Compounds and uses thereof

Abstract

The present disclosure features Compound # imgabs0 # of Formula I or a pharmaceutically acceptable salt thereof as well as formulations containing them. Also disclosed are methods of treating BAF complex related conditions, such as cancer.

Description

[0001] background

[0002] The present invention relates to compounds useful for modulating BRG1 or BRM-associated factor (BAF) complexes. In particular, the present invention relates to compounds useful for treating disorders associated with BAF complex function.

[0003] Chromatin regulation is crucial for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which this gene expression occurs. The human transforming / sucrose non-fermenting (SWI / SNF) chromatin remodeling complex (also known as the BAF complex) possesses two SWI2-like ATPases, termed 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 cancer cell proliferation. 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 tumor cell growth in cells characterized by loss-of-function mutations in BRG1. Inactivation of BRG and / or BRM leads to downstream effects in the cell, including cell cycle arrest and tumor suppression.

[0004] Overview

[0005] The present invention features compounds that can be used to modulate the BAF complex. In some embodiments, the compounds can be used to treat conditions associated with alterations in the BAF complex, such as conditions associated with alterations in one or both of the BRG1 and BRM proteins. The compounds of the invention, alone or in combination with other pharmaceutical agents, can be used to treat such conditions.

[0006] In one aspect, the invention features a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in

[0009] m is 0, 1, 2, or 3;

[0010] k is 0, 1, or 2;

[0011] Each R 1are independently halogen (halo), optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino or cyano;

[0012] Each X is independently halogen, or optionally substituted C1-C6 heteroalkyl;

[0013] L is a linker; and

[0014] B is the degradation part.

[0015] In another aspect, the invention features a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0016]

[0017] in

[0018] m is 0, 1, 2, or 3;

[0019] k is 0, 1, or 2;

[0020] Each R 1 is independently halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C3-C8 cycloalkyl;

[0021] Each X is independently halogen;

[0022] L is a linker; and

[0023] B is the degradation part.

[0024] In some embodiments, the compound has the structure of Formula IA:

[0025]

[0026] In some embodiments, the compound has the structure of Formula IB

[0027]

[0028] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0029] In some embodiments, R 1 is an optionally substituted C1-C6 heteroalkyl. 1 In some embodiments, R 1In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted C1-C6 alkyl. 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. 1 In some embodiments, R 1 is an optionally substituted C3-C8 cycloalkyl. 1 In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted C2-C9 heterocyclyl. 1 In some embodiments, R 1 It is a cyano group.

[0030] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, X is optionally substituted C1-C6 heteroalkyl. In some embodiments, X is methoxy. In some embodiments, X is halogen. In some embodiments, X is F.

[0031] In some embodiments, m is 0.

[0032] In some embodiments, m is 1.

[0033] In some embodiments, R 1 is an optionally substituted C1-C6 heteroalkyl. 1 In some embodiments, R 1 In some embodiments, R 1 is F or Cl.

[0034] In some embodiments, k is 1.

[0035] In some embodiments, k is 0.

[0036] In one aspect, the invention features a compound having the structure of Formula IV or a pharmaceutically acceptable salt thereof:

[0037]

[0038]

[0039] in

[0040] k is 0, 1, or 2;

[0041] Each X is independently halogen;

[0042] L is a linker; and

[0043] B is the degradation part.

[0044] In some embodiments, the degradation moiety B has the structure of Formula A-1:

[0045]

[0046] in

[0047] Y 1 for

[0048] R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0049] R A6 is H or optionally substituted C1-C6 alkyl; and R A7 is H or an optionally substituted C1-C6 alkyl group; or R A6 and R A7 Together with the carbon atoms to which they are bonded, they form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl; or R A6 and R A7 Together with the carbon atoms to which they are respectively bonded, they form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl;

[0050] R A8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0051] R A1 、R A2 、R A3 and R A4 Each of them is independently H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R A1 and R A2 、R A2 and R A3 , and / or R A3 and R A4 Together with their respective attached carbon atoms to form and is an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 carbocyclyl, optionally substituted C2-C9 heteroaryl or C2-C9 heterocyclyl, any of which is optionally substituted by A 2 replace,

[0052] where R A1 、R A2 、R A3 , and R A4 One of them is A 2 ,or A 2 Replacement; and

[0053] A 2 is the bond between the degradable portion and the linker.

[0054] In some embodiments, R A5 In some embodiments, R A5 For H.

[0055] In some embodiments, R A1 、R A2 、R A3 and R A4 Each of which is independently H or A 2 .

[0056] In some embodiments, R A1 A 2 And R A2 、R A3 and R A4 Each of them is H.

[0057] In some embodiments, R A2 A 2 And R A1 、R A3 and R A4 Each of them is H.

[0058] In some embodiments, R A3 A2 And R A1 、R A2 and R A4 Each of them is H.

[0059] In some embodiments, R A4 A 2 And R A1 、R A2 and R A3 Each of them is H.

[0060] In some embodiments, Y 1 for

[0061] In some embodiments, R A6 is H. In some embodiments, R A7 For H.

[0062] In some embodiments, Y 1 for

[0063] In some embodiments, R A8 is H or an optionally substituted C1-C6 alkyl. A8 In some embodiments, R A8 It is a methyl group.

[0064] In some embodiments, the degradation moiety comprises the structure of Formula A2:

[0065]

[0066] In some embodiments, the degradation moiety is

[0067]

[0068] In some embodiments, the degradation moiety comprises the structure of Formula A4:

[0069]

[0070]

[0071] In some embodiments, the degradation moiety is

[0072]

[0073] In some embodiments, the degradation moiety has the structure of Formula A5:

[0074]

[0075] In some embodiments, the degradation moiety has the structure of Formula A6:

[0076]

[0077] In some embodiments, the degradation moiety has the structure of Formula A8:

[0078]

[0079] In some embodiments, the degradation moiety has the structure of Formula A10:

[0080]

[0081] In some embodiments, the degradation moiety has the structure

[0082]

[0083] In some embodiments, the degradation moiety has the structure

[0084]

[0085] In some embodiments, the degradation moiety has the structure of Formula C:

[0086]

[0087] in

[0088] L 4 -N(R B1 )(R B2 ),

[0089] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0090] R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0091] R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0092] R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0093] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0094] v2 is 0, 1, 2, 3, or 4;

[0095] Each R B6 Independently A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino;

[0096] R B7 and R B8 Each of the above is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 aryl;

[0097] R B9 is H or optionally substituted C1-C6 alkyl; and

[0098] A 2 is the bond between the degradable moiety and the linker;

[0099] where R B1 、R B3 and R B6 One and only one of them is A 2 ,

[0100] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the degradation moiety has the structure of Formula C:

[0102]

[0103] in

[0104] L4 -N(R B1 )(R B2 ),

[0105] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0106] R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0107] R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0108] R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0109] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0110] v2 is 0, 1, 2, 3, or 4;

[0111] Each R B6 Independently A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C2-C9 heterocyclic group, 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;

[0112] R B7 and R B8Each of the above is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 aryl;

[0113] R B9 is H or an optionally substituted C1-C6 alkyl group;

[0114] R B10 is H or F; and

[0115] A 2 is the bond between the degradable moiety and the linker;

[0116] where R B1 、R B3 and R B6 One and only one of them is A 2 ,

[0117] or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the degradation moiety has the structure of Formula C3.

[0119]

[0120] In some embodiments, the degradation moiety has the structure of formula C4.

[0121]

[0122] In some embodiments, the degradation moiety has the structure of Formula C1:

[0123]

[0124] In some embodiments, the degradation moiety is

[0125]

[0126] In some embodiments, the degradation moiety is

[0127]

[0128] In some embodiments, the degradation moiety is

[0129]

[0130] In some embodiments, the degradation moiety is

[0131]

[0132] In some embodiments, the degradation moiety is

[0133]

[0134] In some embodiments, the degradation moiety is

[0135]

[0136] In some embodiments, the degradation moiety has the structure of Formula C2:

[0137]

[0138] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0139] In some embodiments, R B9 Bonded to the (S)-stereogenic center.

[0140] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl. B7 In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B8 is H. In some embodiments, R B2 For H.

[0141] In some embodiments, the degradation moiety is

[0142]

[0143] In some embodiments, the degradation moiety has the structure of formula Ca2:

[0144]

[0145] In some embodiments, the degradation moiety has the structure of Formula Cb2:

[0146]

[0147] In some embodiments, the degradation moiety has the structure of Formula Cc2:

[0148]

[0149] In some embodiments, the degradation moiety has the structure of formula Cd2:

[0150]

[0151] In some embodiments, the degradation moiety has the structure of formula Ce2:

[0152]

[0153] In some embodiments, the degradation moiety has the structure of Formula Cf2:

[0154]

[0155]

[0156] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0157] In some embodiments, R B9 Bonded to the (S)-stereoisogenic center.

[0158] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl. B7 In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B3 is optionally substituted C3-C 10 In some embodiments, R B3 In some embodiments, R B3 In some embodiments, R B3 In some embodiments, R B8 is H. In some embodiments, R B2 For H.

[0159] In some embodiments, the degradation moiety is

[0160]

[0161] In some embodiments, the degradation moiety is

[0162]

[0163] In some embodiments, the degradation moiety is

[0164]

[0165] In some embodiments, the degradation moiety is

[0166]

[0167] In some embodiments, the degradation moiety is

[0168]

[0169] In some embodiments, the degradation moiety is

[0170]

[0171] In some embodiments, the degradation moiety is

[0172]

[0173] In some embodiments, the degradation moiety is

[0174]

[0175] In some embodiments, the degradation moiety is

[0176]

[0177] In some embodiments, the degradation moiety has the structure of Formula C5:

[0178]

[0179] in

[0180] L 4 -N(R B1 )(R B2 ),

[0181] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0182] R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0183] RB3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0184] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0185] v2 is 0, 1, 2, 3, or 4;

[0186] Each R B6 Independently A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino;

[0187] R B7 and R B8 Each of the above is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 aryl;

[0188] R B9 is H or an optionally substituted C1-C6 alkyl group;

[0189] R B11 is H, alcohol, boronic acid, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0190] and

[0191] A 2 is the bond between the degradable moiety and the linker;

[0192] where R B1 、R B3 and RB6 One and only one of them is A 2 ,

[0193] or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, R B11 For boric acid.

[0195] In some embodiments, the degradation moiety has the structure of formula C6.

[0196]

[0197] In some embodiments, the degradation moiety has the structure of Formula C1:

[0198]

[0199] In some embodiments, the degradation moiety has the structure of Formula C8:

[0200]

[0201] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0202] In some embodiments, R B9 Bonded to the (S)-stereoisogenic center.

[0203] In some embodiments, v2 is 0. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C1-C6 alkyl. B7 In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B8 is H. In some embodiments, R B2 For H.

[0204] In some embodiments, the degradation moiety is

[0205]

[0206] In some embodiments, the degradation moiety has the structure of Formula D:

[0207]

[0208] in

[0209] L 4 -N(R B1 )(R B2 ),

[0210] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0211] R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0212] R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0213] R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0214] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0215] v2 is 0, 1, 2, 3, or 4;

[0216] Each R B6 Independently A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino;

[0217] R B9is H or optionally substituted C1-C6 alkyl; and

[0218] A 2 is the bond between the degradable moiety and the linker;

[0219] where R B1 、R B3 and R B6 One and only one of them is A 2 ,

[0220] or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the degradation moiety has the structure of formula D3.

[0222]

[0223] In some embodiments, the degradation moiety has the structure of Formula D1:

[0224]

[0225] In some embodiments, the degradation moiety is

[0226]

[0227] In some embodiments, the degradation moiety is

[0228]

[0229] In some embodiments, the degradation moiety is

[0230]

[0231] In some embodiments, the degradation moiety has the structure of Formula D2:

[0232]

[0233] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0234] In some embodiments, R B9 is bonded to the (S)-stereoisogenic center. In some embodiments, R B9 For H.

[0235] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 is H. In some embodiments, RB5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B6 is H. In some embodiments, R B6 In some embodiments, R B6 In some embodiments, R B6 In some embodiments, R B6 In some embodiments, R B6 In some embodiments, R B6 is an optionally substituted C1-C6 heteroalkyl. B6 is an optionally substituted C3-C6 alkynyl. B6 In some embodiments, R B6 It is 3-methoxy-1-propoxy.

[0236] In some embodiments, the degradation moiety is

[0237]

[0238] In some embodiments, the degradation moiety is

[0239]

[0240] In some embodiments, the degradation moiety is

[0241]

[0242] In some embodiments, the degradation moiety is

[0243]

[0244] In some embodiments, the degradation moiety is

[0245]

[0246] In some embodiments, the degradation moiety is

[0247]

[0248] In some embodiments, the degradation moiety is

[0249]

[0250] In some embodiments, the degradation moiety is

[0251]

[0252] In some embodiments, the degradation moiety is

[0253]

[0254] In some embodiments, the degradation moiety is

[0255]

[0256] In some embodiments, the degradation moiety is

[0257]

[0258] In some embodiments, the degradation moiety is

[0259]

[0260] In some embodiments, the degradation moiety is

[0261]

[0262] In some embodiments, the degradation moiety is

[0263]

[0264] In some embodiments, the degradation moiety is

[0265]

[0266] In some embodiments, the degradation moiety is

[0267]

[0268] In some embodiments, the degradation moiety is

[0269]

[0270] In some embodiments, the degradation moiety is

[0271]

[0272] In some embodiments, the degradation moiety is

[0273]

[0274] In some embodiments, the degradation moiety is

[0275]

[0276] In some embodiments, the degradation moiety is

[0277]

[0278] In some embodiments, the degradation moiety is

[0279]

[0280] In some embodiments, the degradation moiety is

[0281] In some embodiments, the degradation moiety is

[0282]

[0283] In some embodiments, the degradation moiety is

[0284]

[0285] In some embodiments, the degradation moiety has the structure of Formula Da:

[0286]

[0287] in

[0288]

[0289] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0290] R B2 is H, optionally substituted C 1- C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0291] R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0292] R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0293] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0294] Each of X1 and X2 is independently C, N or O.

[0295] v2 is 0, 1, 2, 3, or 4;

[0296] Each R B6 Independently A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino;

[0297] R B9 is H or optionally substituted C1-C6 alkyl; and

[0298] A 2 is the bond between the degradable moiety and the linker;

[0299] where R B1 、R B3 and R B6 One and only one of them is A 2 ,

[0300] or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the degradation moiety has the structure of formula Da3.

[0302]

[0303] In some embodiments, the degradation moiety has the structure of formula Dal:

[0304]

[0305] In some embodiments, the degradation moiety has the structure of formula Da2:

[0306]

[0307] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0308] In some embodiments, R B9 Bonded to the (S)-stereoisogenic center.

[0309] In some embodiments, v2 is 0. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B2 is H. In some embodiments, X1 is C. In some embodiments, X2 is N.

[0310] In some embodiments, the degradation moiety is

[0311]

[0312] In some embodiments, the degradation moiety has the structure of Formula E:

[0313]

[0314] in

[0315]

[0316] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0317] R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0318] R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0319] R B4is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0320] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0321] R B9 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclic, or optionally substituted C2-C 10 heterocyclic group;

[0322] B 10 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C 10 heterocyclyl; optionally substituted amino or cyano, and

[0323] A 2 is the bond between the degradable moiety and the linker;

[0324] where R B1 、R B3 and R B6 One and only one of them is A 2 ,

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the degradation moiety has the structure of Formula E3.

[0327]

[0328] In some embodiments, the degradation moiety has the structure of Formula E1:

[0329]

[0330] In some embodiments, the degradation moiety is

[0331]

[0332] In some embodiments, the degradation moiety is

[0333]

[0334] In some embodiments, the degradation moiety has the structure of Formula E2:

[0335]

[0336] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0337] In some embodiments, R B9 Bonded to the (S)-stereoisogenic center.

[0338] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B2 is H. In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 In some embodiments, R B9 is H. In some embodiments, R B9 is an optionally substituted C3-C6 alkynyl. B10 In some embodiments, R B9 is [1.1.1]pentane. In some embodiments, R B9 In some embodiments, R B9 In some embodiments, R B9 In some embodiments, R B10 is H. In some embodiments, R B10 In some embodiments, R B10 is optionally substituted C3-C 10 In some embodiments, R B10 is an optionally substituted C1-C6 alkyl. B10 It is a methyl group.

[0339] In some embodiments, the degradation moiety is

[0340]

[0341] In some embodiments, the degradation moiety is

[0342]

[0343] In some embodiments, the degradation moiety is

[0344]

[0345] In some embodiments, the degradation moiety is

[0346]

[0347] In some embodiments, the degradation moiety is

[0348]

[0349] In some embodiments, the degradation moiety is

[0350]

[0351] In some embodiments, the degradation moiety is

[0352]

[0353] In some embodiments, the degradation moiety is

[0354]

[0355] In some embodiments, the degradation moiety is

[0356]

[0357] In some embodiments, the degradation moiety has the structure of Formula F:

[0358]

[0359] in

[0360] L 4 -N(R B1 )(R B2 ),

[0361] R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0362] R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0363] RB3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0364] R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 aryl;

[0365] R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0366] A 2 is the bond between the degradable moiety and the linker;

[0367] where R B1 or R B3 One and only one of them is A 2 ,

[0368] or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the degradation moiety has the structure of Formula F3.

[0370]

[0371] In some embodiments, the degradation moiety has the structure of Formula F1:

[0372]

[0373] In some embodiments, the degradation moiety is

[0374]

[0375] In some embodiments, the degradation moiety is

[0376]

[0377] In some embodiments, the degradation moiety is

[0378]

[0379] In some embodiments, the degradation moiety has the structure of Formula F2:

[0380]

[0381] In some embodiments, R B9 is an optionally substituted C1-C6 alkyl. B9 It is a methyl group.

[0382] In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C1-C6 alkyl. B3 In some embodiments, R B2 For H.

[0383] In some embodiments, the degradation moiety is

[0384]

[0385] In some embodiments, the linker has the structure of Formula II:

[0386] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 ,

[0387] Formula II

[0388] or a pharmaceutically acceptable salt thereof,

[0389] in

[0390] A 1 is the bond between the linker and the ring system A;

[0391] A 2 is the bond between the degradable moiety and the linker;

[0392] B 1 、B 2 、B 3and B 4 Each of which is independently an optionally substituted C1-C4 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 Aryl C 1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C2-C8 heterocyclic group, optionally substituted C2-C6 heteroaryl, optionally substituted C 6-12 Aryl, O, S, S(O)2, or NR N ;

[0393] Each R N are independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-10 Heterocyclyl, optionally substituted C 2-6 Heteroaryl, or optionally substituted C 1-7 heteroalkyl;

[0394] C 1 and C 2 Each of which is independently a carbonyl group, a thiocarbonyl group, a sulfonyl group, or a phosphoryl group;

[0395] Each of f, g, h, i, j, and k is independently 0 or 1; and

[0396] D is optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-10 Heterocyclyl, optionally substituted C 2-6 Heteroaryl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclic group, or optionally substituted C 1-10 heteroalkyl; or D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j-(B 4 ) k -A 2 .

[0397] In some embodiments, B 1 、B 2 、B 3 and B 4 Each of the above is independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, an optionally substituted C2-C 10 Heterocyclyl, optionally substituted C 2-6 Heteroaryl, O or NR N ; and D is optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-10 Heterocyclyl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1-10 Heteroalkyl, or chemically bonded to A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -To-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .

[0398] In some embodiments, B 1 、B 2 、B 3 and B 4 Each of the above is independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, an optionally substituted C2-C 10 Heterocyclyl, optionally substituted C 2-6 Heteroaryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclic group, O, or NR N .

[0399] In some embodiments, each of B1 and B4 is independently

[0400]

[0401]

[0402]

[0403] In some embodiments, B 1 for

[0404]

[0405]

[0406] In some embodiments, B 4 for

[0407]

[0408]

[0409]

[0410] In some embodiments, C 1 for

[0411] In some embodiments, B 2 is an optionally substituted C1-C4 alkyl group.

[0412] In some embodiments, D is an optionally substituted C1-C 10 alkyl.

[0413] In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0414] In some embodiments, D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .

[0415] In some embodiments, the linker is D. In some embodiments, D is an optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-10 Heterocyclyl, optionally substituted C 2-6 Heteroaryl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1-10 In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C3-C 10 carbocyclyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is:

[0416]

[0417]

[0418] In some embodiments, the linker has the structure

[0419]

[0420]

[0421]

[0422] In some embodiments, the linker has the structure of Formula III:

[0423] A 1 -(B 1 ) f -(C 1 ) g - (B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 ,

[0424] Formula III

[0425] in

[0426] A 1 is the bond between the linker and the ring system A;

[0427] A 2 is the bond between the degradable moiety and the linker;

[0428] B 1 、B 2 、B 3 and B 4 Each of which is independently an optionally substituted ethynyl, an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O)2, or NR N ;

[0429] Each R N are independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2- 4 alkynyl, optionally substituted C 2-10 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 heteroalkyl;

[0430] C 1 and C 2 Each of is independently a carbonyl group, a thiocarbonyl group, a sulfonyl group, or a phosphoryl group; and

[0431] Each of f, g, h, i, j, and k is independently 0 or 1.

[0432] In some embodiments, the linker has the structure -(L 1 )n-, where n is 1, 2 or 3, and each L 1 O, NR N , ethynyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 Aryl, or optionally substituted C3-C 10 Cycloalkyl.

[0433] In some embodiments, at least one L 1 is optionally substituted C2-C 10 In some embodiments, the optionally substituted C2-C 10 The heterocyclyl group is a 4-, 5- or 6-membered monocyclic heterocyclyl group. In some embodiments, the 4-, 5- or 6-membered monocyclic heterocyclyl group is:

[0434]

[0435] In some embodiments, the optionally substituted C2-C 10 The heterocyclic group is a spirocyclic heterocyclic group. In some embodiments, the spirocyclic heterocyclic group is:

[0436]

[0437] In some embodiments, the optionally substituted C2-C 10 The heterocyclic group is a bridged heterocyclic group. In some embodiments, the bridged heterocyclic group is:

[0438]

[0439] In some embodiments, the optional C2-C 10 The heterocyclyl group is a fused bicyclic heterocyclyl group. In some embodiments, the fused bicyclic heterocyclyl group is:

[0440]

[0441] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is -(L 1 ) q -(Optionally Substituted C2-C9 Heteroaryl)-(L 1 ) q-, wherein each q is independently 0 or 1. In some embodiments, the optionally substituted C2-C9 heteroaryl is a 6-membered monocyclic heteroaryl. In some embodiments, the 6-membered monocyclic heteroaryl is:

[0442]

[0443] In some embodiments, at least one L 1 is an optionally substituted C2-C9 heteroaryl. In some embodiments, the linker is:

[0444]

[0445] In some embodiments, at least one L 1 is an optionally substituted C6-C 10 In some embodiments, the optionally substituted C6-C 10 Aryl is a 6-membered monocyclic aryl. In some embodiments, the 6-membered monocyclic aryl is an optionally substituted phenyl.

[0446] In some embodiments, at least one L 1 is optionally substituted C3-C 10 In some embodiments, the optionally substituted C3-C 10 Cycloalkyl is a monocyclic cycloalkyl. In some embodiments, the 6-membered monocyclic cycloalkyl is:

[0447]

[0448] In some embodiments, the optionally substituted C3-C 10 Cycloalkyl is a bridged cycloalkyl. In some embodiments, the bridged cycloalkyl is:

[0449]

[0450] In some embodiments, at least one L 1 For ethynyl.

[0451] In some embodiments, one and only one L 1 is 0. In some embodiments, one and only one L 1 NR N In some embodiments, R N is an optionally substituted C1-C4 alkyl. N For H.

[0452] In some embodiments, the linker is the following structure:

[0453] A1 -(B 1 ) f -(B 2 ) h -(B 3 ) i -(B 4 ) k -A 2 ,

[0454] Among them B 1 、B 2 、B 3 and B 4 Each of which is independently an optionally substituted ethynyl, an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C2-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N .

[0455] In some embodiments, at least one of f, h, i, and k is 1.

[0456] In some embodiments, B 1 、B 2 、B 3 and B 4 Each of the groups is independently O, ethynyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C3-C 10 Cycloalkyl, or optionally substituted C6-C 10 In some embodiments, B 1 、B 2 、B 3 and B 4 Each of the groups is independently an optionally substituted C2-C9 heteroaryl or an optionally substituted C2-C 10 In some embodiments, B 1 and B 4 Each of the

[0457]

[0458]

[0459] In some embodiments, B 1 for:

[0460]

[0461]

[0462] In some embodiments, B 4 for:

[0463]

[0464]

[0465] In some embodiments, B 2 NR N In some embodiments, B 2 In some embodiments, B 2 is an optionally substituted C2-C9 heteroaryl. 2 for:

[0466]

[0467] In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0468] In some embodiments, the linker has the structure

[0469]

[0470]

[0471]

[0472] In some embodiments, the shortest chain of atoms connecting the two valence states of the linker is 2 to 10 atoms long. In some embodiments, the shortest chain of atoms connecting the two valence states of the linker is 6 atoms long.

[0473] In some embodiments, the linker has the structure of the linker of any one of compounds 1-291 in Table 1 (e.g., BRG1 IC 50 With BRM IC 50 In some embodiments, the linker has the structure of the linker of any one of compounds 1-291 in Table 1 (e.g., BRM IC 50In some embodiments, the linker has the structure of the linker of any one of compounds 1-291 in Table 1 (e.g., BRM IC 50 is ++ or better (e.g., +++ or ++++ (e.g., ++++)) and BRG1 IC 50 With BRM IC 50 any compound having a ratio of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) to the total weight of the compound).

[0474] In one aspect, the invention features a compound selected from the group consisting of compounds 1-291 in Table 1 and pharmaceutically acceptable salts thereof. In some embodiments, the compound is any one of compounds 1-291 in Table 1 or a pharmaceutically acceptable salt thereof, wherein BRG1 IC 50 With BRM IC 50 The ratio of the above compounds is at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30). In some embodiments, the compound is any one of compounds 1-291 in Table 1 or a pharmaceutically acceptable salt thereof, and its BRM IC 50 ++ or better, as shown in Table 21 (e.g., +++ or ++++ (e.g., ++++)). In some embodiments, the compound is any one of compounds 1-291 in Table 1 or a pharmaceutically acceptable salt thereof, whose BRM IC 50 is ++ or better as shown in Table 21 (e.g., +++ or ++++ (e.g., ++++)), and BRG1 IC 50 With BRM IC 50 The ratio of the above-mentioned amounts is at least 5 (eg, at least 7, 10, 15, 20, 25, or 30).

[0475] Table 1. Compounds of the present invention

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576] In some embodiments, the compound has a BRG1 IC 50 With BRM IC 50 The ratio of the BRG1 IC to the BRG2 IC is at least 5. In some embodiments, the compound has a BRG1 IC of 50 With BRM IC 50 The ratio of the BRG1 to the BRG2 is at least 7. In some embodiments, the compound has a BRG1 IC 50 With BRM IC 50 The ratio of is at least 10. In some embodiments, the compound has a BRG1IC 50 With BRM IC 50 The ratio of the BRG1 to the BRG2 is at least 15. In some embodiments, the compound has a BRG1 IC 50 With BRM IC 50 The ratio of the BRG1 IC to the BRG2 IC is at least 20. In some embodiments, the compound has a BRG1 IC of 50 With BRM IC 50The ratio of the BRG1 to the BRG2 is at least 25. In some embodiments, the compound has a BRG1 IC 50 With BRM IC 50 The ratio is at least 30.

[0577] In one aspect, the invention features a pharmaceutical composition including any of the aforementioned compounds and a pharmaceutically acceptable excipient.

[0578] In another aspect, the invention features a method of reducing the activity of a BAF complex in a cell, the method involving contacting the cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0579] In some embodiments, the cell is a cancer cell.

[0580] In another aspect, the invention features a method of treating a BAF complex-associated disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the above-described compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0581] In some embodiments, the BAF complex-associated disorder is cancer or a viral infection.

[0582] In a further aspect, the invention features a method of inhibiting BRM, the method involving contacting a cell with an effective amount of any of the above-described compounds (eg, a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0583] In some embodiments, the cell is a cancer cell.

[0584] In another aspect, the invention features a method of inhibiting BRG1, the method involving contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0585] In some embodiments, the cell is a cancer cell.

[0586] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method involving contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0587] In some embodiments, the cell is a cancer cell.

[0588] In another aspect, the invention features a method of treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the above-described compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM-selective compound) or a pharmaceutical composition thereof.

[0589] In some embodiments, the disorder associated with a BRG1 loss-of-function mutation is cancer. In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, e.g., the subject is determined to have a BRG1 loss-of-function cancer (e.g., the cancer has been determined to include cancer cells with BRG1 loss-of-function).

[0590] In another aspect, the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the aforementioned compounds (eg, a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0591] In some embodiments, the cell is a cancer cell.

[0592] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of any of the above-described compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0593] In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0594] In some embodiments of any of the preceding methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0595] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0596] In some embodiments of any of the aforementioned methods, the cancer is resistant or has failed to respond to prior therapy (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolomide, irinotecan, CAR-T therapy, Tamoxifen, docetaxel, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, Gemcitabine, Neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, VEGFR2 inhibitors, folate receptor antagonists, forskolin, forseblum, or PDL1 inhibitors).

[0597] In some embodiments of any of the aforementioned methods, the cancer has or has been determined to have a BRG1 mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is homozygous. In some embodiments of any of the aforementioned methods, the cancer does not have or has been determined to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the aforementioned methods, the cancer does not have or has been determined to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the aforementioned methods, the cancer has or has been determined to have a KRAS mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is located in the ATPase catalytic domain of the protein. In some embodiments of any of the aforementioned methods, the BRG1 mutation is a BRG1 C-terminal deletion.

[0598] In another aspect, the present disclosure provides a method for treating a BAF-related disorder (e.g., cancer or viral infection) in a subject in need thereof, comprising contacting a cell with an effective amount of any one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the condition is a viral infection, and is an infection with a virus of the Retroviridae family, such as a lentivirus (e.g., human immunodeficiency virus (HIV) and delta-retrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II))), a Hepadnaviridae family (e.g., hepatitis B virus (HBV)), a Flaviviridae family (e.g., hepatitis C virus (HCV)), adenoviridae family (e.g., human adenovirus), a Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpes virus 6 (HHV-6), herpes virus K*, CMV, varicella-zoster virus), a Papillomaviridae family (e.g., human papillomavirus (HPV), HPV-1), and adenoviruses. E1)), Parvoviridae (e.g., Parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., Measles virus), Togaviridae (e.g., Rubella virus). In some embodiments, the disease condition is Coffin Siris, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0599] In another aspect, the present disclosure provides a method for treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of any one of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is infection with a virus of the family Retroviridae such as lentivirus (e.g., human immunodeficiency virus (HIV) and delta-retrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II))), Hepadnaviridae (e.g., hepatitis B virus (HBV)), Flaviviridae (e.g., hepatitis C virus (HCV)), Adenoviridae (e.g., human adenovirus), Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpes virus 6 (HHV-6), herpes virus K*, CMV, varicella-zoster virus), Papillomaviridae (e.g., human papillomavirus (HPV), HPV-1), and varicella-zoster virus. E1)), Parvoviridae (e.g., Parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., Measles virus), or Togaviridae (e.g., Rubella virus).

[0600] In some embodiments of any of the aforementioned aspects, the compound is a BRM selective compound. In some embodiments, the BRM selective compound inhibits the level and / or activity of BRM at least 10-fold greater than the level and / or activity of BRG1, and / or the compound binds to BRM at least 10-fold greater than the binding of the compound to BRG1. For example, in some embodiments, the I of the BRM selective compound is C50 or IP 50 Comparison of IC of BRG1 50 or IP 50 In some embodiments of any of the above aspects, the compound is a BRM / BRG1 dual inhibitor compound. In some embodiments, the BRM / BRG1 dual inhibitor compound has similar activity against BRM and BRG1 (e.g., the compound has activity against BRM and BRG1 that is within 10-fold (e.g., less than 5-fold, less than 2-fold)). In some embodiments, the BRM / BRG1 dual inhibitor compound has greater activity against BRM. In some embodiments, the BRM / BRG1 dual inhibitor compound has greater activity against BRM. For example, in some embodiments, the IC of the BRM / BRG1 dual inhibitor compound against BRM is less than 10-fold. 50 or IP 50 In the IC of BRG150 or IP 50 within 10 times of .

[0601] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject in need thereof, comprising administering to the subject an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0602] In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0603] In another aspect, the invention features a method of inhibiting metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, comprising administering an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0604] In another aspect, the invention features a method of inhibiting metastatic colonization of a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, comprising administering an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0605] In another aspect, the 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 hematological cancer cells, the method comprising contacting the cells with an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0606] In some embodiments of any of the aforementioned aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cells are in the subject.

[0607] In some embodiments of any of the aforementioned 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%), as compared to a reference. In some embodiments, the 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%), as compared to a reference. In some embodiments, the 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%).

[0608] In some embodiments, the effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or longer) compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or longer) compared to a reference.

[0609] In some embodiments of any of the aforementioned aspects, the effective amount of the compound reduces the level and / or activity of a 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%), as compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of a BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%), as compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of a BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0610] In some embodiments, the effective amount of the compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference.

[0611] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein and / or the cell or subject has been identified as expressing BRG1 or BRM. In some embodiments, the cancer expresses BRG1 protein and / or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein and / or the cell or subject has been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematological cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the cancer is breast cancer (e.g., 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 carcinoma (e.g., microphthalmia transcription factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is a metastatic cancer (e.g., cancer has spread to the liver). Metastatic cancer can include cells that exhibit migration and / or invasion of migratory cells and / or include cells that exhibit endothelial recruitment and / or angiogenesis. In other embodiments, migratory cancer is cell migration cancer. In other embodiments, cell migration cancer is non-metastatic cell migration cancer. Metastatic cancer can be a cancer that spreads via the surface seeding of the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, metastatic cancer can be a cancer that spreads via the lymphatic system, or a cancer that spreads hematogenously. In some embodiments, the effective amount of the agent that reduces the level and / or activity of BRG1 and / or BRM is an amount that effectively inhibits cancer from colonizing the liver.

[0612] In some embodiments, the cancer harbors a mutation in GNAQ. In some embodiments, the cancer harbors a mutation in GNA11. In some embodiments, the cancer harbors a mutation in PLCB4. In some embodiments, the cancer harbors a mutation in CYSLTR2. In some embodiments, the cancer harbors a mutation in BAP1. In some embodiments, the cancer harbors a mutation in SF3B1. In some embodiments, the cancer harbors a mutation in EIF1AX. In some embodiments, the cancer harbors a TFE3 translocation. In some embodiments, the cancer harbors a TFEB translocation. In some embodiments, the cancer harbors a MITF translocation. In some embodiments, the cancer harbors an EZH2 mutation. In some embodiments, the cancer harbors a SUZ12 mutation. In some embodiments, the cancer harbors an EED mutation.

[0613] In some embodiments, the method further comprises administering to the subject an anti-cancer therapy or contacting the cell with an anti-cancer therapy, such as a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation. In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, such as an antimetabolite, an antimitotic agent, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an antitumor agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulator, a janus-related kinase inhibitor, a phosphatidylinositol 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor.

[0614] In some embodiments, the compounds of the present invention are used in combination with another anticancer therapy for treating uveal melanoma, such as surgery, a MEK inhibitor, and / or a PKC inhibitor. For example, in some embodiments, the method further comprises performing surgery before, after, or simultaneously with the administration of the compounds of the present invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or simultaneously with the administration of the compounds of the present invention.

[0615] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other, and the respective amounts are together effective to treat the subject.

[0616] In some embodiments, the subject or cancer has and / or has been identified as having a BRG1 loss-of-function mutation.

[0617] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to the chemotherapeutic or cytotoxic agent (e.g., by a genetic marker), or is likely to be resistant to the chemotherapeutic or cytotoxic agent (e.g., a cancer that does not respond to the chemotherapeutic or cytotoxic agent). In some embodiments, the cancer is unresponsive to one or more chemotherapeutic agents. In some embodiments, the cancer is resistant to or unresponsive to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, bimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastuzumab or IDE196).

[0618] In some embodiments, the cancer is resistant or unresponsive to a previously administered therapeutic agent used to treat uveal melanoma, such as a MEK inhibitor or a PKC inhibitor. For example, in some embodiments, the cancer is resistant or unresponsive to a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or trametinib) and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0619] In one aspect, the present invention provides a use of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament. In some embodiments, the use is as described herein.

[0620] Chemical terms

[0621] The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0622] For any chemical definition below, the number after the atomic symbol represents the total number of atoms of the element present in a particular chemical moiety. As will be appreciated, as described herein, other atoms (such as H atoms or substituents) may be present if necessary to satisfy the valence of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, the number of carbon atoms mentioned includes the divalent carbons in acetal and ketal groups, but does not include the carbonyl carbon in acyl, ester, carbonate or carbamate groups. The number of oxygen, nitrogen or sulfur atoms mentioned in heteroaryl groups only includes those atoms that form a part of the heterocyclic ring.

[0623] As used herein, the term "acyl" refers to H or an alkyl group attached to the parent molecular group through a carbonyl group as defined herein, and for example, formyl (i.e., formaldehyde), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbon atoms.

[0624] The term "alkyl" as used herein refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0625] Alkylene is a divalent alkyl group. As used herein, the term "alkenyl", alone or in combination with other groups, refers to a straight or branched chain 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).

[0626] As used herein, the term "alkynyl", alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms, e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms.

[0627] The term "amino" as used herein refers to -N(R N1 )2, where each R N1 are independently H, OH, NO2, N(R N2 2. SO2OR N2 、SO2R N2 、SOR N2 , N-protecting groups, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, acyl (eg, acetyl, trifluoroacetyl, or other groups described herein), wherein these R N1 Each of the groups may be optionally substituted; or both R N1 combine to form an alkylene or heteroalkylene group, and wherein each R N2 The amino group of the present invention can be an unsubstituted amino group (i.e., -NH2) or a substituted amino group (i.e., -N(R N1 )2).

[0628] As used herein, the term "aryl" refers to an aromatic mono- or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. When polycyclic, the aryl group contains 2 or 3 rings. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indanyl.

[0629] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group. Unsubstituted aralkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkyl, C6-C 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl, or C1-C 20 Alkyl C6-C 10 In some embodiments, the alkyl and aryl groups are each further substituted with 1, 2, 3, or 4 substituents, as defined herein, as permitted by valence.

[0630] The term "azido" as used herein refers to a -N3 group.

[0631] As used herein, the term "bridged polycycloalkyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges. The bridged polycycloalkyl may be unsubstituted or substituted as defined herein for a cycloalkyl.

[0632] The term "cyano" as used herein refers to a -CN group.

[0633] As used herein, the term "carbocyclyl" refers to a non-aromatic C3-C 12 Monocyclic, bicyclic or tricyclic structures wherein the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl and unsaturated carbocyclyl.

[0634] As used herein, the term "cycloalkyl" refers to saturated, non-aromatic and monovalent mono-, di- or tricyclic groups of 3 to 10, preferably 3 to 6 carbon atoms. Cycloalkyl can be fully saturated or contain one or more double bonds or triple bonds, provided that no ring is aromatic. The term is further illustrated by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl. As used herein, the term "cycloalkoxy" refers to cycloalkyl-O-groups (e.g., cyclopropyloxy and cyclobutyloxy).

[0635] The term "halogen" as used herein refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0636] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein in which one or more of the carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group is further substituted by 1, 2, 3, or 4 substituents, as described herein for the alkyl group. An example of a heteroalkyl group is an "alkoxy" group, which refers to an alkyl-O- group (e.g., methoxy and ethoxy). Heteroalkylene is a divalent heteroalkyl group.

[0637] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group is further substituted with 1, 2, 3, or 4 substituents, as valence permits, as described for alkenyl groups herein. An example of a heteroalkenyl group is "alkenyloxy," which, as used herein, refers to alkenyl-O-. Heteroalkenylene is a divalent heteroalkenyl group.

[0638] As used herein, the term "heteroalkynyl" refers to an alkynyl as defined herein, wherein one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl is further substituted with 1, 2, 3, or 4 substituents, as described herein for alkynyl, as valence permits. An example of a heteroalkynyl is "alkynyloxy," which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl.

[0639] As used herein, term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic group having at least one aromatic ring and containing 1, 2 or 3 ring atoms (wherein the remaining ring atoms are carbon) of 5 to 12 atoms selected from nitrogen, oxygen and sulphur. One or two ring carbon atoms of heteroaryl can be replaced by carbonyl. The example of heteroaryl is pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl and thiazolyl.

[0640] As used herein, the term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroaralkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 heteroaryl, or C1-C 20 In some embodiments, the alkyl and heteroaryl groups are each further substituted with 1, 2, 3, or 4 substituents, as valence permits, as defined herein for the corresponding groups.

[0641] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or tricyclic group having from 3 to 12 atoms, having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0642] As used herein, the term "heterocycloalkyl" refers to an alkyl group substituted by a heterocyclyl group. Unsubstituted heterocycloalkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 Alkyl C2-C9 heterocyclic group, or C1-C20 In some embodiments, the alkyl and heterocyclyl groups are each further substituted with 1, 2, 3, or 4 substituents, as defined herein for the corresponding groups.

[0643] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with an -OH group.

[0644] The term "hydroxy," as used herein, refers to an -OH group.

[0645] As used herein, the term "N-protecting group" refers to those groups intended to protect an amino group from undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd edition (John Wiley & Sons, New York, 1999). N-protecting groups include, but are not limited to, acyl, aryloxy (aryloyl) or carbamoyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids (such as alanine, leucine and phenylalanine); sulfonyl-containing groups such as benzylsulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropylmethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, aralkyl groups such as benzyl, trityl and benzyloxymethyl, and silyl groups such as trimethylsilyl. Preferred N-protecting groups are allyloxycarbonyl (alloc), formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, alanyl, phenylsulfonyl, benzyl, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0646] The term "nitro" as used herein refers to a -NO2 group.

[0647] As used herein, the term "oxo" refers to a divalent oxygen atom (e.g., the structure of an oxo group can be shown as =0). For example, a carbonyl group is a carbon (e.g., an alkyl carbon, an alkenyl carbon, an alkynyl carbon, a heteroalkyl carbon, a heteroalkenyl carbon, a heteroalkynyl carbon, a carbocyclyl carbon, etc.) substituted with an oxo group. Alternatively, a sulfur group can be substituted with one or two oxo groups (e.g., -SO- or -SO2- in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group).

[0648] The term "mercapto" as used herein refers to a -SH group.

[0649] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl can be substituted or unsubstituted. When substituted, unless otherwise indicated, 1, 2, 3, 4, or 5 substituents will be present as valence permits. 1 to 5 substituents are each independently selected from the following groups: acyl, alkyl (e.g., unsubstituted and substituted alkyl, wherein the substituent includes any group described herein, such as aryl, halogen, hydroxy), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxy, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, sulfhydryl, and oxo. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl are optionally substituted by 1, 2, 3, 4 or 5 independently selected from aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, sulfhydryl and oxo. ...

[0650] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist as optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. Optically active forms may be obtained, for example, by resolving racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). That is, some disclosed compounds may exist as each stereoisomer. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are paired stereoisomers whose mirror images are non-superimposable, and the most common reason is that they contain asymmetrically substituted carbon atoms that serve as chiral centers. "Enantiomers" refer to one of a pair of molecules that are mirror images of each other and non-superimposable. Diastereomers are stereoisomers that are unrelated to each other as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating enantiomers from racemates using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Those skilled in the art can easily determine the appropriate techniques and / or methods for separating the enantiomers of the compounds described herein from a racemic mixture. "Racemate" or "racemic mixture" refers to a compound containing two enantiomers, wherein such a mixture does not exhibit optical activity; that is, they do not rotate the plane of polarized light. "Geometric isomers" refers to isomers that differ in the orientation of substituent atoms associated with a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms on each side of the carbon-carbon double bond (except H) can be in E (substituents on the opposite side of the ester of the carbon-carbon double bond) or Z (substituents on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist as atropisomers. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation is sufficiently high to allow separation of the conformers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming a salt of the free base of each isomer of the isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomer pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomer pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving a mixture of isomers of the starting material or final product using any of a variety of well-known chromatographic methods.When the stereochemistry of a disclosed compound is named or depicted by structure, the stereoisomer named or depicted is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the enantiomer depicted or named is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the diastereomer depicted or named is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Optical purity percentage is the ratio of the weight of an enantiomer relative to the weight of the enantiomer plus the weight of its optical isomers. Diastereomeric purity by weight is the ratio of the weight of one diastereomer relative to the weight of all diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a molar basis relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a molar basis. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a molar basis. The percent purity on a molar basis is the ratio of the number of moles of enantiomer to the number of moles of the enantiomer plus the number of moles of its optical isomers. Similarly, the percent purity on a molar basis is the ratio of the moles of diastereomer to the moles of diastereomer plus the moles of its isomers. When a disclosed compound is named or depicted by structure without indication of stereochemistry, and the compound possesses at least one chiral center, it is understood that the name or structure encompasses either enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compounds, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses a diastereomer free of other diastereomers, a plurality of diastereomers free of other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers in which one diastereomer is enriched relative to one or more other diastereomers, or a mixture of diastereomers in which one or more diastereomers is enriched relative to the other diastereomers. The present invention includes all of these forms.

[0651] Compounds of the present disclosure also include all isotopes of atoms present in intermediates or final compounds. "Isotopes" refer to atoms with the same atomic number but different mass numbers, which are caused by the different number of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0652] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are useful due to their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., extended in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H substituted, or one or more carbon atoms are replaced by 13 C or 14 C substitution of carbon. Positron-emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotope-labeled compounds is known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the invention as described herein, by substituting an isotope-labeled reagent for a non-isotope-labeled reagent.

[0653] 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 this disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are 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 the event of conflict, the present specification, including definitions, will control.

[0654] definition

[0655] In this application, unless the context clearly indicates otherwise, (i) the term "a / an" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; and (iii) the terms "comprising" and "including" may be understood to cover the itemized components or steps, whether presented by themselves or with one or more other components or steps.

[0656] As used herein, the terms "about" and "approximately" refer to values ​​that are within 10% above or below the stated value. For example, the term "about 5 nM" refers to a range of 4.5 to 5.5 nM.

[0657] As used herein, the term "administering" refers to administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration can be by any appropriate route to an animal subject (e.g., a human). For example, in some embodiments, administration can be intrabronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

[0658] As used herein, the term "BAF complex" refers to BRG1 or HRBM-associated factor complex in human cells.

[0659] As used herein, the term "BAF complex-associated disorder" refers to a disorder caused or affected by the level of activity of the BAF complex.

[0660] As used herein, the term "BRG1 loss-of-function mutation" refers to a mutation in BRG1 that results in a decrease in protein activity (e.g., a decrease in BRG1 activity of at least 1%, such as a decrease in BRG1 activity of 2%, 5%, 10%, 25%, 50%, or 100%). Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0661] As used herein, the term "BRG1 loss-of-function disorder" refers to a disorder (e.g., cancer) characterized by reduced BRG1 activity (e.g., at least 1% reduction in BRG1 activity, e.g., 2%, 5%, 10%, 25%, 50% or 100% reduction in BRG1 activity).

[0662] The term "cancer" refers to a disease caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0663] As used herein, "combination therapy" or "combination administration" refers to administering two (or more) different agents or treatments to a subject as part of a defined treatment regimen for a specific disease or illness. The treatment regimen defines the dosage and administration cycle of each agent so that the effects of the individual agents on the subject overlap. In some embodiments, the delivery of two or more agents is simultaneous or concurrent, and the agents can be co-formulated. In some embodiments, two or more agents are not co-formulated and are administered in a sequential manner as part of a prescription regimen. In some embodiments, the combined administration of two or more agents or treatments results in a greater reduction in the symptoms or other parameters associated with the condition than observed in a single agent or treatment delivered alone or in the absence of the agent. The effects of the two treatments can be partially additive, completely additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route including, but not limited to, oral, intravenous, intramuscular, and directly absorbed by mucosal tissue. The therapeutic agent 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.

[0664] "Determining the level of a protein or RNA" refers to detecting a protein or RNA directly or indirectly by methods known in the art. "Direct determination" refers to performing a process (e.g., performing an assay or test on a sample or "analyzing a sample" as defined herein) to obtain a physical entity or value. "Indirect determination" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory that directly obtains the physical entity or value). Methods for measuring protein levels generally include, but are not limited to, protein immunoblotting, 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, microcytometry, microscopy, fluorescence activated cell sorting (FACS) and flow cytometry, as well as assays based on protein properties, including but not limited to enzyme activity or interactions 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.

[0665] "Reducing the activity of the BAF complex" refers to reducing the level of activity associated with the BAF complex, or a related downstream effect. A non-limiting example of reducing the activity of the BAF complex is Sox2 activation. The activity level of the BAF complex can be measured using any method known in the art, such as the method described in Kadoch et al. Cell, 2013, 153, 71-85, which is incorporated herein by reference.

[0666] As used herein, the term "degrader" refers to a small molecule compound that includes a degrading moiety, wherein the compound interacts with a protein (e.g., BRG1 and / or BRM) in a manner that results in degradation of the protein, e.g., binding of the compound results in a decrease in protein levels by at least 5%, e.g., in a cell or subject.

[0667] As used herein, the term "degradation moiety" refers to a moiety, such as BRG1 and / or BRM, whose binding results in protein degradation. In one example, the moiety binds to a protease or ubiquitin ligase, such as BRG1 and / or BRM, that metabolizes the protein.

[0668] By "modulating the activity of a BAF complex" is meant altering the level of activity associated with a BAF complex species (e.g., GBAF), or an associated downstream effect. The level of activity of a BAF complex can be measured using any method known in the art, such as that described in Kadoch et al., Cell 153:71-85 (2013), which is incorporated herein by reference.

[0669] By "reducing the activity of BRG1 and / or BRM" is meant reducing the level of activity associated with BRG1 and / or BRM, or a related downstream effect. A non-limiting example of inhibiting BRG1 and / or BRM activity is reducing 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, the agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrader.

[0670] By "reducing BRG1 and / or BRM levels" is meant reducing BRG1 and / or BRM levels in a cell or a subject. The levels of BRG1 and / or BRM can be measured using any method known in the art.

[0671] By "level" is meant the level of a protein or mRNA encoding a protein, as compared to a reference. A reference can be any useful reference as defined herein. By "reduced levels" or "increased levels" of a protein is meant a decrease or increase in the level of a protein, as compared to a reference (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 5% compared to a reference). The level of a protein can be expressed as a mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein or mRNA in the sample.

[0672] As used herein, the term "inhibit BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition 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.

[0673] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, such as a human. Typically, pharmaceutical compositions are manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, caplets, softgels, or syrups); for topical administration (e.g., in the form of a cream, gel, lotion, or ointment); for intravenous administration (e.g., in the form of a sterile solution without microparticle plugs and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0674] As used herein, "pharmaceutically acceptable excipient" refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and has substantially non-toxic and non-inflammatory properties in patients. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration.

[0675] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound, such as any compound of Formula I. Pharmaceutically acceptable salts of any compound described herein may include those salts that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reaction within the scope of reasonable medical judgment and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl and C.G. Wermuth, eds.), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately prepared by reacting a free base group with a suitable organic acid.

[0676] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or, in the case of acidic forms of the compounds of the present invention, the salts may be prepared from inorganic or organic bases. Typically, the compounds are prepared as pharmaceutically acceptable salts or as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing appropriate salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0677] "Reference" refers to any useful reference for comparing protein or RNA levels. A reference can be any sample, standard, standard curve, or level for comparison purposes. A reference 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, such as a "normal control" or a previous sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject without the disease; a sample from a subject diagnosed with the disease but not yet treated with the compounds of the invention; a sample from a subject treated with the compounds of the invention; or a sample of a purified protein or RNA (e.g., any of those described herein) at a known normal concentration. A "reference standard or level" refers to a value or number derived from a reference sample. A "normal control value" is a predetermined value indicating a non-disease state, for example, a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("not higher than X"), or a low threshold ("not lower than X"). For a particular biomarker, a subject with a measured value within the normal control value is generally referred to as being "within normal limits" for that biomarker. A normal reference standard or level can be a value or number obtained from a normal subject who has never suffered from a disease or condition (e.g., cancer); a subject who has been treated with a compound of the invention. In a preferred embodiment, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of purified protein or RNA (e.g., any of those described herein) within the normal reference range can also be used as a reference.

[0678] As used herein, the term "subject" refers to any organism to which a composition according to the present invention can be administered, for example, for experimental, diagnostic, prophylactic and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject can be a person or animal seeking or in need of treatment, requiring treatment, currently receiving treatment, about to receive treatment, or who is under the care of a trained professional for a particular disease or disorder.

[0679] As used herein, the terms "treat," "treated," or "treating" refer to therapeutic treatment or any measure intended to slow down (lessen) an unwanted physiological condition, disorder, or disease or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent of the disorder, condition, or disease; stabilization of the disorder, condition, or disease state (i.e., no worsening); delay in the onset or slowing of the progression of the disorder, condition, or disease; improvement or remission (whether partial or complete) of the disorder, condition, or disease state; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of the disorder, condition, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not receiving treatment. The compounds of the present invention may also be used to "prophylactically" treat or "prevent" the disorder, for example, in a subject at increased risk of developing the disorder.

[0680] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.

[0681] Details

[0682] The present disclosure features compounds that can be used to inhibit BRG1 and optionally BRM. These compounds can be used to modulate the activity of the BAF complex, for example, for treating BAF-related disorders such as cancer (e.g., BRG1 loss-of-function disorders). Exemplary compounds described herein include compounds having a structure according to Formula I or a pharmaceutically acceptable salt thereof.

[0683] In one aspect, the invention features a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0684]

[0685] in

[0686] m is 0, 1, 2, or 3;

[0687] k is 0, 1, or 2;

[0688] Each R 1 is independently halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino or cyano;

[0689] Each X is independently halogen or optionally substituted C1-C6 heteroalkyl;

[0690] L is a linker; and

[0691] B is the degradation part.

[0692] In some embodiments, the compound has the structure of any one of Compounds 1-47 in Table 1 or a pharmaceutically acceptable salt thereof.

[0693] Additional embodiments are described herein, as well as exemplary methods for synthetically producing these compounds.

[0694] Drug uses

[0695] The compounds described herein are useful in the methods of the present invention and, while not being bound by theory, are believed to exert their ability to modulate the level, state, and / or activity of the BAF complex by inhibiting the activity of BRG1 and / or BRM proteins within the BAF complex in mammals. BAF complex-associated disorders include, but are not limited to, disorders associated with loss-of-function mutations in BRG1.

[0696] One aspect of the invention relates to methods for treating a disorder associated with a BRG1 loss-of-function mutation, such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to produce one or more (e.g., two or more, three or more, four or more) of the following: (a) a decrease in tumor size, (b) a decrease in the rate of tumor growth, (c) an increase in tumor cell death, (d) a decrease in tumor progression, (e) a decrease in the number of metastases, (f) a decrease in the rate of metastasis, (g) a decrease in tumor recurrence, (h) an increase in subject survival, (i) an increase in progression-free survival in the subject.

[0697] Treatment of cancer can result in a decrease in the size or volume of a tumor. For example, after treatment, the size of a tumor decreases by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to its size before treatment. Tumor size can be measured by any reproducible measurement method. For example, the size of a tumor can be measured as the diameter of the tumor.

[0698] Treatment of cancer can further result in a reduction in the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of tumors can be measured by any reproducible measurement means, for example, the number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x or 50x).

[0699] Treatment of cancer can reduce the number of metastatic nodules in other tissues or organs away from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of metastatic nodules can be measured by any repeatable measurement means. For example, the number of metastatic nodules can be measured by counting the metastatic nodules visible to the naked eye or under a specified magnification (e.g., 2x, 10x or 50x).

[0700] Compared to untreated subject populations, treating cancer can increase the mean survival time of the subject population treated according to the present invention. For example, the mean survival time increases by more than 30 days (more than 60 days, 90 days or 120 days). The increase in the mean survival time of a population can be measured by any repeatable means. The increase in the mean survival time of a population can be measured, for example, by calculating the mean survival length of a population after starting treatment with the compound of the present invention. The increase in the mean survival time of a population can also be measured, for example, by calculating the mean survival length of a population after completing the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0701] Treatment of cancer can also result in a reduction in the mortality rate of the treated subject population compared to an untreated population. For example, the mortality rate is reduced by more than 2% (e.g., more than 5%, 10% or 25%). The reduction in the mortality rate of the treated subject population can be measured by any reproducible means, for example, by calculating the average number of disease-related deaths of the population per unit time after starting treatment with a pharmaceutically acceptable salt of the present invention. The reduction in the mortality rate of a population can also be measured, for example, by calculating the average number of disease-related deaths of the population per unit time after the first round of treatment with a pharmaceutically acceptable salt of the present invention is completed.

[0702] Exemplary cancers that can be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancers, thymic tumors, adrenocortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0703] Combination preparations and their uses

[0704] The compounds of the present invention may be combined with one or more therapeutic agents. In particular, the therapeutic agent may be a therapeutic agent for the treatment or prophylactic treatment of any of the cancers described herein.

[0705] Combination therapy

[0706] The compounds of the present invention can be used alone or in combination with another therapeutic agent, such as other agents for treating cancer or symptoms associated therewith, or in combination with other types of treatments for treating cancer. In combination therapy, the dose of one or more therapeutic compounds can be reduced from the standard dose when administered alone. For example, the dose can be determined empirically by drug combination and permutation, or can be derived by isobologram analysis (e.g., Black et al., Neurology 65: S3-S6, 2005). In this case, the dose of the compound should provide a therapeutic effect when combined.

[0707] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful for treating cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestogens, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folinic acid (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, carboquinone, tebuconazole, and euridopa; ethyleneimines and methylmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trishydroxymethylmelamine; polyacetyl groups (particularly bratacin and bratacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; spongestatin; CC-1065 (including its synthetic analogues adolesine, carzelesin, and biszelesin); candida albicans (particularly candida albicans 1 and biszelesin); 8); Aplysia; Duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; hyoscyamine; stoloniferol; spongistatin; nitrogen mustards such as chlorambucil, naphthiazolin, clofosamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nembicidin, phenylephrine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozolin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); daptomycins, including daptomycin A; bisphosphonates, such as clodronate; esperamicins; and the neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclarubicin, actinomycin, anthramycin, azaserine, bleomycin, actinomycin C, carrubicin, carmomycin, carmophorin, chromomycin, dactinomycin, daunomycin, detoxibacin, 6-diazo-5-oxo-L-norleucine, (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycins (such as mitomycin C), mycophenolic acid, noramycin, olivomycin, peplomycin, porfibrinocin, puromycin, triferon-doxorubicin, rhodorubicin, streptozocin, streptozocin, tuberculin, ubenimex, zoloft, doxycycline; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as leucovorin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine glycosides, doxifluridine, enocitabine, floxuridine; androgens, such as captestosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; antiadrenergic drugs, such as aminoglutethimide, mitotane, and trilostan; folic acid supplements, such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; betribucil; bisantrene; edatrexate; defofamin; colchicine Amine; diazocone; eflornithine; elliptonium acetate; epothilone; etoglucagon; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids, such as maytansine and ansamitocin; mitoxantrone; mitoxantrone; mopidarol; diamine nitrazepam (nitraerine); pentostatin; methambucil; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizolan; spirogermanamine; tricholomanic acid; triazoline; 2,2′,2″-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, verrucosporin A, baculosporin A, and serpentin); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as Paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), Cremophor-free albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) and docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; Noanto; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a mixture for administration in combination with the first therapeutic agent described herein. Suitable administration regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18: 233a and Douillard et al. (2000) Lancet 355: 1041-7.

[0708] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic used for cancer treatment, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)). In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes 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; recibazumab; belimumab; ipilimumab; brentuximab vedotin; pertuzumab; ado-trastuzumab emtansine; and obinutuzumab. Antibody-drug conjugates are also included.

[0709] The second agent can be a non-drug therapeutic agent. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and / or surgical resection of tumor tissue.

[0710] The second agent can be a checkpoint inhibitor. In one embodiment, the inhibitor of the checkpoint 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 inhibitor of the checkpoint is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the inhibitor of the checkpoint is an agent that interacts with the checkpoint protein, such as an antibody. In some embodiments, the inhibitor of the checkpoint is an agent that interacts with the ligand of the checkpoint protein, such as an antibody. In some embodiments, the inhibitor of the checkpoint is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA4 antibody, such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the inhibitor of the checkpoint is an inhibitor of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., nivolumab / Pembrolizumab / Pidilizumab / CT-011). In some embodiments, the inhibitor of the checkpoint is an inhibitor of PDL1 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of the checkpoint is an inhibitor of PDL2 (e.g., an inhibitory antibody or Fc fusion or a small molecule inhibitor) (e.g., PDL2 / Ig fusion protein, such as AMP 224). In some embodiments, the inhibitor of the checkpoint is an inhibitor of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof (e.g., an inhibitory antibody or a small molecule inhibitor).

[0711] In any combination embodiment described herein, the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately, at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most to 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours, or at most 1-7, 1-14, 1-21, or 1 to 30 days before or after the second therapeutic agent.

[0712] Pharmaceutical composition

[0713] Preferably, the compound of the present invention is formulated into a pharmaceutical composition and administered to a mammal, preferably to a human, in a biocompatible form suitable for in vivo administration. Therefore, 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.

[0714] The compound of the present invention can be used in the form of free alkali, in the form of salt, solvate and in prodrug form.All forms are within the scope of the present invention.As will be appreciated by those skilled in the art, according to the method of the present invention, described compound or its salt, solvate or prodrug can be applied to the patient in various forms according to the selected route of administration.The compound of the present invention can be applied, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration, and pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, epithelial, nasal, intrapulmonary, intrathecal, rectal and topical administration. Parenteral administration can be carried out by continuous infusion in the selected time period.

[0715] The compounds of the present invention can be administered orally, for example, with an inert diluent or with an absorbable edible carrier, or they can be encapsulated in a hard or soft shell gelatin capsule, or they can be compressed into tablets, or they can be incorporated directly with food in the diet. For oral therapeutic administration, the compounds of the present invention can be mixed with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth. Conventional procedures and ingredients for selecting and preparing suitable preparations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19), published in 1999. Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid enough to be easily injectable via a syringe. Compositions for nasal administration can be conveniently formulated into aerosols, drops, gels, and powders. Aerosol formulations typically include solutions or fine suspensions of active substances in physiologically acceptable aqueous or non-aqueous solvents and are typically presented in sterile form in single-dose or multi-dose forms in sealed containers that can be used in the form of cartridges or refills for atomizing devices. Alternatively, the sealed container can be an integrated dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas (such as compressed air) or an organic propellant (such as a fluorochlorocarbon). Aerosol dosage forms can also be in the form of a pump atomizer. 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, gum arabic, or tragacanth, gelatin, and glycerol. Compositions for rectal administration are conveniently in the form of suppositories containing conventional suppository bases such as cocoa butter. The compounds described herein can be administered intratumorally, for example, in the form of intratumoral injections. Intratumoral injections are injections directly into the tumor vasculature and are particularly contemplated for use in discrete, solid, accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein can advantageously be contacted by administering, for example, injections or multiple injections spaced apart at approximately 1 cm intervals to the tumor. In the case of surgery, the present invention can be used preoperatively, for example, to subject inoperable tumors to resection.Where appropriate, continuous administration can also be used, for example, by implanting a catheter into the tumor or tumor vasculature.

[0716] As indicated herein, the compounds of the invention can be administered to animals, such as humans, alone or in combination with a pharmaceutically acceptable carrier in proportions determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0717] dose

[0718] The dosage of the compounds of the present invention and / or compositions comprising the compounds of the present invention may vary according to many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health status and weight of the recipient; the type and extent of symptoms; the frequency of treatment, and the type of concurrent treatment (if any); and the clearance rate of the compound in the animal to be treated. One of ordinary skill in the art can determine the appropriate dosage based on the above factors. The compounds of the present invention may initially be administered at a suitable dosage based on the clinical response, which dosage may be adjusted as needed. In general, when the compounds of the present invention are administered to humans at a daily dosage of, for example, 0.05 mg to 3000 mg (measured in solid form), satisfactory results may be obtained. The dosage range includes, for example, between 10-1000 mg (e.g., 50-800 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.

[0719] Alternatively, the patient's body weight can be used to calculate the dosage. For example, the dosage of the compound or its pharmaceutical composition administered to the patient can be 0.1-100 mg / kg (e.g., 0.25-25 mg / kg). In exemplary, non-limiting embodiments, dosage can be 0.5-5.0 mg / kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg) or 5.0-20 mg / kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg). Example

[0720] The following abbreviations are used throughout the following examples.

[0721] Ac acetyl

[0722] ACN or MeCN Acetonitrile

[0723] AcOH acetic acid

[0724] Ac2O acetic anhydride

[0725] aq. water-containing

[0726] Boc tert-butyloxycarbonyl

[0727] Bu or n-Bu butyl

[0728] CDI 1,1′-carbonyldiimidazole

[0729] DCE or 1,2-DCE 1,2-dichloroethane

[0730] DCM dichloromethane

[0731] DIAD Diisopropyl azodicarboxylate

[0732] DIPEA or DIEA NN-diisopropylethylamine

[0733] DMAP 4-dimethylaminopyridine

[0734] DMB 2,4-dimethoxybenzyl

[0735] DME 1,2-dimethoxyethane

[0736] DMF NN-dimethylformamide

[0737] DMSO dimethyl sulfoxide

[0738] EA or EtOAc Ethyl acetate

[0739] EDCI N-(3-dimethylaminopropyl)-N′-carbodiimide hydrochloride

[0740] equiv equivalent

[0741] Et3N or TEA triethylamine

[0742] EtOH

[0743] FA Formic acid

[0744] h or hr hours

[0745] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (or ester)

[0746] HOAt 1-Hydroxy-7-azabenzotriazole

[0747] HOBt or HOBT 1-hydroxybenzotriazole

[0748] iPr Isopropyl

[0749] MeOH methanol

[0750] Me4t-BuXphos di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphine

[0751] min

[0752] MTBE methyl tert-butyl ether

[0753] n-BuLi n-butyllithium

[0754] NMP 1-Methyl-2-pyrrolidone

[0755] OAc acetate

[0756] Pd / C Palladium / Carbon

[0757] PDC Pyridinium dichromate

[0758] PdCl2(dtbpf) or [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[0759] Pd(dtbpf)Cl2

[0760] PdCl2(dppf) or [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0761] Pd(dppf)Cl2

[0762] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0763] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0764] Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride

[0765] PE petroleum ether

[0766] PPh3 triphenylphosphine

[0767] Pr n-propyl

[0768] Py pyridine

[0769] rac racemic

[0770] Rf retention factor

[0771] rt or rt room temperature

[0772] sat. saturated

[0773] SFC Supercritical Fluid Chromatography

[0774] t-Bu tert-butyl

[0775] tBuXphos-Pd-G3 or [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium;

[0776] tBuXphos Pd G3 or di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine

[0777] t-BuXphos-Pd(gen 3)

[0778] TFA trifluoroacetic acid

[0779] Tf2O trifluoromethanesulfonic anhydride

[0780] THF Tetrahydrofuran

[0781] TLC thin layer chromatography

[0782] Xantphos-Pd-G3 [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium; (5-diphenylphosphino-9,9-dimethyl-xanthen-4-yl)-diphenylphosphine

[0783] XPhos Pd G3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II)

[0784] Example 1. Preparation of compounds

[0785] Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2)

[0786]

[0787] Step 1: Preparation of 2-(3-bromoisoxazol-5-yl)acetic acid.

[0788]

[0789] To a stirred solution of 2-(3-bromo-1,2-oxazol-5-yl)ethan-1-ol (30 g, 156 mmol) in acetone (389 mL) was added Jones reagent (2 M in acetone, 156 mL, 312 mmol) dropwise at 0°C. The resulting solution was stirred at 25°C overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 86.5%) as a brown solid. LCMS (ESI) m / z: [M+H] + =206.08 and 208.08.

[0790] Step 2: Preparation of methyl 2-(3-bromoisoxazol-5-yl)acetate.

[0791]

[0792] A solution of 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 135 mmol) and concentrated H2SO4 (3 mL, 72 mmol) in methanol (250 mL) was stirred at 70 ° C for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc / petroleum ether) to give methyl 2-(3-bromoisoxazol-5-yl)acetate (23.4 g, 79%) as a white solid. LCMS (ESI) m / z: [M+H] + =219.90 and 221.86.

[0793] Step 3: Preparation of methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate.

[0794]

[0795] At 0 ° C, 2-(3-bromoisoxazol-5-yl)acetic acid methyl ester (23.4 g, 106 mmol) and KO t In the stirred solution of Bu (17.8g, 159mmol), 2-iodopropane (13.8mL, 137mmol) is added dropwise. The reaction mixture is stirred at room temperature for 16 hours, then quenched with water / ice. The gained solution is extracted several times with EtOAc. The organic layer washed with salt water combined, and anhydrous Na2SO4 is used, and is under reduced pressure concentrated. Residue is passed through silica gel flash chromatography (EtOAc / petroleum ether) purification to obtain 2-(3-bromoisoxazole-5-yl)-3-methylbutanoic acid methyl ester (16.7g, 60%) as a clear oil.

[0796] Step 4: Preparation of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid.

[0797]

[0798] To a solution of methyl 2-(3-bromo-1,2-oxazol-5-yl)-3-methylbutanoate (16.7 g, 63.7 mmol) in methanol (130 mL) was added potassium hydroxide (35.7 g, 637 mmol). The mixture was stirred at 100 ° C for 4 hours. The mixture was concentrated under vacuum and then diluted with water. The resulting solution was washed with EtOAc and the pH of the aqueous layer was adjusted to pH 5 with 1N HCl. The mixture was extracted with EtOAc several times. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The residue was purified by flash chromatography on silica gel (EtOAc / petroleum ether) to give 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (8.8 g, 70%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =200.15.

[0799] Step 5: Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid.

[0800]

[0801] A solution of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (8.8 g, 44.1 mmol) in HOAc (80 mL) and HBr (80 mL) was stirred at 60° C. for 16 hours. The resulting mixture was concentrated under reduced pressure to give crude 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (8.16 g, quantitative).

[0802] Step 6: Preparation of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate.

[0803]

[0804] To a solution of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (8.16 g, 44.0 mmol) in methanol (30 mL) was slowly added SOCI2 (14.2 mL, 197 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM) to obtain methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (7.79 g, 89%) as a clear oil. LCMS (ESI) m / z: [M+H] + =200.15.

[0805] Step 7: Preparation of methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate.

[0806]

[0807] To a solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (7.79 g, 39.1 mmol) in DMF (90 mL) was added 2-bromo-1,1-diethoxyethane (8.77 mL, 58.6 mmol) and potassium carbonate (10.8 g, 78.2 mmol). The reactants were stirred at 70 ° C overnight. The reaction mixture was cooled, and water was then added to the mixture. The resulting mixture was extracted several times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (EtOAc / heptane) to give methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate (7.8 g, 63%) as a colorless oil. LCMS (ESI) m / z: [M-C2H5O] + =270.30.

[0808] Step 8: Preparation of 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid.

[0809]

[0810] To a solution of methyl 2-[3-(2,2-diethoxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate (7.8 g, 24.7 mmol) in methanol (50 mL) and water (25 mL) was added lithium hydroxide monohydrate (4.14 g, 98.8 mmol). The reaction was stirred at 40 ° C for 2 hours. The pH was adjusted to 4-5 with 1N HCl. The mixture was extracted several times with ethyl acetate and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM / MeOH) to give 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid (6.1 g, 89%) as a colorless oil. LCMS (ESI) m / z: [MH] - =300.21.

[0811] Step 9: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate.

[0812]

[0813] To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0°C was added HATU (8.98 g, 23.5 mmol) followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring at room temperature for 16 hours, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (MeOH / DCM) to give tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.33 g, 98%). LCMS (ESI) m / z: [M+H] + =432.38.

[0814] Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride.

[0815]

[0816] To tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.33 g, 19.3 mmol) was added a solution of HCl in 1,4-dioxane (4N, 50 mL, 200 mmol) at 0°C to give a viscous yellow gum. To the mixture was added 15 mL of MeOH, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was washed with diethyl ether to give (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride, which was used in the next step without further purification.

[0817] Step 11: Preparation of (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1).

[0818]

[0819] To a solution of 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methylbutanoic acid (5.75 g, 19.0 mmol) in DMF (30 mL) was added HATU (8.6 g, 22.7 mmol). After stirring at 20°C for 0.5 hours, a solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (6.97 g, 19.0 mmol) and triethylamine (7.92 mL, 56.9 mmol) in DMF (20 mL) was added to the mixture, and the resulting mixture was stirred at 20°C. The reaction mixture was quenched by adding water and extracted several times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM / MeOH) to give (2S,4R)-1-[2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (10 g, 16.2 mmol) as a white solid. The mixture of diastereomers was separated by chiral SFC chromatography to give (2S,4R)-1-((S)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide and (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0820] Peak 1 of (2S,4R)-1-((S)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide: (2.2 g, 19%). LCMS (ESI) m / z [M+H] + =615.4.

[0821] Peak 2 of (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1): (2.5 g, 21%). LCMS (ESI) m / z [M+H] + =615.4

[0822] Step 12: Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2).

[0823]

[0824] To a stirred solution of H2SO4 (1N, 6.00 mL) and THF (6.00 mL) was added (2S,4R)-1-[(2R)-2-[3-(2-ethoxy-2-methoxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (I-1, 300 mg, 0.499 mmol) in portions at room temperature. The resulting mixture was stirred at 50°C for 8 hours. The resulting mixture was diluted with water and then neutralized with saturated aqueous NaHCO3 to pH ~7. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed twice with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2, 256 mg, 97.3%) as a white solid. LCMS (ESI) m / z: [M+H] + =541.

[0825] Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-3) and

[0826] (2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-4).

[0827]

[0828] Step 1: Preparation of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-perfluorobutylsulfonyl)oxy]-1,2-oxazol-5-yl]butanoate.

[0829]

[0830] At room temperature, to the stirred solution of 2-(3-hydroxyl-1,2-oxazole-5-yl)-3-methylbutanoic acid methyl ester (100.00mg, 0.502mmol, 1.00 equivalent) in MeCN (0.50mL), perfluorobutylsulfonyl fluoride (303.29mg, 1.004mmol, 2.00 equivalent) and K cO (208.13mg, 1.506mmol, 3.00 equivalent). Gained mixture was stirred for 3 hours, then carefully quenched with water at 0 degrees Celsius. Gained mixture was extracted with EA (2x 50mL). The organic layer merged was washed with salt water (50mL) and used anhydrous Na sO dry. After filtration, filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-perfluorobutylsulfonyl)oxy]-1,2-oxazol-5-yl]butanoate (217 mg) as a white solid. LCMS (ESI) m / z: [M+H] + =482.

[0831] Step 2: Preparation of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate.

[0832]

[0833] To a stirred solution of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-perfluorobutylsulfonyl)oxy]-1,2-oxazol-5-yl]butanoate (217.00 mg, 0.451 mmol, 1.00 equiv) in DMF (3.00 mL) at room temperature was added tert-butyl piperazine-1-carboxylate (83.98 mg, 0.451 mmol, 1.00 equiv). The resulting mixture was stirred at 130° C. for 1 hour. The mixture was allowed to cool to room temperature. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0 to 100% over 30 minutes. This provided tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate (54 mg, 32.59%) as a yellow oil. LCMS (ESI) m / z: [M+H]+ =368.

[0834] Step 3: Preparation of 2-[3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid.

[0835]

[0836] At room temperature, to the stirred solution of 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]piperazine-1-carboxylic acid tert-butyl ester (54.00 mg, 0.147 mmol, 1.00 equivalent) in MeOH (0.80 mL), THF (0.80 mL) and H o (0.80 mL) were added, followed by the addition of LiOH.H o (18.50 mg, 0.441 mmol, 3.00 equivalent). The resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 6 with HCl (1 M, aq.), then extracted with EA (2 x 50 mL). The combined organic layer was washed with salt water (50 mL), and dried over anhydrous Na sO , and filtered. The filtrate was concentrated under reduced pressure. This provided 2-[3-[4-(tert-Butyloxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid (52 mg, crude product) as a yellow solid. LCMS (ESI) m / z: [M+H] + =354.

[0837] Step 4: Preparation of tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate.

[0838]

[0839] To a stirred solution of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid (52.00 mg, 0.119 mmol, 1.00 equiv) in DMF (2.00 mL) was added HATU (135.56 mg, 0.357 mmol, 3.00 equiv) and DIEA (76.80 mg, 0.595 mmol, 5.00 equiv) at room temperature. To the above mixture was added (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (70.90 mg, 0.214 mmol, 1.80 equiv) at room temperature. The resulting mixture was stirred for 1 hour. The mixture was purified directly by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0 to 100% over 30 minutes. This afforded tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate (73 mg, 92.12%) as a white solid. LCMS (ESI) m / z: [M+H] + =667.

[0840] Step 5: Preparation of tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate.

[0841]

[0842] Tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl]phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate was purified by SFC using the following conditions: column, CHIRAL ART Amylose-C NEO, 3*25 cm, 5 mm; mobile phase, MeOH. This provided:

[0843] Tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (37 mg, second peak). LCMS (ESI) m / z: [M+H] + =667.

[0844] Tert-butyl 4-(5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (34 mg, first peak). LCMS (ESI) m / z: [M+H] + =667.

[0845] Step 6: Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butyryl]pyrrolidine-2-carboxamide (I-3) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butyryl]pyrrolidine-2-carboxamide (I-4).

[0846]

[0847] To a stirred solution of tert-butyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate (37.00 mg, 0.055 mmol, 1.00 equiv) in DCM (1.50 mL) at 0° C. was added HCl in 1,4-dioxane (1.50 mL, 26.276 mmol, 473.57 equiv). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This afforded I-3 (45 mg, crude product) as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0848] I-4 was prepared according to the same protocol as I-3 and obtained as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0849] The following intermediates in Table 2 were prepared starting from methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-perfluorobutylsulfonyl)oxy]-1,2-oxazol-5-yl]butanoate and the appropriate amine in a similar manner to that described in the preparation of intermediate 1-3.

[0850] Table 2.

[0851]

[0852]

[0853] Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate.

[0854]

[0855] Step 1: Preparation of (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine.

[0856]

[0857] To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (5 g, 35.078 mmol, 1 eq) and NH2OH·HCl (4.93 g, 70.945 mmol, 2.02 eq) in EtOH (250 mL) was added NaOAc (14.48 g, 176.512 mmol, 5.03 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with brine (500 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (E)-N-[(2-chloropyrimidin-5-yl)methylidene]hydroxylamine (4.6 g, crude product) as a light yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =158.

[0858] Step 2: Preparation of (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride.

[0859]

[0860] A solution of (E)-N-[(2-chloropyrimidin-5-yl)methylene]hydroxylamine (4.6 g, 29.195 mmol, 1 eq) and NCS (4.4 g, 32.951 mmol, 1.13 eq) in DMF (150 mL) was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with water (3 x 300 mL), brine (1 x 300 mL), and the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimidoyl chloride (4.8 g, crude product) as a yellow solid. LCMS (ESI) m / z: [M+H] + =192.

[0861] Step 3: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate.

[0862]

[0863] By the solution of (Z)-2-chloro-N-hydroxypyrimidine-5-carbonimido chloride (4.8g, 25.00mmol, 1 equivalent) in EtOAc (80mL) with NaHCO (3g, 35.712mmol, 1.43 equivalents) under dry nitrogen atmosphere at 0 ℃ for 30 minutes, then add 3-butynoic acid methyl ester (2.02g, 20.591mmol, 0.82 equivalents) in batches at 0 ℃. The resulting mixture is stirred at room temperature for 12 hours. The resulting mixture is diluted with water (150mL) and extracted with EtOAc (2x 400mL). The combined organic layer is washed with salt water (1x 400mL) and dried over anhydrous Na SO. After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (2.5 g, 38.64%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =254.

[0864] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid.

[0865]

[0866] By 2-[3-(2-chloropyrimidine-5-yl)-1 in MeOH (50mL), 2-oxazole-5-yl] methyl acetate (3g, 11.828mmol, 1 equivalent) and NaOMe (1.92g, 35.484mmol, 3.00 equivalents) solution under dry nitrogen atmosphere at room temperature stirred 1 hour. With HCl (aq.), the mixture is acidified to pH 6. Residue is dissolved in EtOAc (300mL). The gained mixture is washed with water (2x 300mL). The organic layer merged is washed with salt water (1x 300mL), and is used anhydrous Na2SO4 dry. After filtration, the filtrate is concentrated under reduced pressure to obtain [3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl] acetic acid (2.5g, crude product) as a light yellow solid, which is directly used in the next step without the need for further purification. LCMS (ESI) m / z: [M+H] + =236.

[0867] Step 5: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate.

[0868]

[0869] A solution of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.4 g, 10.204 mmol, 1 eq) and (trimethylsilyl)diazomethane (2.33 g, 20.408 mmol, 2 eq) in DCM (20 mL) and MeOH (5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (1.2 g, 45.77%) as a white solid. LCMS (ESI) m / z: [M+H] + =250.

[0870] Step 6: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate.

[0871]

[0872] By 2-[3-(2-methoxypyrimidine-5-yl)-1,2-oxazole-5-yl] methyl acetate (2.5g, 10.031mmol, 1 equivalent) in THF (20mL) solution with t-BuOK (1.2g, 10.694mmol, 1.07 equivalent) under dry nitrogen atmosphere at 0 ℃ for 30 minutes, then add 2-iodopropane (1.5g, 8.824mmol, 0.88 equivalent) dropwise at 0 ℃. The resulting mixture was stirred at room temperature for 12 hours. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (2x 200mL). The combined organic layer was washed with brine (2x 200mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (310 mg, 10.08%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =292.

[0873] Step 7: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate.

[0874]

[0875] A solution of 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid methyl ester (200 mg, 0.687 mmol, 1 eq) and POCl (1.9 mL, 20.61 mmol, 30 eq) in DMF (1.5 mL) was stirred at 60 ° C for 3 hours under a dry nitrogen atmosphere. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine (2x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid methyl ester (160 mg, crude product) as a brown oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =296.

[0876] Preparation of 2-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(2-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)acetic acid (I-8)

[0877]

[0878] To a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(2-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (30.00 mg, 0.055 mmol, 1.00 equiv) and 2-methyl-2-butene (0.78 mg, 0.011 mmol, 0.20 equiv) in tert-butanol (2 mL) at 0°C was added dropwise a solution of NaClO2 (50.19 mg, 0.550 mmol, 10.00 equiv) and NaH2PO4 (78.77 mg, 0.550 mmol, 10.0 equiv) in water (2.00 mL). The mixture was stirred at 0 ° C for 0.5 hours, then heated to room temperature and stirred for 1.5 hours. The reaction was quenched by adding a mixture of saturated Na2S2O3 solution and brine and extracted with CHCl3 (20 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel chromatography (PE / EtOAc=1:1 to 1:3). This provided intermediate I-8 (15.80 mg, 49.93%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =557.

[0879] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1).

[0880] Preparation of 2-[6-(azetidin-3-yl)cinnolin-3-yl]phenol (Intermediate 1-9).

[0881]

[0882] Step 1: Preparation of tert-butyl 3-[3-(2-methoxy-2-oxoethyl)-4-nitrophenyl]azetidine-1-carboxylate (Intermediate 3).

[0883]

[0884] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (10.33 g, 36.488 mmol, 2.00 equiv) in DMF (10.00 mL) was added I (2.32 g, 9.122 mmol, 0.50 equiv) and Zn (3.58 g, 54.732 mmol, 3.00 equiv) (= solution A) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. At room temperature, to a stirred solution of 2-(5-bromo-2-nitrophenyl)methyl acetate (5.00 g, 18.244 mmol, 1.00 equivalent) in DMF (10.00 mL), Pd (dba) -CHCl (1.89 g, 1.824 mmol, 0.10 equivalent), t-BuXPhos (0.77 g, 1.824 mmol, 0.10 equivalent) and CuI (0.35 g, 1.824 mmol, 0.10 equivalent) (= solution B) were added. Under a nitrogen atmosphere, solution B was added to solution A at 0 ° C. The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction was quenched with water at 0 ° C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (200 mL), then dried over anhydrous Na SO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give intermediate 3 (4.1 g, 64.14%) as a brown oil. LCMS (ESI) m / z: [M+H] + =351.

[0885] Step 2: Preparation of methyl 2-[5-(azetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 4).

[0886]

[0887] To a stirred solution of intermediate 3 (4.10 g, 11.416 mmol, 1.00 equiv) in DCM (32.00 mL) was added TFA (8.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This produced intermediate 4 (3.0 g, crude) as a brown oil. LCMS (ESI) m / z: [M+H] + =251.

[0888] Step 3: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 5).

[0889]

[0890] To a stirred solution of intermediate 4 (3.00 g, 11.988 mmol, 1.00 equiv) in DCM (30.00 mL) was added Ac2O (3.67 g, 35.964 mmol, 3.00 equiv) and Et3N (3.64 g, 35.967 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give intermediate 5 (4.5 g, >100%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =293.

[0891] Step 4: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-2-aminophenyl]acetate (Intermediate 6).

[0892]

[0893] To a stirred solution of intermediate 5 (4.50 g, 15.396 mmol, 1.00 equiv) in MeOH (30.00 mL) was added NH4Cl (8.24 g, 153.960 mmol, 10.00 equiv) and Zn (10.07 g, 153.9960 mmol, 10.0 equiv) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue, and the product was extracted with DCM (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 6 (2.1 g, 52.00%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =263.

[0894] Step 5: Preparation of 5-(1-acetylazetidin-3-yl)-1-amino-3H-indol-2-one (Intermediate 7).

[0895]

[0896] To a stirred solution of Intermediate 6 (2.10 g, 8.006 mmol, 1.00 equiv) in DCM (34.00 mL) at 0°C was added NOBF4 (1.87 g, 16.012 mmol, 2.00 equiv). The resulting mixture was stirred at 0°C for 1 hour. To the above mixture was added SnCl2·2H2O (18.23 g, 80.060 mmol, 10.00 equiv) and concentrated HCl (68.00 mL) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 0 to 100% over 30 minutes; detector, UV 254 / 220 nm. This yielded Intermediate 7 (1.6 g, 81.48%) as a brown oil. LCMS (ESI) m / z: [M+H] + =246.

[0897] Step 6: Preparation of 1-[3-(3-hydroxycinnolin-6-yl)azetidin-1-yl]ethanone (Intermediate 8).

[0898]

[0899] To a stirred solution of intermediate 7 (1.60 g, 5.708 mmol, 1.00 equiv) in DCM (10.00 mL) at 0°C was added Pb(OAc)4 (3.80 g, 8.562 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with MeOH at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0 to 100% gradient over 30 minutes; detector, UV 254 / 220 nm. This produced intermediate 8 (880 mg, 63.38%) as a green oil. LCMS (ESI) m / z: [M+H] + =244.

[0900] Step 7: Preparation of 6-(1-acetylazetidin-3-yl)cinnolin-3-yl trifluoromethanesulfonate (Intermediate 9).

[0901]

[0902] To a stirred solution of intermediate 8 (880.00 mg, 3.617 mmol, 1.00 equiv) in DCM (20.00 mL) at 0°C was added Tf2O (10.21 g, 36.170 mmol, 10.00 equiv) and pyridine (2.86 g, 36.17 mmol, 10.0 equiv). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0 to 100% gradient over 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 9 (415 mg, 30.57%) as a brown oil. LCMS (ESI) m / z: [M+H] + =376.

[0903] Step 8: Preparation of 1-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (Intermediate 11).

[0904]

[0905] To a stirred solution of intermediate 9 (415.00 mg, 1.106 mmol, 1.00 equiv) and 2-hydroxyphenylboronic acid (458.16 mg, 3.320 mmol, 3.00 equiv) in 1,4-dioxane (8.00 mL) and H2O (2.00 mL) was added XPhosPdG3 (187.13 mg, 0.221 mmol, 0.20 equiv) and Cs2CO3 (1.082 g, 3.320 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0 to 100% over 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 11 (254 mg, 71.95%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =320.

[0906] Step 9: Preparation of 2-[6-(azetidin-3-yl)cinnolin-3-yl]phenol (I-9).

[0907]

[0908] To a stirred solution of intermediate 11 (254.00 mg, 0.794 mmol, 1.00 equiv) in MeOH (5.00 mL) and H2O (5.00 mL) was added KOH (133.39 mg, 2.382 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 70°C for 1 hour. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0 to 100% gradient over 30 minutes; detector, UV 254 / 220 nm. This produced I-9 (134 mg, 60.91%) as a white solid. LCMS (ESI) m / z: [M+H] + =278.

[0909] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1).

[0910]

[0911] To a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (29.24 mg, 0.054 mmol, 1.00 equiv) in DMSO (1.00 mL) was added IO-9 (15.00 mg, 0.054 mm mol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture was added NaBH(OAc)3 (34.39 mg, 0.162 mmol, 3.00 equiv) and AcOH (cat.) at room temperature. The resulting mixture was stirred at 60°C for 1 hour. The mixture was allowed to cool to room temperature. The reaction was quenched with water at 0°C and then purified by Chiral-Prep-HPLC using the following conditions: column, Xselect CSH F-phenyl OBD column, 19*250 mm, 5 μm; mobile phase water (0.05% FA) and MeOH (43% MeOH up to 67% in 7 minutes); detector, UV 254 / 220 nm. This produced compound 1 (6.8 mg, 15.50%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ12.16-11.87 (m, 1H), 8.98 (d, J=2.1Hz, 1H), 8.87 (d, J=8.2Hz, 1H), 8.47-8.39 (m, 2H), 8.30-8.15 (m, 1H, FA), 8. 14-8.06 (m, 1H), 8.04-7.94 (m, 2H), 7.47-7.41 (m, 2H), 7.41-7.31 (m, 3H), 7.09-7.00 (m, 2H), 6.10 (s, 1H), 5.25-4.97 (m, 1H), 4.97-4.8 5 (m, 1H), 4.37 (t, J = 7.9Hz, 1H), 4.31-4.23 (m, 1H), 4.18 (t, J = 5.4Hz, 2H), 3.97-3.86 (m, 1H), 3.79 (t, J = 7.3Hz, 2H), 3.73-3.62 (m, 2H), 3.59-3.42 (m, 3H), 2.86 (t, J=5.4Hz, 2H), 2.45 (d, J=6.6Hz, 3H), 2.30-2.13 (m, 1H), 2.08-1.98 (m, 1H), 1.82-1.72 (m, 1H), 1.37 (d, J=7.0 Hz, 3H), 0.96 (d, J=6.6Hz, 3H), 0.81 (d, J=6.6Hz, 3H). LCMS (ESI) m / z: [M+H] + =802.40.

[0912] The compounds in Table 3 were prepared using procedures similar to those used above to prepare compound 1 using the appropriate amine and aldehyde (or ketone).

[0913] Table 3.

[0914]

[0915] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 4) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 5).

[0916]

[0917] Step 1: Preparation of methyl 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 3).

[0918]

[0919] To a stirred solution of 1- (50.00 mg, 0.180 mmol, 1.00 equiv) in DMSO (2.00 mL) was added methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (53.32 mg, 0.180 mmol, 1.00 equiv) and DIEA (69.91 mg, 0.540 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 100° C. for 6 hours. The mixture was allowed to cool to room temperature and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0 to 100% gradient over 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 3 (20 mg, 20.67%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =537.

[0920] Step 2: Preparation of 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 4).

[0921]

[0922] To a stirred solution of intermediate 3 (20.00 mg, 0.037 mmol, 1.00 equiv) in MeOH (1.00 mL) and H2O (1.00 ml) was added LiOH·H2O (4.69 mg, 0.111 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 6 hours. The mixture was acidified to pH 3 with aqueous HCl (1 M). The resulting mixture was concentrated under reduced pressure. This produced intermediate 4 (20 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + =523.

[0923] Step 3: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 6).

[0924]

[0925] To a stirred solution of intermediate 4 (20.00 mg, 0.038 mmol, 1.00 equiv) in DMF (1.00 mL) at room temperature were added PyBOP (59.28 mg, 0.114 mmol, 3 equiv) and DIEA (24.51 mg, 0.190 mmol, 5 equiv). To the above mixture was added (2S,4R-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (12.62 mg, 0.038 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10 mmol / L NH4HCO3), 0 to 100% gradient in 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 6 (5 mg, 15.62%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =836.

[0926] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 4) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 5).

[0927]

[0928] Intermediate 6 (5.00 mg) was purified by Chiral-Prep-HPLC using the following conditions: column, CHIRALPAK ID, 2*25 cm, 5 mm; mobile phase, MtBE (10 mM NH3-MeOH) and MeOH (maintaining 50% MeOH in 29 minutes); detector, UV 254 / 220 nm. This yielded:

[0929] Compound 4 (1.0 mg, 20.00%) was obtained as a white solid. 1 H NMR (400MHz, Methanol-d4) δ8.89-8.77(m, 4H), 8.48(d, J=8.9Hz, 1H), 8.12-8.02(m , 3H), 7.48-7.34(m, 5H), 7.07-7.01(m, 2H), 6.80(s, 1H), 5.08-5.00(m, 1H), 4.74(d , J=8.6Hz, 2H), 4.63-4.49 (m, 1H), 4.49-4.26 (m, 3H), 3.92-3.85 (m, 1H), 3.71-3.59 (m, 3H), 2.47 (d, J=7.8Hz, 3H), 2.23-2.14 (m, 1H), 2.09-1.87 (m, 2H), 1.53 (d, J=7.0 Hz, 3H), 1.10 (d, J=6.6Hz, 3H), 0.93 (d, J=6.6Hz, 3H). LCMS (ESI) m / z: [M+H] + =836.40.

[0930] Compound 5 (0.6 mg, 12.00%) was obtained as a white solid. 1 H NMR (400MHz, Methanol-d4) δ8.89-8.82(m, 2H), 8.82-8.75(m, 2H), 8.48(d, J=8.9Hz, 1H), 8.13-8.02(m, 3H) , 7.41-7.32 (m, 5H), 7.07-7.00 (m, 2H), 6.78 (s, 1H), 5.04-4.96 (m, 1H), 4.78-4.70 (m, 2H), 4.59 (d, J=8.0Hz, 1H), 4.47-4.28(m, 3H), 4.00-3.86(m, 1H), 3.79-3.68(m, 1H), 3.63(s, 2H), 2.44(s, 3H), 2.29-2.11(m, 1H), 2.06-1.86 (m, 2H), 1.49 (d, J=7.0Hz, 3H), 1.10 (d, J=6.7Hz, 3H), 0.95 (d, J=6.7Hz, 3H). LCMS (ESI) m / z: [M+H]+ =836.50.

[0931] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}2-oxoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 6).

[0932]

[0933] To a stirred solution of ({5-[[(2R)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl}oxy)acetic acid (30.11 mg, 0.054 mmol, 1.00 equiv) in DMF (1.00 mL) was added PyBOP (84.44 mg, 0.162 mmol, 3.00 equiv) and DIEA (34.95 mg, 0.270 mmol, 5.00 equiv) at room temperature. To the above mixture was added I-9 (15.00 mg, 0.054 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and CH3CN (42% CH3CN in 7 minutes to 55%); detector, UV254 / 220 nm. This produced compound 6 (15.5 mg, 33.86%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.93-11.69 (m, 1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.50 (d, J = 8.8Hz, 1H), 8.43 (d, J = 7.7Hz, 1H), 8.15-8.07 (m, 2H), 8.02- 7.97(m, 1H), 7.47-7.41(m, 2H), 7.41-7.33(m, 3H), 7.10-7.01(m, 2H), 6 .19(d, J=1.6Hz, 1H), 5.11(d, J=3.7Hz, 1H), 4.97-4.86(m, 1H), 4.80(s, 2H), 4.77-4.65(m, 1H), 4.48-4.34(m, 3H), 4.32-4.18(m, 2H), 4.15-4. 05(m,1H),3.74-3.65(m,2H),3.51-3.42(m,1H),2.47-2.43(m,3H),2.3 1-2.15 (m, 1H), 2.07-1.96 (m, 1H), 1.83-1.69 (m, 1H), 1.37 (d, J=6.9Hz, 3H), 0.96 (d, J=6.6Hz, 3H), 0.80 (d, J=6.6Hz, 3H). LCMS (ESI) m / z: [M+H] + =816.70.

[0934] The compounds in Table 4 were prepared using procedures similar to those used above to prepare compound 6 using the appropriate amine and carboxylic acid.

[0935] Table 4.

[0936]

[0937] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 8).

[0938] Preparation of 2-[7-(azetidin-3-yl)cinnolin-3-yl]phenol (I-10).

[0939]

[0940] Step 1: Preparation of tert-butyl 3-[4-(2-methoxy-2-oxoethyl)-3-nitrophenyl]azetidine-1-carboxylate (Intermediate 2).

[0941]

[0942] A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (12.40 g, 43.784 mmol, 1.2 eq) and I2 (4.63 g, 18.244 mmol, 0.5 eq) in DMF (100 mL) was cooled to 0°C. Zn (7.16 g, 109.461 mmol, 3 eq) was then added portionwise at this temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. CuI (1.39 g, 7.297 mmol, 0.2 eq), Pd(dba)2 (4.20 g, 7.297 mmol, 0.2 eq), XPhos (3.478 g, 7.297 mmol, 0.2 eq) and methyl 2-(4-bromo-2-nitrophenyl)acetate (10 g, 36.487 mmol, 1 eq) were then added. Under nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours. The resulting mixture was filtered through a celite pad, and the filter cake was washed with EtOAc (3x200 mL). The filtrate was washed with water (3x300 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to give intermediate 2 (5 g, 35.20%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =351.

[0943] Step 2: Preparation of methyl 2-[4-(azetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 3).

[0944]

[0945] To a stirred mixture of intermediate 2 (5 g, 14.271 mmol, 1 eq) in DCM (15 mL) was added TFA (5 mL) dropwise. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This produced intermediate 3 (5.5 g, 95.22%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =251.

[0946] Step 3: Preparation of methyl 2-[4-(1-acetylazetidin-3-yl)-2-nitrophenyl]acetate (Intermediate 4).

[0947]

[0948] To a stirred mixture of intermediate 3 (5 g, 13.726 mmol, 1.00 equiv) and Et3N (6.94 g, 68.630 mmol, 5 equiv) in DCM (20 mL) was added Ac2O (2.10 g, 20.589 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (14:1) to give intermediate 4 (3.5 g, 78.52%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =293.

[0949] Step 4: Preparation of methyl 2-[4-(1-acetylazetidin-3-yl)-2-aminophenyl]acetate (Intermediate 5).

[0950]

[0951] A mixture of intermediate 4 (3.5 g, 11.974 mmol, 1 eq) and NHCl (12.81 g, 239.480 mmol, 20 eq) in MeOH (50 mL) was cooled to 0 ° C., followed by the addition of Zn (7.83 g, 119.740 mmol, 10 eq) in portions. The resulting mixture was stirred at 0 ° C. for 1 hour. The resulting mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 5 (2 g, 57.31%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =263.

[0952] Step 5: Preparation of 6-(1-acetylazetidin-3-yl)-1-amino-3H-indol-2-one (Intermediate 6).

[0953]

[0954] A mixture of intermediate 5 (2 g, 7.625 mmol, 1 eq) in DCM (40 mL) was cooled to 0°C. NOBF4 (1.34 g, 11.438 mmol, 1.5 eq) was then added in one portion. The resulting mixture was stirred at 0°C for 1 hour. SnCl2 (11.69 g, 61.000 mmol, 8 eq) in HCl (60 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient over 30 minutes; detector, UV 254 nm. This produced intermediate 6 (600 mg, 28.87%) as a yellow-green solid. LCMS (ESI) m / z: [M+H] + =246.

[0955] Step 6: Preparation of 1-[3-(3-hydroxycinnolin-7-yl)azetidin-1-yl]ethanone (Intermediate 7).

[0956]

[0957] A mixture of intermediate 6 (600 mg, 2.446 mmol, 1 eq) in DCM (10 mL) was cooled to 0°C. Pb(OAc)4 (1301.55 mg, 2.935 mmol, 1.2 eq) was then added portionwise. The resulting mixture was stirred at 0°C for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient over 30 minutes; detector, UV 254 nm. This produced intermediate 7 (400 mg, 60.50%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =244.

[0958] Step 7: Preparation of 7-(1-acetylazetidin-3-yl)cinnolin-3-yl trifluoromethanesulfonate (Intermediate 8).

[0959]

[0960] To a stirred mixture of intermediate 7 (400 mg, 1.644 mmol, 1 eq) and DMAP (40.18 mg, 0.329 mmol, 0.2 eq) in DCM (10 mL) was added TEA (499.17 mg, 4.932 mmol, 3 eq). The mixture was cooled to 0°C. Tf2O (695.86 mg, 2.466 mmol, 1.5 eq) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred at 0°C for another hour. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 8 (400 mg, 58.33%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =376.

[0961] Step 8: Preparation of 1-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}ethanone (Intermediate 9).

[0962]

[0963] To a solution of intermediate 8 (310 mg, 0.826 mmol, 1 equivalent) and 2-hydroxyphenylboronic acid (341.77 mg, 2.478 mmol, 3 equivalents) in dioxane (5 mL) and H2O (1 mL) was added Cs2CO3 (807.34 mg, 2.478 mmol, 3 equivalents) and XPhos Pd G3 (139.83 mg, 0.165 mmol, 0.2 equivalents). After stirring at 80 ° C for 1 hour under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm. This gave intermediate 9 (100 mg, 34.12%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =320.

[0964] Step 9: Preparation of 2-[7-(azetidin-3-yl)cinnolin-3-yl]phenol (I-10).

[0965]

[0966] To a stirred mixture of intermediate 9 (100 mg, 0.313 mmol, 1 eq) in MeOH (3 mL) and H2O (3 mL) was added KOH (175.68 mg, 3.130 mmol, 10 eq) in portions at room temperature. The resulting mixture was stirred at 70°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient over 30 minutes; detector, UV 254 nm. This produced I-10 (92 mg, 95.35%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =278.

[0967] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 8).

[0968]

[0969] To a stirred solution of I-10 (16 mg, 0.058 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (31.19 mg, 0.058 mmol, 1 eq) in DCM (1 mL) and MeOH (1 mL) was added AcOH (3.46 mg, 0.058 mmol, 1 eq) and NaBHCN (10.88 mg, 0.174 mmol, 3 eq). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: column, Kinetex EVO C18 column, 21.2*150 mm, 5 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 25 mL / min; gradient: 35% B to 62% B in 7 minutes, then 62% B; detector, UV 254 / 220 nm. This produced compound 8 (18.1 mg, 38.77%) as a light yellow solid. 1H NMR (300MHz, DMSO-d6) δ12.03 (d, J=6.3Hz, 1H), 8.96 (d, J=22.1Hz, 2H), 8.48-8.32 (m, 2H), 8.13 (d, J=8.5Hz, 2H), 7.99 (d, J=8.7Hz, 1H), 7.50-7 .30(m, 5H), 7.13-6.99(m, 2H), 6.03(d, J=50.8Hz, 1H), .5.11(d, J=3.7H z, 1H), 4.92 (t, J=7.1Hz, 1H), 4.38 (t, J=7.8Hz, 1H), 4.29 (s, 1H), 4.19 (t , J=5.4Hz, 2H), 3.98 (t, J=7.1Hz, 1H), 3.83 (d, J=7.2Hz, 2H), 3.75-3.62 (m, 2H), 3.46 (d, J = 11.2Hz, 3H), 2.89 (s, 2H), 2.46 (d, J = 2.7Hz, 3H), 2.24 (s, 1H), 2.04 (t, J=10.3Hz, 1H), 1.86-1.69 (m, 1H), 1.42 (dd, J=22.1, 7.0Hz, 3H), 0.96 (d, J=6.5Hz, 3H), 0.89-0.73 (m, 3H). LCMS (ESI) m / z: [M+H] + =802.30.

[0970] The compounds in Table 5 were prepared using procedures similar to those used above to prepare compound 8 using the appropriate amine and aldehyde (or ketone).

[0971] Table 5.

[0972]

[0973] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 11) ) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 12)

[0974]

[0975] Step 1: Preparation of methyl 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 2).

[0976]

[0977] To a stirred solution of I-10 (80 mg, 0.288 mmol, 1 eq) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (106.63 mg, 0.288 mol, 1 eq) in DMSO (3.00 mL) was added DIEA (111.85 mg, 0.864 mmol, 3 eq). The resulting mixture was stirred at 100° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and then purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase A: water (0.1% FA), mobile phase B: CH 3 CN; flow rate: 35 mL / min; gradient: 0% B to 100% B in 40 minutes; detector, UV 254 / 220 nm. This gave intermediate 2 (110 mg, 67.51%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =537.

[0978] Step 2: Preparation of 2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 3).

[0979]

[0980] Under nitrogen atmosphere, a solution of LiOH (49.10 mg, 2.050 mmol, 10 equiv) in THF (3.00 mL) and H2O (0.60 mL) was stirred at room temperature for 10 minutes. To the above mixture was added intermediate 2 (110 mg, 0.205 mmol, 1 equiv). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 35 mL / min; gradient: 0% B to 100% B in 40 minutes; detector, UV 254 / 220 nm. This produced intermediate 3 (98 mg, 86.91%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =523.

[0981] Step 3: Preparation of (2S,4R)-4-hydroxy-1-{2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4).

[0982]

[0983] To a stirred solution of intermediate 3 (98 mg, 0.188 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (62.16 mg, 0.188 mmol / 1 eq) in DMF (3.00 mL) was added PyBOP (195.19 mg, 0.376 mmol, 2 eq) and DIEA (72.72 mg, 0.564 mmol, 3 eq). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was then purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 35 mL / min; gradient: 0% B to 100% B in 40 minutes; detector, UV 254 / 220 nm. This produced intermediate 4 (90 mg, 54.54%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =836.

[0984] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1 1) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{3-[3-(2-hydroxyphenyl)cinnolin-7-yl]azetidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl}-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 12).

[0985]

[0986] Intermediate 4 (90 mg) was purified by Chiral-Prep-HPLC using the following conditions: column, CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 10% B to 50% B in 65 minutes; detector, UV 254 / 220 nm. This yielded:

[0987] Compound 11 (30.1 mg, 34.64%) was obtained as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ11.96 (s, 1H), 8.97 (d, J=16.6Hz, 2H), 8.87 (d, J=2.0Hz, 2H), 8.45 (d, J=11.1Hz, 2H), 8.21-8.11 (m, 2H), 8.05 (dd, J=8.6 , 1.7Hz, 1H), 7.45 (d, J=8.2Hz, 2H), 7.41-7.33 (m, 3H), 7.11-7.01 (m, 2H ), 6.90 (d, J = 33.8Hz, 1H), 5.12 (d, J = 3.6Hz, 1H), 4.94 (t, J = 7.3Hz, 1H), 4 .76-4.63(m, 2H), 4.46-4.21(m, 5H), 3.87(d, J=9.7Hz, 1H), 3.82-3.70( m, 1H), 3.51 (t, J = 5.3Hz, 1H), 2.46 (d, J = 4.2Hz, 3H), 2-34 (d, J = 10.2Hz, 1H), 2.05 (t, J=10.5Hz, 1H), 1.87-1.69 (m, 1H), 1.45 (dd, J=31.1, 7.0Hz, 3H), 1.02 (d, J=6.4Hz, 3H), 0.86 (t, J=6.2Hz, 3H). LCMS (ESI) m / z: [M+H] + =836.35.

[0988] Compound 12 (21.0 mg, 24.32%) was obtained as a pale yellow solid. 1H NMR (300MHz, DMSO-d6) δ11.97 (s, 1H), 9.04-8.91 (m, 2H), 8.85 (d, J = 14.4Hz, 2H), 8.48 (s, 1H), 8.28 (d, J = 7.9Hz, 1H), 8.19 (d, J = 8.6Hz , 1H), 8.14 (d, J=7.7Hz, 1H), 8.07 (d, J=6.9Hz, 1H), 7.48 (d, J=7.2Hz, 1H), 7.42-7.22 (m, 4H), 7.11-7.01 (m, 2H), 6.96 (s, 1H), 5.15 (d, J=3.6Hz, 1H), 4.93-4.84 (m, 1H), 4.68 (t, J=8.3Hz, 2H), 4.49-4.25 (m, 5H), 3.96 (d, J=8.9Hz, 1H), 3.63 (s, 1H), 3.51 (s, 1H), 2.41 (s, 3 H), 2.27 (s, 1H), 2.08 (s, 1H), 1.49 (d, J=7.0Hz, 1H), 1.38-1.20 (m, 3H), 1.02 (d, J=6.5Hz, 3H), 0.91-0.81 (m, 3H). LCMS (ESI) m / z: [M+H] + =836.30.

[0989] The compounds in Table 6 were prepared using procedures similar to those used above for the preparation of compound 11 using the appropriate amine and heteroaryl halide.

[0990] Table 6.

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 13) and (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14)

[0998]

[0999] Step 1: Preparation of methyl 2-(2-amino-5-bromophenyl)acetate (Intermediate 2)

[1000]

[1001] At 0 ℃, to the mixture of 2-(5-bromo-2-nitrophenyl) methyl acetate (10.00 g, 36.663 mmol, 1.00 equivalent) and NH4Cl (38.80 g, 733.26 mmol, 20.00 equivalent) in MeOH (150 mL), Zn (47.60 g, 7332.6 mmol, 20.00 equivalent) was added. The resulting mixture was stirred at 0 ℃ for 1 hour. The resulting mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3x100 mL). The combined organic layer was dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient over 10 minutes; detector, UV 254 nm. This gave Intermediate 2 (8.00 g, 89.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =244.

[1002] Step 2: Preparation of 1-amino-5-bromoindolin-2-one (Intermediate 3).

[1003]

[1004] To a mixture of intermediate 2 (8.00 g, 32.921 mmol, 1.00 equiv) in DCM (80 mL) was added NOBF4 (5.72 g, 49.381 mmol, 1.50 equiv) at 0°C. The mixture was stirred for 1 hour, then SnCl2·2H2O (44.4 g, 197.526 mmol, 6.00 equiv) in HCl (50 mL) was added at 0°C. The resulting mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 30% gradient over 10 minutes; detector, UV 254 nm. This gave intermediate 3 (3.71 g, 50.0%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =227.

[1005] Step 3: Preparation of 6-bromocinnolin-3-ol (Intermediate 4).

[1006]

[1007] To a mixture of intermediate 3 (2.00 g, 8.849 mmol, 1.00 equiv) in DCM (30 mL) at 0°C was added Pb(OAc)4 (5.88 g, 13.273 mmol, 1.50 equiv). The mixture was stirred for 20 minutes and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column C18 silica gel; mobile phase, ACN in water, 0% to 30% gradient over 10 minutes; detector, UV 254 nm. This gave intermediate 4 (1.50 g, 75.7%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =225.

[1008] Step 4: Preparation of tert-butyl 4-(3-hydroxycinnolin-6-yl)piperazine-1-carboxylate (Intermediate 5).

[1009]

[1010] To a mixture of intermediate 4 (800.0 mg, 3.571 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.65 g, 14.284 mmol, 4.00 equiv), xanthene (412.6 mg, 0.714 mmol, 0.20 equiv) and t-BuONa (1.028 g, 10.713 mmol, 3.00 equiv) in dioxane (20 mL) was added Pd2(dba)3 (654 mg, 0.714 mmol, 0.20 equiv) under a nitrogen atmosphere. The mixture was stirred at 80°C overnight. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 50% gradient over 10 minutes; detector, UV 254 nm. This gave intermediate 5 (205.0 mg, 17.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =331.

[1011] Step 5: Preparation of tert-butyl 4-(3-(((trifluoromethyl)sulfonyl)oxy)cinnolin-6-yl)piperazine-1-carboxylate (Intermediate 6)

[1012]

[1013] To a mixture of intermediate 5 (205.0 mg, 0.621 mmol, 1.00 equiv) and pyridine (496.8 mg, 6.210 mmol, 10.00 equiv) in DCM (5 mL) was added Tf2O (350.2 mg, 1.242 mmol, 2.00 equiv) at 0°C. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (3x50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 6 (210.0 mg, crude product). LCMS (ESI) m / z: [M+H] + =463.

[1014] Step 6: Preparation of tert-butyl 4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazine-1-carboxylate (Intermediate 7)

[1015]

[1016] To a mixture of intermediate 6 (210.0 mg, 0.453 mmol, 1.00 equiv), (2-hydroxyphenyl)boronic acid (125.0 mg, 0.906 mmol, 2.00 equiv) and Cs2CO3 (441.6 mg, 1.359 mmol, 3.00 equiv) in dioxane (5 mL) and water (1 mL) under a nitrogen atmosphere was added XPhosPdG3 (76.6 mg, 0.090 mmol, 0.20 equiv). The mixture was stirred at 80°C for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 50% gradient over 10 minutes; detector, UV 254 nm. This gave intermediate 7 (110.0 mg, 59.7%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =407.

[1017] Step 7: Preparation of 2-(6-(piperazin-1-yl)cinnolin-3-yl)phenol (I-11)

[1018]

[1019] To a mixture of intermediate 7 (110.0 mg, 0.270 mmol, 1-00 equiv) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give intermediate 8 (160.0 mg, crude product). LCMS (ESI) m / z: [M+H] + =307.

[1020] Step 8: Preparation of methyl 2-(3-(2-(4-(3-(-2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 9).

[1021]

[1022] To a stirred mixture of I-11 (160.0 mg, 0.521 mmol, 1.00 equiv) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (153.6 mg, 0.521 mmol, 1 equiv) in DMSO (3 mL) was added DIEA (336.0 mg, 2.605 mmol, 5.00 equiv) dropwise. The resulting mixture was stirred at 100 ° C for 1 hour. The mixture was allowed to cool to room temperature and the product was precipitated by adding water. The precipitated solid was collected by filtration and washed with water (3x10 mL). This produced intermediate 9 (130.0 mg, 44.1%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =566.

[1023] Step 9: Preparation of 2-(3-(2-(4-(3-(-2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 10).

[1024]

[1025] To a stirred mixture of intermediate 9 (130.0 mg, 0.229 mmol, 1.00 equiv) in MeOH (2 mL) and H2O (1 mL) was added LiOH·H2O (93.8 mg, 2.290 mmol, 10 equiv). After stirring at 60°C for 2 hours, the mixture was cooled to room temperature. The mixture was acidified to pH 6 with 4M aq.HCl. The precipitated solid was collected by filtration and washed with water (3x10 mL). This produced intermediate 10 (150.0 mg, crude product) as a yellow solid. LCMS (ESI) m / z: [M+H] + =552.

[1026] Step 10: Preparation of (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 11).

[1027]

[1028] To a stirred mixture of intermediate 10 (150 mg, 0.264 mmol, 1.00 equiv) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (87.58 mg, 0.264 mmol, 1 equiv) in DMF (4 mL) was added DIEA (102.4 mg, 0.792 mmol, 3.00 equiv) and PyBOP (274.5 mg, 0.528 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 2 hours, and then the mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm. This gave intermediate 11 (130.0 mg, 57.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =865.

[1029] Step 11: Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 13) and (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)cinnolin-6-yl)piperazin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14).

[1030]

[1031] Intermediate 11 (130 mg) was purified by chiral HPLC using the following conditions: column, CHIRALPAK IA, 2*25 cm, 20 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 10% B to 50% B in 30 minutes; detector, UV 254 / 220 nm. This yielded:

[1032] Compound 13 (53.6 mg, 40.82%) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ13.05 (s, 1H), 9.00-8.96 (m, 1H), 8.91-8.86 (m, 2H), 8.6 1 (s, 1H), 8.41 (d, J = 7.6Hz, 1H), 8.26 (d, J = 9.6Hz, 1H), 8.05 (dd, J = 8.3, 1.7Hz, 1 H), 7.90 (dd, J=9.7, 2.5Hz, 1H), 7.48-7.41 (m, 2H), 7.41-7.31 (m, 3H), 7.16 (d, J =2.6Hz, 1H), 7.05-6.97(m, 2H), 6.95(s, 1H), 5.10(d, J=3.7Hz, 1H), 4.97-4.89( m, 1H), 4.39 (t, J=7.9Hz, 1H), 4.31 (s, 1H), 4.05 (t, J=5.4Hz, 4H), 3.86 (d, J=9.7 Hz, 1H), 3.76 (dd, J=10.8, 4.3Hz, 1H), 3.68 (t, J=5.4Hz, 4H), 3.51 (d, J=10.6Hz, 1H), 2.47-2.43(m, 3H), 2.38-2.28(m, 1H), 2.08-1.99(m, 1H), 1.84-1.76(m, 1H) , 1.52-1.36 (m, 3H), 1.05-0.99 (m, 3H), 0.89-0.81 (m, 3H). LCMS (ESI) m / z: [M+H] + =865.30.

[1033] Compound 14 (28.4 mg, 21.8%) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ13.05 (s, 1H), 9.00-8.96 (m, 1H), 8.91-8.86 (m, 2H) , 8.61 (s, 1H), 8.29-8.21 (m, 2H), 8.05 (dd, J=8.3, 1.7Hz, 1H), 7.90 (dd, J=9 .7, 2.5Hz, 1H), 7.52-7.41 (m, 1H), 7.39-7.26 (m, 4H), 7.16 (d, J=2.6Hz, 1H) ,7.05-6.97(m,2H),6.95(s,1H),5.10(d,J=3.7Hz,1H),4.97-4.89(m,1H),4 .39 (t, J=7.9Hz, 1H), 4.33-4.24 (m, 1H), 4.05 (t, J=5.4Hz, 4H), 3.86 (d, J=9 .7Hz, 1H), 3.68 (t, J=5.4Hz, 4H), 3.64-3.60 (m, 1H), 3.29-3.27 (m, 1H), 2.4 7-2.43(m, 3H), 2.38-2.28(m, 1H), 2.08-1.99(m, 1H), 1.84-1.76(m, 1H), 1. 52-1.36 (m, 3H), 1.05-0.99 (m, 3H), 0.89-0.81 (m, 3H). LCMS (ESI) m / z: [M+H] + =865.30.

[1034] Preparation of 7-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-12)

[1035]

[1036] Step 1: Preparation of dimethyl 2-(4-chloro-2-nitrophenyl)malonate (Intermediate 2).

[1037]

[1038] 4-chloro-1-fluoro-2-nitrobenzene (11g, 63mmol), dimethyl malonate (12.5g, 95mmol), Cs CO (41.1g, 126mmol) and DMF (63mL) were stirred at room temperature for 6 hours. The reaction mixture was distributed between the 1M HCl aqueous solution and EtOAc. The organic layer was washed with salt water, used Na SO dried and concentrated to obtain intermediate 2 (18g, 99%) as a yellow oil. The crude product was directly used in the next step without the need for further purification.

[1039] Step 2: Preparation of 2-(4-chloro-2-nitrophenyl)acetic acid (Intermediate 3).

[1040]

[1041] Intermediate 2 was combined with AcOH (30 mL) and concentrated HCl (30 mL) and heated at 95° C. for 16 hours. The mixture was diluted with H O to form a precipitate. The solid was collected by vacuum filtration, washed with H O, hexane / ether (1:1) and dried to give Intermediate 3 (11.2 g, 83%) as a white solid.

[1042] Step 3: Preparation of methyl 2-(4-chloro-2-nitrophenyl)acetate (Intermediate 4).

[1043]

[1044] Intermediate 3 (11.2 g, 52 mmol) was suspended in CH Cl (250 mL). Oxalyl chloride (7 mL, 79 mmol) was added to the mixture, followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room temperature for 1 hour, then added dropwise to MeOH at 0 ° C. The solvent was removed under vacuum to obtain intermediate 4 (12 g, 98%) as a white solid. The crude product was directly used in the next step without the need for further purification.

[1045] Step 4: Preparation of methyl 2-(2-amino-4-chlorophenyl)acetate (Intermediate 5).

[1046]

[1047] At 0 ° C, intermediate 4 (12 g, 51 mmol) was suspended in a mixture of MeOH (200 mL) and NH4Cl (55 g, 1.03 mol). Zinc powder (16.8 g, 257 mmol) was added in one go. The mixture was stirred at room temperature for 2 hours and then filtered through celite. The filtrate was concentrated and then distributed between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give intermediate 5 (9.5 g, 94%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =200.

[1048] Step 5: Preparation of 1-amino-6-chloroindolin-2-one (Intermediate 6).

[1049]

[1050] Intermediate 5 (9.5 g, 48 mmol) was suspended in CH2Cl2 (150 mL) at 0°C. Nitroso tetrafluoroborate (8.4 g, 72 mmol) was added to the mixture in one go. The mixture was stirred at 0°C for 1 hour. The mixture was added directly to a vigorously stirred mixture of SnCl2 dihydrate (43.8 g, 194 mmol) in concentrated HCl (200 mL) at 0°C. The mixture was slowly warmed to room temperature under stirring. After 24 hours, the mixture was filtered. The solid was washed with H2O and ether and then dried to obtain intermediate 6 (6.6 g, 76%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =183.

[1051] Step 6: Preparation of 7-chlorocinnolin-3-ol (Intermediate 7).

[1052]

[1053] Intermediate 6 (6.6 g, 37 mmol) was suspended in toluene (500 mL) at 0°C. Tert-butyl hypochlorite (4 g, 37 mmol) was added to the mixture in one portion. The mixture was stirred at 0°C for 20 minutes. The solid was collected by vacuum filtration, washed with H2O, hexane / ether (1:1) and dried to give Intermediate 7 (3 g, 45%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =181.

[1054] Step 7: Preparation of 7-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 8).

[1055]

[1056] To intermediate 7 (3 g, 16.7 mmol) in CH2Cl2 (20 mL) was added triethylamine (4.7 mL, 33 mmol), 4-(dimethylamino)pyridine (0.2 g, 0.16 mmol) and N-phenylbis(trifluoromethanesulfonimide) (9.0 g, 25 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EtOAc to give intermediate 8 (4.2 g, 82%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =313.

[1057] Step 8: Preparation of 7-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (1-12).

[1058]

[1059] A mixture of intermediate 8 (4.2 g, 13.4 mmol), Pd(dppf)Cl (1 g, 1.3 mmol), KPO (5.6 g, 26.8 mmol) and (2-(methoxymethoxy)phenyl)boronic acid (3 g, 16 mmol) in dioxane (20 mL) / H2O (2 mL) was stirred at 40°C under a nitrogen atmosphere for 1 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-12 (2.8 g, 70%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =301.

[1060] Preparation of 6-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-13)

[1061]

[1062] Step 1: Preparation of dimethyl 2-(5-chloro-2-nitrophenyl)malonate (Intermediate 2).

[1063]

[1064] 4-Chloro-2-fluoro-1-nitrobenzene (16.5 g, 94.5 mmol), dimethyl malonate (18.8 g, 143 mmol), Cs CO (61.6 g, 189 mmol) and DMF (100 mL) were stirred at room temperature for 6 hours. The reaction mixture was distributed between the 1 M HCl aqueous solution and EtOAc. The organic layer was washed with salt water, dried over Na SO and concentrated to obtain intermediate 2 (28 g, 99%) as a yellow oil. The crude product was directly used in the next step without further purification.

[1065] Step 2: Preparation of 2-(5-chloro-2-nitrophenyl)acetic acid (Intermediate 3).

[1066]

[1067] Intermediate 2 was combined with AcOH (30 mL) and concentrated HCl (30 mL) and heated at 95° C. for 16 hours. The mixture was cooled to 0° C. and then diluted with H O to form a precipitate. The solid was collected by vacuum filtration, washed with H O, hexane / ether (1:1) and dried to give Intermediate 3 (17 g, 83%) as a white solid.

[1068] Step 3: Preparation of methyl 2-(5-chloro-2-nitrophenyl)acetate (Intermediate 4).

[1069]

[1070] Intermediate 3 (17g, 78mmol) is suspended in CH2Cl2 (300mL). Oxalyl chloride (10.5mL, 119mmol) is added to the mixture, followed by DMF (0.1mL, 1mmol). The mixture is stirred at room temperature for 1 hour, then added dropwise to MeOH at 0°C. The solvent is removed under vacuum to produce intermediate 4 (18g, 98%) as a white solid. The crude product is directly used in the next step without further purification.

[1071] Step 4: Preparation of methyl 2-(2-amino-5-chlorophenyl)acetate (Intermediate 5).

[1072]

[1073] Intermediate 4 (18 g, 77 mmol) was suspended in a mixture of MeOH (300 mL) and NH4Cl (83 g, 1.53 mol) at 0°C. Zinc powder (25 g, 386 mmol) was added in one go. The mixture was stirred at room temperature for 1 hour and then filtered through celite. The filtrate was concentrated and then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give intermediate 5 (14.3 g, 94%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =200.

[1074] Step 5: Preparation of 1-amino-5-chloroindolin-2-one (Intermediate 6).

[1075]

[1076] Intermediate 5 (14.3 g, 72 mmol) was suspended in CH2Cl2 (200 mL) at 0°C. Nitroso tetrafluoroborate (12.6 g, 108 mmol) was added to the mixture in one portion. The mixture was stirred at 0°C for 1 hour. The mixture was added directly to a vigorously stirred mixture of SnCl2 dihydrate (66 g, 291 mmol) in concentrated HCl (300 mL) at 0°C. The mixture was slowly warmed to room temperature under stirring. After 24 hours, the mixture was filtered. The solid was washed with H2O and ether and then dried to produce intermediate 6 (10 g, 76%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =183.

[1077] Step 6: Preparation of 6-chlorocinnolin-3-ol (Intermediate 7).

[1078]

[1079] Intermediate 6 (10 g, 56 mmol) was suspended in toluene (500 mL) at 0°C. Tert-butyl hypochlorite (6 g, 56 mmol) was added to the mixture in one portion. The mixture was stirred at 0°C for 20 minutes. The solid was collected by vacuum filtration, washed with H2O, hexane / ether (1:1) and dried to give Intermediate 7 (4.5 g, 45%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =181.

[1080] Step 7: Preparation of 6-chlorocinnolin-3-yl-trifluoromethanesulfonate (Intermediate 8).

[1081]

[1082] To intermediate 7 (4.5 g, 25 mmol) in CH2Cl2 (40 mL) was added triethylamine (7 mL, 50 mmol), 4-(dimethylamino)pyridine (0.3 g, 0.25 mmol) and N-phenylbis(trifluoromethanesulfonimide) (13.5 g, 37.5 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EtOAc to give intermediate 8 (6.3 g, 82%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =313.

[1083] Step 8: Preparation of 6-chloro-3-(2-(methoxymethoxy)phenyl)cinnoline (I-13)

[1084]

[1085] A mixture of intermediate 8 (6.3 g, 20.1 mmol), Pd(dppf)Cl (1.5 g, 1.95 mmol), KPO (8.4 g, 40.2 mmol) and (2-(methoxymethoxy)phenyl)boronic acid (4.5 g, 24 mmol) in dioxane (40 mL) / H2O (6 mL) was stirred at room temperature under nitrogen for 2 hours. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-13 (4.1 g, 69%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =301.

[1086] Preparation of 2-(7-bromo-6-chlorocinnolin-3-yl)phenol; methyl ether (I-14)

[1087]

[1088] Step 1: Preparation of 1,3-dimethyl-2-(4-bromo-5-chloro-2-nitrophenyl)malonate (Intermediate 2)

[1089]

[1090] A solution of 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (100g, 393.020mmol, 1 equivalent) and dimethyl malonate (57.12g, 432.322mmol, 1.1 equivalents) in DMF (500mL) was stirred at room temperature for 12 hours. The resulting mixture was diluted with water (300mL). The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (1x1000mL). The combined organic layers were washed with brine (3x1000mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This produced intermediate 2 (140g, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z[M+H] + =366.

[1091] Step 2: Preparation of (4-bromo-5-chloro-2-nitrophenyl)acetic acid (Intermediate 3)

[1092]

[1093] A solution of intermediate 2 (70 g, 190.970 mmol, 1 equivalent) and AcOH (500 mL) in concentrated HCl (500 mL) was stirred at 100 ° C for 12 hours. The mixture was allowed to cool to 0 ° C. The precipitated solid was collected by filtration and washed with water (3x300 mL). The resulting mixture was concentrated under reduced pressure. This produced intermediate 3 (50 g, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =294.

[1094] Step 3: Preparation of methyl 2-(4-bromo-5-chloro-2-nitrophenyl)acetate (Intermediate 4)

[1095]

[1096] A solution of intermediate 3 (50 g, 169.785 mmol, 1 equivalent) and H2SO4 (4 mL) in MeOH (400 mL) was stirred at 60 ° C for 12 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (400 mL). The mixture was neutralized to pH 6 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (1x1000 mL). The combined organic layers were washed with water (3x500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification. This produced intermediate 4 (46 g, crude product) as a yellow solid. LCMS (ESI) m / z[M+H] + =308.

[1097] Step 4: Preparation of methyl 2-(4-bromo-5-chloro-2-nitrophenyl)acetate (Intermediate 5)

[1098]

[1099] A solution of intermediate 4 (50 g, 169.785 mmol, 1 equivalent) and H2SO4 (4 mL) in MeOH (400 mL) was stirred at 60 ° C for 12 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (400 mL). The mixture was neutralized to pH 6 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (1x1000 mL). The combined organic layers were washed with water (3x500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 5 (46 g, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z[M+H] + =278.

[1100] Step 5: Preparation of 1-amino-6-bromo-5-chloro-3H-indol-2-one (Intermediate 6)

[1101]

[1102] A solution of intermediate 5 (16 g, 57.444 mmol, 1 eq) and NOBF4 (10.07 g, 86.166 mmol, 1.5 eq) in DCM (300 mL) was stirred at 0 ° C for 2 hours. To the above mixture was added dropwise SnCl2 (88.06 g, 459.552 mmol, 8.0 eq) in HCl (300 mL) at 0 ° C. The resulting mixture was stirred at room temperature for another 24 hours. The precipitated solid was collected by filtration and washed with water (3x100 mL). The resulting mixture was concentrated under reduced pressure. This produced intermediate 6 (10.4 g, crude product) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z[M+H] + =261.

[1103] Step 6: Preparation of 7-bromo-6-chlorocinnolin-3-ol (Intermediate 7)

[1104]

[1105] At room temperature, to a stirred solution of intermediate 6 (10.4 g, 39.771 mmol, 1 equivalent) in toluene (100 mL) was added tert-butyl hypochlorite (4.32 g, 39.772 mmol, 1.0 equivalent) dropwise. The resulting mixture was stirred at room temperature for 25 minutes. The resulting mixture was filtered and the filter cake was washed with PE (3x50 mL). The filtrate was concentrated under reduced pressure. This produced intermediate 7 (9.5 g, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =259.

[1106] Step 7: Preparation of 7-bromo-6-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 8)

[1107]

[1108] A solution of intermediate 7 (9.5 g, 36.610 mmol, 1 eq) and DMAP (447.27 mg, 3.661 mmol, 0.1 eq) in DCM (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give intermediate 8 (9.4 g, 65.58%) as a white solid. LCMS (ESI) m / z [M+H] + =391.

[1109] Step 8: Preparation of 2-(7-bromo-6-chlorocinnolin-3-yl)phenol; methyl ether (I-14)

[1110]

[1111] To a solution of intermediate 8 (3.00 g, 7.662 mmol, 1 eq) and 2-(methoxymethoxy)phenylboronic acid (1.39 g, 7.662 mmol, 1.0 eq) in dioxane (100 mL) and H2O (25 mL) was added K3PO4 (4.88 g, 22.986 mmol, 3.0 eq) and Pd(dppf)Cl2 (1.12 g, 1.532 mmol, 0.2 eq). After stirring at room temperature under nitrogen atmosphere for 1 h, the mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give I-14 (960 mg, 32.83%) as a yellow solid. LCMS (ESI) m / z [M+H] + =827.

[1112] The following intermediates in Table 7 were prepared in a similar manner as described in the preparation of intermediate 1-14.

[1113] Table 7.

[1114]

[1115]

[1116] Preparation of 6-chloro-7-cyclopropyl-3-[2-(methoxymethoxy)phenyl]cinnoline (I-20)

[1117]

[1118] To a solution of I-14 (1 g, 2.634 mmol, 1 eq) and cyclopropylboronic acid (678.80 mg, 7.902 mmol, 3.0 eq) in dioxane (10 mL) and H2O (2.5 mL) were added K3PO4 (1677.37 mg, 7.902 mmol, 3.0 eq) and Pd(dppf)Cl2 (385.4 mg, 0.527 mmol, 0.2 eq). After stirring at 60 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-20 (380.0 mg, 42.3%) as a yellow solid. LCMS (ESI) m / z [M+H] + =341.

[1119] Preparation of tert-butyl 6-{6-chloro-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2-azaspiro[3.3]heptane-2-carboxylate (I-21)

[1120]

[1121] A solution of Zn (413.32 mg, 6.324 mmol, 6 eq.) and I2 (133.71 mg, 0.527 mmol, 0.5 eq.) in DMF and tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (681.01 mg, 2.108 mmol, 2 eq.) was stirred at 30°C for 2 h under nitrogen atmosphere. Under nitrogen atmosphere, to the above mixture were added I-14 (400 mg, 1.054 mmol, 1 eq), XPhos Pd G3 (178.37 mg, 0.211 mmol, 0.2 eq) and XPhos (100.46 mg, 0.211 mmol, 0.2 eq) portionwise over 5 min at room temperature. The resulting mixture was stirred at 60° C. under nitrogen atmosphere overnight. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30× mL). The combined organic layers were washed with brine (3×20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give I-21 (190 mg, 36.36%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =496.

[1122] Preparation of tert-butyl 6-(6-cyano-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2-azaspiro[3.3]heptane-2-carboxylate (I-22)

[1123]

[1124] To a stirred solution of I-21 (220 mg, 0.444 mmol, 1 eq) and Zn(CN)2 (208.33 mg, 1.776 mmol, 4 eq) in DMF (3 mL) was added XPhosPdG3 (75.09 mg, 0.089 mmol, 0.2 eq) in portions at room temperature. The resulting mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The combined organic layers were washed with brine (2×25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give I-22 (117 mg, 54.21%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=487.

[1125] Preparation of tert-butyl 6-(6-chloro-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1-23).

[1126]

[1127] To a solution of I-14 (340.0 mg, 0.90 mmol, 1.00 equiv) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (435.8 mg, 0.9 mmol, 1.00 equiv) in toluene (10 mL) was added BINAP (111.5 mg, 0.18 mmol, 0.20 equiv), Pd2(dba)3 (164.0 mg, 0.18 mmol, 0.20 equiv) and t-BuONa (172.1 mg, 1.79 mmol, 2.00 equiv). After stirring at 100 ° C. under a nitrogen atmosphere for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc = 10:1 to 2:1 to give I-23 (350.0 mg, 78.6%) as an orange solid. LCMS (ESI) m / z: [M+H] + =497.

[1128]

[1129] Using a procedure similar to 1-22, 1-23 was used to prepare tert-butyl 6-(6-cyano-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1-24).

[1130] Preparation of tert-butyl 6-(6-ethoxy-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-25)

[1131]

[1132] To a stirred solution of I-23 (300.0 mg, 0.604 mmol, 1 eq) and AcONa (149.0 mg, 1.812 mmol, 3 eq) in 1,4-dioxane (2 ml) and EtOH (2 ml) was added di-tert-butyl[2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (51.2 mg, 0.121 mmol, 0.2 eq) and Pd2(dba)3 (110.5 mg, 0.121 mmol, 0.2 eq). The resulting mixture was stirred at 80 ° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give I-25 (210.0 mg, 68.6%) as a yellow solid. LCMS (ESI) m / z [M+H] + =507.

[1133] Preparation of tert-butyl 6-{6-cyclopropyloxy-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-26).

[1134]

[1135] To a solution of I-23 (200 mg, 0.402 mmol, 1 equivalent) and Pd2(dba)3 (36.85 mg, 0.040 mmol, 0.1 equivalent) in dioxane (1.2 mL, 14.165 mmol) and cyclopropanol (1.2 mL) was added CH3COONa (99.03 mg, 1.206 mmol, 3 equivalents) and t-BuXPhos (34.18 mg, 0.080 mmol, 0.2 equivalents). The resulting solution was stirred at 80 ° C for 16 hours (under N2 atmosphere). The mixture was diluted with EtOAc (150 mL) and washed with water (150 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography eluting with 0 to 50% EtOAc in petroleum ether to afford 1-26 (61 mg, 29.23%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =519.

[1136] Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}-6-(dimethylamino)cinnolin-3-yl)phenol (1-27).

[1137]

[1138] A stirred solution of 1-23 (66 mg, 0.131 mmol, 1 eq) in DCM (2 mL, 31.461 mmol, 241.02 eq) and TFA (2 mL, 26.926 mmol, 206.28 eq) was stirred at room temperature under air atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. This yielded 1-27 (48 mg, 91.56%) as a red solid. LCMS (ESI) m / z: [M+H] + =362.

[1139] Preparation of tert-butyl 6-(6-cyano-3-(2-(methoxymethoxy)phenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1-28).

[1140]

[1141] To a solution of I-23 (350.0 mg, 0.70 mmol, 1.00 equiv) in DMF (7 mL) at room temperature were added XPhos (67.1 mg, 0.14 mmol, 0.20 equiv), XPhos Pd G3 (119.2 mg, 0.14 mmol, 0.20 equiv), and Zn(CN)2 (248.1 mg, 2.11 mmol, 3.00 equiv). The mixture was stirred at 100°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H2O (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc = 10:1 to 1:1, to give I-28 (150.0 mg, 43.7%) as an orange solid. LCMS (ESI) m / z: [M+H] + =488.

[1142] Preparation of tert-butyl 6-[6-(difluoromethoxy)-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-30).

[1143]

[1144] Step 1: Preparation of tert-butyl 6-{6-hydroxy-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-29).

[1145]

[1146] To a stirred solution of I-23 (923.0 mg, 1.857 mmol, 1 eq) and KOH (0.31 g, 5.571 mmol, 3 eq) in 1,4-dioxane (5 mL) and H2O (5 mL) was added Pd2(dba)3 (0.34 g, 0.371 mmol, 0.2 eq) and di-tert-butyl[2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (0.16 g, 0.391 mmol, 0.2 eq). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give I-29 (780.0 mg, 87.7%) as a brown solid. LCMS (ESI) m / z: [M+H] + =479.

[1147] Step 2: Preparation of tert-butyl 6-[6-(difluoromethoxy)-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-30).

[1148]

[1149] To a stirred mixture of I-29 (300.0 mg, 0.627 mmol, 1 eq) and Cs2CO3 (612.76 mg, 1.881 mmol, 3 eq) in DMF (6 mL) was added sodium 2-chloro-2,2-difluoroacetate (286.7 mg, 1.881 mmol, 3 eq). The resulting mixture was stirred at 60 ° C for 2 hours. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (6:1) to give I-30 (140.0 mg, 42.2%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =529.

[1150] Preparation of tert-butyl 6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-31).

[1151]

[1152] Step 1: Preparation of tert-butyl 6-{5-chloro-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-35)

[1153]

[1154] To a solution of I-17 (1.00 g, 2.634 mmol, 1 eq), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.52 g, 2.634 mmol, 1 eq) and BINAP (0.33 g, 0.527 mmol, 0.2 eq) in toluene (12 mL) were added Pd2(dba)3 (0.48 g, 0.527 mmol, 0.2 eq) and t-BuONa (0.51 g, 5.268 mmol, 2 eq), and the mixture was stirred at 80 ° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give I-35 (1.00 g, 76.9%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =497.

[1155] Step 2: Preparation of tert-butyl 6-{5-vinyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-36).

[1156]

[1157] To a solution of I-35 (1.00 g, 2.012 mmol, 1 eq) and vinyldifluoro-λ4-boryl)-λ2-fluoranide (0.19 g, 2.01 mmol, 1 eq) in H2O (2 mL) and dioxane (10 mL) were added XPhosPdG3 (0.34 g, 0.402 mmol, 0.2 eq) and Cs2CO3 (1.97 g, 6.036 mmol, 3 eq), and the mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / H2O (5:1) to give I-36 (900.0 mg, 91.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =489.

[1158] Step 3: Preparation of tert-butyl 6-{6-formyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-37).

[1159]

[1160] To a solution of I-36 (840.0 mg, 1.719 mmol, 1 eq) and 2,6-lutidine (368.5 mg, 3.438 mmol, 2 eq) in dioxane (60 mL) and H2O (30 mL) were added NaIO4 (1470.9 mg, 6.876 mmol, 4 eq) and K2OsO4·2H2O (50.9 mg, 0.138 mmol, 0.08 eq), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give I-37 (400.0 mg, 47.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =491.

[1161] Step 4: Preparation of tert-butyl 6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-31).

[1162]

[1163] To a solution of intermediate 4 (400.0 mg, 0.815 mmol, 1 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (234.9 mg, 1.222 mmol, 1.5 eq) in MeOH (6 mL) was added KCO (338.1 mg, 2.445 mmol, 3 eq) and the mixture was stirred at room temperature for 3 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give I-31 (220.0 mg, 55.4%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =487.

[1164]

[1165] Tert-butyl 6-{6-ethynyl-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-32) was prepared in a similar manner as described in the preparation of I-31. LCMS (ESI) m / z: [M+H] + =487.

[1166] Preparation of 7-chloro-6-(difluoromethyl)-3-[2-(methoxymethoxy)phenyl]cinnoline (I-33).

[1167]

[1168] Step 1: Preparation of 7-chloro-6-vinyl-3-[2-(methoxymethoxy)phenyl]cinnoline (Intermediate 2).

[1169]

[1170] To a stirred solution of 1-21 (500.0 mg, 1.317 mmol, 1 eq) and potassium ethylene trifluoroborate (352.9 mg, 2.634 mmol, 2 eq) in dioxane (7.5 mL) and H2O (1.5 mL) were added XPhosPdG3 (222.9 mg, 0.263 mmol, 0.2 eq) and Cs2CO3 (1287.3 mg, 3.951 mmol, 3 eq). The resulting mixture was stirred at 80°C under a nitrogen atmosphere overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (9:1) to give intermediate 2 (350.0 mg, 81.2%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =327.

[1171] Step 2: Preparation of 7-chloro-3-[2-(methoxymethoxy)phenyl]cinnoline-6-carbaldehyde (Intermediate 3).

[1172]

[1173] To a stirred solution of intermediate 2 (350 mg, 1.070 mmol, 1 eq) and NaIO4 (924.6 mg, 4.281 mmol, 4 eq) in dioxane (3 mL) and H2O (3 mL) was added K2OsO4·2H2O (18.1 mg, 0.053 mmol, 0.05 eq) and 2,6-lutidine (228.9 mg, 2.140 mmol, 2 eq) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated sodium thiosulfate (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE / EtOAc 1:1) to give Intermediate 3 (300 mg, 85.2%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =329.

[1174] Step 3: Preparation of 7-chloro-6-(difluoromethyl)-3-[2-(methoxymethoxy)phenyl]cinnoline (I-33).

[1175]

[1176] To a solution of intermediate 3 (300 mg, 0.911 mmol, 1 eq.) in DCM (5 mL) was added BAST (1 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The reaction was quenched with saturated NH4Cl (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc 1:1) to give I-33 (250.0 mg, 78.1%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =351.

[1177]

[1178] 6-Chloro-7-(difluoromethyl)-3-(2-(methoxymethoxy)phenyl)cinnoline (1-34) was prepared using a procedure similar to that described above for 1-33.

[1179] Preparation of tert-butyl 6-[5-(difluoromethyl)-3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-38)

[1180]

[1181] To a stirred solution of I-37 (440.0 mg, 0.897 mmol, 1 eq.) in DCM (5 ml) was added BAST (1 ml) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with saturated NH4Cl (aq.) at 0°C. The aqueous layer was extracted with EtOAc (2 x 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give I-38 (160.0 mg, 34.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =513.

[1182] Preparation of 2-(6-cyclopropyl-7-{2,6-diazaspiro[3.3]heptane-2-yl}cinnolin-3-yl)phenol (I-39)

[1183]

[1184] Step 1: Preparation of 1,3-dimethyl-2-(5-bromo-4-chloro-2-nitrophenyl)malonate (Intermediate 2)

[1185]

[1186] A solution of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (20 g, 78.604 mmol, 1 eq.) and dimethyl malonate (11.42 g, 86.464 mmol, 1.1 eq.) and Cs2CO3 (51.22 g, 157.208 mmol, 2.0 eq.) in DMF (50 mL) was stirred at room temperature for 12 hours. The mixture was acidified to pH 6 with 1N HCl (aq.). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 2 (20 g, 69.4%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z[M+H] + =366.

[1187] Step 2: Preparation of (5-bromo-4-chloro-2-nitrophenyl)acetic acid (Intermediate 3)

[1188]

[1189] A solution of intermediate 2 (20 g, 54.563 mmol, 1 equivalent) and AcOH (250 mL) in HCl (250 mL) was stirred at 100 ° C for 12 hours. The resulting mixture was diluted with water (200 mL). The precipitated solid was collected by filtration and washed with water (3 x 200 mL). The resulting mixture was concentrated under reduced pressure. This produced intermediate 3 (15 g, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =294.

[1190] Step 3: Preparation of methyl 2-(5-bromo-4-chloro-2-nitrophenyl)acetate (Intermediate 4)

[1191]

[1192] To a stirred solution of intermediate 3 (15 g, 50.936 mmol, 1 eq) in MeOH (100 mL) and DCM (400 mL) was added TMSCHN2 (34.91 g, 152.807 mmol, 3 eq) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This produced intermediate 4 (16 g, crude product) as a pale yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =308.

[1193] Step 4: Preparation of methyl 2-(4-chloro-5-cyclopropyl-2-nitrophenyl)acetate (Intermediate 5)

[1194]

[1195] To a solution of intermediate 4 (3.0 g, 9.724 mmol, 1 eq) and cyclopropylboronic acid (1.67 g, 19.448 mmol, 2.0 eq) in dioxane (20 mL) and H2O (5 mL) was added K3PO4 (6.19 g, 29.172 mmol, 3.0 eq) and Pd(dppf)Cl2 (1.42 g, 1.945 mmol, 0.2 eq). After stirring at 60°C under nitrogen atmosphere for 2 h, the mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give intermediate 5 (1.8 g, 68.6%) as a yellow solid. LCMS (ESI) m / z [M+H] + =270.

[1196] Step 5: Preparation of methyl 2-(2-amino-4-chloro-5-cyclopropylphenyl)acetate (Intermediate 6)

[1197]

[1198] To a stirred solution of intermediate 5 (1.8 g, 6.675 mmol, 1 eq) and NHCl (7.14 g, 133.500 mmol, 20 eq) in MeOH (20 mL) was added Zn (8.73 g, 133.540 mmol, 20 eq) in portions at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 6 (1.4 g, crude product) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =240.

[1199] Step 6: Preparation of 1-amino-6-chloro-5-cyclopropyl-3H-indol-2-one (Intermediate 7)

[1200]

[1201] A solution of intermediate 6 (1.8 g, 7.509 mmol, 1 eq) and NOBF4 (1.32 g, 11.264 mmol, 1.5 eq) in DCM (25 mL) was stirred at 0°C for 1 hour. To the above mixture was added SnCl2 (8.63 g, 45.054 mmol, 6.0 eq) in HCl (30 mL) dropwise at 0°C. The resulting mixture was stirred for another 12 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient over 50 minutes; detector, UV 254 nm. This gave intermediate 7 (700.0 mg, 41.8%) as a yellow solid. LCMS (ESI) m / z [M+H] + =223.

[1202] Step 7: Preparation of tert-butyl 6-(6-cyclopropyl-3-hydroxycinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 8)

[1203]

[1204] To a solution of intermediate 7 (300.0 mg, 1.360 mmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (539.1 mg, 2.720 mmol, 2.0 eq) in dioxane (5 mL) was added CsCO (1328.9 mg, 4.080 mmol, 3.0 eq) and Pd-PEPPSI-IPentCl 2-methylpyridine (215.5 mg, 0.272 mmol, 0.2 eq). After stirring at 100°C under a nitrogen atmosphere for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 50% over 50 minutes; detector, UV 254 nm. This gave intermediate 8 (250.0 mg, 48.0%) as a yellow solid. LCMS (ESI) m / z [M+H] + =221.

[1205] Step 8: Preparation of tert-butyl 6-(6-cyclopropyl-3-hydroxycinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 9)

[1206]

[1207] To a solution of intermediate 8 (300.0 mg, 1.360 mmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (539.1 mg, 2.720 mmol, 2.0 eq) in dioxane (5 mL) was added CsCO (1328.9 mg, 4.080 mmol, 3.0 eq) and Pd-PEPPSI-IPentCl 2-methylpyridine (215.5 mg, 0.272 mmol, 0.2 eq). After stirring at 100°C under a nitrogen atmosphere for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 0% to 50% over 50 minutes; detector, UV 254 nm. This gave intermediate 9 (250.0 mg, 48.0%) as a yellow solid. LCMS (ESI) m / z [M+H] + =383.

[1208] Step 9: Preparation of tert-butyl 6-[6-cyclopropyl-3-(trifluoromethanesulfonyloxy)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 10)

[1209]

[1210] To a solution of intermediate 9 (250.0 mg, 0.654 mmol, 1 eq) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (467.0 mg, 1.308 mmol, 2.0 eq) in DCM (5 mL) was added TEA (198.4 mg, 1.962 mmol, 3.0 eq) and DMAP (7.9 mg, 0.065 mmol, 0.1 eq) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with PE / EA (23:67) to give intermediate 10 (270.0 mg, 80.2%) as a yellow oil. LCMS (ESI) m / z [M+H] + =515.

[1211] Step 10: Preparation of tert-butyl 6-[6-cyclopropyl-3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 11)

[1212]

[1213] To a solution of intermediate 10 (210.0 mg, 0.408 mmol, 1 eq) and 2-hydroxyphenylboronic acid (168.8 mg, 1.224 mmol, 3.0 eq) in dioxane (4 mL) and H2O (1 mL) was added K3PO4 (259.4 mg, 1.224 mmol, 3.0 eq) and Pd(dppf)Cl2 (59.4 mg, 0.082 mmol, 0.2 eq). After stirring at 60°C under a nitrogen atmosphere for 1 hour, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 60% over 40 minutes; detector, UV 254 nm. This yielded intermediate 11 (100.0 mg, 53.4%) as a yellow oil. LCMS (ESI) m / z [M+H] + =503.

[1214] Step 11: Preparation of 2-(6-cyclopropyl-7-{2,6-diazaspiro[3.3]heptane-2-yl}cinnolin-3-yl)phenol (I-39)

[1215]

[1216] A solution of intermediate 11 (70.0 mg, 0.153 mmol, 1 eq) and TFA (0.5 mL) in DCM (2 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This produced I-39 (90 mg, crude) as a red solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =359.

[1217]

[1218] 2-(5-Cyclopropyl-7-{2,6-diazaspiro[3.3]heptane-2-yl}cinnolin-3-yl)phenol (I-40) was prepared in a similar manner as described in the preparation of intermediate I-39. LCMS (ESI) m / z [M+H] + =359.

[1219] Preparation of 2-(7-{2,6-diazaspiro[3.3]hept-2-yl}-5-methylcinnolin-3-yl)phenol (1-41).

[1220]

[1221] Step 1: Preparation of 1,3-dimethyl-2-(4-bromo-2-methyl-6-nitrophenyl)malonate (Intermediate 2)

[1222]

[1223] A solution of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (30.00 g, 128.192 mmol, 1.00 equiv) and dimethyl malonate (16.94 g, 128.92 mmol, 1.00 equiv) in DMF (300 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (2 L). The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (3 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 2 (44.00 g, 96.1%) as a light yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =246.

[1224] Step 2: Preparation of (4-bromo-2-methyl-6-nitrophenyl)acetic acid (Intermediate 3).

[1225]

[1226] A solution of intermediate 2 (44.00 g, 127.119 mmol, 1.00 equiv) and AcOH (300 mL) in concentrated HCl (300 mL) was stirred at 100 ° C overnight. The precipitated solid was collected by filtration and washed with water (3 x 300 mL). This gave intermediate 3 (33.00 g, 92.8%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =274.

[1227] Step 3: Preparation of methyl 2-(4-bromo-2-methyl-6-nitrophenyl)acetate (Intermediate 4).

[1228]

[1229] To a stirred solution of intermediate 3 (33.00 g, 120.407 mmol, 1.00 equiv) in DCM (300 mL) was added (COCl) (30.56 g, 240.814 mmol, 2.00 equiv) dropwise at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. At 0 ° C, MeOH (165 mL) was added dropwise to the above mixture over 10 minutes. The resulting mixture was stirred at room temperature for another 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 x 700 mL). The combined organic layers were washed with sodium bicarbonate solution (3 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 4 (35.00 g, 98.88%) as a light yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =288.

[1230] Step 4: Preparation of methyl 2-(2-amino-4-bromo-6-methylphenyl)acetate (Intermediate 5).

[1231]

[1232] To a stirred solution of intermediate 4 (35.00 g, 121.487 mmol, 1.00 equiv) and NHCl (129.97 g, 2429.740 mmol, 20.00 equiv) in MeOH (400 mL) was added Zn (119.14 g, 1822.305 mmol, 15.00 equiv) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 300 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 5 (32.00 g, 63.27%) as a light yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =258.

[1233] Step 5: Preparation of 1-amino-6-bromo-4-methyl-3H-indol-2-one (Intermediate 6).

[1234]

[1235] To a stirred solution of intermediate 5 (32.00 g, 123.976 mmol, 1.00 equiv) in DCM (320 mL) was added NOBF4 (21.72 g, 185.964 mmol, 1.50 equiv) at 0°C. The resulting mixture was stirred at 0°C for 2 hours. To the above mixture was added SnCl2 (118.79 g, 619.880 mmol, 5.00 equiv) and HCl (320 mL) in portions at 0°C over 10 minutes. The resulting mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with water (3 x 300 mL). This produced intermediate 6 (13.00 g, 43.06%) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =241.

[1236] Step 6: Preparation of 7-bromo-5-methylcinnolin-3-ol (Intermediate 7).

[1237]

[1238] To a stirred solution of intermediate 6 (11.00 g, 45.626 mmol, 1.00 equiv) in toluene (200 mL) was added tert-butyl hypochlorite (3.96 g, 36.501 mmol, 0.80 equiv) dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The precipitated solid was collected by filtration and washed with PE (3 x 300 mL). This produced intermediate 7 (11.70 g, 92.2%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =239.

[1239] Step 7: Preparation of tert-butyl 6-(3-hydroxy-5-methylcinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 8).

[1240]

[1241] To a solution of intermediate 7 (2.00 g, 8.366 mmol, 1.00 equiv), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.32 g, 16.732 mmol, 2.00 equiv) and CsCO (8.18 g, 25.098 mmol, 3.00 equiv) in dioxane (25 mL) was added {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloro(2-methyl-1λ4-pyridin-1-yl)palladium (351.8 mg, 0.418 mmol, 0.05 equiv) and the mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (12:1) to give Intermediate 8 (3.40 g, 62.71%) as a black solid. LCMS (ESI) m / z: [M+H] + =257.

[1242] Step 8: Preparation of tert-butyl 6-[5-methyl-3-(trifluoromethanesulfonyloxy)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 9).

[1243]

[1244] At 0 ° C, to a stirred solution of intermediate 8 (3.40 g, 9.539 mmol, 1.00 equivalent) and TEA (2.90 g, 28.617 mmol, 3.00 equivalent) in DCM (40 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonyl methanesulfonamide (5.11 g, 14.308 mmol, 1.50 equivalent). The resulting mixture was stirred at 0 ° C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layer was washed with brine (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (7:3) to give intermediate 9 (1.9 g, 36.7%) as an orange solid. LCMS (ESI) m / z: [M+H] + =489.

[1245] Step 9: Preparation of tert-butyl 6-{3-[2-(methoxymethoxy)phenyl]-5-methylcinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 10).

[1246]

[1247] To a stirred solution of intermediate 9 (1.90 g, 3.890 mmol, 1.00 equivalent) and 2-(methoxymethoxy)phenylboronic acid (707.8 mg, 3.890 mol, 1.00 equivalent) in dioxane (20 mL) and H2O (4 mL) was added Pd(dppf)Cl2 (569.2 mg, 0.778 mmol, 0.20 equivalent) and K3PO4 (2.48 g, 11.670 mmol, 3.00 equivalent). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (500 mL). The aqueous layer was extracted with EtOAc (3 x 400 mL). The combined organic layer was washed with brine (3 x 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:8) to give intermediate 10 (780.0 mg, 42.1%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =477.

[1248] Step 10: Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}-5-methylcinnolin-3-yl)phenol (1-41).

[1249]

[1250] A solution of intermediate 10 (770.0 mg, 1.616 mmol, 1.00 equiv) in DCM (8 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH (0.05% TFA) in water, 0% to 100% gradient over 30 minutes; detector, UV 254 / 220 nm. The resulting mixture was concentrated under vacuum. This produced 1-41 (374.0 mg, 62.6%) as a red solid. LCMS (ESI) m / z: [M+H] + =333.

[1251]

[1252] 2-(6-Methyl-7-(2,6-diazaspiro[3.3]heptane-2-yl)cinnolin-3-yl)phenol (I-42) was prepared in a similar manner as described in the preparation of intermediate I-41. LCMS (ESI) m / z: [M+H] + =333.

[1253] Preparation of 2-(7-{2-azaspiro[3.3]heptane-6-yl}cinnolin-3-yl)phenol (I-43)

[1254]

[1255] Step 1: Ethyl (2E)-3-(4-amino-6-chloropyridazin-3-yl)prop-2-enoate (Intermediate 2)

[1256]

[1257] By 6-iodo-2-azaspiro [3.3] heptane-2-t-butyl formates (4.99g, 15.433mmol, 1.5 equivalents), I in DMF (20mL) (1.31g, 5.144mmol, 0.5 equivalent) and Zn (71.57mg, 1.095mmol, 3 equivalents) solution at room temperature stirred 1.5 hours under nitrogen atmosphere.Under nitrogen atmosphere, at room temperature in gained solution, add 2-(4-bromo-2-nitrophenyl) methyl acetate (2.82g, 10.289mmol, 1 equivalent), CuI (0.98g, 5.144mmol, 0.5 equivalent) and Pd(PPh ) Cl (1.44g, 2.058mmol, 0.2 equivalent).The final reaction mixture is at room temperature stirred under nitrogen atmosphere and spend the night.Required product can be detected by LCMS. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give Intermediate 2 (1.87 g, 46.55%) as a yellow oil. LCMS (ESI) m / z [M+H] + =390.

[1258] Step 2: Preparation of methyl 2-(4-{2-azaspiro[3.3]heptane-6-yl}-2-nitrophenyl)acetate (Intermediate 3)

[1259]

[1260] A mixture of intermediate 2 (1.87 g, 4.790 mmol, 1 eq) and TFA (5 mL) in DCM (15 mL) was stirred at room temperature for 1 hour. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =290.

[1261] Step 3: Preparation of methyl 2-(4-{2-acetyl-2-azaspiro[3.3]heptane-6-yl}-2-nitrophenyl)acetate (Intermediate 4)

[1262]

[1263] A mixture of intermediate 3 (1.37 g, 4.719 mmol, 1 eq) and acetic anhydride (0.96 g, 9.438 mmol, 2 eq) in DCM (13 mL) was stirred at room temperature for 50 minutes. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give intermediate 4 (1.44 g, 91.82%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =332.

[1264] Step 4: Preparation of methyl 2-(4-(2-acetyl-2-azaspiro[3.3]hept-6-yl)-2-aminophenyl)acetate (Intermediate 5)

[1265]

[1266] To a stirred mixture of intermediate 4 (1.44 g, 4.333 mmol, 1 eq) and NHCl (4.64 g, 86.660 mmol, 20 eq) in MeOH (15 mL) was added Zn (5.67 g, 86.660 mmol, 20 eq) in portions at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The residue was dissolved in EtOAc (100 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 5 mL). The resulting mixture was washed with water (2 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =302.

[1267] Step 5: Preparation of 6-{2-acetyl-2-azaspiro[3.3]heptan-6-yl}-1-amino-3H-indol-2-one (Intermediate 6)

[1268]

[1269] To a stirred mixture of intermediate 5 (1.127 g, 3.727 mmol, 1 eq) suspended in DCM (12 mL) at 0°C, NOBF4 (0.65 g, 5.590 mmol, 1.5 eq) was added in one portion. The mixture was stirred at 0°C for 1 hour. The mixture was added directly to a vigorously stirred mixture of SnCl2 (5.71 g, 29.816 mmol, 8 eq) in HCl (6 mL, 197.477 mmol, 181.49 eq) at 0°C. The resulting mixture was stirred at 30°C overnight. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 0% to 40% over 30 minutes; detector, UV 254 nm. This gave intermediate 6 (520 mg, 48.89%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =285.

[1270] Step 6: Preparation of 1-[6-(3-hydroxycinnolin-7-yl)-2-azaspiro[3.3]heptan-2-yl]ethanone (Intermediate 7)

[1271]

[1272] A solution of intermediate 6 (500 mg, 1.752 mmol, 1 eq) and Pb(OAc)4 (932.34 mg, 2.102 mmol, 1.2 eq) in DCM (6 mL) was stirred at room temperature for 20 minutes. The desired product could be detected by LCMS. The resulting mixture was dried in an oven under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 40% gradient over 20 minutes; detector, UV 254 nm. This gave intermediate 7 (232 mg, 46.73%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =283.

[1273] Step 7: Preparation of 7-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)cinnolin-3-yl trifluoromethanesulfonate (Intermediate 8)

[1274]

[1275] A solution of intermediate 7 (250 mg, 0.882 mmol, 1 eq) and Tf2O (1249.68 mg, 4.429 mmol, 5.02 eq) in pyridine (6 mL) was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The residue was dissolved in EtOAc (50 mL). The combined organic layers were washed with water (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =415.

[1276] Step 8: Preparation of 1-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2-azaspiro[3.3]heptan-2-yl}ethanone (Intermediate 9)

[1277]

[1278] To a stirred mixture of intermediate 8 (60 mg, 0.072 mmol, 1 eq., 50%) and 2-hydroxyphenylboronic acid (19.92 mg, 0.144 mmol, 2 eq.) in dioxane (2.5 mL) and H O (0.5 mL) was added XPhos Pd G (12.23 mg, 0.014 mmol, 0.2 eq.) and Cs CO (70.59 mg, 0.216 mmol, 3 eq.). The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 hours. The desired product was detected by LCMS. The crude product (60 mg) was purified by Chiral-Prep-HPLC (NB-Prep-HPLC-01) using the following conditions: column, Xselect CSH C18 OBD column 30*150 mm 5 um; mobile phase, water (0.1% FA) and ACN (35% ACN in 7 minutes to up to 58%) to give intermediate 9 (8.9 mg, 34.08%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.05 (s, 1H), 8.90 (s, 1H), 8.24 (s, 1H), 8.15-8.0 6(m, 2H), 7.86-7.78(m, 1H), 7.41-7.33(m, 1H), 7.09-7.00(m, 2H), 4.31(s, 1H), 4.09 (s, 1H), 4.03 (s, 1H), 3.81 (s, 1H), 3.72 (p, J=8.7Hz, 1H), 2.75-2. 64 (m, 2H), 2.50-2.42 (m, 2H), 1.76 (d, J = 13.2Hz, 3H). LCMS (ESI) m / z: [M+H] + =359.16.

[1279] Step 9: Preparation of 2-(7-{2-azaspiro[3.3]heptane-6-yl}cinnolin-3-yl)phenol (I-43)

[1280]

[1281] A solution of intermediate 9 (122 mg, 0.339 mmol, 1 eq) and KOH (190.44 mg, 3.390 mmol, 10 eq) in MeOH (1.5 mL) and H2O (1.5 mL) was stirred at 70°C overnight. The desired product could be detected by LCMS. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 60% gradient over 40 minutes; detector, UV 254 nm. This gave 1-43 (102 mg, 94.68%) as an off-white solid. LCMS (ESI) m / z [M+H] + =317.

[1282] Preparation of 1-{3-[7-cyclopropyl-3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (1-44).

[1283]

[1284] Step 4: Preparation of tert-butyl 3-[2-chloro-5-(2-methoxy-2-oxoethyl)-4-nitrophenyl]azetidine-1-carboxylate (Intermediate 5).

[1285]

[1286] By 3-iodoazetidine -1- tert-butyl formates (22.94g, 81.035mmol, 1 equivalent) and I in DMF (250mL) (10.28g, 40.517mmol, 0.5 equivalent), Zn (15.89g, 243.105mmol, 3 equivalents) solution under nitrogen atmosphere at room temperature stirred 1 hour.At room temperature, CuI (3.09g, 16.207mmol, 0.2 equivalent), Pd (dppf) Cl (11.86g, 16.207mmol, 0.2 equivalent) and intermediate 4 (25g, 81.035mmol, 1 equivalent) are added into the above mixture.The mixed solution is stirred at room temperature for another 3 hours.Gained mixture is filtered, and filter cake is washed with EtOAc (3x50mL). The filtrate was diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give intermediate 5 (32 g, 97.4%) as a light yellow oil. LCMS (ESI) m / z: [M+H] + =385.

[1287] Step 5: Preparation of methyl 2-[5-(azetidin-3-yl)-4-chloro-2-nitrophenyl]acetate (Intermediate 6).

[1288]

[1289] A solution of intermediate 5 (31 g, 80.559 mmol, 1 eq) in TFA (30 mL) and DCM (90 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. This produced intermediate 6 (40 g, crude product) as a brown oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =285.

[1290] Step 6: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-4-chloro-2-nitrophenyl]acetate (Intermediate 7).

[1291]

[1292] To a stirred solution of intermediate 6 (40 g, crude) and Et3N (21.33 g, 210.747 mmol, 3 eq) in DCM (250 mL) was added Ac2O (7.17 g, 70.249 mmol, 1 eq) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour and concentrated under reduced pressure. The crude product was purified by reverse phase flash method using the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 0% B to 100% B in 40 minutes; 254 / 220 nm) to give intermediate 7 (21 g, 86.9%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =327.

[1293] Step 7: Preparation of methyl 2-[5-(1-acetylazetidin-3-yl)-2-amino-4-chlorophenyl]acetate (Intermediate 8).

[1294]

[1295] To a stirred solution of intermediate 7 (10 g, 30.606 mmol, 1 eq) and NHCl (16.37 g, 306.060 mmol, 10 eq) in MeOH (100 mL) was added Zn (20.01 g, 306.60 mmol, 10 eq) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The mixed solution was filtered and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was concentrated under vacuum, the residue was diluted with water (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 400 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 8 (9.5 g, crude product) as a light yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =297.

[1296] Step 8: Preparation of 5-(1-acetylazetidin-3-yl)-1-amino-6-chloro-3H-indol-2-one (Intermediate 9).

[1297]

[1298] A solution of intermediate 8 (9.5 g, crude) and NOBF4 (5.61 g, 48.019 mmol, 1.5 eq) in DCM (100 mL) was stirred at 0°C for 1 hour. To the above mixture was added SnCl2 (36.81 g, 192.078 mmol, 6 eq) in HCl (100 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The mixed solution was concentrated under reduced pressure. The crude product was purified by reverse phase flash method using the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 0% B to 50% B in 40 minutes; 254 / 220 nm) to give intermediate 9 (5.2 g, 34.8%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =280.

[1299] Step 9: Preparation of 1-[3-(7-chloro-3-hydroxycinnolin-6-yl)azetidin-1-yl]ethanone (Intermediate 10).

[1300]

[1301] To a stirred solution of intermediate 9 (1.5 g, 4.558 mmol, 1 eq., 85%) in DCM (20 mL) was added Pb(OAc)4 (3.03 g, 6.837 mmol, 1.5 eq.) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The mixed solution was concentrated under reduced pressure. The crude product was purified by reverse phase flash method using the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 0% B to 50% B in 40 minutes; 254 / 220 nm) to give intermediate 10 (1.5 g, 94.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =278.

[1302] Step 10: Preparation of 6-(1-acetylazetidin-3-yl)-7-chlorocinnolin-3-yl trifluoromethanesulfonate (Intermediate 11).

[1303]

[1304] To a stirred solution of intermediate 10 (1.5 g, 4.321 mmol, 1 eq., 80%) and Et3N (1.31 g, 12.963 mmol, 3 eq.) in DCM (2 mL) at 0°C was added DMAP (0.26 g, 2.160 mmol, 0.5 eq.) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.54 g, 4.321 mmol, 1 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc 1:1) to give intermediate 11 (1.5 g, 72.0%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =410.

[1305] Step 11: Preparation of 1-{3-[7-chloro-3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (Intermediate 12).

[1306]

[1307] To a stirred solution of intermediate 11 (700.0 mg, 1.708 mmol, 1 eq) and 2-hydroxyphenylboronic acid (353.44 mg, 2.562 mmol, 1.5 eq) in dioxane (70 mL) and H2O (14 mL) was added Pd(dppf)Cl2 (250.00 mg, 0.342 mmol, 0.2 eq) and K3PO4 (1087.85 mg, 5.124 mmol, 3 eq). The resulting mixture was stirred at 60 ° C for 1 hour under a nitrogen atmosphere. The mixture solution was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 0% B to 100% B in 40 minutes; 254 / 220 nm) to afford intermediate 12 (436.0 mg, 68.5%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =354.

[1308] Step 12: Preparation of 1-{3-[7-cyclopropyl-3-(2-hydroxyphenyl)cinnolin-6-yl]azetidin-1-yl}ethanone (Intermediate 13).

[1309]

[1310] To a stirred solution of intermediate 12 (25.0 mg, 0.071 mmol, 1 eq) and potassium cyclopropyltrifluoro-λ-borane (52.28 mg, 0.355 mmol, 5 eq) in toluene (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl2 (10.34 mg, 0.014 mmol, 0.2 eq) and K2CO3 (29.30 mg, 0.213 mmol, 3 eq). The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: XBridge Shield RP 18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 50% B, 50% B in 8 minutes; wavelength: 254 / 220 nm; RT1 (min): 8.86; number of runs: 0) to obtain intermediate 13 (2.8 mg, 11.0%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =741.30.1 H NMR (400 MHz, methanol-d4) δ 8.80 (s, 1H), 8.17-7.95 (m, 3H), 7.40-7.32 (m, 1H), 7.10-6.96 (m, 2H), 4.79 (t, J = 8.5 Hz, 1H), 4.68-4.48 (m, 3H), 4.30 (dd, J = 9.4, 6.3 Hz, 1H), 2.08-2.00 (m, 1H), 1.96 (s, 3H), 1.23-1.13 (m, 2H), 0.97-0.89 (m, 2H).

[1311] Step 13: Preparation of 2-[6-(azetidin-3-yl)-7-cyclopropylcinnolin-3-yl]phenol (1-44).

[1312]

[1313] A solution of intermediate 13 (150.0 mg, 0.417 mmol, 1 eq) and KOH (234.1 mg, 4.170 mmol, 10 eq) in MeOH (2 mL) and H2O (2 mL) was stirred at 60°C overnight. The residue was purified by reverse phase flash method using the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 35 mL / min; gradient: 0% B to 100% B in 40 min; 254 / 220 nm) to give I-44 (61.0 mg, 44.2%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =318.

[1314] Preparation of 2-fluoro-2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-58).

[1315]

[1316] Step 1: Preparation of N,3-dimethoxy-N-methyl-1,2-oxazole-5-carboxamide (Intermediate 2).

[1317]

[1318] To a solution of 3-methoxy-1,2-oxazole-5-carboxylic acid (15 g, 104.823 mmol, 1 equivalent), N,O-dimethylhydroxylamine (7.68 g, 125.788 mmol, 1.2 equivalents) and HATU (47.83 g, 125.7588 mmol, 12 equivalents) in DMF (150 mL) was added DIEA (67.74 g, 524.115 mmol, 5 equivalents). The solution was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (800 mL) and washed with H2O (800 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 39% ethyl acetate in petroleum ether to obtain intermediate 2 (17.6 g, 90.19%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =187.

[1319] Step 2: Preparation of 1-(3-methoxy-1,2-oxazol-5-yl)-2-methylpropan-1-one (Intermediate 3).

[1320]

[1321] Under N2 atmosphere at -78 ℃, to a solution of intermediate 2 (16g, 85.944mmol, 1 equivalent) in THF (150mL) was added bromo(isopropyl)magnesium (25.32g, 171.888mmol, 2 equivalents). The resulting solution was stirred at -78 ℃ for 2 hours. The reaction solution was quenched with MeOH (30mL) and concentrated. The residue was diluted with EtOAc (600mL) and washed with water (3x600mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with an elution gradient of 0-15% ethyl acetate in petroleum ether to obtain intermediate 3 (9.8g, 67.40%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =170.

[1322] Step 3: Preparation of 2-(3-methoxy-1,2-oxazol-5-yl)-3-methyl-2-[(trimethylsilyl)oxy]butanenitrile (Intermediate 4).

[1323]

[1324] To a solution of intermediate 3 (9.8 g, 57.926 mmol, 1 eq) in THF (100 mL) was added trimethylsilyl cyanide (22.99 g, 231.704 mmol, 4 eq) and 18-crown-6 (1.53 g, 5.793 mmol, 0.1 eq). The resulting solution was stirred at 40 ° C for 24 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with EtOAc (2 x 300 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 30% dichloromethane in petroleum ether to obtain intermediate 4 (11.4 g, 73.33%) as a colorless oil. LCMS (ESI) m / z: [M + H] + =269.

[1325] Step 4: Preparation of 2-hydroxy-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutyronitrile (Intermediate 5).

[1326]

[1327] To a solution of intermediate 4 (11.4 g, 42.476 mmol, 1 eq) in DCM (50 mL) and MeOH (50 mL) was added TFA (5 mL). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0 to 33% acetonitrile (0.1% TFA) in water to give intermediate 5 (7.8 g, 93.59%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =197.

[1328] Step 5: Preparation of 2-fluoro-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutyronitrile (Intermediate 5).

[1329]

[1330] To a solution of intermediate 5 (7.8 g, 39.754 mmol, 1 eq) in DCM (60 mL) was added DAST (7.69 g, 47.708 mmol, 1.20 eq) at 0 ° C. The resulting solution was stirred at 0 ° C for 15 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted with DCM (2 x 200 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 500 mL). The layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 50% dichloromethane in petroleum ether to obtain intermediate 6 (4.01 g, 50.89%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =199.

[1331] Step 6: Preparation of 2-fluoro-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 7).

[1332]

[1333] To a solution of intermediate 6 (200 mg, 1.009 mmol, 1 eq) in MeOH (3 mL) and H2O (3 ml) was added NaOH (403.61 mg, 10.090 mmol, 10 eq). The resulting solution was stirred at 80°C for 1 hour. The mixture was acidified to pH 2 with 1M HCl (aq.). The solution was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 7 (220 mg, crude product) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =218.

[1334] Step 7: Preparation of 2-fluoro-2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-58).

[1335]

[1336] To a solution of intermediate 7 (220 mg, 1.013 mmol, 1 equiv) in HOAc (2.5 mL) was added HBr (48% in water, 2.5 mL). The resulting solution was stirred at 60° C. for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash C18 chromatography with an elution gradient of 0 to 25% acetonitrile in water (0.1% FA) to give I-58 (136 mg, 66.09%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ14.12 (s, 1H), 11.55 (s, 1H), 6.16 (s, 1H), 2.72-2.52 (m, 1H), 0.97 (d, J = 6.9Hz, 3H), 0.88 (d, J = 6.8Hz, 3H). LCMS (ESI) m / z: [M+H] + =204.

[1337] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 51).

[1338]

[1339] Step 1: Preparation of tert-butyl 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 2).

[1340]

[1341] To a stirred mixture of 7-chloro-3-[2-(methoxymethoxy)phenyl]cinnoline (6 g, 19.951 mmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.58 g, 7.980 mmol, 1.2 eq) in dioxane (50 mL) was added CsCO (19.50 g, 59.853 mmol, 3 eq) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-methylpyridine) (1.68 g, 1.995 mmol, 0.1 eq) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C for another hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give Intermediate 2 (8 g, 86.69%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =463.

[1342] Step 2: Preparation of 2-(7-{2,6-diazaspiro[3.3]heptan-2-yl}cinnolin-3-yl)phenol (1-45).

[1343]

[1344] A stirred mixture of intermediate 2 (8 g, 17.295 mmol, 1 equiv) in TFA (10 mL) and DCM (30 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 60% gradient over 30 minutes; detector, UV 254 nm. This produced 1-45 (4 g, 72.64%) as a red solid. LCMS (ESI) m / z: [M+H] + =319.

[1345] Step 3: Preparation of methyl 2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 4).

[1346]

[1347] To a stirred mixture of intermediate 3 and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (9.07 g, 18.846 mmol, 2 eq) in NMP (20 mL) was added DIEA (3.65 g, 28.269 mmol, 3 eq) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for another hour. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 90% gradient over 40 minutes; detector, UV 254 nm. This gave intermediate 4 (700 mg, 14.87%) as a red solid. LCMS (ESI) m / z: [M+H] + =500.

[1348] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (Intermediate 5).

[1349]

[1350] A mixture of intermediate 4 (700 mg, 1.401 mmol, 1 eq) and LiOH.H2O (587.94 mg, 14.010 mmol, 10 eq) in MeOH (8 mL) and H2O (2 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was diluted with CH2Cl2 / MeOH (9:1) (100 mL). The resulting mixture was washed with 3 x 100 mL of brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 5 (500 mg, 73.49%) as a red solid. LCMS (ESI) m / z: [M+H] + =486.

[1351] Step 5: Preparation of (2R,4S)-4-hydroxy-1-[2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 6).

[1352]

[1353] To a stirred mixture of intermediate 5 (210 mg, 0.433 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (186.35 mg, 0.563 mmol, 1.3 eq) in DMF (2 mL) was added PyBOP (450.15 mg, 0.866 mmol, 2 eq) and DIEA (226.01 uL, 1.299 mmol, 3 eq) dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional hour. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 90% over 30 minutes; detector, UV 254 nm. This gave intermediate 6 (102 mg, 29.52%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =799.

[1354] Step 6: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 51).

[1355]

[1356] Intermediate 6 was purified by Chiral-Prep-HPLC using the following conditions: column, CHIRALPAKID, 2*25 cm, 5 μm; mobile phase, MtBE (10 mM NH -MeOH) and EtOH- (maintaining 50% EtOH- in 30 minutes); detector, UV 254 nm. This produced 51 (second peak) (47.8 mg, 45.74%) as a red solid. 1 H NMR (400MHz, DMSO-d6) δ12.82 (d, J=4.8Hz, 1H), 9.00 (d, J=6.4Hz, 1H), 8.76 (s, 1H), 8.42 (d, J=7.7Hz, 1H), 8.07-8.01 (m, 1H), 7.96 (d, J=9.0Hz, 1H), 7.50-7.42 (m, 2H), 7.37 (d, J = 8.1Hz, 2H), 7.35-7.25 (m, 2H), 7.01 (d, J = 8.0Hz, 3H), 5.87 ( d, J=42.8Hz, 1H), 5.12 (d, J=3.6Hz, 1H), 5.05-4.85 (m, 1H), 4.37 (t, J=7.7Hz, 1H ), 4.29 (s, 5H), 4.13 (s, 4H), 3.71 (dd, J = 10.6, 4.4Hz, 1H), 3.60 (t, J = 10.6Hz, 1 H), 3.45 (dd, J=14.0, 10.8Hz, 1H), 2.47 (d, J=4.9Hz, 3H), 2.34-2.13 (m, 1H), 2.0 3(t, J=10.0Hz, 1H), 1.79 (ddd, J=12.8, 8-2, 4.9Hz, 1H), 1.43 (dd, J=32.8, 7.0Hz , 3H), 0.96 (d, J=6.5Hz, 3H), 0.82 (dd, J=14.9, 6.7Hz, 3H). LCMS (ESI) m / z: [M+H] + =799.15.

[1357] The compounds in Table 8 were prepared using procedures similar to those used above to prepare compound 51 using the appropriate Boc-diamine and chlorocinnoline.

[1358] Table 8.

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400] Preparation of (2S,4R)-1-[(2S)-2-cyclopropyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 210-001).

[1401]

[1402] Step 1: Preparation of ethyl 2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclopropylacetate (I-46)

[1403]

[1404] To a solution of 4-bromo-1H-1,2,3-triazole (1 g, 6.758 mmol, 1 eq) and ethyl 2-bromo-2-cyclopropylacetate (2.80 g, 13.516 mmol, 2 eq) in DMF (5 mL) was added KCO (1.87 g, 13.516 mmol, 2 eq). The resulting solution was stirred at 60°C for 4 hours. The resulting mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient from 0% to 100% over 30 minutes; detector, UV 254 / 220 nm. I-46 (611 mg, 32.98%) was obtained as a yellow oil. LCMS (ESI) m / z: [M+H] + =274.

[1405]

[1406] Ethyl 2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclobutylacetate (1-47) and ethyl 2-(4-bromo-1H-1,2-3-triazol-1-yl)-3-methylbutanoate (1-48) were prepared from 4-bromo-1H-1,2,3-triazole using a procedure similar to 1-46.

[1407] Step 2: Preparation of (4-bromo-1,2,3-triazol-1-yl)(cyclopropyl)acetic acid (Intermediate 3)

[1408]

[1409] A solution of intermediate 2 (489 mg, 1.784 mmol, 1 eq) and LiOH (213.62 mg, 8.920 mmol, 5 eq) in MeOH (4 mL) in H O (1 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 3 (481 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] + = 245.

[1410] Step 3: Preparation of (2S,4R)-1-[2-(4-bromo-1,2,3-triazol-1-yl)-2-cyclopropylacetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4)

[1411]

[1412] To a stirred solution of intermediate 3 (481 mg, 1.955 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (971.81 mg, 2.933 mmol, 1.5 eq), HOBT (528.28 mg, 3.910 mmol, 2 eq), EDCI (749.46 mg, 3.91 mmol, 2 eq) in DMF (2 mL) was added DIEA (1263.24 mg, 9.775 mmol, 5 eq). The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, gradient from 0% to 100% over 30 minutes; detector, UV 254 / 220 nm. Intermediate 4 (291 mg, 26.61%) was obtained as a yellow solid. LCMS (ESI) m / z: [M+H] + =559.

[1413] Step 4: Preparation of tert-butyl 6-(1-{1-cyclopropyl-2-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-2-oxoethyl}-1,2,3-triazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 5)

[1414]

[1415] A solution of intermediate 4 (281 mg, 0.502 mmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (199.16 mg, 1.004 mmol, 2 eq), Pd-PEPPSI-IPentCl 2-methylpyridine (o-methylpyridine) (42.25 mg, 0.050 mmol, 0.1 eq), and CsCO (327.29 mg, 1.004 mmol, 2 eq) in 1.4-dioxane (2 mL) was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% NH4HCO3) in water, gradient from 0% to 100% over 30 minutes; detector, UV 254 / 220 nm. Intermediate 5 (116 mg, 34.12%) was obtained as a yellow solid. LCMS (ESI) m / z: [M+H] + =677.

[1416] Step 5: Preparation of (2S,4R)-1-[2-cyclopropyl-2-(4-{2,6-diazaspiro[3.3]heptane-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 6)

[1417]

[1418] To a solution of intermediate 5 (106 mg, 0.157 mmol, 1 eq) in DCM (1.5 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, 0% to 100% gradient over 30 minutes; detector, UV 254 / 220 nm to afford intermediate 6 (61 mg, 67.54%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =577.

[1419] Step 6: Preparation of (2S,4R)-1-[2-cyclopropyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-yl}-1,2,3-triazol-1-yl)acetyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 7)

[1420]

[1421] A solution of intermediate 6 (51 mg, 0.088 mmol, 1 eq) and I-12 (22.70 mg, 0.08 mmol, 1 eq), Pd-PEPPSI-IPentCl 2-methylpyridine (9 mg, 0.009 mmol, 0.1 eq), and CsCO (57.63 mg, 0.176 mmol, 2 eq) in 1,4-dioxane (1 mL) was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, gradient from 0% to 100% over 30 minutes; detector, UV 254 / 220 nm to afford intermediate 7 (43 mg, 61.01%) as a red solid. LCMS (ESI) m / z: [M+H] + =797.

[1422] Step 7: Preparation of (2S,4R)-1-[(2S)-2-cyclopropyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl-2,6-diazapyridin[3.3]hept-2-yl}-1,2,3-triazol-1-yl-1-acetyl-]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 210-001)

[1423]

[1424] Intermediate 7 (36 mg) was purified by Chiral-Prep-HPLC using the following conditions: column: CHIRAL ARTCellulose-SB, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: isocratic 50; wavelength: 272 / 210 nm; RT1 (min): 6.75; RT2 (min): 10; sample solvent: MeOH; injection volume: 0.7 mL; number of runs: 4 times to obtain 210-001 (second peak) (9.5 mg, 26.39%) as a yellow solid. 1HNMR (300MHz, DMSO-d6) δ12.83 (s, 1H), 8.99 (s, 1H), 8.76 (s, 1H), 8.42 (d, J=7.6Hz, 1H), 8.11-7. 90 (m, 2H), 7.55 (s, 1H), 7.49-7.27 (m, 6H), 7.01 (d, J = 8.4Hz, 3H), 5.16 (s, 1H), 5.04 (d, J = 8.7Hz, 1 H), 4.93 (s, 1H), 4.35 (d, J=27.2Hz, 6H), 4.05 (s, 4H), 3.65 (s, 1H), 3.52 (s, 1H), 2.46 (s, 3H), 2.04 (s, 1H), 1.80 (s, 1H), 1.53 (s, 1H), 1.38 (d, J=7.1Hz, 3H), 0.73-0.44 (m, 4H). LCMS (ESI) m / z: [M+H] + =797.30.

[1425] The compounds in Table 9 were prepared using procedures similar to those described above for compound 210-001.

[1426] Table 9.

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435]

[1436]

[1437]

[1438]

[1439]

[1440] Preparation of 2-(4-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoic acid (I-49)

[1441]

[1442] Step 1: Preparation of tert-butyl 6-(1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 2)

[1443]

[1444] To a stirred solution of I-48 (1.58 g, 5.722 mmol, 1 eq) and Intermediate 6 (3.40 g, 17.166 mmol, 3 eq) in 1,4-dioxane (30 mL) was added CsCO (5.59 g, 17.166 mmol, 3 eq) and Pd-PEPPSI-IPentCl-2-methylpyridine (0.19 g, 0.229 mmol, 0.04 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere overnight. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient over 25 minutes; detector, UV 254 nm. This yielded Intermediate 2 (2.1 g, 92.10%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =394.

[1445] Step 2: Preparation of ethyl 2-(4-(2,6-diazaspiro[3.3]heptane-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoate (Intermediate 3)

[1446]

[1447] To a solution of intermediate 2 (2.1 g, 5.340 mmol, 1 eq) in DCM (6 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 100% gradient over 30 minutes; detector, UV 254 nm. This produced intermediate 3 (1.4 g, 89.17%) as a colorless oil. LCMS (ESI) m / z [M+H] + =294.

[1448] Step 3: Preparation of ethyl 2-(4-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoate (Intermediate 4)

[1449]

[1450] Under nitrogen atmosphere at room temperature, to the stirring solution of intermediate 3 (1g, 3.409mmol, 1 equivalent) and I-12 (1.31g, 5.114mmol, 1.5 equivalents) in dioxane (10mL) were added CsCO (3.34g, 10.227mmol, 3 equivalents) and Pd-PEPPSI-IPentCl 2-picoline (2.87mg, 0.003mmol, 0.1 equivalent) in batches. The resulting mixture was stirred at 100°C for 2 hours under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (100mL). The combined organic layers were washed with brine (2x 50mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm. This gave intermediate 4 (985 mg, 56.26%) as a yellow solid. LCMS (ESI) m / z [M+H] + =514.

[1451] Step 4: Preparation of 2-(4-(6-(3-(2-hydroxyphenyl)cinnolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoic acid (I-49)

[1452]

[1453] A mixture of intermediate 4 (985 mg, 1.918 mmol, 1 eq) and LiOH.HO (459.32 mg, 19.180 mmol, 10 eq) in MeOH (4 mL) and H2O (2 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was diluted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This produced I-49 (498 mg, 53.48%) as a red solid. LCMS (ESI) m / z [M+H] + =486.

[1454] Preparation of (2S,4R)-N-[(2-chloro-4-ethylphenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide (I-50)

[1455]

[1456] Step 1: Preparation of tert-butyl N-({2-chloro-4-[2-(trimethylsilyl)ethynyl]phenyl}methyl)carbamate (Intermediate 2)

[1457]

[1458] To N-[(4-bromo-2-chlorophenyl) methyl] tert-butyl carbamate (1g, 3.119mmol, 1 equivalent), trimethylsilyl acetylene (919.06mg, 9.357mmol, 3 equivalents), Pd(dppf)Cl2.CH2Cl2 (127.04mg, 0.156mmol, 0.05 equivalent) and CuI (59.40mg, 0.312mmol, 0.1 equivalent) in TEA (10mL) was stirred at 80 ℃ for 4 hours under nitrogen atmosphere. The desired product can be detected by LCMS. The obtained mixture is diluted with water (100mL). The obtained mixture is extracted with EtOAc (2x 100mL). The organic layer merged is washed with salt water (3x 50mL), used anhydrous Na2SO4 dry. After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give Intermediate 2 (1.15 g, crude) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =338.

[1459] Step 2: Preparation of tert-butyl N-[(2-chloro-4-ethynylphenyl)methyl]carbamate (Intermediate 3)

[1460]

[1461] A mixture of intermediate 2 (1.1 g, 3.255 mmol, 1 eq) and K2CO3 (1349.66 mg, 9.765 mmol, 3 eq) in MeOH (10 mL) was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 3 (860 mg, 99.42%) as a brown oil. LCMS (ESI) m / z [M+H] + =266.

[1462] Step 3: Preparation of 1-(2-chloro-4-ethynylphenyl)methanamine (Intermediate 4)

[1463]

[1464] To a stirred solution of intermediate 3 (850 mg, 3.199 mmol, 1 eq) in DCM (5 mL) was added dropwise HCl (gas) in 1,4-dioxane (4 M) (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give intermediate 4 (670 mg, HCl salt) as an off-white solid. LCMS (ESI) m / z: [M+H] + =166.

[1465] Step 4: Preparation of tert-butyl (2S,4R)-2-{[(2-chloro-4-ethynylphenyl)methyl]carbamoyl}-4-hydroxypyrrolidine-1-carboxylate (Intermediate 5)

[1466]

[1467] A mixture of (2S,4R)-1-(tert-butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.865 mmol, 1.00 equiv), EDCI (248.69 mg, 1.297 mmol, 1.5 equiv) and HOBT (175.30 mg, 1.297 mmol, 1.5 equiv) in DMF (3 mL) was stirred at room temperature for 15 minutes. To this mixture was added Intermediate 4 (171.89 mg, 1.038 mmol, 1.2 equiv) and DIEA (335.35 mg, 2.595 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The desired product was detected by LCMS. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 50% in 15 minutes; detector, UV 254 nm to afford intermediate 5 (320 mg, 97.66%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =379.

[1468] Step 5: Preparation of (2S,4R)-N-[(2-chloro-4-ethynylphenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide (I-50)

[1469]

[1470] To a stirred solution of intermediate 5 (310 mg, 0.818 mmol, 1 equiv) in DCM (3 mL) was added dropwise HCl (gas) in 1,4-dioxane (4 M) (3 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to afford I-50 (310 mg, HCl salt) as an off-white solid. LCMS (ESI) m / z: [M+H] + =279.

[1471] Preparation of 2-(3-{2-[(3S)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-52)

[1472]

[1473] Step 1: Preparation of tert-butyl 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 2)

[1474]

[1475] To a stirred mixture of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (1.45 g, 4.489 mmol, 1.5 eq), I2 (0.38 g, 1.496 mmol, 0.5 eq) and Zn (0.59 g, 8.979 mmol, 3 eq) in DMF (9 mL) was added portionwise I-12 (900 mg, 2.993 mmol, 1 eq), xphos (0.29 g, 0.599 mmol, 0.2 eq) and XPhos Pd G3 (0.51 g, 0.59 mmol, 0.2 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 ° C. under a nitrogen atmosphere overnight. This gave intermediate 2 (1 g, 72.40%) as a brown solid. LCMS (ESI) m / z [M+H] + =462.

[1476] Step 2: Preparation of 2-(7-{2-azaspiro[3.3]heptane-6-yl}cinnolin-3-yl)phenol (I-51)

[1477]

[1478] A mixture of intermediate 2 (1 g, 2.167 mmol, 1 eq) in TFA (7.5 mL) and DCM (2.5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This yielded I-51 (1.4 g, 91.62%) as a brown oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =318.

[1479] Step 3: Preparation of ethyl 2-cyclobutyl-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2-azaspiro[3.3]heptane-2-yl}-1,2,3-triazol-1-yl)acetate (Intermediate 4)

[1480]

[1481] To a stirred mixture of I-51 (200 mg, 0.630 mmol, 1 eq) and I-47 (217.88 mg, 0.756 mmol, 1.2 eq) in DMSO (3 mL) was added portionwise CuI (24.00 mg, 0.126 mmol, 0.2 eq), KCO (261.26 mg, 1.890 mmol, 3 eq) and L-proline (14.51 mg, 0.126 mmol, 0.2 eq) at room temperature under nitrogen atmosphere. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 10 minutes; detector, UV 254 nm. This gave intermediate 4 (60 mg, 18.1%) as a brown solid. LCMS (ESI) m / z: [M+H] + =525.

[1482] Step 4: Preparation of 2-(3-{2-[(3S)-3-[3-(2-hydroxyphenyl)thieno[2,3-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (I-52)

[1483]

[1484] A mixture of intermediate 4 (60 mg, 0.12 mmol, 1 eq) and LiOH (24.91 mg, 1.240 mmol, 3 eq) in MeOH (2 mL) and H O (1 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was concentrated under reduced pressure to afford I-52 (40 mg, crude) as a brown solid. LCMS (ESI) m / z [M+H] + =497.

[1485] Preparation of 2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2-azaspiro[3.3]heptane-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoic acid (I-53)

[1486]

[1487] Intermediate 1-53 was prepared as a brown solid using a procedure similar to that described above for the preparation of 1-52 using 1-46 and 1-51. LCMS (ESI) m / z [M+H] + =485.

[1488] Preparation of (2S,4R)-N-[(2-chloro-4-ethylphenyl)methyl]-4-hydroxy-1-[(2S)-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]-2,6-diazaspiro[3.3]heptane-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoyl]pyrrolidine-2-carboxamide (Compound 223-001)

[1489]

[1490] A mixture of I-50 (60.28 mg, 0.216 mmol, 1.50 equiv), I-53 (70 mg, 0.144 mmol, 1.00 equiv), PyBOP (112.54 mg, 0.216 mmol, 1.5 equiv) and DIEA (55.90 mg, 0.432 mmol, 3 equiv) in DMF (1 mL) was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The crude product was purified by Prep-HPLC using the following conditions (column: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; mobile phase A: MtBE (0.1% DEA): EtOH = 50:50; gradient) to give a mixture of the final compounds as a reddish-brown solid (60 mg, 55.77%). LCMS (ESI) m / z: [M+H] + =746.

[1491] The above mixture was purified by chiral HPLC using the following conditions (column: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; mobile phase A: MtBE (0.1% DEA): MeOH = 70:30) to obtain 223-001 (23.5 mg, 38.70%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.76 (s, 1H), 8.67 (t, J=5.9Hz, 1H), 8.03 (d, J=8.2, 1.6Hz, 1H), 7.96 (d, J=9.1Hz, 1H), 7.60-7.54 ( m, 1H), 7.51-7.37 (m, 3H), 7.36-7.25 (m, 2H), 7.05-6.96 (m, 3H), 5.20 (d, J = 3.6Hz, 1H), 5.11 (d, J = 10.4Hz, 1H), 4. 44-4.31 (m, 4H), 4.30 (d, J=4.2Hz, 5H), 4.09-3.99 (m, 4H), 3.86-3.78 (m, 1H), 3.62 (d, J=10.9Hz, 1H), 2.34-2.28 (m, 1H), 2.13-2.03 (m, 1H), 1.97-1.86 (m, 1H), 0.99 (d, J=6.5Hz, 3H), 0.67 (d, J=6.6Hz, 3H). LCMS (ESI) m / z: [M+H] + =746.25.

[1492] The compounds in Table 10 were prepared using procedures similar to those described above for the preparation of compound 223-001 using the appropriate amine and acid (1-53 or analogs).

[1493] Table 10.

[1494]

[1495]

[1496]

[1497]

[1498]

[1499] Preparation of (2S,4R)-4-hydroxy-1-[(2S)-2-(4-{6-[3-(2-hydroxyphenyl)cinnolin-7-yl]spiro[3.3]heptan-2-yl}-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 208-001).

[1500]

[1501] Step 1: Preparation of methyl 6-hydroxyspiro[3.3]heptane-2-carboxylate (Intermediate 2).

[1502]

[1503] To a stirred solution of methyl 6-oxospiro[3.3]heptane-2-carboxylate (5 g, 29.728 mmol, 1 eq) in MeOH (60 mL, 1481.930 mmol, 49.85 eq) was added NaBH4 (1.69 g, 44.592 mmol, 1.5 eq) in an air atmosphere at -4 ° C. The resulting mixture was stirred for another 10 minutes at -4 ° C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3x20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This produced intermediate 2 (4.1 g, 72.93%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =171.

[1504] Step 2: Preparation of methyl 6-[(4-methylbenzenesulfonyl)oxy]spiro[3.3]heptane-2-carboxylate (Intermediate 3).

[1505]

[1506] To a stirred solution of methyl 6-hydroxyspiro[3.3]heptane-2-carboxylate (4 g, 23.501 mmol, 1 eq) and TsCl (5.38 g, 28.201 mmol, 1.2 eq) in DCM (40 mL, 629.224 mmol, 26.77 eq) was added portionwise DMAP (287.11 mg, 2.350 mmol, 0.1 eq) and TEA (7.13 g, 70.503 mmol, 3 eq) at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for another 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give Intermediate 3 (7.6 g, 89.72%) as an off-white oil. LCMS (ESI) m / z: [M+H] + =325.

[1507] Step 3: Preparation of methyl 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}spiro[3.3]heptane-2-carboxylate (Intermediate 4).

[1508]

[1509] A solution of Mn (338.72 mg, 6.164 mmol, 4 eq), KI (255.87 mg, 1.541 mmol, 1 eq), NiBr2.glyme (47.57 mg, 0.154 mmol, 0.1 eq), 2,2-bipyridine (24.07 mg, 0.154-mmol, 0.1 eq), and vitamin B12 (207.07 mg, 0.154-mmol, 0.1 eq) in DMF (10 mL) was stirred at room temperature for 1 hour. Methyl 6-[(4-methylbenzenesulfonyl)oxy]spiro[3.3]heptane-2-carboxylate (500 mg, 1.541 mmol, 1 eq) and 7-chloro-3-[2-(methoxymethoxy)phenyl]cinnoline (463.55 mg, 1.541 mmol, 1 eq) were then added to the reaction mixture. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 80% gradient over 30 minutes; detector, UV 254 nm. This gave intermediate 4 (150 mg, 23.25%) as a brown oil. LCMS (ESI) m / z: [M+H] + =419.

[1510] Step 4: Preparation of 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}spiro[3.3]heptane-2-carbaldehyde (Intermediate 5).

[1511]

[1512] A solution of methyl 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}spiro[3.3]heptane-2-carboxylate (110 mg, 0.263 mmol, 1 eq) in DCM (4 mL) was cooled to -78 ° C. DIBAl-H (56.07 mg, 0.395 mmol, 1.5 eq) was added to the reaction mixture at -78 ° C. The resulting mixture was stirred at -78 ° C for 1 hour under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with water at 0 ° C. The aqueous layer was extracted with EtOAc (3x10 mL). The residue was purified by silica gel column chromatography eluted with PE / EA (1: 1) to give intermediate 5 (55 mg, 53.86%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =389.

[1513] Step 5: Preparation of 7-{6-ethynylspiro[3.3]heptan-2-yl}-3-[2-(methoxymethoxy)phenyl]cinnoline (Intermediate 6).

[1514]

[1515] To a solution of 6-{3-[2-(methoxymethoxy)phenyl]cinnolin-7-yl}spiro[3.3]heptane-2-carbaldehyde (50 mg, 0.129 mmol, 1 eq) in MeOH (2 mL) was added Seyferth-Gilbert homologue (37.09 mg, 0.194 mmol, 1.5 eq) and K2CO3 (53.37 mg, 0.387 mmol, 3 eq). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The desired product could b...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in m is 0, 1, 2 or 3; k is 0, 1, or 2; Each R 1 independently halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino or cyano; Each X is independently halogen, or optionally substituted C1-C6 heteroalkyl; L is a linker; and B is the degradation part.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R 1 is independently halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C3-C8 cycloalkyl; and Each X is independently a halogen.

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula IA:

4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IB: 5 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 1. 6 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 2. 7 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 3.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted C1-C6 heteroalkyl group.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted C1-C6 alkoxy group, or a halogen group.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy or difluoromethoxy.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is F or Cl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted C1-C6 alkyl group.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or difluoromethyl.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted C2-C6 alkynyl group.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 For methylene.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C3-C8 cycloalkoxy group.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1 It is cyclopropane or cyclopropyloxy.

18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted C2-C9 heterocyclic group.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is an optionally substituted amino or cyano group.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein m is 0.

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein k is 0.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein k is 1.

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 20, wherein k is 2.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-20 and 22-23, wherein X is methoxy or F.

25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein the degradation portion B has a structure of formula A-1: in Y 1 for R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A6 is H or an optionally substituted C1-C6 alkyl group; and R A7 is H or an optionally substituted C1-C6 alkyl group; or R A6 and R A7 Together with the carbon atoms to which they are respectively bonded, they form an optionally substituted C3-C6 carbocyclic group or an optionally substituted C2-C5 heterocyclic group; or R A6 and R A7 Together with the carbon atoms to which they are respectively bonded, to form an optionally substituted C3-C6 carbocyclic group or an optionally substituted C2-C5 heterocyclic group; R A8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A1 , R A2 , R A3 and R A4 Each of them is independently H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , and / or R A3 and R A4 Combined with their respective carbon atoms to form and is an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heteroaryl group, or C2-C9 heterocyclic group, any of which is optionally substituted by A 2 replace, Where R A1 , R A2 , R A3 , and R A4 One of them is A 2 ,or A 2 Replacement; and A 2 is the bond between the degradable portion and the linker.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R A5 It is H or methyl.

27. The compound or pharmaceutically acceptable salt thereof according to any one of claims 25 to 26, wherein R A1 A 2 And R A2 , R A3 and R A4 Each of them is H.

28. The compound or pharmaceutically acceptable salt thereof according to any one of claims 25 to 26, wherein R A2 A 2 And R A1 , R A3 and R A4 Each of them is H.

29. The compound or pharmaceutically acceptable salt thereof according to any one of claims 25 to 26, wherein: R A3 A 2 And R A1 , R A2 and R A4 Each of them is H.

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 25 to 26, wherein R A4 A 2 And R A1 , R A2 and R A3 Each of them is H.

31. A compound according to any one of claims 25 to 30, or a pharmaceutically acceptable salt thereof, wherein Y 1 for 32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R A6 for H, and R A7 For H.

33. A compound according to any one of claims 25 to 30, or a pharmaceutically acceptable salt thereof, wherein Y 1 for 34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R A8 It is H or methyl.

35. The compound or pharmaceutically acceptable salt thereof of any one of claims 25 to 28, wherein the degradation portion has a structure of Formula A2 or Formula A4:

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 37. The compound or pharmaceutically acceptable salt thereof of any one of claims 25 to 30, wherein the degradation portion has a structure of Formula A5, Formula A6, Formula A8 or Formula A10:

38. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has the structure:

39. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of Formula C: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 Independently for A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B7 and R B8 Each of the above is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 Aryl; R B9 is H or an optionally substituted C1-C6 alkyl; R B10 is H or F; and A 2 is the bond between the degradable moiety and the linker; Where R B1 , R B3 and R B6 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

40. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula C: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 Independently for A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B7 and R B8 Each of the above is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 Aryl; R B9 is H or optionally substituted C1-C6 alkyl; and A 2 is the bond between the degradable moiety and the linker; Where R B1 , R B3 and R B6 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

41. The compound of claims 39-40 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of Formula C3 or Formula C1:

42. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of formula C4:

43. The compound of any one of claims 39-40 or a pharmaceutically acceptable salt thereof, wherein the degradation portion is 44. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 45. The compound of any one of claims 39-40 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of Formula C2:

46. ​​The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of Formula Ca2, Formula Cb2, Formula Cc2, Formula Cd2, Formula Ce2 or Formula Cf2:

47. The compound of any one of claims 39-42 and 45-46 or a pharmaceutically acceptable salt thereof, wherein R B9 is an optionally substituted C1-C6 alkyl group.

48. The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein R B9 It is methyl.

49. The compound of any one of claims 39-42 and 45-48, or a pharmaceutically acceptable salt thereof, wherein RB9 is bonded to the (S)-stereoisomerogenic center.

50. The compound or pharmaceutically acceptable salt thereof of any one of claims 39-42 and 45-49, wherein v2 is 0.

51. The compound of any one of claims 39-42 and 45-50 or a pharmaceutically acceptable salt thereof, wherein R B4 For H.

52. The compound of any one of claims 39-42 and 45-51 or a pharmaceutically acceptable salt thereof, wherein R B5 For H.

53. The compound of any one of claims 39-42 and 45-52 or a pharmaceutically acceptable salt thereof, wherein R B7 is an optionally substituted C1-C6 alkyl group.

54. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein R B7 It is methyl.

55. The compound of any one of claims 39-42 and 45-54 or a pharmaceutically acceptable salt thereof, wherein R B3 is an optionally substituted C1-C6 alkyl group.

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein R B3 It is isopropyl or fluoro-2-methylpropane.

57. The compound of any one of claims 39-42 and 45-54 or a pharmaceutically acceptable salt thereof, wherein R B3 is an optionally substituted C3-C 10 Carbocyclic group.

58. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein R B3 It is cyclopropane.

59. The compound of any one of claims 39-42 and 45-58 or a pharmaceutically acceptable salt thereof, wherein R B8 For H.

60. The compound of any one of claims 39-42 and 45-59 or a pharmaceutically acceptable salt thereof, wherein R B2 For H.

61. The compound of any one of claims 39-40 or a pharmaceutically acceptable salt thereof, wherein the degradation portion is 62. The compound of any one of claims 39 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 63. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 64. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 65. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of Formula C5: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C 1- C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 Independently for A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B7 and R B8 Each of the above is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 Aryl; R B9 is H or an optionally substituted C1-C6 alkyl; R B11 is H, alcohol, boric acid, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; and A 2 is the bond between the degradable moiety and the linker; Where R B1 , R B3 and R B6 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

66. The compound of claim 65 or a pharmaceutically acceptable salt thereof, wherein R B11 It is boric acid.

67. The compound of any one of claims 65-66, or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of Formula C6, Formula C7, or Formula C8.

68. A compound according to any one of claims 65-66 or a pharmaceutically acceptable salt thereof, wherein R B9 is an optionally substituted C1-C6 alkyl group.

69. The compound of claim 68 or a pharmaceutically acceptable salt thereof, wherein R B9 It is methyl.

70. The compound of any one of claims 65-69 or a pharmaceutically acceptable salt thereof, wherein R B9 Bonded to the (S)-stereoisomerogenic center.

71. The compound of any one of claims 65-70 or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

72. The compound of any one of claims 65-71 or a pharmaceutically acceptable salt thereof, wherein R B5 For H.

73. The compound of any one of claims 65-72 or a pharmaceutically acceptable salt thereof, wherein R B7 is an optionally substituted C1-C6 alkyl group.

74. The compound of claim 73 or a pharmaceutically acceptable salt thereof, wherein in some embodiments, R B7 It is methyl.

75. The compound of any one of claims 65-74 or a pharmaceutically acceptable salt thereof, wherein R B3 is an optionally substituted C1-C6 alkyl group.

76. The compound of claim 75 or a pharmaceutically acceptable salt thereof, wherein R B3 It is isopropyl.

77. The compound of any one of claims 65-76 or a pharmaceutically acceptable salt thereof, wherein R B8 For H.

78. The compound of any one of claims 65-77 or a pharmaceutically acceptable salt thereof, wherein R B2 For H.

79. The compound of any one of claims 65 and 664, or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 80. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula D: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C 1- C6 alkyl C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6 Independently for A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B9 is H or optionally substituted C1-C6 alkyl; and A 2 is the bond between the degradable moiety and the linker; Where R B1 , R B3 and R B6 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

81. The compound of claim 80 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula D3 or Formula D1:

82. The compound of any one of claims 80-81 or a pharmaceutically acceptable salt thereof, wherein the degradation portion is 83. The compound of claim 80 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula D2:

84. The compound of any one of claims 80 and 83, or a pharmaceutically acceptable salt thereof, wherein R B9 is an optionally substituted C1-C6 alkyl group.

85. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein R B9 It is methyl.

86. The compound of any one of claims 80 and 83-85, or a pharmaceutically acceptable salt thereof, wherein R B9 Bonded to the (S)-stereoisomerogenic center.

87. The compound of any one of claims 80 and 83, or a pharmaceutically acceptable salt thereof, wherein R B9 For H.

88. The compound or pharmaceutically acceptable salt thereof of any one of claims 80 and 83-87, wherein v2 is 0.

89. The compound or pharmaceutically acceptable salt thereof of any one of claims 80 and 83-87, wherein v2 is 1.

90. The compound or pharmaceutically acceptable salt thereof of any one of claims 80 and 83-87, wherein v2 is 2.

91. The compound of any one of claims 80 and 83-90, or a pharmaceutically acceptable salt thereof, wherein R B4 For H.

92. The compound of any one of claims 80 and 83-91, or a pharmaceutically acceptable salt thereof, wherein R B5 For H.

93. The compound or pharmaceutically acceptable salt thereof of any one of claims 80 and 83-92, wherein R B3 is an optionally substituted C1-C6 alkyl group.

94. The compound of claim 93 or a pharmaceutically acceptable salt thereof, wherein R B3 It is isopropyl.

95. The compound of any one of claims 80 and 83-94, or a pharmaceutically acceptable salt thereof, wherein R B6 For H.

96. The compound of any one of claims 80 and 83-94, or a pharmaceutically acceptable salt thereof, wherein R B6 is fluorine, chlorine or bromine.

97. The compound of any one of claims 80 and 83-94, or a pharmaceutically acceptable salt thereof, wherein R B6 It is cyano.

98. The compound of any one of claims 80 and 83-94, or a pharmaceutically acceptable salt thereof, wherein R B6 is an optionally substituted C1-C6 heteroalkyl group.

99. The compound of claim 98 or a pharmaceutically acceptable salt thereof, wherein R B6 It is methoxy or 3-methoxy-1-propoxy.

100. The compound of any one of claims 80 and 83-94, or a pharmaceutically acceptable salt thereof, wherein R B6 is an optionally substituted C3-C6 alkynyl group.

101. The compound of claim 80 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 102. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of formula Da: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; RB 5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; Each of X1 and X2 is independently C, N or O. v2 is 0, 1, 2, 3, or 4; Each R B6 Independently for A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C9 heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino; R B9 is H or optionally substituted C1-C6 alkyl; and A 2 is the bond between the degradable moiety and the linker; Where R B1 , R B3 and R B6 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

103. The compound of claim 102 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of formula Da3, formula Da1 or formula Da2.

104. The compound of any one of claims 102-103 or a pharmaceutically acceptable salt thereof, wherein R B9 is an optionally substituted C1-C6 alkyl group.

105. The compound of claim 104 or a pharmaceutically acceptable salt thereof, wherein R B9 It is methyl.

106. The compound of any one of claims 102-105 or a pharmaceutically acceptable salt thereof, wherein R B9 Bonded to the (S)-stereoisomerogenic center.

107. The compound of any one of claims 102-106 or a pharmaceutically acceptable salt thereof, wherein v2 is 0.

108. The compound of any one of claims 102-107 or a pharmaceutically acceptable salt thereof, wherein R B4 For H.

109. The compound of any one of claims 102-108 or a pharmaceutically acceptable salt thereof, wherein R B5 For H.

110. The compound of any one of claims 102-109 or a pharmaceutically acceptable salt thereof, wherein R B3 is an optionally substituted C1-C6 alkyl group.

111. The compound of claim 110 or a pharmaceutically acceptable salt thereof, wherein R B3 It is isopropyl.

112. The compound of any one of claims 102-111, or a pharmaceutically acceptable salt thereof, wherein X1 is C and X2 is N.

113. The compound of claim 102 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 114. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula E: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B9 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 carbocyclic group, or optionally substituted C2-C 10 Heterocyclic group; B 10 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C 10 Carbocyclic, optionally substituted C2-C 10 heterocyclic group; optionally substituted amino or cyano group, and A 2 is the bond between the degradable moiety and the linker; Where R B1 , R B3 and R B6 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

115. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of E3 or E1.

116. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 117. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula E2:

118. The compound of claims 114-115 or a pharmaceutically acceptable salt thereof, wherein R B9 is an optionally substituted C1-C6 alkyl group.

119. The compound of claim 118 or a pharmaceutically acceptable salt thereof, wherein R B9 It is methyl.

120. The compound of any one of claims 114-115 or a pharmaceutically acceptable salt thereof, wherein R B9 is an optionally substituted C3-C6 alkynyl group.

121. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115, wherein R B9 [1.1.1]pentane, cyclopropane, cyclobutene or cyclopentane.

122. The compound of any one of claims 114-115 and 117-121 or a pharmaceutically acceptable salt thereof, wherein R B9 Bonded to the (S)-stereoisomerogenic center.

123. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115, wherein R B9 For H.

124. The compound of any one of claims 114-115 and 117-123 or a pharmaceutically acceptable salt thereof, wherein R B4 For H.

125. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115 and 117-124, wherein R B5 For H.

126. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115 and 117-125, wherein R B3 is an optionally substituted C1-C6 alkyl group.

127. The compound of claim 126 or a pharmaceutically acceptable salt thereof, wherein R B3 It is isopropyl.

128. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115 and 117-127, wherein R B2 For H.

129. The compound or pharmaceutically acceptable salt thereof of any one of claims 114-115 and 117-1285, wherein R is absent. B10 .

130. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115 and 117-128, wherein R B10 It is H or cyano.

131. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115 and 117-128, wherein R B10 is an optionally substituted C3-C 10 Carbocyclic group, 132. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 114-115 and 117-128, wherein R B10 is an optionally substituted C 1- C6 alkyl.

133. The compound of claim 132 or a pharmaceutically acceptable salt thereof, wherein R B10 It is methyl.

134. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 135. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula F: in L 4 -N(R B1 )(R B2 ), R B1 H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 carbocyclic group, or optionally substituted C1-C6 alkyl C6-C 10 Aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; A 2 is the bond between the degradable moiety and the linker; Where R B1 or R B3 One and only one of them is A 2 , or a pharmaceutically acceptable salt thereof.

136. The compound of claim 135 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has a structure of E3 or E1.

137. The compound of claim 135 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 138. The compound of claim 135 or a pharmaceutically acceptable salt thereof, wherein the degradation moiety has a structure of Formula F2: Formula F2 139. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138, wherein R B9 is an optionally substituted C1-C6 alkyl group.

140. The compound of claim 139 or a pharmaceutically acceptable salt thereof, wherein R B9 It is methyl.

141. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138-140, wherein R B4 For H.

142. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138-141, wherein R B5 For H.

143. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138-142, wherein R B3 is an optionally substituted C1-C6 alkyl group.

144. The compound of claim 143 or a pharmaceutically acceptable salt thereof, wherein R B3 It is isopropyl.

145. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 135 and 138-144, wherein R B2 For H.

146. The compound of claim 135 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 147. The compound of any one of claims 1 to 146, or a pharmaceutically acceptable salt thereof, wherein the linker has a structure of Formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 , Formula II or a pharmaceutically acceptable salt thereof, in A 1 is the bond between the linker and the ring system A; A 2 is the bond between the degradable moiety and the linker; B 1 , B 2 , B 3 and B 4 Each of the above is independently an optionally substituted C1-C4 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 Aryl C 1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C8 heterocyclic group, optionally substituted C2-C6 heteroaryl group, optionally substituted C 6-12 Aryl, O, S, S(O)2, or NR N ; Each R N are independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-10 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, or optionally substituted C 1-7 heteroalkyl; C 1 and C 2 Each of is independently a carbonyl group, a thiocarbonyl group, a sulfonyl group, or a phosphoryl group; Each of f, g, h, i, j, and k is independently 0 or 1; and D is optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-10 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclic group, or optionally substituted C 1-10 heteroalkyl; or D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .

148. The compound of claim 147 or a pharmaceutically acceptable salt thereof, wherein A 1 is the bond between the linker and the benzopyridazine core ring system; A 2 is the bond between the degradable moiety and the linker; B 1 , B 2 , B 3 and B 4 Each of the above is independently an optionally substituted C1-C4 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 Aryl C 1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C2-C8 heterocyclic group, optionally substituted C2-C6 heteroaryl group, optionally substituted C 6-12 Aryl, O, S, S(O)2, or NR N ; Each R N are independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-10 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, or optionally substituted C 1-7 heteroalkyl; C 1 and C 2 Each of is independently a carbonyl group, a thiocarbonyl group, a sulfonyl group, or a phosphoryl group; Each of f, g, h, i, j, and k is independently 0 or 1; and D is optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-6 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1-10 heteroalkyl; or D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .

149. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147-148, wherein B 1 , B 2 , B 3 and B 4 Each of the above is independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, an optionally substituted C2-C 10 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, O, or NR N .

150. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147-148, wherein B 1 , B 2 , B 3 and B 4 Each of the above is independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, an optionally substituted C2-C8 heterocyclyl, an optionally substituted C 2-6 Heteroaryl, or O.

151. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147 to 150, wherein B 1 and B 4 Each of the 152. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147 to 150, wherein B 1 and B 4 Each of the 153. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147 to 151, wherein B 1 for 154. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147-151 and 153, wherein B 4 for 155. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147 to 154, wherein C 1 for 156. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147 to 155, wherein B 2 is an optionally substituted C1-C4 alkyl group.

157. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147 to 156, wherein D is an optionally substituted C1-C 10 alkyl.

158. The compound of any one of claims 147 to 157, or a pharmaceutically acceptable salt thereof, wherein f is 1.

159. The compound of any one of claims 147 to 158, or a pharmaceutically acceptable salt thereof, wherein g, h, I and j are 0.

160. The compound of any one of claims 147 to 159, or a pharmaceutically acceptable salt thereof, wherein k is 0.

161. The compound of any one of claims 147 to 159, or a pharmaceutically acceptable salt thereof, wherein k is 1.

162. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is absent and the linker is A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .

163. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147-156 and 158-161, wherein D is an optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-10 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1-10 Heteroalkyl.

164. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted C3-C 10 Cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1.

165. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted C3-C 10 Cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0.

166. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted C3-C 10 Cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1.

167. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147-156 and 158-161, wherein D is an optionally substituted C3-C 10 Cycloalkyl, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0.

168. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted C3-C 10 For a carbocyclic group, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1.

169. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted C3-C 10 For a carbocyclic group, f is 1, g is 0, h is 0, I is 0, j is 0, and k is 0.

170. The compound of any one of claims 147-156 and 158-161, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted C3-C 10 For a carbocyclic group, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 1.

171. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 147-156 and 158-161, wherein D is an optionally substituted C3-C 10 For a carbocyclic group, f is 0, g is 0, h is 0, i is 0, j is 0, and k is 0.

172. The compound of any one of claims 147-156 and 158-161 or a pharmaceutically acceptable salt thereof, wherein D is:

173. The compound of claim 147 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure:

174. The compound of any one of claims 147-148, or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure:

175. The compound of any one of claims 1 to 146, or a pharmaceutically acceptable salt thereof, wherein the linker has a structure of Formula III: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 , Formula III in A 1 is the bond between the linker and the ring system A; A 2 is the bond between the degradable moiety and the linker; B 1 , B 2 , B 3 and B 4 Each of the above is independently an optionally substituted ethynyl, an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Carbocyclic, optionally substituted C2-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O)2, or NR N ; Each R N are independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-10 Heterocyclic group, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 heteroalkyl; C 1 and C 2 Each of is independently a carbonyl group, a thiocarbonyl group, a sulfonyl group, or a phosphoryl group; and Each of f, g, h, i, j and k is independently 0 or 1.

176. The compound of claim 175 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure -(L 1 ) n -, where n is 1, 2, or 3, and each L 1 O, NR independently N , ethynyl, optionally substituted C2-C 10 heterocyclic group, optionally substituted C2-C9 heteroaryl group, optionally substituted C6-C 10 Aryl, or optionally substituted C3-C 10 Cycloalkyl.

177. The compound of claim 176 or a pharmaceutically acceptable salt thereof, wherein at least one L 1 is an optionally substituted C2-C 10 Heterocyclic group.

178. The compound of claim 177 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C2-C 10 The heterocyclic group is a 4-, 5- or 6-membered monocyclic heterocyclic group, a spirocyclic heterocyclic group, a bridged heterocyclic group or a fused bicyclic heterocyclic group.

179. The compound of claim 178 or a pharmaceutically acceptable salt thereof, wherein the C2-C 10 The heterocyclic group is:

180. The compound of any one of claims 176 to 179, or a pharmaceutically acceptable salt thereof, wherein at least one L 1 is an optionally substituted C2-C9 heteroaryl group.

181. The compound of any one of claims 176 to 180, or a pharmaceutically acceptable salt thereof, wherein the linker is -(L 1 ) q -(Optionally Substituted C2-C9 Heteroaryl)-(L 1 ) q -, where each q is independently 0 or 1.

182. The compound of claim 180 or 181, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C2-C9 heteroaryl is a 6-membered monocyclic heteroaryl.

183. The compound of claim 182 or a pharmaceutically acceptable salt thereof, wherein the 6-membered monocyclic heteroaryl is:

184. The compound of any one of claims 176 to 183, or a pharmaceutically acceptable salt thereof, wherein at least one L 1 is an optionally substituted C6-C 10 Aryl.

185. The compound according to claim 184, wherein the optionally substituted C6-C 10 Aryl is optionally substituted phenyl.

186. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 176 to 185, wherein at least one L 1 is an optionally substituted C3-C 10 Cycloalkyl.

187. The compound of claim 186 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C3-C 10 Cycloalkyl is:

188. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 176 to 187, wherein at least one L 1 It is ethynyl.

189. A compound or pharmaceutically acceptable salt thereof according to any one of claims 176 to 188, wherein one and only one L 1 is O.

190. A compound or pharmaceutically acceptable salt thereof according to any one of claims 176 to 188, wherein one and only one L 1 NR N .

191. The compound of claim 190 or a pharmaceutically acceptable salt thereof, wherein R N is H or optionally substituted C1-C4 alkyl.

192. The compound of claim 175 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure: A 1 -(B 1 ) f -(B 2 ) h -(B 3 ) i -(B 4 ) k -A 2 , Among them B 1 , B 2 , B 3 and B 4 Each of the above is independently an optionally substituted ethynyl, an optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C2-C 10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, or NR N .

193. The compound of claim 175 or 192, or a pharmaceutically acceptable salt thereof, wherein at least one of f, h, i and k is 1.

194. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 or 192 to 193, wherein B 1 , B 2 , B 3 and B 4 Each of the above is independently O, ethynyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C 10 Heterocyclic group, optionally substituted C3-C 10 Cycloalkyl, or optionally substituted C6-C 10 Aryl.

195. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 and 192 to 194, wherein B 1 , B 2 , B 3 and B 4 Each of the groups is independently an optionally substituted C2-C9 heteroaryl or an optionally substituted C2-C 10 Heterocyclic group.

196. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 and 192 to 195, wherein B 1 and B 4 Each of the 197. The compound of claim 196 or a pharmaceutically acceptable salt thereof, wherein B 1 for 198. The compound of claim 196 or 197 or a pharmaceutically acceptable salt thereof, wherein B 4 for 199. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 175 and 192 to 198, wherein B 2 For NH 200. The compound of any one of claims 175 and 192 to 199, or a pharmaceutically acceptable salt thereof, wherein f is 0.

201. The compound of any one of claims 175 and 191 to 199, or a pharmaceutically acceptable salt thereof, wherein f is 1.

202. The compound of any one of claims 175 and 192 to 201, or a pharmaceutically acceptable salt thereof, wherein g, h, I and j are 0.

203. The compound or pharmaceutically acceptable salt thereof of any one of claims 175 and 192 to 202, wherein k is 0.

204. The compound or pharmaceutically acceptable salt thereof of any one of claims 175 and 192 to 202, wherein k is 1.

205. The compound of claim 175 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure:

206. A compound selected from Compounds 1-291 in Table 1 and pharmaceutically acceptable salts thereof.

207. The compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC 50 With BRM IC 50 The ratio is at least 5.

208. The compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC 50 With BRM IC 50 The ratio is at least 10.

209. The compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC 50 With BRM IC 50 The ratio is at least 20.

210. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 206, wherein the compound has a BRG1 IC 50 With BRM IC 50 The ratio is at least 30.

211. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 210 and a pharmaceutically acceptable excipient.

212. A method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 210 or a pharmaceutical composition of claim 211.

213. The method of claim 212, wherein the BAF complex-associated disorder is cancer or a viral infection.

214. A method of treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 210 or a pharmaceutical composition of claim 211.

215. The method of claim 214, wherein the disorder associated with a BRG1 loss-of-function mutation is cancer.

216. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-210 or a pharmaceutical composition of claim 211.

217. The method of any one of claims 212-216, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumors, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

218. The method of claim 217, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

219. The method of claim 217, wherein the cancer is non-small cell lung cancer.

220. The method of claim 217, wherein the cancer is a soft tissue sarcoma.

221. A method of treating a cancer selected from melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 210 or a pharmaceutical composition of claim 211.

222. Use of a compound according to any one of claims 1 to 210 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 211 for treatment.

223. Use of a compound according to any one of claims 1 to 210 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 211 for treating cancer.

224. The use of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 223, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

225. The use of a compound according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

226. The use of a compound according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is non-small cell lung cancer.

227. The use of a compound according to claim 223, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is a soft tissue sarcoma.

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