Cinnoline derivatives useful as BAF modulators

Abstract

The present disclosure features compounds of Formula (I), Formula (I) wherein L is a linker; and B has the structure: Formula (Il) or pharmaceutically acceptable salts thereof, and formulations containing the same. Methods of treating BAF complex-related disorders, such as cancer, are also disclosed.

Description

[0001] CINNOLINE DERIVATIVES USEFUL AS BAF MODULATORS

[0002] Background

[0003] The invention relates to compounds useful for modulating BRG1- or BRM-associated factors (BAF) complexes. In particular, the invention relates to compounds useful for treatment of disorders associated with BAF complex function.

[0004] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which such gene expression occurs. The human Switch / Sucrose Non-Fermentable (SWI / SNF) chromatin remodeling complex, also known as BAF complex, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcription activator BRG1 , also known as ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is needed for cancer cell proliferation. BRM, also known as probable global transcription activator SNF2L2 and / or ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell growth in cells characterized by loss of BRG1 function mutations. Deactivation of BRG and / or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.

[0005] Summary

[0006] The present invention features compounds useful for modulating a BAF complex. In some embodiments, the compounds are useful for the treatment of disorders associated with an alteration in a BAF complex, e.g., a disorder associated with an alteration in one or both of the BRG1 and BRM proteins. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating such disorders.

[0007] In an aspect, the invention features a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:

[0008] Formula I wherein m is 0, 1 , 2, or 3; k is 0, 1 , or 2; each R1is, independently, halo, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Cs-Ca cycloalkyl, optionally substituted Ca-Ca cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano; each X is, independently, halo or optionally substituted Ci-Ca heteroalkyl; L is a linker; and

[0009] B has the structure:

[0010] RB1is H, A2, optionally substituted Ci-C@ alkyl, or optionally substituted Ci-C@ heteroalkyl;

[0011] RB2is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0012] RB3is A2, optionally substituted Ci-Cs alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted Ci-C@ alkyl Ce-Cw aryl;

[0013] RB4is O-RB4Aor boronic acid;

[0014] RB4Ais H, optionally substituted Ci-C@ alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Cs-C-io aryl, optionally substituted Ci-Ce alkyl C3-C10 carbocyclyl, or optionally substituted Ci-Ce alkyl Cs-Cw aryl;

[0015] RB5is H, optionally substituted Ci-C@ alkyl, or optionally substituted Ci-Ce heteroalkyl; v2 is 0, 1 , 2, 3, or 4; each RB6is, independently, A2, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; each of RB7and RB8is, independently, H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ce-C-io aryl; RB9and RB11are, independently, H or optionally substituted Ci-Ce alkyl;

[0016] RB1° is H or F; and

[0017] A2is a bond between B and the linker; wherein one and only one of RB1, RB3, and RB6is A2.

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

[0019] Formula l-A

[0020] In some embodiments, the compound has the structure of Formula l-B

[0021] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 0. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 1 . In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 2. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 3.

[0022] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is optionally substituted Ci-Ce heteroalkyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is Ci-Ce alkoxy. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is methoxy. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is halo. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is F or Cl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is optionally substituted Ci-Cs alkyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is methyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is difluoromethoxy. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is difluoromethyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is optionally substituted C2-C6 alkynyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is methyne.

[0023] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is optionally substituted C3-C8 cycloalkyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is cyclopropane. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is cyclopropoxy. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is optionally substituted C2-C9 heterocyclyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is optionally substituted amino. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is cyano. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, R1is independently selected from methoxy, F, Cl, methyl, difluoromethoxy, difluoromethyl, methyne, cyclopropane, cyclopropoxy, and cyano.

[0024] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, k is 0. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, k is 1 . In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, k is 2.

[0025] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, X is optionally substituted Ci-Ce heteroalkyl. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, X is methoxy. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, X is halo. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, X is F. where the compound has the structure of Formula I, Formula l-A, or Formula l-B, X is independently selected from methoxy and F.

[0026] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 0, and k is 0.

[0027] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 1 , k is 0, and R1is methoxy, F, Cl, methyl, difluoromethoxy, difluoromethyl, methyne, cyclopropane, cyclopropoxy, or cyano.

[0028] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 2, k is 0, and R1is independently selected from methoxy, F, Cl, methyl, difluoromethoxy, difluoromethyl, methyne, cyclopropane, cyclopropoxy, and cyano.

[0029] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 1 , k is 0, and R1is methoxy, F, Cl, or methyl.

[0030] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 2, k is 0, and R1is independently selected from methoxy, F, Cl, or methyl.

[0031] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 0, k is 1 , and X is methoxy or F.

[0032] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 0, k is 2, and X is independently selected from methoxy and F. In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 1 , k is 1 , R1is methoxy, F, Cl, methyl, difluoromethoxy, difluoromethyl, methyne, cyclopropane, cyclopropoxy, or cyano, and X is methoxy or F.

[0033] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, m is 1 , k is 2, R1is methoxy, F, Cl, methyl, difluoromethoxy, difluoromethyl, methyne, cyclopropane, cyclopropoxy, or cyano, and X is independently selected from methoxy and F.

[0034] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula ll-A:

[0035] Formula ll-A

[0036] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-A1 : Formula II-A1

[0037] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-A2: Formula II-A2

[0038] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-A3:

[0039] Formula II-A3

[0040] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-A4:

[0041] Formula II-A4 In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-A5:

[0042] Formula II-A5

[0043] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-A6:

[0044]

[0045] Formula II-A6

[0046] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula ll-B:

[0047] Formula ll-B

[0048] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-B1 : Formula II-B1

[0049] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-B2:

[0050] Formula II-B2

[0051] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-B3:

[0052] Formula II-B3

[0053] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-B4:

[0054] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-B5:

[0055]

[0056] Formula II-B5

[0057] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-B6:

[0058] Formula II-B6

[0059] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula ll-C:

[0060] Formula ll-C

[0061] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-C1 :

[0062]

[0063] Formula II-C1

[0064] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-C2:

[0065] Formula II-C2

[0066] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-C3:

[0067] Formula II-C3

[0068] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-C4:

[0069] Formula II-C4

[0070] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-C5:

[0071] Formula II-C5

[0072] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-C6:

[0073] Formula II-C6

[0074] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula ll-D:

[0075]

[0076] Formula ll-D

[0077] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-D1 :

[0078] Formula II-D1

[0079] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-D2: Formula II-D2

[0080] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-D3:

[0081]

[0082] Formula II-D3

[0083] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-D4:

[0084] Formula II-D4

[0085] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-D5:

[0086] Formula II-D5

[0087] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B has the structure of Formula II-D6:

[0088] Formula II-D6

[0089] In some embodiments, where B has the structure of Formula II, ll-A, II-A3, ll-B, II-B3, ll-C,

[0090] II-C3, ll-D, or II-D3, L4is

[0091] In some embodiments, where B has the structure of Formula II, ll-A, II-A3, ll-B, II-B3, ll-C, II-C3, ll-D, or II-D3, L4is

[0092] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A3, ll-B, II- B1 , II-B3, ll-C, II-C1 , II-C3, ll-D, II-D1 , or II-D3, RB2is H or halogen.

[0093] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB3is optionally substituted Ci-Ce alkyl. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II-B1 , II-B2, ll-C, II- C1 , II-C2, ll-D, II-D1 , or II-D2, RB3is isopropyl or fluoro-2-methylpropane.

[0094] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, or II-B6, RB4Ais H or optionally substituted Ci- Ce alkyl. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II-A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, or II-B6, RB4Ais H or methyl.

[0095] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB5is H.

[0096] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, II-B6, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, II- C6, ll-D, II-D1 , II-D2, II-D3, II-D4, II-D5, or II-D6, v2 is 0. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II-A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II- B5, II-B6, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, II-C6, ll-D, II-D1 , II-D2, II-D3, II-D4, II-D5, or II-D6, v2 is 1 or 2 and RB6is halogen or methyl. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II-A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, II-B6, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, II-C6, ll-D, II-D1 , II-D2, II-D3, II-D4, II-D5, or II-D6, v2 is 1 or 2 and each RB6is independently selected from F, Cl or methyl.

[0097] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, ll-D, II-D1 , II-D2, II-D3, II-D4, or II-D5, RB7is H or halogen. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II-A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, ll-D, II-D1 , II-D2, II-D3, II-D4, or II-D5, RB7is H, F or Cl.

[0098] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, II-B6, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, II- C6, ll-D, II-D1 , II-D2, II-D3, II-D4, II-D5, or II-D6, RB8is H or halogen. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II-A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, II-B6, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, II-C6, ll-D, II-D1 , II-D2, II-D3, II-D4, II- D5, or II-D6, RB8is H, F or Cl.

[0099] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB9is optionally substituted Ci-C6alkyl. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II-B1 , II-B2, ll-C, II- C1 , II-C2, ll-D, II-D1 , or II-D2, RB9is methyl or difluoromethyl. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II-B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB9is bonded to (S)-stereogenic center. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II-B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB9is methyl or difluoromethyl and bonded to (S)-stereogenic center.

[0100] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, or II-A6, RB1° is H. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II-A4, II-A5, or II-A6, RB10is F.

[0101] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, II-A6, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, II-B6, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, or II- C6, RB11is H or methyl.

[0102] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, ll-D, II-D1 , II-D2, II-D3, II-D4, or II-D5, RB7is H, F or Cl; and RB8is H, F or Cl.

[0103] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, ll-D, II-D1 , II-D2, II-D3, II-D4, or II-D5, RB7is H, F or Cl; RB8is H, F or Cl; and v2 is 0.

[0104] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, II-C5, ll-D, II-D1 , II-D2, II-D3, II-D4, or II-D5, RB7is H, F or Cl; RB8is H, F or Cl; and v2 is 1 or 2 and each RB6is independently selected from F, Cl, or methyl. In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, or II-C5, RB7is H, F or Cl; RB8is H, F or Cl; and RB11is H or methyl.

[0105] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, or II-C5, RB7is H, F or Cl; RB8is H, F or Cl; v2 is 0; and RB11is H or methyl.

[0106] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, II-A3, II- A4, II-A5, ll-B, II-B1 , II-B2, II-B3, II-B4, II-B5, ll-C, II-C1 , II-C2, II-C3, II-C4, or II-C5, RB7is H, F or Cl; RB8is H, F or Cl; v2 is 1 or 2 and each RB6is independently selected from F, Cl, or methyl; and RB11is H or methyl.

[0107] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, I l-D, II-D1 , or II-D2, RB3is optionally substituted Ci-C6alkyl, RB5is H; and RB9is optionally substituted CI-CB alkyl .

[0108] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, I l-D, II-D1 , or II-D2, RB3is optionally substituted Ci-C6alkyl, RB5is H; and RB9is optionally substituted Ci-C@ alkyl bonded to (S)-stereogenic center.

[0109] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is optionally substituted Ci-Ce alkyl.

[0110] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is optionally substituted Ci-Ce alkyl bonded to (S)-stereogenic center.

[0111] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is methyl or difluoromethyl.

[0112] In some embodiments, where B has the structure of Formula II, ll-A, II-A1 , II-A2, ll-B, II- B1 , II-B2, ll-C, II-C1 , II-C2, ll-D, II-D1 , or II-D2, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is methyl or difluoromethyl bonded to (S)-stereogenic center.

[0113] In some embodiments, where B has the structure of Formula II, ll-A, ll-B, ll-C, or ll-D, L4is n

[0114] RB2 BB2 , orR, RB2is H or halogen, RB3is optionally substituted Ci-Ce alkyl, RB5is H; and RB9is optionally substituted Ci-Ce alkyl.

[0115] In some embodiments, where B has the structure of Formula II, ll-A, ll-B, ll-C, or ll-D, L4

[0116] B

[0117] RB2 BB2 , orR, RB2is H or halogen, RB3is optionally substituted Ci-Ce alkyl, RB5is H; and RB9is optionally substituted Ci-Ce alkyl bonded to (S)-stereogenic center.

[0118] In some embodiments, where B has the structure of Formula II, I l-A, ll-B, I l-C, or I l-D, L4is rB2, orrB2, RB2is H or halogen, RB3is isopropyl or fluoro-2- methylpropane, RB5is H; and RB9is optionally substituted Ci-Ce alkyl.

[0119] In some embodiments, where B has the structure of Formula II, I l-A, ll-B, I l-C, or I l-D, L4is RB2is H or halogen, RB3is isopropyl or fluoro-2- methylpropane, RB5is H; and RB9is optionally substituted Ci-Ce alkyl bonded to (S)-stereogenic center.

[0120] In some embodiments, where B has the structure of Formula II, I l-A, ll-B, I l-C, or I l-D, L4is RB2is H or halogen, RB3is isopropyl or fluoro-2- methylpropane, RB5is H; and RB9is methyl or difluoromethyl.

[0121] In some embodiments, where B has the structure of Formula II, I l-A, ll-B, I l-C, or I l-D, L4 rB2, orrB2, RB2is H or halogen, RB3is isopropyl or fluoro-2- methylpropane, RB5is H; and RB9is methyl or difluoromethyl bonded to (S)-stereogenic center.

[0122] In some embodiments, where B has the structure of Formula II, I l-A, ll-B, I l-C, or I l-D, L4 n

[0123] RB2 r~>B2 , orR, RB2is H or halogen, RB3is optionally substituted Ci-Ce alkyl, RB5is H; and RB9is optionally substituted Ci-Ce alkyl. In some embodiments, where B has the structure of Formula II, I l-A, I l-B, I l-C, or I l-D, L4is

[0124] R , RB2is H or halogen, RB3is optionally substituted Ci-C@ alkyl, RB5is H; and RB9is optionally substituted Ci-Ce alkyl bonded to (S)-stereogenic center.

[0125] In some embodiments, where B has the structure of Formula II, I l-A, I l-B, I l-C, or I l-D, L4is , RB2is H or halogen, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is optionally substituted Ci-Ce alkyl.

[0126] In some embodiments, where B has the structure of Formula II, I l-A, I l-B, I l-C, or I l-D, L4is

[0127] R , RB2is H or halogen, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is optionally substituted Ci-Ce alkyl bonded to (S)-stereogenic center.

[0128] In some embodiments, where B has the structure of Formula II, I l-A, I l-B, I l-C, or I l-D, L4is

[0129] L | - / <x° J'NI r2nB2

[0130] R , RB2is H or halogen, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is methyl or difluoromethyl.

[0131] In some embodiments, where B has the structure of Formula II, I l-A, I l-B, I l-C, or I l-D, L4is , RB2is H or halogen, RB3is isopropyl or fluoro-2-methylpropane, RB5is H; and RB9is methyl or difluoromethyl bonded to (S)-stereogenic center.

[0132] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0133]

[0134] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0135] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0136]

[0137] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0138] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0139]

[0140] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from n some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0141]

[0142] In some embodiments, where the compound has the structure of Formula I, Formula l-A, or Formula l-B, B is selected from

[0143] In some embodiments, the linker has the structure of Formula III: A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2, Formula III or a pharmaceutically acceptable salt thereof, where

[0144] A1is a bond between the linker and ring system A;

[0145] A2is a bond between B and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkyl, optionally substituted Cs-C-io aryl, optionally substituted Cs-C-io aryl C1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C15-12 aryl, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl; each of C1and C2is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is, independently, 0 or 1 ; and

[0146] D is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, optionally substituted C6-12 aryl, optionally substituted C2-C10 polyethylene glycol, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-10 heteroalkyl; or D is absent, and the linker is A1-(B1)f-(C1)g-(B2)h-(B3)r(C2)r(B4)k- A2.

[0147] In some embodiments, each of B1and B4is, independently,

[0148] ,

[0149] In some embodiments, B2is optionally substituted C1-C4 alkyl. In some embodiments, D is optionally substituted C1-C10 alkyl.

[0150] 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 . In some embodiments, D is absent, and the linker is A1-(B1)f-(C1)g-(B2)h-(B3)i-(C2)j-(B4) -

[0151] A2. In some embodiments, the linker is D. In some embodiments, D is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, optionally substituted Ce-12 aryl, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkyl. In some embodiments, D is optionally substituted C3-C10 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 C3-C10 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 C3-C10 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 C3- C10 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 C3-C10 carbocyclyl, 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 C3-C10 carbocyclyl, 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 C3-C10 carbocyclyl, f is 0, g is 0, h is 0, i is 0, j is 0, and, k is 1 . In some embodiments, D is optionally substituted C3-C10 carbocyclyl, f is 0, g is 0, h is 0, i is 0, j is 0, and, k is 0. In some embodiments, D is:

[0152] In some embodiments, the linker has the structure of

[0153]

[0154] In some embodiments, the linker has the structure of

[0155]

[0156] In some embodiments, the linker has the structure of

[0157] In some embodiments, the linker has the structure of

[0158] In some embodiments, the shortest chain of atoms connecting two valencies of the linker is 2 to 10 atoms long. In some embodiments, the shortest chain of atoms connecting two valencies of the linker is 6 atoms long.

[0159] Table 1. Compounds of the Invention

[0160]

[0161]

[0162] In an aspect, the invention features a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient.

[0163] In another aspect, the invention features a method of treating a BAF complex-related disorder in a subject in need thereof, the method involving 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 pharmaceutical composition thereof.

[0164] In some embodiments, the BAF complex-related disorder is cancer or a viral infection.

[0165] In another aspect, the invention features a method of treating a disorder related to a BRG1 loss of function mutation in a subject in need thereof, the method involving 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 pharmaceutical composition thereof.

[0166] In some embodiments, the disorder related to a BRG1 loss of function mutation is cancer. In other embodiments, the subject is determined to have a BRG1 loss of function disorder, for example, is determined to have a BRG1 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of BRG1 function).

[0167] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including 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 pharmaceutical composition thereof.

[0168] 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, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.

[0169] 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, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0170] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0171] In some embodiments of any of the foregoing methods, the cancer has or has been determined to have BRG1 mutations. In some embodiments of any of the foregoing methods, the BRG1 mutations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been 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 has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has, or has been 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.

[0172] In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof. This method includes 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 pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae 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*, 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), or Togaviridae family (e.g., Rubella virus).

[0173] In some embodiments of any of the foregoing aspects, the compound is a BRM-selective compound. In some embodiments, the BRM-selective compound inhibits the level and / or activity of BRM at least 10-fold greater than the compound inhibits the level and / or activity of BRG1 and / or the compound binds to BRM at least 10-fold greater than the compound binds to BRG1 . For example, in some embodiments, a BRM-selective compound has an IC50 or IP50 that is at least 10-fold lower than the IC50 or IP50 against BRG1 . In some embodiments of any of the foregoing aspects, the compound is a BRM / BRG1 dual inhibitor compound. In some embodiments, the BRM / BRG1 dual inhibitor compound has similar activity against both BRM and BRG1 (e.g., the activity of the compound against BRM and BRG1 with 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 IC50 or IP50 against BRM that is within 10-fold of the IC50 or IP50 against BRG1 .

[0174] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0175] In another aspect, the invention features a method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0176] In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0177] In some embodiments, the cancer expresses BRG1 and / or BRM protein and / or the subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein and / or the subject has been identified as expressing BRG1 . In some embodiments, the cancer expresses BRM protein and / or the 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 hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is a bone cancer (e.g., Ewing’s sarcoma). In some embodiments, the cancer is a renal cell carcinoma (e.g., a 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). The metastatic cancer can include cells exhibiting migration and / or invasion of migrating cells and / or include cells exhibiting endothelial recruitment and / or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. Alternatively, the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously. In some embodiments, the effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colonization of the cancer to the liver. 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 EIF1 AX. 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.

[0178] In some embodiments, the subject or cancer has and / or has been identified as having a BRG1 loss of function mutation.

[0179] In an aspect, the invention provides the use of any of the foregoing compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound), or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions in the manufacture of a medicament. In some embodiments, the use is as described for the methods described herein.

[0180] Chemical Terms

[0181] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0182] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups 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 ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[0183] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0184] An alkylene is a divalent alkyl group. The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0185] The term “alkynyl ,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0186] The term “amino,” as used herein, represents -N(RN 1)2, wherein each RN1is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO?RN2, SORN2, an / V-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1groups can be optionally substituted; or two RN1combine to form an alkylene or heteroalkylene, and wherein each RN2is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN 1)2).

[0187] The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical 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 1 H-indenyl.

[0188] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci-Ce alkyl Ce-Cio aryl, C1-C10 alkyl Ce-Cio aryl, or C1-C20 alkyl Ce-Cio aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0189] The term “azido,” as used herein, represents a -N3 group.

[0190] The term “cyano,” as used herein, represents a -CN group.

[0191] The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

[0192] The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, and monovalent mono- di-, or tricyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. The cycloalkyl group may be fully saturated or contain 1 or more double or triple bonds, provided that no ring is aromatic. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The term “cycloalkoxy” as used herein, refers to cycloalkyl-O- groups (e.g., cyclopropoxy and cyclobutoxy).

[0193] The term “halo,” or “halogen” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0194] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group is further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group is further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O- A heteroalkenylene is a divalent heteroalkenyl group.

[0195] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group is further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O- A heteroalkynylene is a divalent heteroalkynyl group.

[0196] The term “heteroaryl,” as used herein, refers to a monocyclic, bicyclic, or tricyclic radical 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 with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0197] The term “heterocyclyl," as used herein, refers a monocyclic, bicyclic, or tricyclic radical having 3 to 12 atoms having at least one ring containing 1 , 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.

[0198] The term “hydroxyl,” as used herein, represents an -OH group.

[0199] The term “ / V-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used / V-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999). / V-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, a- 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- 20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l - methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t- butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4- nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, ad a manty I oxy carbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred / V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0200] The term “nitro,” as used herein, represents an -NO2 group.

[0201] The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =0). For example, a carbonyl group is a carbon (e.g., alkyl carbon, alkenyl carbon, alkynyl carbon, heteroalkyl carbon, heteroalkenyl carbon, heteroalkynyl carbon, carbocyclyl carbon, etc.) substituted with oxo. Alternatively, sulfur may be substituted with one or two oxo groups (e.g., -SO- or -SO?- within a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group).

[0202] The term “thiol,” as used herein, represents an -SH group.

[0203] The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will be 1 , 2, 3, 4, or 5 substituents present, valency permitting, unless otherwise specified. The 1 to 5 substituents are each, independently, selected from the group consisting of acyl, alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, thiol, and oxo. Each of the substituents is unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each respective group. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, thiol, and oxo. Each of the substituents is unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each respective group. In some embodiments, the substituents are themselves unsubstituted.

[0204] Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture using conventional resolution techniques. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0205] Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

[0206] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isoto pically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36CI,123l and125l. In some embodiments, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon.

[0207] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps. As used herein, the terms “about” and “approximately" refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[0208] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route.

[0209] As used herein, the term “BAF complex” refers to the BRG1- or HRBM-associated factors complex in a human cell.

[0210] As used herein, the term “BAF complex-related disorder” refers to a disorder that is caused or affected by the level of activity of a BAF complex.

[0211] As used herein, the term “BRG1 loss of function mutation” refers to a mutation in BRG1 that leads to the protein having diminished activity (e.g., at least 1 % reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss of function mutations include, but are not limited to, a homozygous BRG1 mutation and a deletion at the C-terminus of BRG1 .

[0212] As used herein, the term “BRG1 loss of function disorder" refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., at least 1 % reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).

[0213] The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0214] As used herein, the term “degrader” refers to a small molecule compound, wherein the compound interacts with a protein (e.g., BRG1 and / or BRM) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject.

[0215] By “modulating the activity of a BAF complex,” is meant altering the level of an activity related to a BAF complex (e.g., GBAF), or a related downstream effect. The activity level of a BAF complex may be measured using any method known in the art, e.g., the methods described in Kadoch et al, Cell 153:71-85 (2013), the methods of which are herein incorporated by reference.

[0216] By “reducing the activity of BRG1 and / or BRM,” is meant decreasing the level of an activity related to an BRG1 and / or BRM, or a related downstream effect. A non-limiting example of inhibition of an activity of BRG1 and / or BRM is decreasing the level of a BAF complex in a cell. The activity level of BRG1 and / or BRM may be measured using any method known in the art. In some embodiments, an agent which reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrader.

[0217] By “reducing the level of BRG1 and / or BRM,” is meant decreasing the level of BRG1 and / or BRM in a cell or subject. The level of BRG1 and / or BRM may be measured using any method known in the art. By “level” is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein is meant a decrease or increase in protein level, as compared to a reference. A level of a protein may be expressed in mass / vol (e.g., g / dL, mg / mL, pg / mL, ng / mL) or percentage relative to total protein or mRNA in a sample.

[0218] As used herein, the term “inhibiting BRM” refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or the bromodomain of the protein. BRM inhibition may be determined using methods known in the art, e.g., a BRM ATPase assay, a Nano DSF assay, or a BRM Luciferase cell assay.

[0219] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet); or in any other pharmaceutically acceptable formulation.

[0220] A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and noninflammatory in a patient.

[0221] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in 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 a free base group with a suitable organic acid.

[0222] By a “reference” is meant any useful reference used to compare protein or RNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference.

[0223] As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0224] As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0225] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0226] Detailed Description

[0227] The present disclosure features compounds useful for the inhibition of BRG1 and optionally BRM. These compounds may be used to modulate the activity of a BAF complex, for example, for the treatment of a BAF-related disorder, such as cancer (e.g., BRG1-loss of function disorders). Exemplary compounds described herein include compounds having a structure according to Formula I, or a pharmaceutically acceptable salt thereof.

[0228] In an aspect, the invention features a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:

[0229] Formula I wherein m is 0, 1 , 2, or 3; k is 0, 1 , or 2; each R1is, independently, halo, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ca-Cs cycloalkyl, optionally substituted Ca-Cs cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano; each X is, independently, halo or optionally substituted Ci-Ce heteroalkyl;

[0230] L is a linker; and

[0231] B has the structure:

[0232] RB1is H, A2, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl; RB2is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0233] RB3is A2, optionally substituted Ci-Cs alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cio aryl, optionally substituted Ci-Ce alkyl C3-C10 carbocyclyl, or optionally substituted Ci-Ce alkyl Ce-Cw aryl;

[0234] RB4is O-RB4Aor boronic acid;

[0235] RB4Ais H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, optionally substituted Ci-Ce alkyl C3-C10 carbocyclyl, or optionally substituted Ci-Ce alkyl Cs-Cw aryl;

[0236] RB5is H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl; v2 is 0, 1 , 2, 3, or 4; each RB6is, independently, A2, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Cs-Cw aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; each of RB7and RBSis, independently, H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ce-C-io aryl;

[0237] RB9and RB11are, independently, H or optionally substituted Ci-Ce alkyl;

[0238] RB1° is H or F; and

[0239] A2is a bond between B and the linker; wherein one and only one of RB1, RB3, and RB6is A2.

[0240] In some embodiments, the compound has the structure of any one of compounds 1-19 in Table 1 , or pharmaceutically acceptable salt thereof.

[0241] Other embodiments, as well as exemplary methods for the synthesis of production of these compounds, are described herein.

[0242] The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their ability to modulate the level, status, and / or activity of a BAF complex, i.e., by inhibiting the activity of the BRG1 and / or BRM proteins within the BAF complex in a mammal. BAF complex-related disorders include, but are not limited to, BRG1 loss of function mutation-related disorders.

[0243] An aspect of the present invention relates to methods of treating disorders related to BRG1 loss of function mutations such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, nonmelanoma 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) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, (i) increased progression free survival of subject.

[0244] T reating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.

[0245] Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0246] Treating cancer can result in a decrease in 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 greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).

[0247] Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

[0248] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a compound provided herein, or pharmaceutically acceptable salt thereof.

[0249] Exemplary cancers that may be treated by the 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 carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer and penile cancer.

[0250] The compounds provided herein, or a pharmaceutically acceptable salt thereof, can be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. More particularly, the compounds of Formula I provided herein, or a pharmaceutically acceptable salt thereof, can be formulated as pharmaceutical compositions. Such pharmaceutical compositions and processes for preparing the same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., eds., 21 st ed., Mack Publishing Co., 2005)).

[0251] The compounds provided herein, or a pharmaceutically acceptable salt thereof, and their pharmaceutical compositions can be administered by a variety of routes. Such routes of administration include oral, intravenous and intramuscular.

[0252] The compounds provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents.

[0253] The compounds provided herein, or a pharmaceutically acceptable salt thereof, can be a component in a pharmaceutical composition for the treatment of cancer with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

[0254] The compounds provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents for simultaneous, separate or sequential administration.

[0255] The compounds provided herein, or a pharmaceutically acceptable salt thereof, are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 100 mg / kg of body weight. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, and therefore the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0256] Preparation of Compounds

[0257] The following abbreviations are used throughout the Examples below.

[0258] ACN or MeCN acetonitrile aq. aqueous

[0259] Boc tert-butoxycarbonyl

[0260] DCM dichloromethane

[0261] DIEA N.N-diisopropylethylamine

[0262] DMF N.N-dimethylformamide

[0263] DMSO dimethyl sulfoxide

[0264] EA or EtOAc ethyl acetate

[0265] EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride equiv equivalents

[0266] ESI electrospray ionisation

[0267] EtOH ethyl alcohol

[0268] FA formic acid h or hr hour

[0269] HATU 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate

[0270] Hex Hexanes

[0271] HOAc acetic acid

[0272] HOBt or HOBT 1 -hydroxybenzotriazole hydrate

[0273] KOAc potassium acetate

[0274] L-selectride lithium tri-s-butylborohydride

[0275] MeOH methyl alcohol

[0276] MeMgBr methylmagnesium bromide min minute

[0277] MtBE tert-butyl methyl ether

[0278] LCMS liquid chromatography-mass spectrometry

[0279] NBS n-bromosuccinimide

[0280] NCS n-chlorosuccinimide n-BuLi n-butylithium

[0281] NMP 1 -methyl-2-pyrrolidinone

[0282] RdCI2(AMPHOS)2 dichlorobis{[4-(N,N-dimethylamino)phenyl]di-t- butylphosphino}palladium(ll)

[0283] Pd(dppf)CI2[1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) Pd-PEPPSI-IHeptCI dichloro[1 ,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll)

[0284] Pd-PEPPSI-IPentCI dichloro[1 ,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll)

[0285] PE petroleum ether

[0286] Prep-TLC preparative thin layer chromatography

[0287] PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate rt room temperature sat. saturated selectfluor 1 -chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2. 2]octane bis(tetrafluoroborate)

[0288] TEA triethylamine t-BuOK Potassium tert-butoxide

[0289] TFA trifluoroacetic acid

[0290] THF tetrahydrofuran

[0291] TMSI trimethylsilyl iodide

[0292] XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 biphenyl)[2-(2'-amino-1 ,1 '-biph eny I)] pallad iu m(l I) methanesulfonate oate. r step 1 step 2

[0293] 1 2

[0294] Step 1: Preparation of 2-(3-bromoisoxazol-5-yl)ethan-1 -ol (Intermediate 1)

[0295] A solution of 3-butyn-1 -ol (552.89 g, 7888.26 mmol, 4 equiv) and KHCO3 (592.30 g, 5916.197 mmol, 3 equiv) in EtOAc (2600 ml_) and H2O (260 mL) was stirred at room temperature. To the above mixture was added 1-bromo- / V-hydroxymethanecarbonimidoyl bromide (400.00 g in EA (840 mL), 1972.066 mmol, 1.00 equiv) dropwise over 60 min at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The reaction mixture was washed with water (500 mL x 2) and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (30:1) to afford Intermediate 1 (338.2 g, 88.98%) as off-white solid. LCMS (ESI) m / z [M+H]+=192.

[0296] Step 2: Preparation of 2-(3-bromoisoxazol-5-yl)acetic acid (Intermediate 2)

[0297] A solution of Intermediate 1 (360.00 g) in acetone (3600 mL) was stirred at 0 degrees C under nitrogen atmosphere. To the above mixture was added Jones reagent (1760.00 mL) dropwise over 1 h at 0 degrees C. The resulting mixture was stirred for additional overnight at room temperature. The reaction was quenched with water / lce at 0 degrees C. The resulting mixture was extracted with EtOAc (1000 mL x 3). The combined organic layers were washed with water (500 mL x 2), the organic layer was dried over anhydrous Na2SO . After filtration, the filtrate was concentrated under reduced pressure to afford Intermediate 2 (348.6 g, crude) as a green solid that was used directly without further purification. (LCMS (ESI) m / z [M+H]+=206.

[0298] A solution of Intermediate 2 (397.6 g, 1930.144 mmol, 1 .00 equiv) and H2SO4 (18.92 g, 193.014 mmol, 0.1 equiv) in EtOH (2000 mL) was stirred for 2 h at 70 degrees C. The reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (3000 mL), washed with water (500 mL x 2), the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (35:1) to afford Intermediate 3 (355 g, 78.61%) as a colorless oil. (LCMS (ESI) m / z [M+H]+=234.

[0299] Step 4: Preparation of ethyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (Intermediate 4)

[0300] To a stirred solution of t-BuOK (244.51 g, 2179.031 mmol, 1.5 equiv) and Intermediate s (340.00 g, 1452.687 mmol, 1 .00 equiv) in THF (2000 mL) was added 2-iodopropane (321 .03 g, 1888.493 mmol, 1 .3 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with Water / lce at 0 degrees C. The resulting mixture was extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with water (500 mL x 1), dried over anhydrous NasSCM. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (10:1) to afford Intermediate 4 (284.1 g, 70.82%) as a colorless oil. (LCMS (ESI) m / z [M+H]+=276.

[0301] To a stirred solution of Intermediate 4 (90.00 g, 325.933 mmol, 1 .00 equiv) in MeOH (270 mL) were added a solution of KOH (274.30 g, 4888.995 mmol, 15.00 equiv) in MeOH (210 mL) at 0 degrees C. The reaction mixture was stirred for overnight at 80 degrees C. The resulting solution was acidified to pH 4 with 1 M solution of HCI (aq.) and concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (1800 mL) and filtered. The filter cake was washed with EtOAc (100 mL x 3). The filtrate was concentrated under reduced pressure to afford Intermediate 5 (62.9 g, 96.88%) as a yellow oil that was used directly without further pur

[0302] To a stirred solution of Intermediate 5 (62.90 g, 315.754 mmol, 1.00 equiv) in HOAc (450.00 mL) was added 48% HBr (450.00 mL) at room temperature. The resulting mixture was stirred for 16 h at 60 degrees C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (containing 0.05% FA). Pure fractions were evaporated to dryness to afford Intermediate 6 (43.3 g, 74.05%) as a white solid. LCMS (ESI) m / z: [M+H]+= 186.

[0303] Step 7: Preparation of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate

[0304] To a stirred solution of Intermediate 6 (20 g, 108.004 mmol, 1 .00 equiv) in MeOH (72 mL) was added SOCh (35.26 mL, 486.059 mmol, 4.50 equiv) at 0 degrees C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, elution gradient 0 to 100% THF in petroleum ether. Pure fractions were evaporated to dryness to afford Intermediate 7 (15.1 g, 70.18%) as an off-white solid.1H NMR (400 MHz, DMSO-cfe) 6 11.24 (s, 1 H), 5.95 (s, 1 H), 3.71 - 3.58 (m, 4H), 2.32 - 2.20 (m, 1 H), 0.88 (dd, J = 34.2, 6.7 Hz, 6H). LCMS (ESI) m / z: [M+H]+= 200.

[0305] 8

[0306] To a solution of (4-bromo-2-nitrophenyl)methanol (5.00 g, 21.549 mmol, 1.00 equiv) and 2-methoxy-benzylamine (4.43 g, 32.323 mmol, 1.50 equiv) in EtOH (200 mL) and H2O (100 mL) was added CSOH.H2O (10.86 g, 64.647 mmol, 3.00 equiv). The mixture was stirred overnight at 100 degrees C. The resulting mixture was concentrated under vacuum and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with bnne (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in PE from 0% to 50% to afford Intermediate 8 (3.00 g, 39.7%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 315 / 317.1H NMR (300 MHz, DMSO-d6) <5 8.73 (s, 1 H), 8.63 (s, 1 H), 8.12 (d, J = 8.8 Hz, 1 H), 8.06 - 7.96 (m, 2H), 7.59 - 7.48 (m, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 3.90 (s, 3H).

[0307] Step 2: Preparation of2-(7-bromocinnolin-3-yl)phenol (Intermediate 9)

[0308] To a solution of Intermediate 8 (3.00 g, 0.010 mmol, 1 .00 equiv) in DCM (50 mL) was added 1 M BBra (100 mL, 0.100 mmol, 10.00 equiv). After stirring for an hour at 0 degress C, the precipitated solids were collected by filtration and washed with saturated sodium bicarbonate solution (50 mL x 3) and water (50 mL x 3). The solid was dried under reduced pressure to afford Intermediate 9 (2.5 g, 87.2%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 301 / 303.

[0309] To a stirred solution of Intermediate 7 (30 g, 150.598 mmol, 1 equiv) and K2CO3 (62.44 g, 451.794 mmol, 3 equiv) in CH3CN (300 mL) was added perfluorobutanesulfonyl fluoride (54.10 mL, 301 .196 mmol, 2 equiv) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (1 .2 L) then washed with (2 x 400 mL) of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (30:1) to afford Intermediate 10 (69 g, 92.82%) as a light brown oil. LCMS (ESI) m / z: [M+H]+= 482.

[0310] A solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (42.64 g, 215.0 mmol, 1 .5 equiv) and DIEA (74.9 mL, 430.09 mmol, 3 equiv) in NMP (560 mL) was stirred for 20 min at room temperature under nitrogen atmosphere. To the above mixture was added Intermediate 10 (69 g, 143.365 mmol, 1 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 3 h at 1 10°C under nitrogen atmosphere, then cooled to rt and diluted with ethyl acetate (2.5 L). The resulting mixture was washed with 4 x 750 mL of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted afford Intermediate 11 (32.19 g, 59.17%) as a light yellow viscous oil. = 380. tion of methyl 2-(3-{2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3- ediate 12). A mixture of Intermediate 11 (10 g, 26.3 mmol, 1 equiv) and TFA (40 mL, 538.3 mmol, 20.4 equiv) in CH2CI2 (100 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. This resulted in Intermediate 12 (7.36 g, 99.98%) as a light brown oil. LCMS (ESI) m / z: [M+H]+= 280.

[0311] / mixture of Intermediate 12 (7.36 g, 26.348 mmol, 1 equiv), intermediate 9 (7.93 g, 26.348 mmol, 1 equiv), Pd-PEPPSI-IPentCI 2-methylpyridine (o-picoline) (1.11 g, 1.317 mmol, 0.05 equiv) and CS2CO3 (25.75 g, 79.044 mmol, 3 equiv) in 1 ,4-dioxane (220 mL) was stirred for 3 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with CH2CI2 (2 x 500 mL). The combined organic layers were washed with water (2 x 250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc : CH2CI2 (1 :20) to afford Intermediate 13 (11 .3 g, 84.99%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 500.

[0312] Step 5: Preparation of 2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6- diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 14).

[0313] A mixture of Intermediate 13 (11.3 g, 22.619 mmol, 1 equiv) and LiOH (2N) (100 mL, 200.000 mmol, 8.84 equiv) in MeOH (100 mL) and THF (100 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with 1 N HCL The precipitated solids were collected by filtration and washed with water (3 x 20 mL). The resulting solid was dried in an oven. This resulted in Intermediate 14 (10.5 g, 95.60%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 486.

[0314] A mixture of Intermediate 14 (10.45 g, 21.522 mmol, 1 equiv), methyl (2S,4R)-4- hydroxypyrrolidine-2-carboxylate hydrochloride (4.30 g, 23.674 mmol, 1.1 equiv), DIEA (11.25 mL, 64.566 mmol, 3 equiv) and PyBOP (13.44 g, 25.826 mmol, 1 .2 equiv) in DMF (204 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) at 10°C. The precipitated solids were collected by filtration and washed with MeCN : H2<D=1 :2 (2 x 150 mL). The residue was purified by silica gel column chromatography, eluted with =10:1) (3:1) to afford Intermediate 15 (12 g, 91 .00%) as an orange solid. H]+= 613.

[0315] Step 7: Preparation 1-[2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]- 2,6-diazaspiro[3.3]heptan-2- methylbutanoyl]pyrrolidine-2-carboxylic acid (Intermediate 16).

[0316] A solution of Intermediate 15 (12 g, 19.586 mmol, 1 equiv) and LiOH (2N) (120 mL, 240.000 mmol, 12.25 equiv) in MeOH (120 mL) and THF (120 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water (1000 mL). The mixture was acidified to pH 5 with HCI (1 N) at 0°C. The precipitated solids were collected by filtration and washed with MeCN : H2O=1 :2 (2 x 100 mL). The resulting solid was dried in an oven. The crude product was used in the next step directly without further purification. This resulted in Intermediate 16 (10.97 g, 93.56%) as a reddish brown solid. LCMS (ESI) m / z: [M+H]+= 599. Step 8: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7- yl]-2, 6-diazaspiro[3.3]heptan-2-yi}- 1, 2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidine-2-carboxylic acid (intermediate 17).

[0317] The crude Intermediate 16 (3 g) was purified by Preparative HPLC with the following conditions Column: (S, S)-WHELK-O1-Kromasil, 5*25 cm, 10 pm; Mobile Phase A: Hex (0.1% FA)-HPLC, Mobile Phase B: EtOH: ACN=5: 1 ; Flow rate: 140 mL / min; Gradient: isocratic 50% to afford Intermediate 17 (1 .26 g, 43.0%) as a red solid. LCMS (ESI) m / z: [M+H]+= 599.

[0318] To a stirred solution of tert-butyl N-[(1 S)-1-(4-bromophenyl) ethyl] carbamate (5 g, 16.656 mmol, 1 equiv) and bis(pinacolato)diboron (8.46 g, 33.312 mmol, 2 equiv) in 1 ,4-dioxane (50 mL) were added Pd(dppf)Cl2 (1.22 g, 1.666 mmol, 0.1 equiv) and KOAc (3.27 g, 33.312 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (500 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 25% EtOAc in petroleum ether to afford Intermediate 18 (7.6 g, crude) as a yellow oil. LCMS (ESI) m / z: [M+H]+=348. Step 2: Preparation of tert-butyl N-[(1S)-1-[4-(2-methylpyrazol-3-yl) phenyl] ethyl] carbamate (Intermediate 19).

[0319] To a stirred solution of Intermediate 18 (5 g, 14.398 mmol, 1 equiv) and 5-bromo-1- methylpyrazole (3.48 g, 21.597 mmol, 1.5 equiv) in 1 ,4-dioxane (3 ml_), H2O (12 mL) were added Pd(dppf)Cl2 (1.05 g, 1.440 mmol, 0.1 equiv) and K2CO3 (3.98 g, 28.796 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (500 ml). The combined organic layers were washed with water (300 ml x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 33% EtOAc in petroleum ether to afford Intermediate 19 (3.7 g, 85.26%) as a white solid. LCMS (ESI) m / z: [M+H]+=302.

[0320] Step 3: Preparation of (1S)-1-[4-(2-methylpyrazol-3-yl) phenyl] ethanamine (Intermediate

[0321] A solution of Intermediate 19 (3.7 g, 12.276 mmol, 1 equiv) in HCI (4M in 1 ,4-dioxane, 10 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford Intermediate 20 (4 g, HCI salt) as a white solid. LCMS (ESI) m / z: [M+H]+=202.

[0322] Preparation of(2S,4R)-N-[(1S)-1-[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]ethyl]-4-hydroxy- 1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol- 5-yl)-3-methylbutanoyi]pyrrolidine-2-carboxamide (Compound 1).

[0323]

[0324] To a stirred solution of Intermediate 20 (500 mg, 2.484 mmol, 1 equiv) and TEA (1 .26 g, 12.420 mmol, 5 equiv) in DCM (8 mL) was added benzyl (2,5-dioxopyrrolidin-1 -yl) carbonate (928.66 mg, 3.726 mmol, 1 .5 equiv) at 0 °C. The resulting solution was stirred at 25 °C for 2 h. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (150mL x 3). The combined organic layers were washed with H2O (150 mL x 3), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 28% EtOAc in petroleum ether to afford Intermediate 21 (800 mg, 96.01%) as a light yellow oil. LCMS (ESI) m / z: [M+H]+= 336.

[0325] To a stirred solution of Intermediate 21 (830 mg, 2.475 mmol, 1 equiv) in DMF (10 mL) was added Selectfluor (1314.98 mg, 3.713 mmol, 1.5 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H2O (1 OOmL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 30% EtOAc in petroleum ether to afford Intermediate 22 (560 mg, 64.04%) as a colorless oil. LCMS (ESI) m / z: [M+H]+=354.

[0326] Step 3: Preparation of (1S)-1-[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]ethanamine (Intermediate 23).

[0327] To a stirred solution of Intermediate 22 (250 mg, 0.7 mmol, 1 equiv) in MeCN (4 mL) was added TMSI (283 mg, 1 .4 mmol, 2 equiv) at 0 °C. The resulting solution was stirred at 25 °C for 2h. The reaction was quenched by the addition of MeOH (5 mL) at 25 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash C18 chromatography, elution gradient 0 to 25% ACN in water to afford Intermediate 23 (80 mg, 51 .58%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 220.

[0328] A solution of Intermediate 17 (30.03 mg, 0.050 mmol, 1 equiv) in DMF (1 .5 mL) was treated with EDCI (19.23 mg, 0.100 mmol, 2 equiv) and HOBt (13.56 mg, 0.100 mmol, 2 equiv) for 60 min at 25 °C followed by the addition of Intermediate 23 (22 mg, 0.100 mmol, 2 equiv) and DIEA (32.42 mg, 0.250 mmol, 5 equiv) in portions at 25 °C. The resulting mixture was stirred for an additional 2h at 25 °C. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 41 % B to 56% B to afford Compound 1 (7.8 mg, 19.44%) as an orange solid.1H NMR (300 MHz, DMSO-d6) 6 12.85 (s, 1 H), 8.78 (s, 1 H), 8.49 (s, 1 H), 8.01 (dd, J = 23.5, 9.2 Hz, 1 H), 7.98 - 7.89 (m, 1 H), 7.64 - 7.51 (m, 1 H), 7.64 - 7.40 (m, 4H), 7.32 (td, J = 8.6, 6.7 Hz, 2H), 7.04 (s, 3H), 5.94 (s, 1 H), 5.16 (s, 1 H), 4.88 (d, J = 12.0 Hz, 1 H), 4.33 - 4.21 (m, 1 H), 4.43 (s, 5H), 4.15 (s, 4H), 3.82 (s, 3H), 3.83 - 3.69 (m, 1 H), 3.63 (d, J = 10.6 Hz, 1 H), 3.48 (s, 1 H), 2.33 - 2.16 (m, 1 H), 2.08 (d, J = 9.4 Hz, 1 H), 1 .86 (s, 1 H), 1 .45 (dd, J = 24.5, 7.9 Hz, 3H), 1 .00 (s, 3H), 0.85 (t, J = 6.0 Hz, 3H). LCMS (ESI) m / z: [M+H]+=800.40.

[0329] The compounds in Table 2 were prepared using procedures similar to those used above for the preparation of Compound 1.

[0330] Table 2.

[0331] 24

[0332] A solution of 4-bromo-3-fluoro-2-methylbenzaldehyde (3 g, 13.823 mmol, 1 equiv) and (R)-2-methylpropane-2-sulfinamide (1 .68 g, 13.823 mmol, 1 equiv) in THF (30 mL) was treated with Titanium(IV) ethoxide (9.46 g, 41 .469 mmol, 3 equiv). The resulting mixture was stirred at 60°C. The resulting mixture was extracted with EtOAc (2 x 150mL). The combined organic layers were washed with water (4 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 20% EtOAc in petroleum ether to afford Intermediate 24 (4.073 g, 92.02%) as a white solid. LCMS (ESI) m / z: [M+H]+= 322.

[0333] To a stirred solution of Intermediate 24 (3.8 g, 11 .867 mmol, 1 equiv) in THF was added MeMgBr (3M in Et2O, 19.78 mL, 59.335 mmol, 5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for an additional 0.5 h at room temperature. The resulting mixture was extracted with EtOAc (1 x 300 mL). The combined organic layers were washed with water (3 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 22% EtOAc in petroleum ether to afford Intermediate 25 (3.337 g, 83.63%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=338.

[0334] A solution of Intermediate 25 (220 mg, 0.654 mmol, 1 equiv), 1-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazole (204.20 mg, 0.981 mmol, 1.5 equiv), XPhos Pd G3 (55.38mg, 0.065mmol, O.lequiv) and CS2CO3 (426.57mg, 1.309mmol, 2equiv) in 1 ,4-dioxane (4 mL) and H2O (1 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (1 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1 :1) to afford Intermediate 26 (220 mg, 99.50%) as a light yellow oil. LCMS (ESI) m / z: [M+H]+= 338.

[0335] Step 4: Preparation of (1S)-1-[3-fluoro-2-methyl-4-(2-methylpyrazol-3-yl)phenyl]ethanamine (Intermediate 27).

[0336] A solution of Intermediate 26 (220 mg, 0.652 mmol, 1 equiv) in HCI (4 M in 1 ,4-dioxane, 2.5 mL) and MeOH (2.5 mL) was stirred for 0.5h at room temperature. The resulting mixture was concentrated under vacuum to afford Intermediate 27 (203 mg, HCI salt) as a white solid. LCMS (ESI) m / z: [M+H]+=235.

[0337] Step 5: Preparation of (2S,4R)-N-[(1 S)-1 -[3-fluoro-2-methyl-4-(2-methylpyrazol-3- yl)phenyl]ethyl]-4- hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6- diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidine-2-carboxamide (Compound 5).

[0338] A solution of Intermediate 17 (25.66 mg, 0.043 mmol, 1 equiv) in DMF (0.5 mL) was treated with EDCI (16.43 mg, 0.085 mmol, 2 equiv) and HOBT (11 .58 mg, 0.085 mmol, 2 equiv) for 1 h at room temperature followed by the addition of intermediate 27 (15 mg, 0.064 mmol, 1 .5 equiv) and DIEA (27.70 mg, 0.213 mmol, 5 equiv) in portions at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; to afford Compound 5 (19.9 mg, 56.18%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) <5 12.81 (s, 1 H), 8.91 - 8.42 (m, 2H), 8.03 (d, J = 8.2, 1 .7 Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 7.52 - 7.50 (m, 1 H), 7.36 - 7.21 (m, 4H), 7.05 - 6.96 (m, 3H), 6.37 - 6.34 (m, 1 H), 5.87 (d, J = 43.0 Hz, 1 H), 5.16 - 4.98 (m, 2H), 4.38 - 4.30 (m, 6H), 4.12 (s, 4H), 3.77 - 3.55 (m, 5H), 3.43 (d, J = 10.7 Hz, 1 H), 2.30 - 2.13 (m, 4H), 2.04 - 1.99 (m, 1 H), 1.78 - 1.71 (m, 1 H), 1.46 - 1.34 (m, 3H), 0.96 (t, J = 6.9 Hz, 3H), 0.85 - 0.79 (m, 3H). LCMS (ESI) m / z: [M+H]+=814.40.

[0339] The compounds in Table 3 were prepared using procedures similar to those used above for the preparation of Compound 5. Table 3.

[0340] Step 1 : preparation of tert-butyl 6-[4-chloro-5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2- oxazol-3-yl]-2, 6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 28).

[0341] To a stirred solution of Intermediate 11 (3 g, 2.635 mmol, 1 equiv) and NBS (1.22 g, 3.162 mmol, 1.2 equiv) in DMF (60 mL). The resulting solution was stirred at 60 °C for 2 h. The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was washed with 2 x 150 mL of water. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % FA), 30% to 60% gradient in 30 min. This resulted in Intermediate 28 (2.84 g, 73.34%) as a brown oil. LCMS (ESI) m / z: [M+H]+=458 / 460.

[0342] Step 2: preparation of tert-butyl 6-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-4-methyl-1 ,2- oxazol-3-yl]-2, 6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 29).

[0343] To a stirred solution of Intermediate 28 (2.84 g, 6.196 mmol, 1 equiv) and trimethyl- 1 ,3,5,2,4,6-trioxatriborinane (4.67 g, 18.588 mmol, 3 equiv, 50%) in dioxane (56 mL), H2O (14 mL) was added PdCl2(AMPHOS)2 (0.44 g, 0.620 mmol, 0.1 equiv) and K3PO4 (3.95 g, 18.588 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 60°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % FA), 30% to 70% gradient in 30 min. This resulted in Intermediate 29 (2.2 g, 90.24%) as a brown oil. LCMS (ESI) m / z:

[0344] To a stirred solution of Intermediate 29 (2.87 g, 7.294 mmol, 1 equiv) in CH2CI2 (30 mL) was added TFA (30 mL, 403.892 mmol, 55.37 equiv) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in Intermediate 30 (2.2 g, 93.24%) as a brown solid. LCMS (ESI) m / z: [M+H]+=294.

[0345] To a stirred solution of Intermediate 30 (2.2 g, 7.499 mmol, 1 equiv) and Intermediate 9 (1 .81 g, 5.999 mmol, 0.8 equiv) in dioxane (60 mL) was added CS2CO3 (7.33 g, 22.497 mmol, 3 equiv) and Pd-PEPPSI-IHeptCI 2-methylpyridine (0.37 g, 0.375 mmol, 0.05 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (400 mL). The resulting mixture was washed with 2 x 150 mL of water. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % FA), 30% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 31 (1 .6 g, 41 .54%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=514.

[0346] To a stirred solution of Intermediate 31 (1.6 g, 3.115 mmol, 1 equiv) in MeOH (40 mL) was added 0.1 N LiOH (40 mL) dropwise. The resulting mixture was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with HCI (1 N aq.). The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was washed with 2 x 100 mL of water. The resulting mixture was concentrated under vacuum. This resulted in Intermediate 32 (1 .2 g, 78.68%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=500.

[0347] To a stirred solution of Intermediate 32 (1 g, 2.002 mmol, 1 equiv) and methyl (2S,4R)-4- hydroxypyrrolidine-2-carboxylate (319.62 mg, 2.202 mmol, 1.1 equiv) in DMF (50 mL) was added PyBOP (1250.03 mg, 2.402 mmol, 1.2 equiv) and DIEA (776.15 mg, 6.006 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with 3 x 200 mL of water. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / (EA: MeOH=10:1) (1 :1) to afford Intermediate 33 (780 mg, 62.18%) as an

[0348] To a stirred solution of Intermediate 33 (780 mg, 1 .245 mmol, 1 equiv) in MeOH (10 mL) was added 0.1 M LiOH (10 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was monitored by LCMS. The mixture was allowed to cool down to 0°C. The mixture was acidified to pH 5 with HCI (1 N aq.). The precipitated solids were collected by filtration and washed with water (3 x 50 mL). This resulted in Intermediate 34 (600 mg, 78.68%) as a red solid. LCMS (ESI) m / z: [M+H]+=613.

[0349] Step 8: preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7- yl]-2,6-diazaspiro[3.3]heptan-2-yl)-4-methyl-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidine-2- carboxylic acid (Intermediate 35)

[0350] Intermediate 34 (600 mg, 0.979 mmol, 1 equiv) was purified by Prep-Chiral with the following conditions (Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 pm; Mobile Phase A: MtBE(0.1% FA)--HPLC, Mobile Phase B: MeOH--HPLC; Flow rate: 40 mL / min; Gradient: isocratic 15%) to afford Intermediate 35 (470 mg, 78.33%) as a red solid. LCMS (ESI) m / z: [M+H]+=613.

[0351] To a solution of Intermediate 35 (25.0 mg, 0.041 mmol, 1 equiv) and Intermediate 23 (13.42 mg, 0.061 mmol, 1 .5 equiv) in DMF (2 mL) were added DIEA (31 .6 mg, 0.246 mmol, 6 equiv) and PyBOP (31 .8 mg, 0.061 mmol, 1 .5 equiv). The resulting mixture was stirred for 1 .5 h at room temperature, the crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Phenyl OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HC03+0.05% NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 42% B to 54%B to afford Compound 13 (10.0 mg, 30.1 %) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) < 12.82 (s, 1 H), 8.76 (s, 1 H), 8.44 (d, J = 7.7 Hz, 1 H), 8.03 (dd, J = 8.1 , 1.6 Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 7.62 - 7.54 (m, 1 H), 7.54 - 7.39 (m, 4H), 7.37 - 7.23 (m, 2H), 7.06 - 6.95 (m, 3H), 5.11 (d, J = 3.7 Hz, 1 H), 4.95 (p, J = 7.0 Hz, 1 H), 4.36 (t, J = 7.7 Hz, 1 H), 4.29 (s, 5H), 4.25 - 4.15 (m, 4H), 3.84 - 3.79 (m, 3H), 3.79 - 3.71 (m, 1 H), 3.57 (d, J = 10.2 Hz, 1 H), 3.27 - 3.15 (m, 1 H), 2.44 - 2.25 (m, 1 H), 2.06 - 1.96 (m, 1 H), 1.92 (s, 3H), 1.85 - 1.74 (m, 1 H), 1.54 - 1.31 (m, 3H), 1.05 - 0.89 (m, 3H), 0.80 - 0.65 (m, 3H). LCMS (ESI) m / z: [M+H]+= 814.38 Preparation of methyl (2S,4R)-4-hydroxy-1-[2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6- diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoyl]pyrrolidine-2-carboxylic acid

[0352] Step 1: Preparation of ethyl 2-(4-bromo-1 ,2,3-triazol-1 -yl)-3-methylbutanoate(lntermediate 36) To a stirred solution of 4-bromo-1 H-1 ,2,3-triazole (40 g, 270.338 mmol, 1 equiv) and ethyl

[0353] 2-bromo-3-methylbutanoate (84.78 g, 405.507 mmol, 1.5 equiv) in DMF (450 mL) was added K2CO3 (112.09 g, 811.014 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 3 h at 60 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was diluted with water (1000 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (3 x 500 mL), dried over anhydrous NasSCM. The residue was purified by silica gel column chromatography, eluted 4%) to afford Intermediate 36 (24.4 g, 32.69%) as a colourless oil. +H]+= 276 / 278.

[0354] Step 2: Preparation of tert-butyl 6-[1-(1-etho tan-2-yl)-1,2,3-triazol-4- yl]-2,6-diazaspiro [3.3]heptane-2-carboxylate (Interm

[0355] To a stirred solution of Intermediate 36 (24 g, 86.914 mmol, 1 equiv) and tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (25.85 g, 130.371 mmol, 1.5 equiv) in 1 ,4-dioxane (300 ml_) were added Pd-PEPPSI-IPentCI 2-methylpyridine (o-picoline) (3.66 g, 4.346 mmol, 0.05 equiv) and CS2CO3 (84.96 g, 260.742 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (1000 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) (35%) to afford Intermediate 37 (24.98 g, 73.04%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 394.

[0356] To a stirred solution of Intermediate 37 (24.98 g, 63.484 mmol, 1 equiv) in DCM (480 mL) was added TFA (94.26 mL, 1269.045 mmol, 19.99 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in Intermediate 38 (33.3 g, 89.40%) as a light yellow oil. LCMS (ESI)

[0357] To a stirred solution of Intermediate 38 (33.3 g, 51 .079 mmol, 1 equiv, 45%) and 2-(7- chlorocinnolin-3-yl)phenol (12.46 g, 48.525 mmol, 0.95 equiv) in 1 ,4-dioxane (480 mL) was added

[0358] CS2CO3 (49.93 g, 153.237 mmol, 3 equiv) and Pd-PEPPSI-IPentCI 2-methylpyridme (o-picohne) (2.09 g, 2.488 mmol, 0.05 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 15 h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (1000 mL), extracted with EtOAc (3 x 500 mL) and dried over anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (3:2) (41%) to afford Intermediate 39 (13 g, 49.55%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 514.

[0359] To a stirred solution of Intermediate 39 (13 g, 25.31 1 mmol, 1 equiv) in EtOH (480 mL) was added LiOH (240 mL, 2N.aq) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to 0°C. The mixture was acidified to pH 6 with 1 N HCI (aq.). The precipitated solids were collected by filtration and washed with water (2 x 200 mL). The resulting solid was dried in an oven. This resulted in intermediate 40 (9.6 g, purity 96%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 486.

[0360] Step 6: Preparation of methyl (2S,4R)-4-hydroxy-1-[2-(4-{6-[3-(2-hydroxyphenyl)cinnolin- 7-yl]-2, 6-diazaspiro[3.3]heptan-2-yl}- 1, 2, 3-triazol-1-yl)-3-methylbutanoyl]pyrrolidine-2-carboxylate (Intermediate 41).

[0361] To a stirred solution of Intermediate 40 (9.6 g, 19.771 mmol, 1 equiv) and HATU (7.52 g, 19.771 mmol, 1 equiv) in DMF (300 mL) was added DIEA (10.33 mL, 59.313 mmol, 3 equiv) and methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (3.77 g, 20.760 mmol, 1.05 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (900 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (3 x 300 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in Intermediate 41 (11.08 g, 87.81 %) as an orange solid. LCMS (ESI) m / z: [M+H]+= 613.

[0362] Step 7; Preparation of (2S,4R)-4-hydroxy-1-[2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]- 2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoyl]pyrrolidine-2-carboxylic acid (intermediate 42).

[0363] To a stirred solution of Intermediate 41 (11.08 g, 18.084 mmol, 1 equiv) in MeOH (220 mL) was added LIOH (220 mL, 2N.aq) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The mixture was allowed to cool down to 0°C. The mixture was acidified to pH 6 with 1 N HCI (aq.). The precipitated solids were collected by filtration and washed with water (2 x 200 mL). The resulting solid was dried in an oven. The filtrate was extracted with DCM (3 x 400mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in Intermediate 42 (10.3 g, 95.14%) as a dark red solid. LCMS (ESI) m / z: [M+H]+= 599.

[0364] A solution of Intermediate 42 (25 mg, 0.042 mmol, 1 equiv), (1 S)-1-[4-(4-fluoro-2- methylpyrazol-3-yl)phenyl]ethanamine hydrochloride (21 .36 mg, 0.084 mmol, 2 equiv), PyBOP (32.60 mg, 0.063 mmol, 1.5 equiv) and DIEA (29.10 uL, 0.168 mmol, 4 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (3 mL). The organic layers were washed with water (3 x 1 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10:1) to afford Compound 14 (7.1 mg, 21.06%) as a light orange solid.1H NMR (300 MHz, DMSO-d6) 6 12.86 (s, 1 H), 8.96 - 8.51 (m, 2H), 8.10 - 7.90 (m, 2H), 7.64 - 7.40 (m, 6H), 7.37 - 7.23 (m, 2H), 7.11 - 6.95 (m, 3H), 5.21 (s, 1 H), 5.11 (d, J = 10.3 Hz, 1 H), 4.96 (t, J = 7.5 Hz, 1 H), 4.35 (d, J = 34.3 Hz, 6H), 4.05 (t, J = 6.0 Hz, 4H), 3.80 (d, J = 3.5 Hz, 4H), 3.63 (d, J = 10.9 Hz, 1 H), 2.42 (s, 1 H), 2.08 (t, J = 10.6 Hz, 1 H), 1.80 (t, J = 12.2 Hz, 1 H), 1.58 - 1.35 (m, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.67 (d, J = 6.5 Hz, 3H). LCMS (ESI) m / z: [M+H]+= 799.37.

[0365] The compounds in Table 4 were prepared using procedures similar to those used above for the preparation of Compound.

[0366] Table 4. Step 1: Preparation of tert-butyl 6-[4-chloro-5-(1 -methoxy-3-methyl-1 -oxobutan-2-yl)-1 ,2-oxazol-3- yl]-2, 6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 43).

[0367] To a stirred solution of Intermediate 11 (3 g, 2.6 mmol, 1 equiv) and NCS (1.22 g, 3.162 mmol, 1.2 equiv) in DMF (60 mL). The resulting solution was stirred at 60°C for 2h. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was washed with (2 x 150 mL) of water. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % FA), 30% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 43 (2.84 g, 73.34%) as a brown oil.

[0368] A solution of Intermediate 43 (4.505 g, 10.884 mmol, 1 equiv) and TFA (15 mL) in CH2CI2 (60 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. This resulted in Intermediate 44 (4.62 g, TFA salt) as a brown oil. LCMS (ESI) m / z: [M+H]+= 314.

[0369] A solution of Intermediate 44 (3.5 g, 11.154 mmol, 1 equiv), intermediate 9 (3.36 g, 11.154 mmol, 1 equiv), Pd-PEPPSI-IPentCI 2-methylpyridine (o-picoline) (469.13 mg, 0.558 mmol, 0.05 equiv) and CS2CO3 (10.90 g, 33.462 mmol, 3.00 equiv) in dioxane (105 mL) was stirred for 2h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (250 mL). The organic layers were washed with water (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (8:1) to afford Intermediate 45 (3.35 g, 39.37%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 534.

[0370] Step 4: Preparation of2-(4-chloro-3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6- diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 46).

[0371] A solution of Intermediate 45 (3.33 g, 6.236 mmol, 1 equiv) and LIOH (2N) (110 mL) in MeOH (110 mL) was stirred for 1 h at room temperature. The reaction dilute with water / ice (110 mL) at 0°C. The mixture was acidified to pH 5 with HCI (1 N aq.). The precipitated solids were collected by filtration and washed with H2O / MeOH (2:1). The resulting crude solid was dried in an oven. This resulted in Intermediate 46 (2.53 g, 70.22%) as a red solid. LCMS (ESI) m / z: [M+H]+= 520.

[0372] / solution of Intermediate 46 (2 g, 3.846 mmol, 1 equiv), methyl (2S,4R)-4- hydroxypyrrolidine-2-carboxylate hydrochloride (1.05 g, 5.769 mmol, 1.5 equiv), PyBOP (3.00 g, 5.769 mmol, 1.5 equiv) and DIEA (3.35 mL, 19.230 mmol, 5 equiv) in DMF (80 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (160 mL). The organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 100% gradient in 30 min; hold 30 min at 52%; detector, UV 254 nm. The crude product (1 .94 g) was purified by Prep-HPLC with the following conditions (Column: NN-DAICEL DCpak P4VP, 3.0*100 mm, 3.0 urn; Mobile Phase B: EtOH; Flow rate: 2 mL / min; Gradient: isocratic 10-50%% B; Wave Length: 254nm+PDA nm) to afford Intermediate 47 (1 .48 g, 53.52%) as an orange solid. LCMS (ESI) m / z: [M+H]+= 647.

[0373] Step 6; Preparation of (2S,4R)-1-[2-(4-chloro-3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6- diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxypyrroHdine-2-carboxylic acid (Intermediate 48).

[0374] A solution of Intermediate 47 (1 .46 g, 2.256 mmol, 1 equiv) and LiOH (2N) (30 mL) in MeOH (30 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water (60 mL). The mixture was allowed to cool down to 0°C and acidified to pH 5 with HCI (1 N aq.). The precipitated solids were collected by filtration and washed with MeOH. The resulting solid was dried in an oven. This resulted in Intermediate 48 (1.42 g, 94.44%) as a red solid. LCMS (ESI) m / z: [M+H]+= 633.

[0375] Intermediate 48 (1 .42 g) was purified by Prep-Chiral with the following conditions (Column: CHIRAL ART Amylose-SA, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: DCM=1 : 1 (0.2%DEA); Flow rate: 90 mL / min; Gradient: isocratic 55% B; Column Temperature (°C) : 35; Back Pressure(bar): 100; Wave Length: 270 / 334 nm; RT1 (min): 3.17; RT2(min): 6.38; Sample Solvent: MEOH; Injection Volume: 0.5 mL) to afford intermediate 49 (560 mg, 39.44%) (second peak) as an orange solid. LCMS (ESI) m / z: [M+H]+= 633.

[0376] Preparation of (2S,4R)-1-[(2R)-2-(4-chloro-3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2, 6- diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-fluoro-2- methylpyrazol-3-yl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide (Compound 17).

[0377]

[0378] A solution of Intermediate 49 (30 mg, 0.047 mmol, 1 equiv) in DMF (1 .5 mL) was treated with EDCI (18.17 mg, 0.094 mmol, 2 equiv) and HOBt (12.81 mg, 0.094 mmol, 2 equiv) for 1 h at room temperature followed by the addition of intermediate 23 (20.78 mg, 0.094 mmol, 2 equiv) and DIEA (30.62 mg, 0.235 mmol, 5 equiv) in portions at 25 °C. The resulting mixture was stirred for additional 2h at 25°C. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 49% B to 54% B in 10 min; Wave Length: 254nm / 220nm nm; RT1 (min): 9.1) to afford Compound 17 (16.2 mg, 40.97%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 12.81 (s, 1 H), 8.76 (s, 1 H), 8.45 (d, J = 7.7 Hz, 1 H), 8.06 - 8.00 (m, 1 H), 7.96 (d, J = 9.0 Hz, 1 H), 7.57 (d, J = 4.6 Hz, 1 H), 7.53 - 7.41 (m, 4H), 7.36 - 7.25 (m, 2H), 7.05 - 6.96 (m, 3H), 5.15 (d, J = 3.8 Hz, 1 H), 4.95 (p, J = 7.2 Hz, 1 H), 4.42 - 4.27 (m, 10H), 3.79 (s, 4H), 3.67 (d, J = 10.3 Hz, 1 H), 3.38 (s, 1 H), 2.41 (s, 1 H), 2.08 - 1 .99 (m, 1 H), 1.86 - 1.73 (m, 1 H), 1 .40 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.89 - 0.82 (m, 1 H), 0.81 (dd, J = 25.6, 7.0 Hz, 2H). LCMS

[0379] (ESI) m / z: [M+H]+=834.15.

[0380] The compounds in Table 5 were prepared using procedures similar to those used above for the preparation of Compound 17.

[0381] Table 5.

[0382] A solution of dibromobenzene (10 g, 42.390 mmol, 1 equiv) in THF (100 mL) was stirred for 5 min at -78 °C under nitrogen atmosphere. To the above mixture was added n-BuLi (135.77 mg, 2.119 mmol, 1 equiv) dropwise over 3 min at -78 °C. The resulting mixture was stirred for additional 0.5 h at -78 °C. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at -78 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SC>4. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / PE to afford Intermediate 50 (11 g, crude) as a light yellow oil. LCMS (ESI) m / z: [M+H]+= 235.

[0383] A solution of Intermediate 50 (10 g, 42.548 mmol, 1 equiv) and (S)-2-methylpropane-2- sulfinamide (10.31 g, 85.096 mmol, 2 equiv), tetrakis (propan-2-yloxy) titanium (36.28 g, 127.644 mmol, 3 equiv) in THF (80 mL) was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (100:1) to afford Intermediate 51 (6.3 g, crude) as brown oil. LCMS (ESI) m / z [M+H]+= 338.

[0384] Step 3: Preparation of (S)-N-((R)-1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane- 2-sulfinamide (Intermediate 52)

[0385] A solution of Intermediate 51 (6.3 g, 18.627 mmol, 1 equiv) in THF (80 mL) was stirred for 5 mins at -78 °C under nitrogen atmosphere. To the above mixture was added L-selectride (7.08 g, 37.254 mmol, 2 equiv) dropwise over 5 mins at -78 °C. The resulting mixture was stirred for additional 1 .5 h at -78 °C. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in Intermediate 52 (5.5 g, crude) as a brown oil. LCMS (ESI) m / z [M+H]+= 340.

[0386] Step 4: Preparation of (R)-1-(4-bromophenyl)-2,2-difluoroethan-1 -amine (Intermediate 53)

[0387] To a solution of Intermediate 52 (5.5 g, 16.166 mmol, 1 equiv) in MeOH (6 mL) was added 4N HCI (gas) in 1 ,4-dioxane (2 mL). The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was neutralized to pH 8 with DIEA. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 10% gradient in 30 min; detector, UV 254 / 220 nm. This resulted in Intermediate 53 (1 .25 g, 32.7%) as a white solid. LCMS (ESI) m / z [M+H]+= 236.

[0388] Step 5: Preparation of tert-butyl (R)-(1-(4-bromophenyl)-2,2-difluoroethyl)carbamate (intermediate 54)

[0389] To a solution of Intermediate 53 (1 g, 4.236 mmol, 1 equiv) in EtOH (20 mL) was added (BOC)2Q (2.77 g, 12.708 mmol, 3 equiv). The resulting mixture was stirred for 1 .5 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / PE (4:1) to afford Intermediate 54 (985 mg, 69.2%) as a white solid. LCMS (ESI) m / z [M-56]+= 280.

[0390] A solution of Intermediate 54 (980.0 mg, 2.915 mmol, 1 equiv) and 1-methyl-5-(4 ,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyrazole (909.83 mg, 4.373 mmol, 1.5 equiv), CS2CO3 (2849.4 mg, 8.745 mmol, 3 equiv), XPhos Pd G3 (493.5 mg, 0.583 mmol, 0.2 equiv) in dioxane (7.5 mL) and H2O (1 .5 mL) was stirred for 2 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 / 220 nm. This resulted in Intermediate 55 (850.0 mg, 86.4%) as a yellow solid. LCMS (ESI) m / z [M+H]+= 338. Step 7: Preparation of tert-butyl (R)-(2,2-difluoro-1-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)ethyl)carbamate (Intermediate 56)

[0391] To a solution of Intermediate 55 (850.0 mg, 2.519 mmol, 1 equiv) in DMF (10 mL) was added Selectfluor (2.68 g, 7.557 mmol, 3 equiv). The resulting mixture was stirred overnight at 50 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C silica gel; mobile phase, MeCN in Water (0.1 % FA), 0% to 100% gradient in 30 min; detector, UV 254 / 220 nm. This resulted in Intermediate 56 (173.0 mg, 19.3%) as light brown oil. LCMS (ESI) m / z [M+H]+= 356.

[0392] A solution of Intermediate 56 (75 mg, 0.211 mmol, 1 equiv) in DCM (1 .5 mL) was added 4N HCI (gas) in 1 ,4-dioxane (3 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 57 (89.0 mg, crude) as light yellow oil. LCMS (ESI) m / z [M+H]+= 256.

[0393] Step 9: Preparation of (2S,4R)-N-((R)-2,2-difluoro-1-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)ethyl)-4-hydroxy-1-((R)-2-(3-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6 diazaspiro[3.3]heptan-2-yl)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide (Compound 19) A solution of intermediate 17 (20 mg, 0.033 mmol, 1.00 equiv) and Intermediate 57 (11.09 mg, 0.043 mmol, 1.3 equiv), DIEA (12.95 mg, 0.099 mmol, 3 equiv) in DMF (1 mL) was stirred for 2 h at room temperature. The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RPis OBD Column 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 45% B in 9 min; Wave Length: 254nm / 200nm nm; RT1 (min): 8.1) to afford Compound 19 (14.0 mg, 45.4%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 6 12.81 (s, 1 H), 9.50 - 8.85 (m, 1 H), 8.76 (s, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 2H), 7.63 - 7.54 (m, 3H), 7.36 - 7.24 (m, 2H), 7.04 - 6.96 (m, 3H), 6.56 - 6.12 (m, 1 H), 5.89 (s, 1 H), 5.43 (s, 1 H), 5.21 - 4.95 (m, 1 H), 4.55 (t, J = 7.7 Hz, 1 H), 4.38 (s, 2H), 4.28 (s, 3H), 4.11 (s, 4H), 3.84 - 3.75 (m, 4H), 3.62 (d, J =

[0394] 9.7 Hz, 1 H), 3.46 (d, J = 10.7 Hz, 1 H), 2.21 - 2.05 (m, 2H), 1 .95 (s, 1 H), 0.89 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.9 Hz, 3H). LCMS (ESI) m / z: [M+H]+= 836.40.

[0395] The compounds in Table 6 were prepared using procedures similar to those used above for the preparation of Compounds 1 , 5, 13, 14, 17, and 19. Table 6.

[0396] Degradation of BRM and BRG1

[0397] This example demonstrates the ability of the compounds of the disclosure to degrade a HIBit-BRM or HIBit-BRG1 fusion protein in a cell-based degradation assay.

[0398] Procedure: A stable HeLa cell line expressing HiBiT-BRM was generated. On day 0, 5000 cells were seeded in 40 pL of media into each well of 384-well cell culture plates. On day 1 , cells were treated with 120 nL DMSO or 120 nL of 3-fold serially DMSO-diluted compounds (10 points in duplicate with 30 pM as final top dose). Subsequently plates were incubated for 24 h in a standard tissue culture incubator and equilibrated at room temperature for 15 minutes. Nano- Glo HiBiT Lytic Detection System (Promega N3050) reagent was freshly prepared and 20 ul was added to each well. Upon addition of this LgBit-containing reagent, the HiBiT and LgBiT proteins associate to form the luminescent NanoBiT luciferase. The plates were shaken for 10 minutes at room temperature and the bioluminescence read using an EnVision plate reader (PerkinElmer).

[0399] For measurement of BRG1 degradation, a stable HeLa cell line expressing HIBit-BRG1 and Lg Bit was generated. The same protocol as above was then followed.

[0400] The degradation% was calculated using the following formula: % degradation = 100%- 100% x (Lumsampie - LurriLc) I (Lumnc -Lurrnc). DMSO treated cells are employed as High Control (HC) and 2 pM of a known BRM / BRG1 degrader standard treated cells are employed as Low Control (LC). The data was fit to a four parameter, non-linear curve fit to calculate IC50 (pM) values as shown in Table 21 .

[0401] Results: As shown in Table 7 below, the compounds of the invention degraded BRM and / or BRG1 .

[0402] Table 7.

[0403] “+” indicates inhibitory effect of > 1000 nM; “++” indicates inhibitory effect of > 100 nM;

[0404] “+++” indicates inhibitory effect of > 10 nM; “++++” indicates inhibitory effect of < 10 nM;

[0405] “NT” indicates not tested; “NC” indicates not calculated; “A” indicates maximum degradation > 75%; “B” indicates maximum degradation > 50%; and “C” indicates maximum degradation < 50%. Determination of Time-Dependent Inhibition of CYP3A4

[0406] This example demonstrates that the compounds of the disclosure do not demonstrate meaningful time-dependent inhibition of CYP3A4.

[0407] Procedure: 10 mM stock solutions of test compounds in DMSO were prepared and then diluted with DMSO to prepare solutions with final concentrations of the test compounds of 0 pM, 0.15 pM, 0.5 pM, 1.5 pM, 5 pM, 15 pM, and 50 pM. Solutions of mifepristone in DMSO were prepared af final concentrations of 0.1 pM, 0.3 pM, 1 pM, 3 pM, 10 pM, and 30 pM as a positive control. A substrate stock solution of midazolam was also prepared at a final concentration of 1 pM. A phosphate buffer solution was prepared by adding a solution of 3.4 g of potassium dihydrogen phosphate and 250 mL of pure water to a stirred solution of 7.098 g of disodium hydrogen phosphate and 500 mL of pure water until the pH reached 7.4. An NADPH solution was prepared freshly prior to use by dissolving 8.334 mg / mL NADPH in phosphate buffer. Finally, a master solution was prepared by mixing 167 pL of 100 mM phosphate buffer and 2 pL of 20 mg / mL microsomes.

[0408] 169 pL of the master solution and 1 pL of multiple concentrations of test compound or positive control compounds working solutions were dispensed in a 96 deep well plate. The plate was then placed into a water bath and pre-warmed at 37 °C for 5 minutes.

[0409] For the time zero data points, 10 pL of substrate and then 20 pL of 10 mM NADPH solution were added to the plate immediately after the pre-incubation step to start the reaction at the final concentration of 1 mM. The reaction was carried out in the 37 °C water bath for the appropriate time as listed in Table X.

[0410] For 30-minute plus NADPH data points, 10 pL of substrate was immediately added to the plate after the pre-incubation step, and then 30 minutes later, 20 pL of 10 mM NADPH solution was added to start the reaction at the final concentration of 1 mM. The reaction was carried out in the 37 °C water bath for the appropriate time as listed in Table X.

[0411] For 30-minute minus NADPH data points, 10 pL of substrate and 20 pL of 10 mM NADPH solution were both added to the plate 30 minutes after the pre-incubation step to start the reaction at the final concentration of 1 mM. The reaction was carried out in the 37 °C water bath for the appropriate time as listed in Table X.

[0412] At the predetermined time point listed in Table X, the reaction was quenched by the addition of 300 pL of quench solution (cold acetonitrile with 3% formic acid, 200 nM alprazolam, 200 nM labetalol and 200 nM tolbutamide). The plate was then centrifuged at 3.22 g for 50 minutes at 4 °C. 150 pL of the supernatant was transferred to a new plate. The supernatant was diluted with 150 pL pure water, if necessary and mixed well. The samples were then analyzed using UPLC-MS / MS.

[0413] The automatic peak integration areas were checked for all of the samples and the Analyte Peak Area and Internal Standard Peak Area were exported into excel spreadsheet. The inhibition of CYP450 in human liver microsomes was measured as the percentage decrease in the activity of marker metabolite formation compared to non-inhibited solvent controls (= 100% activity). The percentage of remaining activity was calculated as Area Ratio test compound / Area Ratio vehicie*1 00%, wherein the Area Ratio is Peak Area Analyte / Peak Area internal standard. The mean of the enzyme activity (% of non-inhibited control) for each concentration was plotted against the inhibitor concentration and fitted to an IC50 curve using Graphpad Prism 8.

[0414] Results: As shown in Table 8 below, the compounds of the invention were found to not meaningfully inhibit CYP3A4 at either time zero or after 30 minutes of incubation.

[0415] Table 8.

[0416] Other Embodiments

[0417] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

[0418] While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are in the claims.

Claims

Claims1 . A compound, or a pharmaceutically acceptable salt thereof, of Formula I:Formula I wherein m is 0, 1 , 2, or 3; k is 0, 1 , or ; each R1is, independently, halo, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano; each X is, independently, halo or optionally substituted Ci-Ce heteroalkyl;L is a linker; andB has the structure:RB1is H, A2, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;RB2is H, halogen, optionally substituted Ci-Cs alkyl, or optionally substituted Ci-Ce heteroalkyl;RB3is A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, optionally substituted Ci-Ce alkyl C3-C10 carbocyclyl, or optionally substituted Ci-C@ alkyl Ce-Cw aryl;RB4is O-RB4Aor boronic acid;RB4Ais H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted CI-CB alkyl C3-C10 carbocyclyl, or optionally substituted Ci- Ce alkyl Ce-Cio aryl;RB5is H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Cs heteroalkyl; v2 is 0, 1 , 2, 3, or 4; each RB6is, independently, A2, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; each of RB7and RBSis, independently, H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted CB-CIO aryl;RB9and RB11are, independently, H or optionally substituted Ci-Ce alkyl;RB1° is H or F; andA2is a bond between B and the linker; wherein one and only one of RB1, RB3, and RB6is A2, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula l-A:Formula l-A3. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0.

4. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 1 .

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1is methoxy or difluoromethoxy.

6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1is F or Cl.

7. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1is methyl, or difluoromethyl.

8. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein k is 0.

9. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein k is 1 .

10. The compound of any one of claims 1 -7 and 9, or a pharmaceutically acceptable salt thereof, wherein X is methoxy or F.11 . The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, wherein B has the structure of Formula ll-A:Formula ll-A12. The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, wherein B has the structure of Formula ll-B:Formula ll-B13. The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, wherein B has the structure of Formula ll-C:Formula ll-C14. The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, wherein B has the structure of Formula ll-D:Formula ll-D15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L4is16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L4is17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein RB2is H, or halogen.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein RB9is optionally substituted Ci-Ce alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein RB9is methyl or difluoromethyl.

20. The compound of any one of claims 1 -19, or a pharmaceutically acceptable salt thereof, wherein RB9is bonded to (S)-stereogenic center.21 . The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

22. The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, wherein v2 is 1 or 2 and each RB6is independently selected from halogen or methyl.

23. The compound of any one of claims 1 -22, or a pharmaceutically acceptable salt thereof, wherein RB5is H.

24. The compound of any one of claims 1 -23, or a pharmaceutically acceptable salt thereof, wherein RB3is isopropyl or fluoro-2-methylpropane.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein RB3is isopropyl.

26. The compound of any one of claims 1 -25, or a pharmaceutically acceptable salt thereof, wherein RB7is H or halogen.

27. The compound of any one of claims 1 -26, or a pharmaceutically acceptable salt thereof, wherein RB8is H or halogen.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein RB8is H, F or Cl.

29. The compound of any one of claims 1-13 and 15-28, or a pharmaceutically acceptable salt thereof, wherein RB11is H or methyl.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of Formula III:A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2,Formula III or a pharmaceutically acceptable salt thereof, whereinA1is a bond between the linker and the ring system A;A2is a bond between B and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkyl, optionally substituted Ce-C-io aryl, optionally substituted Ce-C-io aryl C1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-12 aryl, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted CM alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl; each of C1and C2is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is, independently, 0 or 1 ; andD is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, optionallysubstituted Ce-12 aryl, optionally substituted C2-C10 polyethylene glycol, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-10 heteroalkyl; or D is absent, and the linker is A1-(B1)f-(C1)g-(B2)h-(B3),-(C2)r(B4)k-A2.31 . The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of32. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of33. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of34. A compound according to claim 1 selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

35. A compound according to claim 1 selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound of any one of claims 1 to 35 and a pharmaceutically acceptable excipient.

37. A method of treating a BAF complex-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 35 or a pharmaceutical composition of claim 36.

38. The method of claim 37, wherein the BAF complex-related disorder is cancer or a viral infection.

39. A method of treating a disorder related to a BRG1 loss of function mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 35 or a pharmaceutical composition of claim 36.

40. The method of claim 39, wherein the disorder related to a BRG1 loss of function mutation is cancer.41 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 35 or a pharmaceutical composition of claim 36.

42. The method of any one of claims 37-41 , wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, nonmelanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.

43. The method of claim 42, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

44. The method of claim 42, wherein the cancer is non-small cell lung cancer.

45. The method of claim 42, wherein the cancer is soft tissue sarcoma.

46. A method of treating a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and a hematologic cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 35 or a pharmaceutical composition of claim 36.

47. A compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 36, for use in therapy.

48. A compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 36, for use in treating cancer.

49. The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 48, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma,gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.

50. The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 48, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.51 . The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 48, wherein the cancer is non-small cell lung cancer.

52. The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to claim 48, wherein the cancer is soft tissue sarcoma.

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