Compound and its use

Abstract

The present disclosure features compounds and methods useful for treating BAF complex-associated disorders.

Description

Background Art

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

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human switch / sucrose non-fermentable (SWI / SNF) chromatin remodeling complex, also known as the BAF complex, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is required for the growth of cancer cells. BRM, also known as the putative global transcriptional activator SNF2L2 and / or the ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for the growth of tumor cells in cells characterized by loss-of-function mutations of BRG1. Deactivation of BRG and / or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.

Summary of the Invention

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

[0004] In one aspect, the present invention is a compound having the structure of Formula I, wherein A-L-B Formula I In the formula, L is a linker, B is a degradation moiety, A has the structure of Formula II, [Chemical formula] In the formula, X 1 is N or CH, X 2 and X 3 are independently N, CH, or C(CH3), R 1 is H, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 wherein, R 2 and R 5 each are independently H or optionally substituted C1-C6 alkyl, R 3 is H, optionally substituted C1-C6 alkyl, or a bond between A and the linker, R 4 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 wherein, R 7 and R 8 each are independently optionally substituted C1-C6 alkyl, Het is a 5- or 6-membered heteroarylene, G 1 is optionally substituted C6-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene, G 2is absent, -O-, C1-C6 alkylene optionally substituted, C1-C6 alkenylene optionally substituted, C1-C6 heteroalkylene optionally substituted, C2-C9 heterocyclyl C1-C6 alkylene optionally substituted, or C2-C9 heteroaryl C1-C6 alkylene optionally substituted, G 3 is absent, C6-C 10 arylene optionally substituted, C6-C 10 cycloalkylene optionally substituted, C2-C9 heterocyclylene optionally substituted, or C2-C9 heteroarylene optionally substituted, A 1 is H, or a bond between A and the linker, provided that formula II contains only one bond between A and the said linker, a compound, or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, R 3 is H or C1-C6 alkyl optionally substituted, and A 1 is a bond between A and the linker. In some embodiments, R 3 is a bond between A and the linker, and A 1 is H.

[0006] In some embodiments, R 2 is hydrogen.

[0007] In some embodiments, R 5 is hydrogen. In other embodiments, R 5 is C1-C6 alkyl optionally substituted, for example, methyl.

[0008] In some embodiments, X 1 , X 2 , and X 3 are CH. In some embodiments, X 1 is N, and X 2 and X3 is CH. In some embodiments, X 3 is N, and X 1 and X 2 are CH. In some embodiments, X 2 is N, and X 1 and X 3 are CH. In some embodiments, X 1 is CH, and X 2 and X 3 are C(CH3). In some embodiments, X 1 and X 3 are CH, and X 2 is C(CH3).

[0009] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is optionally substituted C1-C6 alkyl, e.g., R 3 is methyl.

[0010] In further embodiments, R 4 is hydrogen. In other embodiments, R 4 is optionally substituted C1-C6 alkyl, e.g., methyl, tert-butyl, iso-propyl, iso-butyl, or tert-pentyl. In further embodiments, R 4 is optionally substituted C1-C6 heteroalkyl, e.g.,

Chemical formula

[0011] In some embodiments, Het is

Chemical formula

Chemical formula

[0012] In some embodiments, G 2 is absent. In some embodiments, G 2 is optionally substituted C1-C6 alkylene, for example, G 2 is [Chem.] is. In further embodiments, G 2 is optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heterocyclyl C1-C6 alkylene, for example, [Chem.] is. In certain embodiments, G 2 is optionally substituted C1-C6 alkenylene, for example, [Chem.] is.

[0013] In some embodiments, G 1 is optionally substituted C6-C 10 arylene, for example, [Chem.] is.

[0014] In other embodiments, G 1 is optionally substituted C2-C9 heteroarylene, for example, [Chem.] is.

[0015] In further embodiments, G 1is an optionally substituted C2-C9 heterocyclylene, for example, [Chemical formula] .

[0016] In some embodiments, G 3 is absent.

[0017] In further embodiments, G 3 is an optionally substituted C6-C 10 arylene, for example, [Chemical formula] .

[0018] In still further embodiments, G 3 is an optionally substituted C2-C9 heterocyclylene, for example, [Chemical formula] [Chemical formula] . In some embodiments, G 3 is [Chemical formula] , and R 9a , R 9b , R 9c , and R 9d are independently A 1 , H, halogen, hydroxyl, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 heteroalkyl, and each of R 9e and R 9f is independently H or A 1 . In still other embodiments, G 3 is [Chemical formula] , and X4 is O or CR 10i R 10j wherein each of R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i 、and R 10j is independently H, halogen, cyano, amino, hydroxyl, allyl, heteroallyl, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or two of them in combination with the carbon to which they are attached to form C=O.

[0019] In yet another embodiment, G 3 is optionally substituted C2-C9 heteroarylene, for example,

Chemical formula

Chemical formula

[0020] In a further embodiment, G 3 is optionally substituted C6-C 10 cycloalkylene, for example,

Chemical formula

[0021] In some embodiments, A 1 、G 1 、G 2 、and G 3 combine to form optionally substituted C6-C 10 aryl, for example,

Chemical formula

[0022] In other embodiments, A 1 , G 1 , G 2 , and G 3 combine to form an optionally substituted C2-C9 heteroaryl, for example,

Chemical formula

[0023] In a further embodiment, A 1 , G 1 , G 2 , and G 3 combine to form an optionally substituted C2-C9 heterocyclyl, for example,

Chemical formula

[0024] In certain embodiments, R 1 is hydrogen. In other embodiments, R 1 is an optionally substituted C1-C6 acyl, for example, acetyl. In a further embodiment, R 1 is an optionally substituted C1-C6 alkyl, for example, methyl, tert-butyl, isopropyl, or

Chemical formula

Chemical formula

Chemical formula

[0025] In a further embodiment, R1 is -SO2R 6 In some embodiments, R 6 is optionally substituted C1-C6 alkyl, such as methyl, iso-propyl, or

Chemical formula

Chemical formula

[0026] In some embodiments, the cleavage moiety is a ubiquitin ligase binding moiety.

[0027] In some embodiments, the ubiquitin ligase binding moiety includes a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a murine double minute 2 homolog (MDM2), or a von Hippel-Lindau (VHL) ligand, or a derivative or analog thereof.

[0028] In some embodiments, the cleavage moiety is a ubiquitin ligase binding moiety.

[0029] In some embodiments, the ubiquitin ligase binding moiety includes a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a murine double minute 2 homolog (MDM2), or a von Hippel-Lindau (VHL) ligand, or a derivative or analog thereof.

[0030] In some embodiments, the cleavage moiety is a structure of formula Y,

Chemical formula

Chem.

Chem.

[0031] In some embodiments, T 1 is a bond. In some embodiments, T 1 is

Chem.

[0032] In some embodiments, T 2 is

Chem.

Chem.

[0033] In some embodiments, the structure of formula Y is the structure of formula Y1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the structure of formula Y is the structure of formula Y2, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the structure of formula Y is the structure of formula Z, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, u1 is 1. In some embodiments, u1 is 2. In some embodiments, u1 is 3.

[0037] In some embodiments, the structure of formula Z is the structure of formula AA, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the structure of formula Z is the structure of formula AB, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the structure of formula Z is the structure of formula AC, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0. In some embodiments, v1 is 1. In some embodiments, v1 is 2. In some embodiments, v1 is 3.

[0041] In some embodiments, the structure of formula AA is the structure of formula AA1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the structure of formula AB is the structure of formula AB1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the structure of formula AC is the structure of formula AC1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, J is absent. In some embodiments, J is an optionally substituted C3-C 10 carbocyclylene or an optionally substituted C6-C 10 arylene. In some embodiments, J is an optionally substituted C2-C9 heterocyclylene or an optionally substituted C2-C9 heteroarylene.

[0045] In some embodiments, J is an optionally substituted heterocyclylene. In some embodiments, J is an optionally substituted C6-C 10 arylene.

[0046] In some embodiments, the structure of formula AA is the structure of formula AA2,

Chemical formula

[0047] In some embodiments, the structure of formula AA is the structure of formula AA3,

Chemical formula

[0048] In some embodiments, the structure of formula AA is the structure of formula AA4,

Chemical formula

[0049] In some embodiments, R A5 is H or an optionally substituted C1-C6 alkyl. In some embodiments, R A5 is H or methyl. In some embodiments, R A5 is H. In some embodiments, R A5 is methyl.

[0050] In some embodiments, the structure of formula AA is the structure of formula A,

Chemical formula

Chemical formula

[0051] In some embodiments, each of R A1 R A2 R A3 and R A4 is independently H, A 2 halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted C2-C9 heterocyclic, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino, or R A1 and R A2 R A2 and R A3 and / or R A3 and R A4 combine together with the carbon atoms to which each is attached to [Chemistry] to form [Chemistry] is optionally substituted C6-C 10 aryl, optionally substituted C3-C 10 carbocyclic, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclic, any of which is optionally substituted with A 2 and one of R A1 R A2 R A3 and R A4 is A 2 or [Chemistry] is substituted with A 2 and has a structure or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, each of R A1 R A2 R A3 and R A4 is H, A 2 halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclic, hydroxyl, optionally substituted amino, or R A1 and R A2 R A2 and R A3 or R A3 and R A4 combine together with the carbon atom to which each is attached to form [Chemistry] to form [Chemistry] is optionally A 2 is an optionally substituted C2-C9 heterocyclyl optionally substituted with A, R A1 , R A2 , R A3 , and R A4 one of which is A 2 or

Chemical formula

[0053] In some embodiments, each of R A1 , R A2 , R A3 , and R A4 is independently H, A 2 , F,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0054] In some embodiments, R A1 is A 2 In some embodiments, R A2 is A 2 In some embodiments, R A3 is A 2 In some embodiments, R A4 is A 2 In some embodiments, R A5 is A 2 is.

[0055] In some embodiments, R A5 is H or optionally substituted C1-C6 alkyl.

[0056] In some embodiments, R A5 is H or

Chemical formula

Chemical formula

[0057] In some embodiments, Y 1 is

Chemical formula

Chemical formula

Chemical formula

[0058] In some embodiments, RA6 and R A7 Each of which is independently H, F, [Chemical formula] or R A6 and R A7 together with the carbon atom to which each is attached form [Chemical formula] .

[0059] In some embodiments, Y 1 is [Chemical formula] .

[0060] In some embodiments, the structure of formula A is the structure of formula A1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the structure of formula A is the structure of formula A2, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the structure of formula A is the structure of formula A3, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the structure of formula A is the structure of formula A4, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the structure of Formula A is the structure of Formula A5,

Chemical formula

[0065] In some embodiments, the structure of Formula A is the structure of Formula A6,

Chemical formula

[0066] In some embodiments, the structure of Formula A is the structure of Formula A7,

Chemical formula

[0067] In some embodiments, the structure of Formula A is the structure of Formula A8,

Chemical formula

[0068] In some embodiments, the structure of Formula A is the structure of Formula A9,

Chemical formula

[0069] In some embodiments, the structure of Formula A is the structure of Formula A10,

Chemical formula

[0070] In some embodiments, the structure of Formula A is [Chemical formula] or a derivative or analog thereof.

[0071] In some embodiments, the structure of Formula A is [Chemical formula] as follows.

[0072] In some embodiments, the structure of Formula A is [Chemical formula] or a derivative or analog thereof.

[0073] In some embodiments, [Chemical formula] is [Chemical formula] wherein R A9 is H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.

[0074] In some embodiments, the structure of Formula A is [Chemical formula] as follows.

[0075] In some embodiments, R A9 is H, A 2 , or optionally substituted C1-C6 alkyl. In some embodiments, R A9 is H, A 2 , or methyl. In some embodiments, R 9A is H. In some embodiments, R 9A is methyl. In some embodiments, R A9is A 2 is the case.

[0076] In some embodiments, the structure of Formula A is

Chemical formula

[0077] In some embodiments, the structure of Formula AA is the structure of Formula B,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0078] In some embodiments, each of R A1 R A2 R A3 and R A4 is H, A 2 halogen, C1-C6 alkyl optionally substituted, C1-C6 heteroalkyl optionally substituted, -O-C3-C6 carbocyclic optionally substituted, hydroxyl, amino optionally substituted, or R A1 and R A2 R A2 and R A3 or R A3 and R A4 combine together with the carbon atom to which each is attached to form

Chemical formula

Chemical formula

[0079] In some embodiments, each of R A1 , R A2 , R A3 , and R A4 is independently H, A 2 , F, [Chem.] or R A1 and R A2 , R A2 and R A3 , or R A3 and R A4 combine with the carbon atom to which each is attached to form [Chem.] , [Chem.] is an optionally substituted C2-C9 heterocyclyl optionally substituted with A 2 , and one of R A1 , R A2 , R A3 , and R A4 is A 2 or [Chem.] is replaced by A 2 .

[0080] In some embodiments, R A1 is A 2 . In some embodiments, R A2 is A 2 . In some embodiments, R A3 is A2 It is. In some embodiments, R A4 is A 2 It is. In some embodiments, R A5 is A 2 It is.

[0081] In some embodiments, R A5 is H or optionally substituted C1-C6 alkyl.

[0082] In some embodiments, R A5 is H or

Chemical formula

Chemical formula

[0083] In some embodiments, the structure of formula B is the structure of formula B1,

Chemical formula

[0084] In some embodiments, the structure of formula B is the structure of formula B2,

Chemical formula

[0085] In some embodiments, the structure of formula B is the structure of formula B3,

Chemical formula

[0086] In some embodiments, the structure of formula B is the structure of formula B4, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the structure of Formula B is [Chemical formula] as follows. In some embodiments, the structure of Formula B is [Chemical formula] as follows. In some embodiments, the structure of Formula B is [Chemical formula] as follows.

[0088] In some embodiments, the ubiquitin ligase binding moiety comprises a von Hippel-Lindau ligand.

[0089] In some embodiments, the von Hippel-Lindau ligand [Chemical formula] has the structure of or a derivative or analog thereof.

[0090] In some embodiments, the cleavage moiety has the structure of Formula C, [Chemical formula] wherein R B1 and R B9 are independently H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3 is A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl C3-C 10 carbocyclic, or optionally substituted C1-C6 alkyl C6-C 10 aryl, and R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl C3-C 10 carbocyclic, or optionally substituted C1-C6 alkyl C6-C 10 aryl, and R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and v2 is 0, 1, 2, 3, or 4, and each R B6 is independently halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted C2-C9 heterocyclic, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, and R B7 and R B8 each is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 aryl, and R B1 , R B3 , RB6 and R B9 One of 2 is a structure, or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the structure of Formula C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0092] In some embodiments, the degrader moiety is the degrader moiety described in International Patent Publication No. 2019 / 195201, which is incorporated herein by reference.

[0093] In some embodiments, the degrader moiety is a structure of Formula D,

Chemical formula

[0094] In some embodiments, the structure of formula D is

Chemical formula

[0095] In some embodiments, the cleaving agent moiety has the structure of formula E,

Chemical formula

[0096] In some embodiments, the structure of Formula E is

Chemical formula

[0097] In some embodiments, the cleavage moiety is a structure of Formula FA,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0098] In some embodiments, the compound of Formula FA has the structure of Formula FA1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the cleavage moiety has the structure of Formula FB, [Chemical formula] wherein [Chemical formula] is [Chemical formula] or is a bicyclic moiety substituted with A 2 and one or more groups independently selected from H, R FF1 , and oxo, A 2 is the bond between the cleaving agent and the linker, Y Fa is CR Fb R Fc , C=O, C=S, C=CH2, SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH, P(O)NH2, Y Fb and each of Y Fg is independently NH, NR FF1 , CH2, CHR FF1 , C(R FF1 )2, O, or S, Y Fc is CR Fd R Fe , C=O, C=S, C=CH2, SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH, P(O)NH2, R Fb R Fc R Fd RFe , R Ff , and R Fg each is independently H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclic, hydroxyl, alkoxy, amino, -NH alkyl, or -N alkyl2, or R Fb and R Fc combine together with the carbon atom to which each is attached to form a 3, 4, 5, or 6 - membered spirocarbocyclene, or a 4, 5, or 6 - membered spiroheterocyclene containing 1 or 2 heteroatoms selected from N and O, or R Fd and R Fe combine together with the carbon atom to which each is attached to form a 3, 4, 5, or 6 - membered spirocarbocyclene, or a 4, 5, or 6 - membered spiroheterocyclene containing 1 or 2 heteroatoms selected from N and O, or R Ff and R Fg combine together with the carbon atom to which each is attached to form a 3, 4, 5, or 6 - membered spirocarbocyclene, or a 4, 5, or 6 - membered spiroheterocyclene containing 1 or 2 heteroatoms selected from N and O, or R Fd and R Fb combine together with the carbon atom to which each is attached to form a 1, 2, 3, or 4 - carbon bridged ring, or R Fd and R Ff combine together with the carbon atom to which each is attached to form a 1, 2, 3, or 4 - carbon bridged ring, or R Fb and R Fg combine together with the carbon atom to which each is attached to form a 1, 2, 3, or 4 - carbon bridged ring, Y Fd and Y Ff each is independently CH2, CHR FF2 , C(R FF2 )2, C(O), N, NH, NR FF3, O, S, or S(O), and Y Fe is Y containing 1 to 5 consecutive carbon atoms forming a 3- to 8-membered ring, Fd and Y Ff is a bond or divalent moiety attached to Y, wherein 1, 2, or 3 carbon atoms may be replaced by nitrogen, oxygen, or sulfur atoms, one of the ring atoms is substituted with A 2 and the other is substituted with one or more groups independently selected from H and R FF1 and the consecutive atoms of Y Y Fe may be connected via a single bond or a double bond, each R FF1 is independently H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclic, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclic, alkylamino, alkylhydroxyl, or haloalkyl, each R FF2 is independently alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, -C(O)H, -C(O)OH, -C(O)(aliphatic containing alkyl), -C(O)O(aliphatic containing alkyl), -NH(aliphatic containing alkyl), -N(aliphatic containing alkyl)(aliphatic containing alkyl), -NHSO2alkyl, -N(alkyl)SO2alkyl, -NHSO2aryl, -N(alkyl)SO2aryl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, -SH, -Salkyl, or haloalkyl, R FF3 is alkyl, alkenyl, alkynyl, -C(O)H, -C(O)OH, -C(O)alkyl, or -C(O)Oalkyl, Y Fd or Y Ff is substituted with A 2 when Y Fecomprises a structure, or a pharmaceutically acceptable salt thereof, which is a bond.

[0100] In some embodiments, the compound of formula FB has the structure of formula FB1,

Chemical formula

[0101] In some embodiments, the cleavage moiety has the structure of formula F1,

Chemical formula

[0102] In some embodiments, R F1 is absent. In some embodiments, R F1 is O.

[0103] In some embodiments, the structure of formula F1 is

Chemical formula

[0104] In some embodiments, the cleavage moiety has the structural formula F2,

Chemical formula

[0105] In some embodiments, Y 2 is NH. In some embodiments, Y 2 is CH2.

[0106] In some embodiments, the structure of Formula F2 is

Chemical formula

[0107] In some embodiments, the cleavage moiety is a structural formula G,

Chemical formula

[0108] In some embodiments, Y 3 is NH. In some embodiments, Y 3 is CH2.

[0109] In some embodiments, the structure of Formula G is

Chemical formula

[0110] The cleavage moiety may also include structures found in, for example, WO2017 / 197036, WO2019 / 204354, WO2019 / 236483, WO2020 / 010177, and WO2020 / 010227, each of which is incorporated herein by reference in its entirety.

[0111] In some embodiments, the linker has a structure of Formula III, A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 )k -A 2 Formula III In the formula, A 1 is a bond between A and the linker, and A 2 is a bond between the linker and B, and B 1 , B 2 , B 3 , and B 4 each independently is optionally substituted C1-C2 alkyl, optionally substituted C1-C2 heteroalkyl, O, S, S(O)2, or NR N where each R N independently is H, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, or optionally substituted C 1-7 heteroalkyl, and each of C 1 and C 2 independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, and each of f, g, h, i, j, and k independently is 0 or 1, and D is optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C2-C 12 polyethylene glycol, or optionally substituted C 1-12 heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is a chemical bond that binds to -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond that binds to.

[0112] In some embodiments, B 1 , B 2 , B 3 , and B 4 each independently is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or NR N .

[0113] In some embodiments, each R N is independently H or optionally substituted C1-C4 alkyl.

[0114] In some embodiments, each R N is independently H or methyl.

[0115] In some embodiments, B 1 and B 4 each independently is

Chemical formula

[0116] In some embodiments, B 1 is

Chemical formula

[0117] In some embodiments, C 1 and C 2 each independently is

Chemical formula

[0118] In some embodiments, C 1 is

Chemical formula

[0119] In some embodiments, B2 is NR N In some embodiments, B 2 is optionally substituted C1-C4 alkyl.

[0120] In some embodiments, f is 0. In some embodiments, f is 1. 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, j is 0. In some embodiments, k is 0.

[0121] In some embodiments, D is optionally substituted C 1-12 alkyl, optionally substituted C2-C 12 polyethylene glycol, or optionally substituted C 1-12 heteroalkyl. In some embodiments, D is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is a chemical bond that binds to -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 In some embodiments, the linker has the structure of

[0122] In some embodiments, the linker has the structure of

Chemical formula

Chemical formula

[0123] In some embodiments, W is

Chemical formula

Chemical formula

Chemical formula

[0124] In some embodiments, each of R x1 and R x2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C6 carbocyclic.

[0125] In some embodiments, each of R x1 and R x2 is independently H or optionally substituted C1-C6 alkyl.

[0126] In some embodiments, R x1 and R x2 are each independently H or methyl.

[0127] In some embodiments, R x1 and R x2 combine together with the carbon atom to which each is attached to form an optionally substituted C3-C6 carbocyclic or an optionally substituted C2-C5 heterocyclic group.

[0128] In some embodiments, R x1 and R x2 combine together with the carbon atom to which each is attached to form an optionally substituted C3-C6 carbocyclic group.

[0129] In some embodiments, R x1 and R x2 combine together with the carbon atom to which each is attached to form cyclopropyl.

[0130] In some embodiments, each of R y1 , R y2 , R y3 , and R y4 is independently H or an optionally substituted C1-C6 alkyl.

[0131] In some embodiments, each of R y1 , R y2 , R y3 , and R y4 is independently H or methyl.

[0132] In some embodiments, the linker is

Chemical formula

Chemical formula

Chemical formula

[0133] In some embodiments, the linker has the structure of Formula IV, A 1 -(E 1 ) p1 -(F 1 )-(C 3 ) m1 -(E 3 ) n1 -(C 4 ) m2 -(F 2 ) o1 -(E 3 ) n2 -(F 3 ) o2 -(E 2 ) p2 -A 2 Formula IV wherein A 1 is the bond between the linker and A, and A 2 is the bond between B and the linker, and each of m1, m2, n1, n2, o1, o2, p1, and p2 is independently 0 or 1, and each of E 1 and E 2 is independently O, S, NR N , optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C2-C 10 polyethylene glycol, or optionally substituted C 1-10 heteroalkyl, and each E 3 is independently optionally substituted C 1-10 alkyl, optionally substituted C 1-10 heteroalkyl, O, S, or NR N , and each R N is independently H, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, or optionally substituted C 1-7 heteroalkyl, where C 3 and C 4 each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, and F 1 , F 2 , and F 3 each independently is optionally substituted C3-C 10 carbocyclyl, optionally substituted C 2-10 heterocyclyl, optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[0134] In some embodiments, the linker has the structure of Formula IVa. A 1 -(F 1 )-(C 3 ) m1 -(E 2 ) p2 -A 2 Formula IVa

[0135] In some embodiments, the linker has the structure of Formula IVb. A 1 -(E 1 )-(F 1 )-(E 2 ) p2 -A 2 Formula IVb

[0136] In some embodiments, the linker has the structure of Formula IVc. A 1 -(E 1 ) p1 -(F 1 )-(F 2 )-(E 2 )-A 2 Formula IVc

[0137] In some embodiments, the linker has the structure of Formula IVd. A 1 -(E 1 ) p1 -(F 1 )-(C 3 ) m1 -(E 3 ) n -(C 4 ) m2 -(F 2 )-(E 2 ) p2 -A 2 Formula IVd

[0138] In some embodiments, the linker has the structure of Formula IVe. A 1 -(F 1 )-A 2 Formula IVe

[0139] In some embodiments, the linker has the structure of Formula IVf, A 1 -(E 1 ) p1 -(F 1 )-(C 3 ) m1 -(E 3 ) n1 -(C 4 ) m2 -(F 2 ) o1 -(F 3 ) o2 -(E 2 ) p2 -A 2 Formula IVf Wherein A 1 is the bond between the linker and A, A 2 is the bond between B and the linker, and each of m1, m2, n1, o1, o2, p1, and p2 is independently 0 or 1, and each of E 1 and E 2 is independently O, S, NR N , optionally substituted C 1-10Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1-10 Is heteroalkyl, and E 3 Are independently, optionally substituted C 1-2 Alkyl, optionally substituted C 1-2 Heteroalkyl, O, S, or NR N And each R N Is independently, H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 Is heteroalkyl, and C 3 And C 4 Each of which is independently, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, and F 1 F 2 And F 3 Each of which is independently, optionally substituted C3-C 10 Carbocyclic, optionally substituted C 2-10 Heterocyclyl, optionally substituted C6-C 10 Aryl, or optionally substituted C2-C9 heteroaryl.

[0140] In some embodiments, each R N Is independently, H or optionally substituted C 1-4 Alkyl.

[0141] In some embodiments, each R N Is independently, H or methyl.

[0142] In some embodiments, E 1 And E 2 Each of which is independently, NRN , C optionally substituted 1-10 alkyl, C2-C optionally substituted 10 polyethylene glycol, or C optionally substituted 1-10 is heteroalkyl.

[0143] In some embodiments, E 1 and E 2 each independently is C optionally substituted 1-10 alkyl or C optionally substituted 1-10 is heteroalkyl.

[0144] In some embodiments, E 1 is [Chemical formula] , where z1 is 0, 1, or 2, z2 is 0, 1, 2, 3, 4, 5, or 6, and each of R z1 and R z2 is independently H, halogen, C1-C6 alkyl optionally substituted, C1-C6 heteroalkyl optionally substituted, or C3-C6 carbocyclic optionally substituted, or R x1 and R x2 together with the carbon atom to which each is attached combine to form C3-C6 carbocyclic optionally substituted or C2-C5 heterocyclic optionally substituted, and each of R a and R b is independently H, C1-C6 alkyl optionally substituted, C1-C6 heteroalkyl optionally substituted, or C3-C6 carbocyclic optionally substituted.

[0145] In some embodiments, z1 is 0. In some embodiments, z1 is 1.

[0146] In some embodiments, R z1 and R z2Each of them is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C6 carbocyclic.

[0147] In some embodiments, R z1 and R z2 are each independently H or optionally substituted C1-C6 alkyl.

[0148] In some embodiments, R z1 and R z2 are each independently H or methyl.

[0149] In some embodiments, R z1 and R z2 combine together with the carbon atom to which each is attached to form an optionally substituted C3-C6 carbocyclic or an optionally substituted C2-C5 heterocyclic.

[0150] In some embodiments, R z1 and R z2 combine together with the carbon atom to which each is attached to form an optionally substituted C3-C6 carbocyclic.

[0151] In some embodiments, R z1 and R z2 combine together with the carbon atom to which each is attached to form cyclopropyl.

[0152] In some embodiments, R a and R b are each independently H or form an optionally substituted C1-C6 alkyl.

[0153] In some embodiments, R a and R b are each independently H or methyl.

[0154] In some embodiments, E 2 is [Chemical formula] where z3 is 0, 1, 2, 3, 4, 5, or 6, z4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, z5 is 0, 1, 2, 3, or 4, z6 is 1, 2, 3, or 4, and each of R z3 and R z4 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C6 carbocyclic, or R x1 and R x2 together with the carbon atom to which each is attached combine to form an optionally substituted C3-C6 carbocyclic or optionally substituted C2-C5 heterocyclic, and R c is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C6 carbocyclic.

[0155] In some embodiments, z3 is 0, 1, 2, or 3.

[0156] In some embodiments, z4 is 0, 1, 2, 3, 4, 5, or 6.

[0157] In some embodiments, z5 is 0, 1, or 2.

[0158] In some embodiments, z6 is 1 or 2.

[0159] In some embodiments, each of R z3 and R z4 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C6 carbocyclic.

[0160] In some embodiments, R z3 and R z4 each independently is H or optionally substituted C1-C6 alkyl.

[0161] In some embodiments, R z3 and R z4 each independently is H or methyl.

[0162] In some embodiments, R z3 and R z4 together with the carbon atom to which each is attached combine to form an optionally substituted C3-C6 carbocyclic or an optionally substituted C2-C5 heterocyclic.

[0163] In some embodiments, R z3 and R z4 together with the carbon atom to which each is attached combine to form an optionally substituted C3-C6 carbocyclic.

[0164] In some embodiments, R z3 and R z4 together with the carbon atom to which each is attached combine to form cyclopropyl.

[0165] In some embodiments, R c is H or optionally substituted C1-C6 alkyl.

[0166] In some embodiments, R c is H or methyl.

[0167] In some embodiments, E 3 is optionally substituted C 1-2 alkyl, optionally substituted C 1-2 heteroalkyl. In some embodiments, E 3 is O, S, or NR N wherein.

[0168] In some embodiments, E 3 is optionally substituted C 1-2 alkyl.

[0169] In some embodiments, E 3 is

Chemical formula

[0170] In some embodiments, each of F 1 , F 2 , or F 3 is independently optionally substituted C3-C 10 carbocyclic. In some embodiments, the C3-C 10 carbocyclic is monocyclic. In some embodiments, the C3-C 10 carbocyclic is polycyclic. In some embodiments, the C3-C 10 carbocyclic is bicyclic. In some embodiments, the C3-C 10 carbocyclic is bridged. In some embodiments, the C3-C 10 carbocyclic is fused. In some embodiments, the C3-C 10 carbocyclic is spirocyclic.

[0171] In some embodiments, the C3-C 10 carbocyclic is

Chemical formula

Chemical formula

[0172] In some embodiments, F 1 , F 2 , or F 3Each of them is independently a C2-C6 heterocycle optionally substituted. In some embodiments, C 2- The C9 heterocycle is monocyclic. In some embodiments, C 2- The C9 heterocycle is polycyclic. In some embodiments, C 2- The C9 heterocycle is bicyclic. In some embodiments, C 2- The C9 heterocycle is bridged. In some embodiments, C 2- The C9 heterocycle is fused. In some embodiments, C 2- The C9 heterocycle is spirocyclic.

[0173] In some embodiments, the C2-C6 heterocycle is

Chemical formula

Chemical formula

[0174] In some embodiments, each of F 1 , F 2 , or F 3 is independently an optionally substituted C6-C 10 aryl. In some embodiments, each of F 1 , F 2 , or F 3 is independently an optionally substituted C2-C9 heteroaryl.

[0175] In some embodiments, each of C 3 and C 4 is independently

Chemical formula

[0176] In some embodiments, C 3 is

Chem.

[0177] In some embodiments, the linker is

Chem.

Chem.

Chem.

Chem.

Chem.

[0178] In some embodiments, the compound is any one of Compounds 1 to 169 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of Compounds 170 to 297 in Table 1, or a pharmaceutically acceptable salt thereof.

[0179] In one aspect, the compound is any one of Compounds 1 to 297 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of Compounds 1 to 169 in Table 1, or a pharmaceutically acceptable salt thereof.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

[0180] In one aspect, the present invention features a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0181] In another aspect, the present invention features a method of reducing the activity of the BAF complex in a cell, the method comprising contacting the cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0182] In some embodiments, the cell is a cancer cell.

[0183] In another aspect, the present invention features a method of treating a subject in need of treating a BAF complex-related disorder, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0184] In some embodiments, the BAF complex-related disorder is cancer.

[0185] In a further aspect, the present invention features a method of inhibiting BRM, the method comprising contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0186] In some embodiments, the cell is a cancer cell.

[0187] In another aspect, the present invention features a method of inhibiting BRG1, the method comprising contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0188] In some embodiments, the cell is a cancer cell.

[0189] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method comprising contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0190] In some embodiments, the cell is a cancer cell.

[0191] In another aspect, the invention features a method of treating a disorder associated with a loss-of-function mutation of BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0192] In some embodiments, the disorder associated with a loss-of-function mutation of BRG1 is cancer. In other embodiments, the subject is determined to have a loss-of-function disorder of BRG1, e.g., is determined to have a cancer with a loss-of-function of BRG1 (e.g., the cancer is determined to comprise cancer cells with a loss-of-function of BRG1).

[0193] In another aspect, the invention features a method of inducing apoptosis in a cell, the method comprising contacting the cell with 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.

[0194] In some embodiments, the cell is a cancer cell.

[0195] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0196] In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, or penile cancer.

[0197] In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0198] In some embodiments of any of the foregoing methods, the cancer is drug-resistant cancer or has responded poorly to previous therapies (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolomide, irinotecan, CAR-T therapy, trastuzumab, pertuzumab, tamoxifen, capecitabine, docetaxel, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, pemetrexed, protein-bound paclitaxel, doxorubicin, gemcitabine, bevacizumab, eribulin, neratinib, PARP inhibitors, brilanestrant, mTOR inhibitors, topotecan, gemcitabine, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabulin, or PD-L1 inhibitors).

[0199] In some embodiments of any of the foregoing methods, the cancer has or is determined to have one or more BRG1 mutations. In some embodiments of any of the foregoing methods, the one or more BRG1 mutations are homozygous. In some embodiments of any of the foregoing methods, the one or more BRG1 mutations are in the ATPase catalytic domain of the protein. In some embodiments of any of the foregoing methods, the one or more BRG1 mutations are deletions at the C-terminus of BRG1. In some embodiments of any of the foregoing methods, the cancer has not or is determined not to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer has not or is determined not to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has or is determined to have a KRAS mutation.

[0200] In another aspect, the present disclosure provides a method of treating a subject in need of treating a BAF-related disorder (e.g., cancer or viral infection). The method includes contacting the cells with an effective amount of any of the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a viral infection. In some embodiments, the viral infection is by a virus of the family Retroviridae (e.g., human immunodeficiency virus (HIV) and deltaretrovirus (e.g., human T-cell leukemia virus type I (HTLV-I), human T-cell leukemia virus type II (HTLV-II))), the family Hepadnaviridae (e.g., hepatitis B virus (HBV)), the family Flaviviridae (e.g., hepatitis C virus (HCV)), the family Adenoviridae (e.g., human adenovirus), the family Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), the family Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1)), the family Parvoviridae (e.g., parvovirus B19), the family Polyomaviridae (e.g., JC virus and BK virus), the family Paramyxoviridae (e.g., measles virus), the family Togaviridae (e.g., rubella virus). In some embodiments, the disorder is Coffin-Siris, neurofibromatosis (e.g., NF-1, NF-2, or schwannoma), or multiple meningiomas.

[0201] In another aspect, the present disclosure provides a method for treating a subject in need of treating a viral infection. The method includes administering to the subject an effective amount of any of the foregoing compounds, or a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is caused by a virus of the family Retroviridae (e.g., human immunodeficiency virus (HIV) and deltaretrovirus (e.g., human T-cell leukemia virus type I (HTLV-I), human T-cell leukemia virus type II (HTLV-II))), the family Hepadnaviridae (e.g., hepatitis B virus (HBV)), the family Flaviviridae (e.g., hepatitis C virus (HCV)), the family Adenoviridae (e.g., human adenovirus), the family Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), the family Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1)), the family Parvoviridae (e.g., parvovirus B19), the family Polyomaviridae (e.g., JC virus and BK virus), the family Paramyxoviridae (e.g., measles virus), or the family Togaviridae (e.g., rubella virus).

[0202] 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 by at least 10-fold greater than it inhibits the level and / or activity of BRG1, and / or the compound binds to BRM by at least 10-fold greater than it binds to BRG1. For example, in some embodiments, the BRM-selective compound has an IC 50 or IP 50 that is at least 10-fold lower than the IC 50 or IP50 It has. 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 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, the BRM / BRG1 dual inhibitor compound has an IC 50 or IP 50 within 10-fold of that against BRM, and has an IC 50 or IP 50 against BRG1.

[0203] In another aspect, the present invention features a method of treating a subject in need of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer, the method comprising administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0204] In another aspect, the present invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0205] In another aspect, the present invention features a method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer in a subject, the method comprising administering an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0206] In another aspect, the present invention features a method of suppressing metastatic colony formation (e.g., metastatic colony formation to the liver and / or brain) of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer in a subject, the method comprising administering an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0207] In another aspect, the present invention features a method of reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer cells, the method comprising contacting the cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0208] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cells are within a subject.

[0209] In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the compound reduces the level and / or activity of BRG1 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the compound reduces the level and / or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0210] In some embodiments, an effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, an effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0211] In some embodiments of any of the above aspects, an effective amount of the compound reduces the level and / or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the compound reduces the level and / or activity of BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the compound reduces the level and / or activity of BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0212] In some embodiments, the effective amount of the compound reduces the level and / or activity of the BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound reduces the level and / or activity of the BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0213] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein, and / or the cell or subject is identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein, and / or the cell or subject is identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein, and / or the cell or subject is identified as expressing BRM. In some embodiments, the cancer is a melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a blood cancer, such as multiple myeloma, large cell lymphoma, acute T cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic lymphoma and lymphocytic lymphoma, B cell lymphoma, acute lymphoblastic leukemia (e.g., T cell acute lymphoblastic leukemia or B cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin lymphoma. In some embodiments, the cancer is breast cancer (e.g., ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer). In some embodiments, the cancer is bone cancer (e.g., Ewing sarcoma). In some embodiments, the cancer is renal cell cancer (e.g., microphthalmia transcription factor (MITF) family translocation renal cell cancer (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). Metastatic cancer may include cells that exhibit migration and / or invasion of migratory cells, and / or may include cells that exhibit endothelial mobilization and / or angiogenesis. In other embodiments, the cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. Metastatic cancer can be a cancer that spreads through seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid space. Alternatively, metastatic cancer can be a cancer that spreads via the lymphatic system or hematogenously.In some embodiments, an agent in an amount effective to reduce the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colony formation of cancer to the liver and / or brain.

[0214] In some embodiments, the cancer has a mutation in GNAQ. In some embodiments, the cancer has a mutation in GNA11. In some embodiments, the cancer has a mutation in PLCB4. In some embodiments, the cancer has a mutation in CYSLTR2. In some embodiments, the cancer has a mutation in BAP1. In some embodiments, the cancer has a mutation in SF3B1. In some embodiments, the cancer has a mutation in EIF1AX. In some embodiments, the cancer has a TFE3 translocation. In some embodiments, the cancer has a TFEB translocation. In some embodiments, the cancer has a MITF translocation. In some embodiments, the cancer has an EZH2 mutation. In some embodiments, the cancer has a SUZ12 mutation. In some embodiments, the cancer has an EED mutation.

[0215] In some embodiments, the method further comprises administering to the subject or contacting the cells with an anti-cancer therapy, such as a chemotherapeutic agent or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation. In some embodiments, the anti-cancer therapy is a chemotherapeutic agent or cytotoxic agent, such as an antimetabolite, antimitotic agent, antitumor agent, antibiotic, asparagine-specific enzyme, bisphosphonate, antineoplastic agent, alkylating agent, DNA repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulator, Janus-related kinase inhibitor, phosphoinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor.

[0216] In some embodiments, the compounds of the invention are used in combination with another anti-cancer therapy, a MEK inhibitor, and / or a PKC inhibitor that are used in the treatment of uveal melanoma, such as surgery. For example, in some embodiments, the method further comprises performing surgery before, after, or at the same time as the administration of the compounds of the invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or at the same time as the administration of the compounds of the invention.

[0217] In some embodiments, the anti-cancer therapy and the compounds of the invention are each administered in an amount effective to treat the subject together within 28 days of each other.

[0218] In some embodiments, the subject or cancer has and / or is identified as having a loss-of-function mutation in BRG1. In some embodiments, the subject or cancer has and / or is identified as having a loss-of-function mutation in BRM.

[0219] In some embodiments, the cancer is resistant to one or more chemotherapeutic agents or cytotoxic agents (e.g., the cancer is determined to be resistant to a chemotherapeutic agent or cytotoxic agent (such as by a genetic marker), or is determined to be likely resistant to a chemotherapeutic agent or cytotoxic agent (such as a cancer that did not respond to a chemotherapeutic agent or cytotoxic agent)). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic agents or cytotoxic agents. In some embodiments, the cancer is resistant to, or has failed to respond to, dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0220] In some embodiments, the cancer is resistant to, or has failed to respond to, a previously administered therapeutic agent used in the treatment of melanoma, such as a MEK inhibitor or a PKC inhibitor. For example, in some embodiments, the cancer is resistant to, or has failed to respond to, a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or trametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0221] Chemical terms The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0222] For any of the following chemical definitions, the numbers following the atomic symbols indicate the total number of atoms of that element present in the particular chemical moiety. As will be understood, other atoms such as H atoms, or substituents described herein, may be present as necessary to satisfy the valency of the atoms. For example, 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 divalent carbon in acetal and ketal groups, but does not include carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group includes only those atoms that form part of the heterocyclic ring.

[0223] As used herein, the term "acyl" represents an H or alkyl group bonded to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbon atoms.

[0224] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical having 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms). "Alkylene" is a divalent alkyl group.

[0225] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms), alone or in combination with other groups. "Alkenylene" is a divalent alkenyl group.

[0226] As used herein, the term "alkynyl", alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having from 2 to 20 carbon atoms (e.g., from 2 to 16 carbon atoms, from 2 to 10 carbon atoms, from 2 to 6 carbon atoms, or 2 carbon atoms). "Alkynylene" is a divalent alkynyl group.

[0227] As used herein, the term "amino" represents -N(R N1 )2, where each R N1 is independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and each of these listed R N1 groups may optionally be substituted, or two R N1 s may combine to form alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino groups of the present invention can be unsubstituted amino (i.e., -NH2) or substituted amino (i.e., -N(R N1 )2).

[0228] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. "Arylene" is a divalent aryl group.

[0229] As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are those having 7 to 30 carbons (e.g., C1-C6 alkyl C6-C 10 aryl, C1-C 10 alkyl C6-C 10 aryl, or C1-C 20 alkyl C6-C 10 aryl, etc.) having 7 to 16 or 7 to 20 carbons. In some embodiments, the alkyl and aryl may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0230] As used herein, the term "azide" represents the -N3 group.

[0231] As used herein, the term "bridged cyclil" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges.

[0232] As used herein, the term "cyano" represents the -CN group.

[0233] As used herein, the term "carbosicryl" refers to a non-aromatic C3-C 12 monocyclic, bicyclic or tricyclic structure in which the ring is formed by carbon atoms. The carbosicryl structure includes cycloalkyl groups and unsaturated carbosicryl radicals.

[0234] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent monocyclic or polycyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. "Cycloalkyl" is a divalent cycloalkyl group.

[0235] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0236] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, wherein one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy", which as used herein refers to alkyl-O- (e.g., methoxy and ethoxy). "Heteroalkylene" is a divalent heteroalkyl group.

[0237] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy", which as used herein refers to alkenyl-O-. "Heteroalkenylene" is a divalent heteroalkenyl group.

[0238] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein, wherein one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy", which as used herein refers to alkynyl-O-. "Heteroalkynylene" is a divalent heteroalkynyl group.

[0239] As used herein, the term "heteroaryl" refers to a structure where X is O or NR and R is H or optionally substituted alkyl [Chemical Formula] which is represented by

[0240] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring, containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl. "Heteroarylene" is a divalent heteroaryl group.

[0241] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups have 7 to 30 carbons (e.g., C1-C6 alkyl C2-C9 heteroaryl, C1-C 10 alkyl C2-C9 heteroaryl, or C1-C 20 alkyl C2-C9 heteroaryl, etc., 7 to 16 or 7 to 20 carbons). In some embodiments, the alkyl and heteroaryl may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0242] As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic radical having 3 to 12 atoms with at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and the aromatic ring does not contain any N, O, or S atoms. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. "Heterocyclylene" is a divalent heterocyclyl group.

[0243] As used herein, the term "heterocyclylalkyl" represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are those having 7 to 30 carbons (e.g., C1-C6 alkyl C2-C9 heterocyclyl, C1-C 10 alkyl C2-C9 heterocyclyl, or C1-C 20 alkyl C2-C9 heterocyclyl, etc., having 7 to 16 or 7 to 20 carbons). In some embodiments, the alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0244] As used herein, the term "hydroxyalkyl" represents an alkyl group substituted with an -OH group.

[0245] As used herein, the term "hydroxyl" represents an -OH group.

[0246] As used herein, the term "N-protecting group" refers to a group intended to protect an amino group from unwanted reactions during a synthetic procedure. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).Examples of N-protecting groups include, but are not limited to, formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L, or D,L-amino acids such as alanine, leucine, and phenylalanine, acyl, aroyl, or carbamyl groups; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups are allock, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanine, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0247] As used herein, the term "nitro" represents a -NO2 group.

[0248] As used herein, the term "oxo" represents a =O group.

[0249] As used herein, the term "thiol" represents a -SH group.

[0250] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclic groups may or may not be substituted. When substituted, unless otherwise specified, generally 1 to 4 substituents are present. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclic (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclic, amino (e.g., NH2 or mono- or dialkylamino), azide, cyano, nitro, oxo, or thiol. Aryl, carbocyclic (e.g., cycloalkyl), heteroaryl, and heterocyclic groups may also be substituted with alkyl (unsubstituted and substituted, e.g., arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0251] The compounds of the present invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, for example, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. The optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or by asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly a pair of stereoisomers that cannot be superimposed because they contain an asymmetrically substituted carbon atom that functions as a chiral center. Enantiomers are mirror images of each other and mean one of a pair of molecules that cannot be superimposed. Diastereomers are most commonly stereoisomers that are not related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the spatial arrangement of the substituents around one or more chiral carbon atoms. The enantiomers of a compound can be prepared, for example, by separating the enantiomers from a racemate using one or more well-known techniques and methods such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating the enantiomers of the compounds described herein from a racemic mixture can be readily determined by those skilled in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, and such a mixture does not exhibit optical activity, i.e., they do not rotate the plane of polarization. "Geometric isomers" means isomers in which the orientation of the substituted atoms is different in relation to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of a carbon-carbon double bond can be in the E (the substituent is on the opposite side of the carbon-carbon double bond of the ester) or Z (the substituent is oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the configuration with respect to the core molecule. Certain disclosed compounds can exist in atropisomeric forms.Atropisomers are stereoisomers resulting from restricted rotation around a single bond where the steric strain barrier to rotation is high enough to allow isolation of the conformational isomers. The compounds of the present invention can be prepared as individual isomers by enantioselective synthesis or resolution from a mixture of isomers. Conventional resolution techniques include forming salts of the free bases of each isomer of an isomer pair using an optically active acid (subsequently followed by fractional crystallization and regeneration of the free base), forming salts of the acid form of each isomer of an isomer pair using an optically active amine (subsequently followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each of the isomers of an isomer pair using an optically pure acid, amine, or alcohol (subsequently followed by chromatographic separation and removal of the chiral auxiliary), or resolving a mixture of isomers of either the starting material or the final product using various well-known chromatographic methods. When the stereochemistry of the disclosed compounds is named or indicated by structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to other stereoisomers. When a single enantiomer is named or indicated by structure, the indicated or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure. When a single diastereomer is named or indicated by structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure. The percent optical purity is the ratio of the weight of the enantiomer or the weight of the enantiomer and its optical isomer. The diastereomeric purity by weight is the ratio of the weight of one diastereomer or the weight of all diastereomers. When the stereochemistry of the disclosed compounds is named or indicated by structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to other stereoisomers.When a single enantiomer is named or indicated by structure, the indicated or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in molar fraction. When a single diastereomer is named or indicated by structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in molar fraction. The purity percentage by molar fraction is the ratio of the moles of the enantiomer, or the moles of the enantiomer and the moles of its optical isomer. Similarly, the purity percentage by molar fraction is the ratio of the moles of the diastereomer, or the moles of the diastereomer and the moles of its isomer. When the disclosed compound is named or indicated by structure without showing stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass the enantiomer of the compound without the corresponding optical isomer, the racemic mixture of the compound, the mixture of the compound, or the mixture in which one enantiomer is enriched relative to the corresponding optical isomer. When the disclosed compound is named or indicated by structure without showing stereochemistry and has two or more chiral centers, the name or structure should be understood to encompass the diastereomer without other diastereomers, some diastereomers without other diastereomer pairs, the mixture of diastereomers, the mixture of diastereomer pairs, the mixture of diastereomers in which one diastereomer is enriched relative to the other diastereomer, or the mixture of diastereomers in which one or more diastereomers are enriched relative to the other diastereomers. The present invention encompasses all of these forms.

[0252] The compounds of the present disclosure also include all isotopes of atoms present in the intermediate or final compounds. "Isotope" refers to atoms that have the same atomic number but different mass numbers, resulting from different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0253] Unless otherwise specified, the structures shown in this specification also mean that they include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, etc., isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. Isotope-labeled compounds (e.g., those labeled with 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful due to the ease of their preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic benefits (e.g., increased in vivo half-life or reduced required dose) due to greater metabolic stability. In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C or 14 C enriched carbon. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to procedures similar to those disclosed for the compounds of the invention described herein.

[0254] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present disclosure are described herein. Other suitable methods and materials known in the art may also be used. Those materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0255] Definitions As used in this application, unless specifically stated otherwise in context, (i) the term "a" can be understood to mean "at least one", (ii) the term "or" can be understood to mean "and / or", and (iii) the terms "comprising" and "including" can be understood to encompass the listed components or steps, whether presented by themselves or in conjunction with one or more additional components or steps.

[0256] As used herein, the terms "about" and "approximately" refer to values within 10% of the value being described. For example, the term "about 5 nM" refers to the range of 4.5 - 5.5 nM.

[0257] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route. For example, in some embodiments, administration is by bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by tracheal instillation), transdermal, vaginal, and intravitreal.

[0258] As used herein, the term "BAF complex" refers to a BRG1 or HRBM-related factor complex in human cells.

[0259] As used herein, the term "BAF complex-related disorder" refers to a disorder caused by or affected by the level and / or activity of the BAF complex.

[0260] As used herein, the term "loss-of-function mutation of BRG1" refers to a mutation in BRG1 that results in a protein having a reduced activity (e.g., a reduction of at least 1% of BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction of BRG1 activity). Exemplary loss-of-function mutations of BRG1 include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0261] As used herein, the term "loss-of-function disorder of BRG1" refers to a disorder (e.g., cancer) that exhibits a reduction of BRG1 activity (e.g., a reduction of at least 1% of BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction of BRG1 activity).

[0262] The term "cancer" refers to a condition caused by the proliferation of malignant tumor cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0263] As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dosage and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of two or more agents is simultaneous or concurrent, and the agents may be co-formulated. In some embodiments, two or more agents are not co-formulated and are administered in a sequential manner as part of the prescribed regimen. In some embodiments, the administration of two or more agents or combined treatments is such that the reduction in symptoms, or other parameters associated with the disorder, is greater than that observed with one agent or treatment delivered alone or in the absence of the other. The effects of the two treatments can be partially additive, fully additive, or supra-additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent can be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the combination can be administered by intravenous injection, while the second therapeutic agent of the combination can be administered orally.

[0264] As used herein, "cmpd" refers to a compound.

[0265] "Determining the level of a protein or RNA" means detecting the protein or RNA by a method known in the art, either directly or indirectly. "Determining directly" means performing a process to obtain a physical entity or value (e.g., performing an assay or test on a sample, or "analyzing a sample" as the term is defined herein). "Determining indirectly" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory that has directly obtained a physical entity or value). Methods for measuring protein levels generally include, but are not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC) mass spectrometry, microsite cytometry, microscopy, fluorescence-activated cell sorting (FACS), and flow cytometry, as well as assays based on the properties of the protein, including but not limited to enzyme activity or interaction with other protein partners. Methods for measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0266] "Reducing the activity of the BAF complex" means reducing the level of activity associated with the BAF complex or associated downstream effects. A non-limiting example of reducing the activity of the BAF complex is the activation of Sox2. The activity level of the BAF complex can be measured using any method known in the art, e.g., the method described in Kadoch et al. Cell, 2013, 153, 71-85, which is incorporated herein by reference.

[0267] As used herein, the term "degrader" refers to a small molecule compound that includes a degrading moiety, and the compound interacts with a protein (e.g., BRG1 and / or BRM) in a manner that results in degradation of the protein (e.g., the binding of the compound results in at least a 5% reduction in the level of the protein in, for example, a cell or subject).

[0268] As used herein, the term "degrading moiety" refers to a moiety whose binding results in degradation of a protein (e.g., BRG1 and / or BRM). In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes the protein (e.g., BRG1 and / or BRM).

[0269] "Modulating the activity of the BAF complex" means changing the level of an activity associated with the BAF complex (e.g., GBAF) or an associated downstream effect. The activity level of the BAF complex can be measured using any method known in the art, e.g., the method described in Kadoch et al, Cell 153:71-85 (2013), which is incorporated herein by reference.

[0270] "Reducing the activity of BRG1 and / or BRM" means decreasing the level of an activity associated with BRG1 and / or BRM or an associated downstream effect. Non-limiting examples of inhibiting the activity of BRG1 and / or BRM include decreasing the level of the BAF complex in a cell. The activity level of BRG1 and / or BRM can be measured using any method known in the art. In some embodiments, an agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrader.

[0271] "Reducing the level of BRG1 and / or BRM" means decreasing the level of BRG1 and / or BRM in a cell or subject. The level of BRG1 and / or BRM can be measured using any method known in the art.

[0272] As used herein, "level" means the level of a protein or mRNA encoding the protein as compared to a reference substance. The reference substance can be any useful reference substance as defined herein. A "decreased level" or "increased level" of a protein means a decrease or increase in the protein level as compared to the reference substance (e.g., a decrease or increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200% as compared to the reference substance; a decrease or increase of less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase of about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). The level of a protein can be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein or mRNA in a sample.

[0273] As used herein, the term "inhibiting BRM and / or BRG1" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of the protein. BRM and / or BRG1 inhibition can be determined using methods known in the art, such as a BRM ATPase assay, a Nano DSF assay, or a BRM luciferase cell assay.

[0274] As used herein, the term "pharmaceutical composition" refers to a composition comprising a compound described herein, formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, such as a human. Typically, a pharmaceutical composition is manufactured or sold under the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a mammalian disease. A pharmaceutical composition can be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, caplets, gelcaps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as a sterile solution free of particulate embolizing material and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0275] As used herein, "pharmaceutically acceptable excipient" refers to any component below a compound having the properties described herein (e.g., a vehicle capable of suspending or dissolving an active compound) and being substantially non-toxic and non-inflammatory in a patient. Excipients can include, for example, anti-adhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavoring agents, fragrances, lubricants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration.

[0276] As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of a compound, e.g., any compound of Formula I or II. Pharmaceutically acceptable salts of any of the compounds described herein are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, within the scope of sound medical judgment, and include salts that 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 Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base moiety with a suitable organic acid.

[0277] The compounds of the invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts containing an inorganic or organic acid, or, in the case of the acidic form of the compounds of the invention, the salts may be prepared from inorganic or organic bases. Often, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as appropriate methods for preparing the salts, are well known in the art. The salts can be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0278] "Reference substance" means any useful reference substance used to compare protein or RNA levels. A reference substance can be any sample, standard, standard curve, or level used for comparison purposes. A reference substance can be a normal reference sample or reference standard or level. A "reference sample" can be, for example, a control, such as a predetermined negative control value like a "normal control", or a previous sample taken from the same subject; a sample from a normal healthy subject such as normal cells or normal tissue; a sample from a subject without a disease (e.g., cells or tissue); a sample from a subject diagnosed with a disease but not yet treated with the compounds of the present invention; a sample from a subject treated with the compounds of the present invention; or a sample of a purified protein or RNA at a known normal concentration (e.g., any of those described herein). "Reference standard or level" means a value or numerical value derived from a reference sample. A "normal control value" is a predetermined value indicating a non-diseased state, 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 ("X or less"), or a low threshold ("X or more"). A subject having a measurement within the normal control value of a particular biomarker is typically said to be "within the normal range" of that biomarker. A normal reference standard or level can be a value or number derived from a normal subject without a disease or disorder (e.g., cancer); a subject treated with the compounds of the present invention. In a preferred embodiment, the reference sample, standard, or level matches the sample subject sample according to at least one of the following criteria: age, weight, gender, disease stage, and overall health. A standard curve of the level of a purified protein or RNA within a normal reference range, e.g., any of those described herein, can also be used as a reference.

[0279] As used herein, the term "subject" refers to any organism to which a composition according to the present invention can be administered for, e.g., experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal, such as mammals like mice, rats, rabbits, non-human primates, and humans. A subject can be a human or an animal that is seeking or in need of treatment, demanding treatment, receiving treatment, to receive treatment in the future, or being treated by an expert trained in a particular disease or condition.

[0280] As used herein, the terms "treating," "being treated," or "treatment" mean a therapeutic intervention or any means, the purpose of which is to slow down (reduce) an undesirable physiological state, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder, or disease; stabilization (i.e., not worsening) of a condition, disorder, or disease; delay or slowing in the onset of progression of a condition, disorder, or disease; amelioration or remission (partial or complete) of a condition, disorder, or disease state; improvement in at least one measurable physical parameter not necessarily distinguishable by the patient; or enhancement or improvement of a condition, disorder, or disease. Treatment includes inducing a clinically significant response without undue levels of side effects. Treatment also includes prolonging survival as compared to a predicted survival period in the absence of treatment. The compounds of the present invention can also be used, for example, to "prophylactically treat" or "prevent" a disorder in a subject at increased risk of developing the disorder.

[0281] As used herein, the terms "variant" and "derivative" are used interchangeably and refer to natural-occurring, synthetic, and semi-synthetic analogs of the compounds, peptides, proteins, or other substances described herein. Variants or derivatives of the compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the original material.

[0282] Details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will become apparent from the description and claims.

Best Mode for Carrying Out the Invention

[0283] The present disclosure features compounds useful for reducing the level and / or activity of BRG1 and / or BRM. These compounds can be used, for example, to modulate the activity of the BAF complex for the treatment of BAF-related disorders such as cancer. Exemplary compounds described herein include compounds having a structure according to Formula I, wherein A-L-B Formula I In the formula, L is a linker, B is a cleavage moiety, A has a structure according to Formula II,

Chemical Formula

[0284] In some embodiments, R 3 is H or optionally substituted C1-C6 alkyl, and A 1 is a bond between A and the linker. In some embodiments, R 3 is a bond between A and the linker, and A 1 is H.

[0285] In some embodiments, the compound is any one of Compounds 1 to 297 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of Compounds 1 to 169 in Table 1, or a pharmaceutically acceptable salt thereof.

[0286] Other embodiments, as well as exemplary methods for the synthesis of these compounds, are described herein.

[0287] Pharmaceutical Use The compounds described herein are useful in the methods of the invention and, without being bound by theory, are believed to exert their ability to modulate the level, state, and / or activity of the BAF complex, i.e., by reducing the level and / or activity of BRG1 and / or BRM proteins in mammalian cells. BAF complex-related disorders include, but are not limited to, disorders associated with loss-of-function mutations of BRG1 and / or BRM.

[0288] One aspect of the present invention relates to a method of treating a disorder associated with a loss-of-function mutation of BRG1 and / or BRM in a subject in need of treatment for a disorder such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer). In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of (a) reduction in tumor size, (b) reduction in tumor growth rate, (c) increase in tumor cell death, (d) reduction in tumor progression, (e) reduction in the number of metastases, (f) reduction in the rate of metastasis, (g) decrease in tumor recurrence, (h) increase in the survival rate of the subject, and (i) increase in the progression-free survival period of the subject.

[0289] Treatment of cancer can result in a reduction in the size or volume of the tumor. For example, after treatment, the tumor size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) relative to its size prior to treatment. The size of the tumor can be measured by any reproducible means of measurement. For example, the size of the tumor can be measured as the diameter of the tumor.

[0290] Treatment of cancer can further result in a decrease in the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) relative to the number prior to treatment. The number of tumors can be measured by any reproducible means of measurement, and for example, the number of tumors can be measured by counting tumors that are visible to the naked eye or visible at a particular magnification (e.g., 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold).

[0291] Cancer treatment can lead to a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the number before treatment. The number of metastatic nodules can be measured by any reproducible measuring means. For example, the number of metastatic nodules can be measured by counting the metastatic nodules that are visible to the naked eye or visible at a specific magnification (e.g., 2-fold, 10-fold, or 50-fold).

[0292] Treating cancer can result in an increase in the average survival time of a population of subjects treated according to the present invention compared to an untreated population of subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of the population can be measured by any reproducible means. The increase in the average survival time of the population can be measured, for example, by calculating the length of the average survival period after the start of treatment with the compound of the present invention for the population. The increase in the average survival time of the population can also be measured, for example, by calculating the length of the average survival period after the completion of the first round of treatment with a pharmaceutically acceptable salt of the compound of the present invention for the population.

[0293] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects compared to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., 5%, 10%, or more than 25%). The decrease in the mortality rate of the population of treated subjects can be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time after the start of treatment with a pharmaceutically acceptable salt of the present invention for the population. The decrease in the mortality rate of the population can also be measured, for example, by calculating the average number of disease-related deaths per unit time after the completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention for the population.

[0294] Exemplary cancers that can be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, and penile cancer.

[0295] Combination formulations and their use The compounds of the present invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any cancer described herein.

[0296] Combination therapy The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as other agents that treat cancer or related symptoms, or in combination with other types of treatment for treating cancer. In combination therapy, the dosage of one or more therapeutic compounds can be reduced from the standard dosage when administered alone. For example, the dosage can be determined empirically from the drug combinations and permutations, or can be estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds when combined should provide a therapeutic effect.

[0297] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful for the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, as well as gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bratasin and bratasinone); camptothecin (including the synthetic analog topotecan); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eribulin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbiquine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as engine antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin omega 1 (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein engine antibiotic chromophore), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodrubicin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demeclocycline; diaziquone; elfomithine; elliptinium acetate;Epothilone; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); Razoxane; Rizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2’,2’’-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, verracurin A, roridin A, and anguidine); Urethane; Vin desine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacitabine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Taxoids, e.g., Taxol (registered trademark) paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABraxane (registered trademark), albumin-engineered nanoparticle formulation of paclitaxel without cremophor (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere (registered trademark) docetaxel (Rhone-Poulenc Rorer, Antony, France); Chlorambucil; Gemzar (registered trademark) gemcitabine; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine (registered trademark) vinorelbine; Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine;Also included are any pharmaceutically acceptable salts, acids, or derivatives thereof as described above. In a cocktail administered in combination with the first therapeutic agent described herein, two or more chemotherapeutic agents can be used. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.;

[0298] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biological agent such as a cytokine used in cancer treatment (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-VEGF agent, such as an anti-angiogenic agent such as bevacizumab (Avastin®). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that stimulates a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Such agents include rituximab, daclizumab, basiliximab, palivizumab, infliximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, adalimumab, omalizumab, tositumomab-I-131, efalizumab, cetuximab, bevacizumab, natalizumab, tocilizumab, panitumumab, ranibizumab, eculizumab, certolizumab pegol, golimumab, canakinumab, ustekinumab, ofatumumab, denosumab, motavizumab, labetuzumab, belimumab, ipilimumab, brentuximab vedotin, pertuzumab, ado-trastuzumab emtansine, and obinutuzumab. Antibody-drug conjugates are also included.

[0299] The second agent can be a therapeutic agent that is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical resection of tumor tissue.

[0300] The second agent can be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of PD-1 (e.g., nivolumab; pembrolizumab; pidilizumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of PDL1 (e.g., atezolizumab; durvalumab; avelumab; BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of B7-H3 (e.g., enobrutuzumab), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.

[0301] In any of the embodiments of the combinations described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent can be administered immediately before, immediately after, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1 to 7, 1 to 14, 1 to 21, or 1 to 30 days before or after the second therapeutic agent.

[0302] Pharmaceutical composition The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biologically compatible form suitable for in vivo administration. Thus, in one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention mixed with a suitable diluent, carrier, or excipient.

[0303] The compounds of the present invention can be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the present invention. According to the methods of the present invention, as will be understood by those skilled in the art, the compounds described, or their salts, solvates, or prodrugs can be administered to a patient in various forms depending on the selected route of administration. The compounds of the present invention can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, trans-epithelial, nasal, intralung, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period.

[0304] The compounds of the present invention can be administered orally, for example, together with an inert diluent or an assimilable edible carrier, or can be enclosed in hard or soft shell gelatin capsules, or can be compressed into tablets, or can be incorporated directly with the food of a diet. For oral therapeutic administration, the compounds of the present invention may be incorporated with excipients and used in the form of digestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in alcohol with or without glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, and in oils. These preparations can contain preservatives to prevent the growth of microorganisms under normal storage and use conditions. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003, 20th ed.) and The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that it can be easily administered via a syringe. Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are provided in a sterile form in a sealed container, usually in the form of a cartridge or refill for use with a nebulizer, in single or multiple dose amounts. Alternatively, the sealed container can be a single dispensing device such as a single-dose nasal inhaler or aerosol dispenser fitted with a metering valve, intended for disposal after use.When the dosage form includes an aerosol dispenser, it contains a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage form can also take the form of a pump sprayer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. The compounds described herein can be administered, for example, intratumorally as an intratumoral injection. Intratumoral injection is a direct injection into the tumor vasculature and is particularly contemplated for individual solid accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein can be advantageously contacted, for example, by administering an injection or multiple injections to the tumor at approximately 1 cm intervals. In the case of surgical intervention, the present invention can be used preoperatively, such as to subject inoperable tumors to resection. Continuous administration can also be applied, where appropriate, for example, by implanting a catheter into the tumor or tumor vasculature.

[0305] The compounds of the present invention can be administered to animals, such as humans, alone or in combination with a pharmaceutically acceptable carrier, as described herein, the ratio being determined by the solubility and chemical nature of the compound, the selected route of administration, and standard pharmaceutical practice.

[0306] Dosage The dosage of the compound of the present invention and / or the composition containing the compound of the present invention can vary depending on many factors such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and degree of the symptoms; the frequency of treatment, and if any, the type of combination therapy; and the clearance rate of the compound in the animal being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention can be initially administered at a suitable dosage that can be adjusted if necessary according to the clinical response. Generally, satisfactory results can be obtained when the compound of the present invention is administered to humans at a daily dosage of, for example, 0.05 mg to 3000 mg (measured in solid form). The dosage range includes, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0307] Alternatively, the dosage can be calculated using the patient's weight. For example, the dosage of the compound or its pharmaceutical composition administered to a patient can range from 0.1 to 100 mg / kg.

Example

[0308] Example 1. Synthesis of the compound of the present invention Preparation of tert-butyl N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]ethoxy)ethoxy]ethyl]carbamate trifluoroacetate (I-1)

Chemical formula

Chemical formula

[0309] Step 2: Preparation of 5-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione trifluoroacetate (I-1)

Chemical Structure

Table 2-1

Table 2-2

[0310] Preparation of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]butanoic acid (I-11)

Chemical formula

Chemical formula

[0311] Step 2: Preparation of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]butanoic acid (I-11)

Chem.

Table 3

[0312] Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (I-17)

Chem.

Chem.

[0313] Step 2: Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (I-17)

Chemical Structure

Table 4

[0314] Preparation of 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (I-23)

Chemical formula

Chemical formula

[0315] Step 2: Preparation of [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetic acid (I-100)

Chem.

[0316] Step 3: Preparation of methyl 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylate (C)

Chem.

[0317] Step 4: Preparation of 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (I-23)

Chem.

[0318] Preparation of methyl 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (I-24)

Chem.

[0319] Preparation of N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamide (I-25)

Chemical Structure

Chemical Structure

[0320] Step 2: Preparation of N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamide formate (I-25)

Chem.

[0321] Preparation of N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamide (I-26)

Chem.

[0322] Preparation of 4-[[3-(4-Aminobutanesulfonyl)propyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-27)

Chemical Structure

Chemical Structure

[0323] Step 2: Preparation of tert-Butyl N-[4-[(4-Methylbenzenesulfonyl)oxy]butyl]carbamate (C)

Chemical Structure

[0324] Step 3: Preparation of tert-butyl N-[4-(acetylsulfanyl)butyl]carbamate (D)

Chemical formula

[0325] Step 4: Preparation of benzyl N-[3-([4-[(tert-butoxycarbonyl)amino]butyl]sulfanyl)propyl]carbamate (E)

Chemical formula

[0326] Step 5: Preparation of benzyl N-(3-[4-[(tert-butoxycarbonyl)amino]butanesulfonyl]propyl)carbamate (F)

Chemical formula

[0327] Step 6: Preparation of tert-butyl N-[4-(3-aminopropanesulfonyl)butyl]carbamate (G)

Chemical formula

[0328] Step 7: Preparation of tert-butyl N-[4-(3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]propanesulfonyl)butyl]carbamate (H)

Chemical Structure

[0329] Step 8: Preparation of 4-[[3-(4-aminobutanesulfonyl)propyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-27)

Chem.

[0330] Preparation of 4-[[2-(2-aminoethanesulfonyl)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-28)

Chem.

Chem.

[0331] Step 2: Preparation of tert-butyl N-[2-[2-(1,3-dioxoisoindol-2-yl)ethanesulfonyl]ethyl]carbamate (C)

Chemical formula

[0332] Step 3: Preparation of tert-butyl N-[2-(2-aminoethanesulfonyl)ethyl]carbamate (D) [Chemical formula] Hydrazine hydrate (0.89 g, 17.781 mmol, 2.00 equivalents) was added to a stirred mixture of C (3.40 g, 8.891 mmol, 1.00 equivalent) in EtOH (100 mL) at 80 °C. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The suspension was filtered, and the filter cake was washed with EtOH (100 mL). The filtrate was concentrated under reduced pressure to obtain D (crude, 1.88 g, 77.94%) as a white solid. LCMS (ESI) m / z: [M+H] + = 253.

[0333] Step 4: Preparation of N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethanesulfonyl)ethyl]carbamate (E) [Chemical formula] DIEA (2.89 g, 22.352 mmol, 3.00 equivalents) was added dropwise to a mixture of D (1.88 g, 7.451 mmol, 1.00 equivalent) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (2.26 g, 8.196 mmol, 1.10 equivalents) in NMP (25.00 mL) at 90 °C under a nitrogen atmosphere. The resulting mixture was stirred for 12 hours and then extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to obtain E (1.58 g, 40.03%) as a yellow solid. LCMS (ESI) m / z: [M+H] + = 509.

[0334] Step 5: Preparation of 4-[[2-(2-aminoethanesulfonyl)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; trifluoroacetate (I-28) [Chemical formula] To a stirred mixture of E (1.54 g, 3.028 mmol, 1.00 equiv) in DCM (20 mL), trifluoroacetaldehyde (5.0 mL) was added dropwise at 25 °C under a nitrogen atmosphere. After 1 hour, the resulting mixture was concentrated under vacuum. Thereby, I-28 (1.68 g, 122.25%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.95 (s, 4H), 7.65 (dd, 1H), 7.18 (d, 1H), 7.12 (d, 1H), 6.84 (t, 1H), 5.07 (dd, 1H), 3.80 (q, 2H), 3.63 (m, 3H), 3.51 (t, 7H), 3.29 (dt, 4H), 2.89 (ddd, 1H), 2.70 (s, 1H), 2.65 - 2.52 (m, 2H), 2.18 (t, 1H), 2.03 (ddd, 1H), 1.96 - 1.84 (m, 1H). LCMS (ESI) m / z: [M + H] + = 409.11.

[0335] Preparation of 4-(2-[2-[(2-aminoethyl)(methyl)amino]ethoxy]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-29) [Chemical formula] Step 1: Preparation of 2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethanol (B) [Chemical formula] Diethylene glycol (A, 12.72 g, 119.863 mmol, 1.00 equivalent) was dissolved in THF (105.00 mL) at 0 °C. NaOH (3.60 g, 89.897 mmol, 0.75 equivalent) in 45 mL of water was added dropwise to the solution. After stirring for 30 minutes, this solution was added dropwise at 0 °C to a solution of p-toluenesulfonyl chloride (11.43 g, 59.932 mmol, 0.5 equivalent) in THF (45.00 mL). After the addition was complete, the aqueous solution was treated with 10% HCl and then extracted with dichloromethane. The organic layer was washed with distilled water and dried over MgSO4. After removing the solvent, the residue was purified by column chromatography (petroleum ether / THF = 1:1 v / v). B (12.56 g, 40.26%) was obtained as a colorless oil. LCMS (ESI) m / z: [M+H] + =261.

[0336] Step 2: Preparation of 2-[2-(methylamino)ethoxy]ethanol (C)

Chemical formula

[0337] Step 3: Preparation of benzyl N-[2-(2-hydroxyethoxy)ethyl]-N-methylcarbamate (D)

Chemical formula

[0338] Step 4: Preparation of benzyl N-methyl-N-(2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethyl)carbamate (E)

Chemical formula

[0339] Step 5: Preparation of benzyl N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]-N-methylcarbamate (F)

Chem.

[0340] Step 6: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-(methylamino)ethoxy]ethoxy]isoindole-1,3-dione (G)

Chem.

[0341] Step 7: Preparation of tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl](methyl)amino]ethyl)carbamate (H) [Chemical formula] To a solution of G (1.06 g, 2.824 mmol, 1.00 equivalent) in DMF (10.00 mL) was added tert-butyl N-(2-oxoethyl)carbamate (539.41 mg, 3.389 mmol, 1.2 equivalents) and NaBH(OAc)3 (1.80 g, 8.471 mmol, 3 equivalents). The resulting solution was stirred at room temperature for 2 hours. After aqueous workup, extraction with DCM, and concentration under reduced pressure, the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give H (386 mg, 26.36%) as a pale yellow solid; LCMS (ESI) m / z: [M+H] + =519.

[0342] Step 8: Preparation of 4-(2-[2-[(2-aminoethyl)(methyl)amino]ethoxy]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-29) [Chemical formula] To a solution of H (511.00 mg, 0.985 mmol, 1.00 equivalent) in DCM (5.00 mL) was added TFA (5.00 mL, 67.315 mmol, 68.31 equivalents). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated and the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, gradient from 0% to 100% over 45 minutes; detector, UV 220 nm. This gave I-29 (307 mg, 73.86%) as a brown oil; 11H NMR (300 MHz, DMSO-d6) δ 11.70 - 10.30 (m, 1H), 8.18 (s, 1H, formic acid), 7.83 (dd, 1H), 7.51 (dd, 2H), 5.09 (dd, 1H), 4.41 - 4.32 (m, 2H), 3.84 - 3.75 (m, 2H), 3.63 (d, 2H), 2.99 - 2.80 (m, 3H), 2.65 - 2.58 (m, 5H), 2.24 (s, 3H), 2.08 (s, 1H), 1.98 - 2.06 (m, 1H); LCMS (ESI) m / z: [M + H] + = 419.

[0343] Preparation of 4-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-30)

Chemical formula

Chemical formula

[0344] Step 2: Preparation of tert-butyl 3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]methyl)azetidine-1-carboxylate (D)

Chemical Structure

[0345] Step 3: Preparation of 4-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-30)

Chemical Structure

[0346] Preparation of 5-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-31)

Chemical Structure

[0347] Preparation of 4-[2-(azetidin-3-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-32)

Chemical Structure

Chemical Structure

[0348] Step 2: Preparation of tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (C)

Chemical formula

[0349] Step 3: Preparation of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (D)

Chemical formula

[0350] Step 4: Preparation of tert-butyl 3-[2-[(4-methylbenzenesulfonyl)oxy]ethyl]azetidine-1-carboxylate (E)

Chemical formula

[0351] Step 5: Preparation of tert-butyl 3-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethyl)azetidine-1-carboxylate (F)

Chemical formula

[0352] Step 6: Preparation of 4-[2-(azetidin-3-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-32)

Chemical Structure

[0353] Preparation of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-33) [Chemical formula] Step 1: Preparation of tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (B) [Chemical formula] To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (A, 2.50 g, 14.433 mmol, 1.00 eq) and p-toluenesulfonyl chloride (4.13 g, 21.650 mmol, 1.50 eq) in DCM, DMAP (264.49 mg, 2.165 mmol, 0.15 eq) and TEA (4.38 g, 43.300 mmol, 3.00 eq) were added portionwise at 0 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to afford B (4.4 g, 93.11%) as a brown oil. LCMS (ESI) m / z: [M+H] + = 328.

[0354] Step 2: Preparation of tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate (C) [Chemical formula] To a stirred solution of B (4.40 g, 13.439 mmol, 1.00 equiv) and KI (0.22 g, 1.344 mmol, 0.10 equiv) in DMF, KHCO3 (4.04 g, 40.318 mmol, 3.00 equiv) was added portionwise. After stirring at 100 °C for 8 h, the resulting mixture was extracted with EtOAc (3 × 150 mL), and the organic extracts were concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient from 10% to 50% over 10 min; detector, UV 254 nm. Thereby, C (1.73 g, 29.98%) was obtained as a grayish white solid. LCMS (ESI) m / z: [M+H] + = 430.

[0355] Step 3: Preparation of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-33) [Chemical formula] A solution of C (1.53 g, 3.563 mmol, 1.00 equiv) and TFA (5.00 mL, 67.315 mmol, 18.89 equiv) in DCM was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient from 10% to 50% over 10 min; detector, UV 254 nm. Thereby, I-33 (1.08 g, 96.43%) was obtained as a white solid. 1 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.25 (s, formic acid, 1H), 7.88 (d, 1H), 7.32 (d, 2H), 5.30 (p, 1H), 5.13 (dd, 1H), 4.31 (dd, 2H), 3.89 (dd, 2H), 2.99 - 2.80 (m, 1H), 2.68 - 2.52 (m, 2H), 2.13 - 1.97 (m, 1H). LCMS (ESI) m / z: [M+H] + = 330.05.

[0356] Preparation of 5-[2-(4-aminopiperidin-1-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-34)

Chemical Structure

Chemical Structure

[0357] Step 2: Preparation of tert-butyl N-[1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidin-4-yl]carbamate (C)

Chemical Structure

[0358] Step 3: Preparation of 5-[2-(4-aminopiperidin-1-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-34) [Chemical formula] To a solution of C (1.66 g, 3.316 mmol, 1.00 equiv) in DCM (10.00 mL) was added TFA (10.00 mL, 134.630 mmol, 40.60 equiv). The resulting solution was stirred at room temperature for 3 h. After concentration, the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / 0.1% formic acid in water, gradient from 0% to 100% over 45 min; detector, UV220 nm. This afforded I-34 (840 mg, 62.52%) as a white solid; 11H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.52 - 8.26 (m, 2H), 8.16 (s, 1H, formic acid), 7.88 (d, 1H), 7.51 (d, 1H), 7.40 (dd, 1H), 5.14 (dd, 1H), 4.49 (t, 2H), 3.47 (d, 2H), 3.37 - 2.28 (m, 2H), 3.29 - 3.19 (m, 1H), 3.03 - 2.70 (m, 3H), 2.67 - 2.62 (m, 1H), 2.61 - 2.55 (m, 1H), 2.14 - 1.98 (m, 3H), 1.88 - 1.68 (m, 2H). LCMS (ESI) m / z: + = 401.17.

[0359] Preparation of 5 - [7 - azaspiro[3.5]nonan - 2 - yloxy] - 2 - (2,6 - dioxopiperidin - 3 - yl)isoindole - 1,3 - dione formate (I - 35)

Chemical formula

Chemical formula

[0360] Step 2: Preparation of 5-[7-azaspiro[3.5]nonan-2-yloxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-35)

Chemical Structure

[0361] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[2-(piperazin-1-yl)ethoxy]isoindole-1,3-dione formate (I-36)

Chemical Structure

Chemical Structure

[0362] Step 2: Preparation of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (C)

Chemical formula

[0363] Step 3: Preparation of tert-butyl 4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperazine-1-carboxylate (D)

Chemical formula

[0364] Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[2-(piperazin-1-yl)ethoxy]isoindole-1,3-dione formate (I-36)

Chemical Structure

[0365] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[3-(piperazin-1-yl)propoxy]isoindole-1,3-dione formate (I-37)

Chemical formula

Chemical formula

[0366] Step 2: Preparation of tert-Butyl 4-(3-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]propyl)piperazine-1-carboxylate (C)

Chemical Structure

[0367] Step 3: Preparation of 2-(2,6-Dioxopiperidin-3-yl)-5-[3-(piperazin-1-yl)propoxy]isoindole-1,3-dione formate (I-37)

Chemical Structure

[0368] Preparation of 5-[4-(4-aminopiperidin-1-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-38)

Chemical Structure

Chemical Structure

[0369] Step 2: Preparation of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butanal (C)

Chemical Structure

[0370] Step 3: Preparation of tert-butyl N-[1-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butyl)piperidin-4-yl]carbamate (D)

Chemical Structure

[0371] Step 4: Preparation of 5-[4-(4-aminopiperidin-1-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-38)

Chemical Structure

[0372] Preparation of 5-[4-(azetidin-3-ylmethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-40) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione formate (I-39)

Chemical Structure

Chemical Structure

[0373] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione formate (I-39)

Chemical Structure

[0374] Step 3: Preparation of tert-butyl 3-([4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl)azetidine-1-carboxylate (C)

Chemical formula

[0375] Step 4: Preparation of 5-[4-(azetidin-3-ylmethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-40)

Chemical formula

[0376] Preparation of 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoic acid (I-41)

Chemical formula

Chemical formula

[0377] Step 2: Preparation of 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoic acid (I-41) [Chemical formula] A solution of B (2.1 g, 4.5 mmol) in DCM (20 mL) and TFA (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography under the following conditions: column, C18 spherical column; mobile phase, MeOH in water, gradient from 10% to 30% over 50 min; detector, UV254 nm to give 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoic acid (I-41) (0.78 g, 42.2%) as a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 12.03 (broad, 1H), 11.10 (singlet, 1H), 7.68 (doublet, J = 8.5 Hz, 1H), 7.35 (doublet, J = 1.7 Hz, 1H), 7.27 (doublet of doublets, J = 8.6, 2.0 Hz, 1H), 5.08 (doublet of doublets, J = 12.8, 5.4 Hz, 1H), 3.49 - 3.40 (multiplet, 4H), 2.96 - 2.80 (multiplet, 1H), 2.67 - 2.52 (multiplet, 8H), 2.44 (triplet, J = 6.9 Hz, 2H), 2.07 - 1.97 (multiplet, 1H). LCMS (ESI) m / z + = 415.10.

[0378] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione trifluoroacetate (I-42)

Chemical Structure

Chemical Structure

[0379] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione trifluoroacetate (I-42)

Chemical formula

[0380] Preparation of 5 - ((2 - aminoethyl)amino)-2-(2,6 - dioxopiperidin - 3 - yl)isoindoline - 1,3 - dione trifluoroacetate (I - 43)

Chemical Structure

Chemical Structure

[0381] Step 2: Preparation of 2 - (2,6 - dioxopiperidin - 3 - yl)-5 - fluoroisoindoline - 1,3 - dione (C)

Chemical Structure

[0382] Step 3: Preparation of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)carbamate (D) [Chemical formula] To a solution of tert-butyl N-(2-aminoethyl)carbamate (2.9 g, 18.1 mmol, 1.0 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (C, 5.0 g, 18.1 mmol, 1.0 equiv) in DMF (50 mL), DIEA (4.7 g, 36.2 mmol, 2.00 equiv) was added. The mixture was stirred at 80 °C for 2 h and then cooled to room temperature and poured into water (500 mL). The resulting mixture was extracted with EtOAc (500 mL × 3). The combined organic layers were concentrated and the residue was purified by reverse flash chromatography under the following conditions: column, C18 spherical column; mobile phase, ACN in water, gradient from 0% to 100% over 50 min; 70 ml / min; detector, UV254 nm to afford the desired product tert-butyl N-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]amino]ethyl)carbamate (D, 1.5 g, 19.5%) as a yellow solid. LCMS (ESI) m / z: [M+H] +=417.

[0383] Step 4: Preparation of 5-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (I-43)

Chemical formula

[0384] Preparation of 5-(2-Aminoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (I-44)

Chemical formula

[0385] Step 2: Preparation of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)carbamate (C) [Chemical] To a stirred solution of B (1.0 g, 3.6 mmol, 1.0 equiv) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.98 g, 4.4 mmol, 1.2 equiv) in DMF (10 mL), DIEA (0.94 g, 7.3 mmol, 2.0 equiv) was added under a nitrogen atmosphere. After stirring at 80 °C for 2 h, water (100 mL) was added and the mixture was subsequently extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure until dry and the residue was purified by reverse flash chromatography under the following conditions: column, C18 spherical column; mobile phase, ACN in water, gradient from 0% to 100% over 50 min; 70 ml / min; detector, UV254 nm to give C (1.7 g, 94.4%) as a yellow oily substance. LCMS (ESI) m / z: [M+H] + = 418.

[0386] Step 3: Preparation of 5-(2-aminoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; trifluoroacetate (I-44)

Chemical Structure

[0387] Preparation of 3-(4-((2-aminoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-45)

Chemical Structure

Chemical Structure

[0388] Step 2: Preparation of 3-(4-((2-aminoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-45)

Chemical formula

[0389] Preparation of 3-(6-((2-aminoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-46)

Chemical formula

[0390] Step 2: Preparation of 3-(6-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C) [Chemical formula] B (510.00 mg, 1.861 mmol, 1.00 equivalent), 3-aminopiperidine-2,6-dione (395.00 mg, 3.083 mmol, 1.66 equivalents), and DIEA (777.00 mg, 6.012 mmol, 3.23 equivalents) were dissolved in ACN (10.00 mL). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with DCM:ACN (3:1) to give C (410 mg, 76.17%) as a dark green solid. LCMS (ESI) m / z: [M+H] + = 290.

[0391] Step 3: Preparation of 3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (D) [Chemical formula] C (410.00 mg, 1.417 mmol, 1.00 equiv) and 10% Pd / C (80.00 mg, 0.752 mmol, 0.53 equiv) were suspended in DMF (15.00 mL). The reaction mixture was stirred overnight at room temperature under 1 atm of hydrogen. The mixture was filtered through Celite and the filtrate was concentrated to afford D (350 mg, 95.24%) as a brown solid. LCMS (ESI) m / z: [M+H] + = 260.

[0392] Step 4: Preparation of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)amino)ethyl)carbamate (E)

Chem.

[0393] Step 5: Preparation of 3-(6-((2-aminoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-46)

Chem.

[0394] Preparation of 3-(5-((2-aminoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-47)

Chemical formula

Chemical formula

[0395] Step 2: Preparation of 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C)

Chemical formula

[0396] Step 3: Preparation of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (D)

Chemical Structure

[0397] Step 4: Preparation of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethyl)carbamate (E)

Chemical Structure

[0398] Step 5: Preparation of 3-(5-((2-aminoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-47)

Chemical formula

[0399] Preparation of 3-(6-((6-aminohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-48) and 3-(5-((6-aminohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-49)

Chemical formula

[0400] Preparation of 7-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]heptanoic acid (I-50)

Chemical Structure

[0401] Preparation of [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]spiro[3.3]heptane-2-carboxylic acid (I-51)

Chemical Structure

[0402] Preparation of 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoic acid (I-52)

Chemical Structure

Chemical Structure

[0403] Step 2: Preparation of Intermediate 13 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoic acid (I-52)

Chemical Structure

Table 5-1

Table 5-2

Table 5-3

Table 5-4

[0404] (2S,4R)-1-[(2S)-2-(2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-70) Preparation

Chem.

Chem.

[0405] Step 2: Preparation of (2S,4R)-1-[(2S)-2-(2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-70) [Chemical formula] TFA (3 mL) was added dropwise to a solution of B (1.45 g, 2.014 mmol, 1 equiv) in DCM (15 mL). After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give I-70 (1.05 g, 84.11%) as a greyish white solid. 11H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 7.51 - 7.42 (m, 4H), 4.72 (s, 1H), 4.63 - 4.49 (m, 3H), 4.46 - 4.35 (m, 1H), 4.16 - 4.03 (m, 2H), 3.94 - 3.79 (m, 2H), 3.77 - 3.62 (m, 8H), 3.59 (t, J = 5.2 Hz, 2H), 2.99 - 2.87 (m, 2H), 2.50 (s, 3H), 2.30 - 2.21 (m, 1H), 2.19 - 2.06 (m, 1H), 1.13 - 0.98 (m, 9H). LCMS (ESI) m / z: [M + H] += 620.30

Table 6

[0406] (S)-13-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanoic acid (I-75) Preparation

Chemical Structure

Chemical Structure

[0407] Step 2: Preparation of (S)-benzyl 13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecan-1-oate (C) [Chemical formula] To a solution of B (836.17 mg, 2.68 mmol) in DCM (10 mL) was added HATU (1.32 g, 3.48 mmol) and DIEA (900.50 mg, 6.97 mmol, 1.21 mL). Then, (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (1 g, 2.14 mmol, HCl) was added. The mixture was stirred at 30 °C for 2 h. The mixture was concentrated under vacuum to afford a yellow solid. The residue was purified by reverse-phase flash (0.1% formic acid in water / ACN) and the fractions were lyophilized to give C (1.2 g, 1.66 mmol, 71.28% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + = 725.4. 1 H NMR (400 MHz, chloroform-d) δ = 8.69 (s, 1H), 7.42 - 7.32 (m, 11H), 4.77 - 4.75 (m, 1H), 4.63 - 4.47 (m, 3H), 4.37 - 4.32 (m, 1H), 4.24 - 4.17 (m, 3H), 4.13 (d, J = 11.6 Hz, 1H), 4.09 - 3.94 (m, 2H), 3.77 - 3.68 (m, 9H), 3.63 - 3.59 (m, 1H), 2.64 - 2.56 (m, 1H), 2.54 (s, 3H), 2.19 - 2.08 (m, 1H), 1.00 - 0.92 (m, 9H) ppm.

[0408] Step 3: Preparation of (S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecan-1-oic acid (I-75)

Chemical formula

Table 7

[0409] Preparation of 2-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (I-78)

Chemical formula

Chemical formula

[0410] Step 2: Preparation of methyl 2-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2-azaspiro[3.3]heptane-6-carboxylate (C)

Chemical formula

[0411] Step 3: Preparation of 2-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (I-78) [Chemical formula] To a solution of C (60.00 mg, 0.096 mmol, 1.00 equivalent) in THF (3.00 mL) and water (1.00 mL) was added LiOH (5.74 mg, 0.240 mmol, 3.00 equivalents). The solution was stirred at room temperature for 3 hours and the mixture was acidified to pH 5 with acetic acid. The mixture was directly purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient from 10% to 100% over 15 minutes; detector, UV 254 nm. Thereby, I-78 (42 mg, 71.61%) was obtained as a white solid. LCMS (ESI) m / z: [M+H] + =612.

[0412] [6-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2,6-diazaspiro[3.3]heptan-2-yl]acetic acid (I-79) preparation [Chemical formula] Step 1: Preparation of tert-butyl 6-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (B) [Chem.] A (200.00 mg, 0.394 mmol, 1.00 equiv), K2CO3 (136.28 mg, 0.986 mmol, 2.50 equiv), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (156.41 mg, 0.789 mmol, 2.00 equiv) were added to DMF (5.00 mL). The mixture was reacted at room temperature for 24 h. The resulting mixture was diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. After removal of the organic solvent, the residue was purified by preparative TLC (5% MeOH in EtOAc) to give B (90 mg, 34.11%) as a white solid. LCMS (ESI) m / z: [M+H] + = 669.

[0413] Step 2: (2S,4R)-1-[(2S)-2-(2-[2,6-Diazaspiro[3.3]heptan-2-yl]acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (C) [Chem.] B (60.00 mg, 0.090 mmol, 1.00 equiv) was dissolved in DCM (5.00 mL), followed by the addition of TFA (1.00 mL, 13.463 mmol, 150.08 equiv). The mixture was reacted for 1 h. After removal of the solvent, the crude product C was used without further purification. LCMS (ESI) m / z: [M+H] + = 569.

[0414] Step 3: Preparation of tert-butyl 2-[6-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2,6-diazaspiro[3.3]heptan-2-yl]acetate (D)

Chemical formula

[0415] Step 4: Preparation of [6-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)-2,6-diazaspiro[3.3]heptan-2-yl]acetic acid (I-79)

Chemical formula

[0416] Preparation of 1-([(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)piperidine-4-carboxylic acid (I-80)

Chemical formula

Chemical formula

[0417] Step 2: Preparation of tert-butyl 1-[2-oxo-2-(sodiooxy)ethyl]piperidine-4-carboxylate (C)

Chem.

[0418] Step 3: Preparation of tert-butyl 1-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)piperidine-4-carboxylate (D)

Chem.

[0419] Step 4: Preparation of 1-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)piperidine-4-carboxylic acid (I-80)

Chemical formula

[0420] Preparation of 4-(5-aminopent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-81)

Chemical formula

Chemical Structure

[0421] Step 2: Preparation of tert-butyl N-[5-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]penta-4-yn-1-yl]carbamate (C)

Chemical Structure

[0422] Step 3: Preparation of 4-(5-aminopent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-81) [Chemical formula] To a stirred solution of C (1.10 g, 2.503 mmol, 1 equiv) in dichloromethane (6 mL) was added TFA (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give I-81 (890 mg, 91.2%) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.97 - 7.73 (m, 6H), 5.14 (dd, 1H), 3.09 - 2.97 (m, 2H), 2.96 - 2.84 (m, 1H), 2.67 (t, 3H), 2.62 - 2.54 (m, 1H), 2.12 - 2.02 (m, 1H), 1.82 - 1.94 (m, 2H). LCMS (ESI) m / z: [M+H] + = 340.12.

[0423] Preparation of 5-[2-[4-(aminomethyl)piperidin-1-yl]ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-82)

Chemical Structure

Chemical Structure

[0424] Step 2: Preparation of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (C) [Chemical formula] To a mixture of t-BuOH (5.00 mL) / water (5.00 mL) / THF (1.00 mL), B (250 mg, 0.80 mmol, 1.00 equivalent), NMO (99 mg, 0.80 mmol, 1.5 equivalents), and K2OsO4 dihydrate (15 mg, 0.04 mmol, 0.050 equivalent) were added. The resulting suspension was stirred at room temperature for 24 hours, after which time a clear solution remained. The reaction was quenched with saturated Na2S2O3 (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After removing the solvent, the residue was dissolved in a water (5.00 mL) / acetone (5.00 mL) mixture together with NaIO4 (255.20 mg, 1.19 mmol, 1.50 equivalents). The reaction was stirred at room temperature for 2 hours and then the solvent was removed under vacuum. The residue was suspended in 20 mL of EtOAc. After filtration, the remaining liquid was concentrated under vacuum and the residue was purified by preparative TLC (EtOAc / petroleum ether = 1:1, v / v) to give C (120 mg, 47.7%) as a grayish white solid. LCMS (ESI) m / z: [M-H] - = 315.

[0425] Step 3: Preparation of tert-butyl N-[[1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidin-4-yl]methyl]carbamate (D) [Chemical formula] A solution of C (120 mg, 0.379 mmol, 1.00 equiv) and tert-butyl N-(piperidin-4-ylmethyl)carbamate (81 mg, 0.38 mmol, 1.0 equiv) in DMF (10.00 mL) was added STAB (120 mg, 0.569 mmol, 1.50 equiv) all at once. The reaction mixture was stirred at room temperature overnight. After concentration, the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water in ACN, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. Thereby, D (130 mg, 66.7%) was obtained as a white solid. LCMS (ESI) m / z: [M+H] + =515.

[0426] Step 4: Preparation of 5-[2-[4-(aminomethyl)piperidin-1-yl]ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-82)

Chem.

[0427] Preparation of 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylic acid (I-83)

Chem.

Chem.

[0428] Step 2: Preparation of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (C) [Chemical formula] To a solution of B (3.14 g, 9.991 mmol, 1.00 equiv) in 1,4-dioxane (30.00 mL) was added NaIO4 (10.68 g, 49.953 mmol, 5.00 equiv), water (3.00 mL), and 2,6-lutidine (3.21 g, 29.972 mmol, 3 equiv). To this mixture was added K2OsO4 dihydrate (0.37 g, 0.999 mmol, 0.1 equiv) at room temperature, and the reaction was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. This afforded C (1.83 g, 57.92%) as a pale brown solid; LCMS (ESI) m / z: + = 317.

[0429] Step 3: Preparation of tert-butyl 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylate (D)

Chemical Structure

[0430] Step 4: Preparation of 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylic acid (I-83)

Chemical Structure

[0431] Preparation of 4,5-dimethyl-1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (I-84)

Chemical Structure

Chemical Structure

[0432] Step 2: Preparation of tert-butyl 4,5-dimethyl-1H-pyrrole-3-carboxylate (C)

Chemical Structure

[0433] Step 3: Preparation of tert-butyl 4,5-dimethyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylate (D)

Chemical formula

[0434] Step 4: Preparation of 4,5-Dimethyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (I-84) [Chemical formula] To a solution of D (80 mg, 0.29 mmol) in 1,4-dioxane (2 mL) was added 4 M hydrochloric acid in 1,4-dioxane (2 mL). The mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure to give I-84 (50 mg, crude) as a purple solid. LCMS (ESI) m / z = [M+H] += 218.2.

[0435] Preparation of 5-[4-(4-Aminopiperidin-1-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-85) [Chemical formula] Step 1: Preparation of 2-(2,6-Dioxopiperidin-3-yl)-5-(penta-4-en-1-yloxy)isoindole-1,3-dione (B) [Chemical formula] To a stirred mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (A, 500.00 mg, 1.823 mmol, 1.00 equivalent) and KHCO3 (273.81 mg, 2.735 mmol, 1.50 equivalent) in DMF (10.00 mL) were added 5-bromo-1-pentene (326.07 mg, 2.188 mmol, 1.20 equivalent) and KI (30.27 mg, 0.182 mmol, 0.10 equivalent) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65 °C overnight under a nitrogen atmosphere, then cooled and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (1:1 petroleum ether / EtOAc) to give B (400 mg, 64.08%) as a white solid. LCMS (ESI) m / z = [M+H]+ = 343.

[0436] Step 2: Preparation of 4 - [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butanal (C)

Chemical Structure

[0437] Step 3: Preparation of tert-butyl N-[1-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butyl)piperidin-4-yl]carbamate (D)

Chemical Structure

[0438] Step 4: Preparation of 5-[4-(4-aminopiperidin-1-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-85)

Chemical Structure

[0439] Preparation of tert-butyl 2-[(4-bromo-2-pyridyl)-methyl-amino]acetate (I-86)

Chemical Structure

[0440] Preparation of 2-(2,6-dioxo-3-piperidyl)-4-[2-oxo-2-[4-(4-piperidyl)-1-piperidyl]ethoxy]isoindoline-1,3-dione (I-87)

Chemical Structure

Chemical Structure

[0441] Step 2: Preparation of 2-(2,6-dioxo-3-piperidyl)-4-[2-oxo-2-[4-(4-piperidyl)-1-piperidyl]ethoxy]isoindoline-1,3-dione (I-87)

Chemical Structure

Table 8

[0442] Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (I-90) and N-(2-((4-(3-bromophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (I-92)

Chemical Structure

Chemical Structure

[0443] Step 2: Preparation of tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (C)

Chemical formula

[0444] Step 3: Preparation of 2-amino-N-(4-(3-bromophenyl)thiazol-2-yl)acetamide hydrochloride (D)

Chemical Structure

[0445] Step 4: Preparation of N-(2-((4-(3-bromophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (I-92) [Chemistry] To a solution of D (8.4 g, 24.09 mmol) and 1-methylsulfonylpyrrole-3-carboxylic acid (5.47 g, 28.91 mmol) in DCM (100 mL), HATU (10.99 g, 28.91 mmol) and DIEA (18.68 g, 144.56 mmol, 25.18 mL) were added. The mixture was stirred at 20 °C for 16 h. The resulting suspension was filtered, triturated with MTBE (50 mL × 2) to obtain a filter cake, which was dried under vacuum to give I-92 (10 g, 20.58 mmol, 85.43% yield) as a white solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 12.40 - 12.35 (m, 1H), 8.69 - 8.66 (m, 1H), 8.11 - 8.10 (m, 1H), 7.92 - 7.90 (m, 1H), 7.85 - 7.84 (m, 1H), 7.78 (s, 1H), 7.53 - 7.51 (m, 1H), 7.42 - 7.38 (m, 1H), 7.32 - 7.30 (m, 1H), 6.78 - 6.77 (m, 1H), 4.14 (d, J = 6.0 Hz, 2H), 3.57 (s, 3H). LCMS (ESI) m / z: [M + H] + = 484.8

[0446] Step 5: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (I-90) [Chemistry] A solution of I-92 (1.5 g, 3.10 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.18 g, 4.65 mmol) in 1,4-dioxane (15 mL) was added with Pd(dppf)Cl2 (227.07 mg, 0.310 mmol) and KOAc (913.69 mg, 9.31 mmol). The mixture was stirred at 80 °C for 2 h, then poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was suspended in 1:1 petroleum ether / EtOAc (20 mL), filtered, and the filtrate was concentrated under vacuum to give I-90 (6.5 g, 12.00 mmol, yield 96.71%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ = 12.45 (s, 1H), 8.67 (t, J = 6.0 Hz, 1H), 8.29 (s, 1H), 8.01 (br d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 2.8 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 4.14 (d, J = 6.0 Hz, 2H), 3.57 (s, 3H), 1.31 (s, 12H). LCMS (ESI) m / z: [M+H] + = 531.2

[0447] Preparation of tert-butyl 1-(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)cyclopropanecarboxylate (I-91)

Chemical formula

Chemical formula

[0448] Step 2: Preparation of tert-butyl 1-(4-bromopyridin-2-yl)cyclopropanecarboxylate (C)

Chemical formula

[0449] Step 3: Preparation of tert-butyl 1-(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)cyclopropanecarboxylate (D)

Chem.

[0450] Step 4: Preparation of 1-(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)cyclopropanecarboxylic acid (I-91)

Chem.

[0451] Preparation of Compound 11-N-[2-[[4-[3-[2-[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]cyclopropyl]-4-pyridyl]phenyl]thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonylpyrrole-3-carboxamide

Chem.

Table 9-1

Table 9-2

Table 9-3

Table 9-4

Table 9-5

Table 9-6

Table 9-7

[0452] Preparation of N-(2-((4-(3’-(aminomethyl)-[1,1’-biphenyl]-3-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (I-93)

Chemical Structure

Chemical formula

[0453] Step 2: Preparation of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (C)

Chemical formula

[0454] Step 3: Preparation of tert-butyl ((3’-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)-[1,1’-biphenyl]-3-yl)methyl)carbamate (D)

Chemical formula

[0455] Step 4: Preparation of N-(2-((4-(3’-(aminomethyl)-[1,1’-biphenyl]-3-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (I-93)

Chemical formula

[0456] Preparation of compound 1-N-(2-((4-(3’-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-3,12-dioxo-6,9-dioxa-2,13-diazapentadecyl)-[1,1’-biphenyl]-3-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide

Chemical Structure

Table 10-1

Table 10-2

Table 10-3

Table 10-4

Table 10-5

Table 10-6

[0457] Preparation of 2-(methyl(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)amino)acetic acid (I-94)

Chem.

[0458] Preparation of Compound 9 - N-(2 - ((4-(3-(2 - ((2 - ((2 - (2 - (2 - (2 - ((2,6 - dioxopiperidin - 3 - yl)-1,3 - dioxoisoindolin - 4 - yl)amino)ethoxy)ethoxy)ethyl)amino)-2 - oxoethyl)(methyl)amino)pyridin - 4 - yl)phenyl)thiazol - 2 - yl)amino)-2 - oxoethyl)-1-(methylsulfonyl)-1H - pyrrole - 3 - carboxamide

Chem.

Table 11 - 1

Table 11 - 2

Table 11 - 3

Table 11 - 4

Table 11 - 5

[0459] Compound 123 - N - [2 - [[4 - [3 - [2 - [[2 - [4 - [1 - [2 - [2 - (2,6 - dioxo - 3 - piperidyl) - 1,3 - dioxoisoindolin - 4 - yl]oxyacetyl] - 4 - piperidyl] - 1 - piperidyl] - 2 - oxo - ethyl] - methyl - amino] - 4 - pyridyl]phenyl]thiazol - 2 - yl]amino] - 2 - oxo - ethyl] - 4,5 - dimethyl - 1 - methylsulfonyl - pyrrole - 3 - carboxamide [Chemical formula] Step 1: Preparation of 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-amine (B) [Chemical formula] To a solution of 4-(3-bromophenyl)thiazol-2-amine (A, 20 g, 78.39 mmol) and bis(pinacol)diborane (29.86 g, 117.59 mmol) in 1,4-dioxane (200 mL) were added Pd(dppf)Cl2 (5.74 g, 7.84 mmol) and KOAc (23.08 g, 235.17 mmol). The mixture was stirred at 70 °C for 2 hours, then diluted with water (2 L) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over Na2SO and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc 10:1 - 5:1) to give B (21 g, 78.98%) as a brown solid. LCMS (ESI) m / z: [M+H] + = 303.1. 1 H NMR (400 MHz, CDCl3) δ = 8.20 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 5.64 (s, 2H), 1.38 (s, 12H) ppm.

[0460] Step 2: Preparation of intermediate 5 tert-butyl 2-[[4-[3-(2-aminothiazol-4-yl)phenyl]-2-pyridyl]-methyl-amino]acetate (C) [Chemical formula] A mixture of B (13.2 g, 43.83 mmol), I-86 (14.57 g, 48.21 mmol), K3PO4 (27.91 g, 131.48 mmol), and di-tert-butyl(cyclopentyl)phosphanedichloropalladium(II) (2.86 g, 4.38 mmol) in 1,4-dioxane (150 mL) / water (40 mL) was degassed and purged three times with nitrogen. The mixture was stirred at 80 °C for 2 h, then diluted with water (1 L) and extracted with EtOAc (300 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc 10:1 to 1:1). This solid material was successively triturated with MeOH (200 mL) to afford C (15 g, 35.94 mmol, 63.13%) as a brown solid. LCMS (ESI) m / z: [M+H] + = 397.2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.15 - 8.08 (m, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.17 (s, 1H), 7.09 (s, 2H), 6.92 - 6.90 (m, 1H), 6.86 (s, 1H), 4.28 (s, 2H), 3.12 (s, 3H), 1.37 (s, 9H) ppm.

[0461] Step 3: Preparation of tert-butyl 2-((4-(3-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)(methyl)amino)acetate (D)

Chemical formula

[0462] Step 4: Preparation of tert-butyl 2-[[4-[3-[2-[(2-aminoacetyl)amino]thiazol-4-yl]phenyl]-2-pyridyl]-methyl-amino]acetate (E)

Chemical Structure

[0463] Step 5: Preparation of tert-butyl 2-[[4-[3-[2-[[2-[(4,5-dimethyl-1-methylsulfonyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]-methyl-amino]acetate (F)

Chemical Structure

[0464] Step 6: Preparation of Intermediate 12 2-[[4-[3-[2-[[2-[(4,5-Dimethyl-1-methylsulfonyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]-methyl-amino]acetic acid (I-95) [Chemical Structure] A mixture of F (430 mg, 0.66 mmol) in HCl (6M, 20 mL) was stirred at 30 °C for 15 h. The reaction mixture was filtered and the filter cake was triturated with petroleum ether / EtOAc (10:1) to afford I-95 (260 mg, 57.35% yield) as a grey solid. LCMS (ESI) m / z: [M+H] + = 597.2. 1 1H NMR (400 MHz, DMSO-d6) δ = 12.44 (br s, 1H), 8.54 - 8.51 (m, 1H), 8.34 (s, 1H), 8.16 (d, J = 6.4 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.88 - 7.87 (m, 2H), 7.81 (s, 1H), 7.67 - 7.63 (m, 1H), 7.51 (s, 1H), 7.39 (d, J = 6.4 Hz, 1H), 4.70 (s, 2H), 4.11 (d, J = 5.6 Hz, 2H), 3.49 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H) ppm.

[0465] Step 7: Preparation of N-[2-[[4-[3-[2-[[2-[4-[1-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]oxyacetyl]-4-piperidyl]-1-piperidyl]-2-oxo-ethyl]-methyl-amino]-4-pyridyl]phenyl]thiazol-2-yl]amino]-2-oxo-ethyl]-4,5-dimethyl-1-methylsulfonyl-pyrrole-3-carboxamide (Compound 123)

Chemical formula

Table 12

[0466] Compound 91 - N - [2 - [[4 - [3 - [2 - [[2 - [5 - [[2 - (2,6 - dioxo - 3 - piperidyl) - 1,3 - dioxoisoindolin - 4 - yl]amino]pentylamino] - 2 - oxo - ethyl] - methyl - amino] - 4 - pyridyl]phenyl]thiazol - 2 - yl]amino] - 2 - oxo - ethyl] - 1 - isopropylsulfonyl - 4,5 - dimethyl - pyrrole - 3 - carboxamide

Chem.

[0467] Step 2: Preparation of 2-[[4-[3-[2-[[2-[(1-isopropylsulfonyl-4,5-dimethyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]-methyl-amino]acetic acid (C) [Chemistry] A mixture of B (620 mg, 0.91 mmol) in HCl (6 M, 20 mL) was stirred at 30 °C for 15 h. The mixture was filtered and then triturated with petroleum ether / EtOAc (10:1) to afford C (320 mg, yield 47.83%) as a pink solid. LCMS (ESI) m / z: [M+H] + = 625.2. 1 H NMR (400 MHz, DMSO-d6) δ = 12.44 (br s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.89 - 7.86 (m, 2H), 7.77 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 6.4 Hz, 1H), 4.68 (s, 2H), 4.10 (sd, J = 5.2 Hz, 2H), 3.77 - 3.71 (m, 1H), 3.32 (s, 3H), 2.29 (s, 3H), 2.11 (s, 3H), 1.23 (s, 3H), 1.22 (s, 3H) ppm.

[0468] Step 3: Preparation of N-[2-[[4-[3-[2-[[2-[5-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]pentylamino]-2-oxo-ethyl]-methyl-amino]-4-pyridyl]phenyl]thiazol-2-yl]amino]-2-oxo-ethyl]-1-isopropylsulfonyl-4,5-dimethyl-pyrrole-3-carboxamide (Compound 91)

Chemical Structure

Table 13

[0469] Preparation of 2-[methyl-[4-[3-[2-[[2-[(5-methyl-1-methylsulfonyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]amino]acetic acid (I-102)

Chem.

Chem.

[0470] Step 2: Preparation of tert-butyl 5-methyl-1H-pyrrole-3-carboxylate (C)

Chem.

[0471] Step 3: Preparation of tert-butyl 5-methyl-1-methylsulfonyl-pyrrole-3-carboxylate (D)

Chemical formula

[0472] Step 4: Preparation of (E)-5-methyl-1-methylsulfonyl-pyrrole-3-carboxylic acid

Chemical Structure

[0473] Step 5: Preparation of tert-butyl 2-[methyl-[4-[3-[2-[[2-[(5-methyl-1-methylsulfonyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]amino]acetate (F)

Chemical Structure

[0474] Step 6: Preparation of 2-[methyl-[4-[3-[2-[[2-[(5-methyl-1-methylsulfonyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]amino]acetic acid (I-102)

Chemical Structure

[0475] Preparation of Compound 122 - N-(2-((4-(3-(2-((2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)(methyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide [Chemical Structure] To a mixture of 2-[methyl-[4-[3-[2-[[2-[(5-methyl-1-methylsulfonyl-pyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]amino]acetic acid (I-102, 40 mg, 0.064 mmol) and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (I-9, 26.13 mg, 0.064 mmol) in DMF (1 mL) was added DIEA (41.75 mg, 0.32 mmol, 56.27 μL). The mixture was stirred at 30 °C for 15 minutes, then EDCI (18.58 mg, 0.096 mmol) and HOBt (13.10 mg, 0.096 mmol) were added. After stirring for an additional 16 hours, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 26% - 56%, 10 minutes) to give Compound 122 (9.9 mg, 14.48%) as a yellow solid. LCMS (ESI) m / z: [M+H] + = 969.5. 11H NMR (400 MHz, DMSO-d6) δ = 12.44 - 12.36 (m, 1H), 11.11 (d, J = 4.4 Hz, 1H), 8.63 - 8.60 (m, 1H), 8.19 (s, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 - 7.87 (m, 1H), 7.78 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.92 - 6.90 (m, 1H), 6.85 (s, 1H), 6.60 - 6.57 (m, 1H), 6.48 (s, 1H), 5.06 - 5.02 (m, 1H), 4.20 (s, 2H), 4.11 (d, J = 5.6 Hz, 2H), 3.58 - 3.56 (m, 2H), 3.53 (s, 3H), 3.50 - 3.48 (m, 4H), 3.45 - 3.38 (m, 4H), 3.23 - 3.19 (m, 2H), 3.16 (d, J = 5.2 Hz, 1H), 3.11 (s, 3H), 2.90 - 2.81 (m, 1H), 2.58 (d, J = 2.4 Hz, 1H), 2.40 (s, 3H), 2.07 - 1.96 (m, 1H) ppm.

Table 14

[0476] Preparation of N-[2-[[4-[3-[2-(2-Aminoethoxy)-4-pyridyl]phenyl]thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (I-96)

Chemical formula

Chemical formula

[0477] Step 2: Preparation of tert-butyl N-[2-[[4-[3-[2-[[2-[(1-methylsulfonylpyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]oxy]ethyl]carbamate (C)

Chemical Structure

[0478] Step 3: Preparation of N-[2-[[4-[3-[2-(2-aminoethoxy)-4-pyridyl]phenyl]thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (I-96)

Chemical formula

[0479] Preparation of Compound 36 - N - [2 - [[4 - [3 - [2 - [2 - [4 - [2 - (2,6 - Dioxo - 3 - piperidyl) - 1,3 - dioxoisoindolin - 4 - yl]oxybutanoylamino]ethoxy] - 4 - pyridyl]phenyl]thiazol - 2 - yl]amino] - 2 - oxo - ethyl] - 1 - methylsulfonyl - pyrrole - 3 - carboxamide [Chemical Structure] A solution of N-[2-[[4-[3-[2-(2-aminoethoxy)-4-pyridyl]phenyl]thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (I-96, 30 mg, 0.052 mmol), 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxybutanoic acid (I-11, 22.48 mg, 0.06 mmol), EDCI (19.93 mg, 0.103 mmol), and HOBt (14.05 mg, 0.103 mmol) in DMF (1 mL) was added with DIEA (33.59 mg, 0.259 mmol, 45.28 μL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was purified directly by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 μm; mobile phase: [0.225% formic acid in water / ACN: 38% - 68%, 9 min]) to give Compound 36 (14.03 mg, yield 28.94%) as a white solid. LCMS (ESI) m / z: [M+H] + = 883.2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.76 - 8.74 (m, 1H), 8.32 - 8.22 (m, 2H), 8.16 - 8.14 (m, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.89 - 7.69 (m, 4H), 7.60 - 7.30 (m, 5H), 7.14 (s, 1H), 6.79 - 6.78 (m, 1H), 5.09 - 5.06 (m, 1H), 4.40 - 4.13 (m, 6H), 3.59 (s, 3H), 3.51 - 3.47 (m, 2H), 2.94 - 2.81 (m, 1H), 2.62 - 2.53 (m, 2H), 2.34 - 2.32 (m, 2H), 2.06 - 1.94 (m, 3H) ppm.

Table 15-1

Table 15-2

[0480] Preparation of 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(2-piperazin-1-ylpyridin-4-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (I-97)

Chem.

Chem.

[0481] Step 2: Preparation of tert-butyl 4-[4-[3-[2-[[2-[(1-methylsulfonylpyrrole-3-carbonyl)amino]acetyl]amino]thiazol-4-yl]phenyl]-2-pyridyl]piperazine-1-carboxylate (C)

Chem.

[0482] Step 3: Preparation of 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(2-piperazin-1-yl-4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (I-97)

Chemical Structure

[0483] Preparation of Compound 31 - N - [2 - [[4 - [3 - [2 - [4 - [3 - [2 - [2 - [[2 - (2,6 - Dioxo - 3 - piperidyl) - 1,3 - dioxo - isoindolin - 4 - yl]amino]ethoxy]ethoxy]propanoyl]piperazin - 1 - yl] - 4 - pyridyl]phenyl]thiazol - 2 - yl]amino] - 2 - oxo - ethyl] - 1 - methylsulfonyl - pyrrole - 3 - carboxamide

Chemical Structure

Table 16 - 1

Table 16 - 2

Table 16 - 3

[0484] Preparation of 2 - methyl - 2 - [3 - [3 - [2 - [[2 - [(1 - methylsulfonylpyrrole - 3 - carbonyl)amino]acetyl]amino]thiazol - 4 - yl]phenyl]pyrazol - 1 - yl]propanoic acid (I - 98)

Chemical Structure

Chemical Structure

Claims

1. Formula I A-L-B Formula I A compound having the structure of, wherein L is a linker, and the linker has the structure of Formula III or Formula IV, Formula III is A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ -(D)-(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ Formula III is, wherein A １ is the bond between A and the linker, A ２ is the bond between the linker and B, B １ 、B ２ 、B ３ 、and B ４ each independently is optionally substituted C １ -C ４ alkyl, optionally substituted C １ -C ４ heteroalkyl, O, S, S(O) ２ 、or NR Ｎ is, Each R Ｎ independently is H, optionally substituted C １－４ alkyl, optionally substituted C ２－４ alkenyl, optionally substituted C ２－４ alkynyl, optionally substituted C ２－６ heterocyclyl, optionally substituted C ６－１２ aryl, or optionally substituted C １－７ heteroalkyl, C １ and C ２ each independently is carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, each of f, g, h, i, j, and k independently is 0 or 1, D is optionally substituted C １－１２ alkyl, optionally substituted C ２－１２ alkenyl, optionally substituted C ２－１２ alkynyl, optionally substituted C ２ -C １２ polyethylene glycol, or optionally substituted C １－１２ heteroalkyl, or A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ - is a chemical bond that binds to -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ and is a chemical bond, Formula IV is A １ -(E １ ) ｐ１ -(F １ )-(C ３ ) ｍ１ -(E ３ ) ｎ１ -(C ４ ) ｍ２ -(F ２ ) ｏ１ -(E ３ ) ｎ２ -(F ３ ) ｏ２ -(E ２ ) ｐ２ -A ２ Formula IV is, wherein, A １ is the bond between the linker and A, A ２ is the bond between B and the linker, Each of m1, m2, n1, n2, o1, o2, p1, and p2 is independently 0 or 1, E １ and E ２ each is independently O, S, NR Ｎ , optionally substituted C １－１０ alkyl, optionally substituted C ２－１０ alkenyl, optionally substituted C ２－１０ alkynyl, optionally substituted C ２ -C １０ polyethylene glycol, or optionally substituted C １－１０ heteroalkyl, each E ３ is independently optionally substituted C １－１０ alkyl, optionally substituted C １－１０ heteroalkyl, O, S, or NR Ｎ and each R Ｎ is independently H, optionally substituted C １－４ alkyl, optionally substituted C ２－４ alkenyl, optionally substituted C ２－４ alkynyl, optionally substituted C ２－６ heterocyclyl, optionally substituted C ６－１２ aryl, or optionally substituted C １－７ heteroalkyl, C ３ and C ４ each is independently carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, F １ , F ２ , and F ３ each is independently optionally substituted C ３ -C １０ carbocyclic, optionally substituted C ２－１０ heterocyclyl, optionally substituted C ６ -C １０ aryl, or optionally substituted C ２ -C ９ heteroaryl, B is, [Chemical Formula 1] a degradation moiety represented by the structure of, or [Chemical Formula 2] a degradation moiety represented by the structure of, wherein A2 is a bond between the degradation moiety and the linker, A has the structure of Formula II [Chemical Formula 3] and in the formula, X １ is CH, X ２ and X ３ are CH, R １ is H, optionally substituted C １ -C ６ acyl, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ２ -C ９ heterocyclyl, or -SO ２ R ６ and R ２ and R ５ each independently is H or optionally substituted C １ -C ６ alkyl, R ３ is H, optionally substituted C １ -C ６ alkyl, or a bond between A and the linker, R ４ is H, optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl, R ６ is optionally substituted C １ -C ６alkyl or -NR ７ R ８ and R ７ and R ８ each independently is optionally substituted C １ -C ６ alkyl, Het is thiazole, G １ is phenyl or naphthyl, G ２ is absent, G ３ is absent, phenyl, or pyridine, A １ is H, or a bond between A and the linker, provided that Formula II contains only one bond between A and the linker, a compound, or a pharmaceutically acceptable salt thereof.

2. R ２ is H, the compound or a pharmaceutically acceptable salt thereof according to Claim 1.

3. R ５ is H, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 2.

4. R ４ is H, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 3.

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

6. R １ is 【Chemical Formula 4】 , the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 4.

7. R １ is - SO ２ R ６ The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

8. R ６ is optionally substituted C １ -C ６ alkyl. The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. R １ is 【Chemical Formula 5】 The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

10. The linker has the structure of Formula III. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. B １ and B ４ each independently is 【Chemical Formula 6】 The compound according to claim 10 or a pharmaceutically acceptable salt thereof.

12. The linker is 【Chemical Formula 7】 has the structure of wherein x1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, x2 is 0, 1, 2, 3, 4, 5, or 6, x3 is 1 or 2, x4 is 1 or 2, W is 【Chemical Formula 8】 and R ｘ１ and R ｘ２ each independently is H, halogen, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, or optionally substituted C ３ -C ６ is carbocyclic, or R ｘ１ and R ｘ２ together with the carbon atom to which each is attached combine to form an optionally substituted C ３ -C ６ carbocyclic or optionally substituted C ２ -C ５ heterocyclic, and R ｙ１ R ｙ２ R ｙ３ and R ｙ４ each independently is H, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, or optionally substituted C ３ -C ６ carbocyclic, a compound according to claim 10 or 11 or a pharmaceutically acceptable salt thereof.

13. The linker is 【Chemical Formula 9-1】 【Chemical Formula 9-2】 【Chemical Formula 9-3】 【Chemical Formula 9-4】 having the structure of, a compound according to any one of claims 10 to 12 or a pharmaceutically acceptable salt thereof.

14. The linker has the structure of Formula IV, a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

15. The linker is 【Chemical Formula 10-1】 【Chemical Formula 10-2】 【Chemical 10-3】 【Chemical 10-4】 【Chemical 10-5】 The compound according to claim 14 or a pharmaceutically acceptable salt thereof having the structure of.

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

17. The pharmaceutical composition according to claim 16 for treating BAF complex-related disorders in a subject in need thereof.

18. The pharmaceutical composition according to claim 17, wherein the BAF complex-related disorder is cancer or a viral infection.

19. The pharmaceutical composition according to claim 16 for treating cancer in a subject in need thereof.

20. The pharmaceutical composition according to claim 19, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, fetal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, or penile cancer.

Images