is H or optionally substituted C １ ~C ６ alkyl, R Ｂ１１ is H, alcohol, boric acid, optionally substituted C １ ~C ６ alkyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ６ ~C １０ aryl, optionally substituted C １ ~C ６ alkyl C ３ ~C １０ carbocyclic, or optionally substituted C １ ~C ６ alkyl C ６ ~C １０ aryl, and A ２ is a bond between the decomposition part and the linker, R Ｂ１ 、 R Ｂ３ 、 and R Ｂ６ Only one and only one of is A ２ The compound according to any one of claims 1 to 24 having the structure of formula C5 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

36. The degradation moiety is 【Chemical Formula 30】 The compound according to claim 35, or a pharmaceutically acceptable salt thereof.

37. The degradation moiety is Formula D, 【Chemical 31】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 32】 it is, R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is, independently, A ２ , halogen, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted C ３ -C １０ carbocyclyl, optionally substituted C ２ -C ９ heterocyclyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heteroaryl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ９ is H or optionally substituted C １ -C ６ -alkyl, A ２ is a bond between the decomposition part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one and only one of which is A ２ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, having the structure of formula D or a pharmaceutically acceptable salt thereof.

38. The degradation moiety is 【Chemical 33】 The compound according to claim 37, or a pharmaceutically acceptable salt thereof.

39. The degradation moiety is 【Chemical 34】 【Chemical 35】 The compound according to claim 37, or a pharmaceutically acceptable salt thereof.

40. The degradation moiety is Formula Da, 【Chemical 36】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical 37】 it is, R Ｂ１ is H, A ２ , optionally substituted C １ to C ６ alkyl, or optionally substituted C １ to C ６ heteroalkyl, and R Ｂ２ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, optionally substituted C １ ~C ６ alkyl, optionally substituted C ３ ~C １０ carbocyclic, optionally substituted C ６ ~C １０ aryl, optionally substituted C １ ~C ６ alkyl C ３ ~C １０ carbocyclic, or optionally substituted C １ ~C ６ alkyl C ６ ~C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and X １ and X ２ each independently is C, N, or O, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ is independently A ２ , halogen, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ２ to C ９ heterocyclic, optionally substituted C ６ to C １０ aryl, optionally substituted C ２ to C ９ heteroaryl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino, R Ｂ９ is H or optionally substituted C １ -C ６ to C alkyl, A ２ is the bond between the decomposition part and the linker, R Ｂ１ 、 R Ｂ３ 、 and R Ｂ６ Only one and only one of is A ２ The compound according to any one of claims 1 to 24 having the structure of formula Da or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

41. The degradation moiety is 【Chemical Formula 38】 The compound according to claim 40, or a pharmaceutically acceptable salt thereof.

42. wherein the cleavage moiety is of formula E, 【Chemical 39】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 40】 and R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, C optionally substituted with １ -C ６ alkyl, or C optionally substituted with １ -C ６ heteroalkyl, and R Ｂ３ is A ２ optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ９ is H, optionally substituted C １ ~C ６ alkyl, optionally substituted C ３ ~C ６ alkynyl, optionally substituted C ３ ~C １０ carbocyclic, or optionally substituted C ２ ~C １０ heterocyclic, and B １０ is H, optionally substituted C １ to C ６ alkyl, optionally substituted C ３ to C ６ alkynyl, optionally substituted C ３ to C １０ carbocyclic, optionally substituted C ２ to C １０ heterocyclic, optionally substituted amino, or cyano, and A ２ is a bond between the decomposition part and the linker, R Ｂ１ , R Ｂ３ , and R Ｂ６ Only one and only one of is A ２ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, having the structure of formula E or a pharmaceutically acceptable salt thereof.

43. wherein the cleavage moiety is 【Chemical 41】 The compound according to claim 42, or a pharmaceutically acceptable salt thereof.

44. wherein the cleavage moiety is of formula F, 【Chemical Formula 42】 wherein, L ４ is -N(R Ｂ１ )(R Ｂ２ ), 【Chemical Formula 43】 and R Ｂ１ is H, A ２ , optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and R Ｂ２ is H, C optionally substituted with １ -C ６ alkyl, or C optionally substituted with １ -C ６ heteroalkyl, and R Ｂ３ is A ２ , optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ６ alkyl C ３ -C １０ carbocyclic, or optionally substituted C １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ４ is H, C optionally substituted with １ -C ６ alkyl, C optionally substituted with ３ -C １０ carbocyclic, C optionally substituted with ６ -C １０ aryl, C optionally substituted with １ -C ６ alkyl C ３ -C １０ carbocyclic, or C optionally substituted with １ -C ６ alkyl C ６ -C １０ aryl, and R Ｂ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ heteroalkyl, and A ２ is a bond between the decomposition part and the linker, R Ｂ１ or R Ｂ３ Only one of which is A ２ The compound according to any one of claims 1 to 24, having the structure of formula F or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.

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

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

47. wherein the linker is 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 has the structure of a pharmaceutically acceptable salt thereof, wherein, A １ is a bond between the linker and the ring system A, A ２ is a bond between the decomposition part and the linker, B １ 、B ２ 、B ３ 、and B ４ each of which is, independently, optionally substituted C １ -C ４ alkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ６ -C １０ arylC １～４ alkyl, optionally substituted C １ -C ４ heteroalkyl, optionally substituted C ３ -C １０ cycloalkyl, optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ２ -C １０ heterocyclic, optionally substituted C ２ -C ６ heteroaryl, optionally substituted C ６～１２ aryl, O, S, S(O) ２ , or NR Ｎ and Each R Ｎ is independently H, optionally substituted C １～４ alkyl, optionally substituted C ２～４ alkenyl, optionally substituted C ２～４ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ２～６ heteroaryl, or optionally substituted C １～７ heteroalkyl, and C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, D is C optionally substituted １～１０ alkyl, C optionally substituted ２～１０ alkenyl, C optionally substituted ２～１０ alkynyl, C optionally substituted ２～１０ heterocyclyl, C optionally substituted ２～６ heteroaryl, C optionally substituted ６～１２ aryl, C optionally substituted ２ ~C １０ polyethylene glycol, C optionally substituted ３ ~C １０ cycloalkyl, C optionally substituted ３ ~C １０ carbocyclyl, or C optionally substituted １～１０ is heteroalkyl, or D is absent and the linker is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof.

48. A １ is a bond between the linker and the benzopyridazine core ring system, A ２ is the bond between the decomposition part and the linker, B １ 、B ２ 、B ３ 、and B ４ each of which is, independently, optionally substituted C １ -C ４ -alkyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C ６ -C １０ -arylC １～４ -alkyl, optionally substituted C １ -C ４ -heteroalkyl, optionally substituted C ３ -C １０ -cycloalkyl, optionally substituted C ２ -C ８ -heterocyclyl, optionally substituted C ２ -C ６ -heteroaryl, optionally substituted C ６～１２ -aryl, O, S, S(O) ２ 、or NR Ｎ and is Each R Ｎ is, independently, H, optionally substituted C １～４ alkyl, optionally substituted C ２～４ alkenyl, optionally substituted C ２～４ alkynyl, optionally substituted C ２～６ heterocyclyl, optionally substituted C ２～６ heteroaryl, or optionally substituted C １～７ heteroalkyl, and C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, D is C optionally substituted １～１０ alkyl, C optionally substituted ２～１０ alkenyl, C optionally substituted ２～１０ alkynyl, C optionally substituted ２～６ heterocyclyl, C optionally substituted ２～６ heteroaryl, C optionally substituted ６～１２ aryl, C optionally substituted ２ ~C １０ polyethylene glycol, or C optionally substituted １～１０ is heteroalkyl, or D is absent and the linker is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ The compound according to claim 47, or a pharmaceutically acceptable salt thereof.

49. The compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure 【Chemical Formula 46】 【Chemical 47】

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

51. wherein the linker has the structure of formula III, A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ 、 Formula III wherein, A １ is a bond between the linker and ring system A, A ２ is a bond between the decomposition part and the linker, B １ 、 B ２ 、 B ３ 、 and B ４ each of which is, independently, optionally substituted ethynyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C ３ -C １０ -cycloalkyl, optionally substituted C ３ -C １０ -carbocyclic, optionally substituted C ２ -C １０ -heterocyclic, optionally substituted C ２ -C ９ -heteroaryl, O, S, S(O) ２ , or NR Ｎ and Each R Ｎ is, independently, H, optionally substituted C １～４ alkyl, optionally substituted C ２～４ alkenyl, optionally substituted C ２～４ alkynyl, optionally substituted C ２～１０ heterocyclyl, optionally substituted C ６～１２ aryl, or optionally substituted C １～７ heteroalkyl, and C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k is independently 0 or 1, the compound according to any one of claims 1 to 146, or a pharmaceutically acceptable salt thereof.

52. The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure 【Chemical 49】 【Chemical 50】 【Chemical 51】

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

54. A method for treating a BAF complex-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 52 or the pharmaceutical composition according to claim 53.

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

56. A method for treating a disorder associated with a loss-of-function mutation of BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 52 or the pharmaceutical composition according to claim 53.

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

58. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 52 or a pharmaceutical composition according to claim 53.

59. The method according to any one of claims 54 to 58, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, or penile cancer.

60. The method according to claim 59, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

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

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

63. A method for treating cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, and blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 52 or a pharmaceutical composition according to claim 53.

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

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

66. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 65, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, or penile cancer.

67. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 65, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

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

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

Images