Pyrazine derivatives and uses thereof

Abstract

The present disclosure features compounds of Formula I, # imgabs0 # or a pharmaceutically acceptable salt thereof, and formulations containing the same. Methods of treating BAF complex related disorders such as cancer are also disclosed.

Description

Background of the Invention

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

[0003] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which such gene expression occurs. The human switch / sucrose non-fermenting (SWI / SNF) chromatin remodeling complex (also known as the BAF complex) has two SWI2-like ATPases, called BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1 (also known as the ATP-dependent chromatin remodeling factor 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 possible global transcriptional activator SNF2L2 and / or the ATP-dependent chromatin remodeling factor 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 BRG1 loss-of-function mutations. Inactivation of BRG and / or BRM leads to downstream effects in cells, including cell cycle arrest and tumor suppression. SUMMARY OF THE INVENTION

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

[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] Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl group containing at least one N;

[0010] m is 0, 1, 2, or 3;

[0011] k is 0, 1, or 2;

[0012] Each R 1 are independently halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C6 Heteroalkyl, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted CH 2 -C 3 -C 8 Cycloalkyl;

[0013] Each X is independently a halogen;

[0014] L is a linker; and

[0015] B is the degradation part.

[0016] In some embodiments, the compound has the structure of Formula IA:

[0017]

[0018] Where R 2 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl, optionally substituted C 2 -C 9 A heterocyclic group or a bond to -LB.

[0019] In some embodiments, the compound has the structure of Formula IB:

[0020]

[0021] In some embodiments, the compound has the structure of Formula IC:

[0022]

[0023] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, X is Cl or F.

[0024] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, R 1 is an optionally substituted C 1 -C 6 In some embodiments, R 1 In some embodiments, R 1 It is difluoromethyl.

[0025] In some embodiments, R 2 is H. In some embodiments, R2 is an optionally substituted C 1 -C 6 In some embodiments, R 2 is an optionally substituted C 3 -C 8 In some embodiments, R 2 is an optionally substituted C 2 -C 9 In some embodiments, R 2 It is H, CH 3 ,

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

[0027]

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

[0029] In some embodiments, R 1 In some embodiments, k is 0.

[0030] In some embodiments, the compound has the structure of Formula IE:

[0031]

[0032] In some embodiments, the compound has the structure of Formula IF:

[0033]

[0034] In some embodiments, the compound has the structure of Formula IG:

[0035]

[0036] In some embodiments, the compound has the structure of Formula IH:

[0037]

[0038] In some embodiments, the compound has the structure of Formula II:

[0039]

[0040] In some embodiments, the compound has the structure of Formula IJ:

[0041]

[0042] In some embodiments, the compound has the structure of Formula IK:

[0043]

[0044] In some embodiments, the compound has the structure of Formula IL:

[0045]

[0046] In some embodiments, the compound has the structure of Formula IM:

[0047]

[0048] In some embodiments, the compound has the structure of Formula IN:

[0049]

[0050] In some embodiments, the compound has the structure of Formula IO:

[0051]

[0052] In some embodiments, the compound has the structure of Formula IP:

[0053]

[0054] In some embodiments, the compound has the structure of Formula IQ:

[0055]

[0056] In some embodiments, the compound has the structure of Formula IR:

[0057]

[0058] In some embodiments, the compound has the structure of Formula IS:

[0059]

[0060] In some embodiments, the compound has the structure of Formula IT:

[0061]

[0062] In some embodiments, the compound has the structure of Formula IU:

[0063]

[0064] In some embodiments, the compound has the structure of Formula IV:

[0065]

[0066] In some embodiments, the compound has the structure of Formula IW:

[0067]

[0068] In some embodiments, the degradation moiety B has the structure of Formula A-1:

[0069]

[0070]

[0071] in

[0072] Y 1 yes

[0073] R A5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0074] R A6 is H or optionally substituted C 1 -C 6 alkyl; and R A7 is H or optionally substituted C 1 -C 6 Alkyl; or R A6 and R A7 Together with the carbon atoms to which they are bonded, they form an optionally substituted C 3 -C 6 Carbocyclic or optionally substituted C 2 -C 5 heterocyclic group; or R A6 and R A7 Together with the carbon atoms to which they are bonded, they form an optionally substituted C 3 -C 6 Carbocyclic or optionally substituted C 2 -C 5 Heterocyclic group;

[0075] R A8 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0076] R A1 , R A2 , R A3 and R A4 Each independently is H, A 2 , halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Heteroalkenyl, optionally substituted -OC 3 -C 6 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 the carbon atoms to which they are attached to form and is an optionally substituted C 6 -C 10 Aryl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heteroaryl, or C 2 -C 9 Heterocyclic group, any one of which is optionally replaced by A 2 replace,

[0077] Where R A1 , R A2 , R A3 and R A4 One of them is A 2 ,or A 2 Replacement; and

[0078] A 2 It is the bond between the degradable part and the linker.

[0079] In some embodiments, R A5 is H or methyl. In some embodiments, R A5 It's H.

[0080] In some embodiments, R A1 , R A2 , R A3 and R A4 Each independently is H or A 2 .

[0081] In some embodiments, R A1 Yes A 2 And R A2 , R A3 and R A4 Each is H.

[0082] In some embodiments, R A2 Yes A 2 And R A1 , R A3 and R A4 Each is H.

[0083] In some embodiments, R A3 Yes A 2 And R A1 , R A2 and R A4 Each is H.

[0084] In some embodiments, R A4 Yes A 2 And R A1 , R A2 and R A3 Each is H.

[0085] In some embodiments, Y 1 yes

[0086] In some embodiments, R A6 is H. In some embodiments, R A7 It's H.

[0087] In some embodiments, Y 1 yes

[0088] In some embodiments, R A8 is H or optionally substituted C 1 -C 6 In some embodiments, R A8 is H or methyl. In some embodiments, R A8 It's methyl.

[0089] In some embodiments, the degradation moiety comprises the structure of Formula A2:

[0090]

[0091] In some embodiments, the degradation moiety is

[0092]

[0093] In some embodiments, the degradation moiety comprises the structure of Formula A4:

[0094]

[0095] In some embodiments, the degradation moiety is

[0096]

[0097] In some embodiments, the degradation moiety has the structure of Formula A5:

[0098]

[0099] In some embodiments, the degradation moiety has the structure of Formula A6:

[0100]

[0101] In some embodiments, the degradation moiety has the structure of Formula A8:

[0102]

[0103] In some embodiments, the degradation moiety has the structure of Formula A10:

[0104]

[0105] In some embodiments, the degradation moiety has the following structure:

[0106]

[0107] In some embodiments, the degradation moiety has the following structure:

[0108]

[0109] In some embodiments, the degradation moiety has the structure of Formula C:

[0110]

[0111] in

[0112] L 4 Yes-N(RB1 )(R B2 ),

[0113] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0114] R B2 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0115] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0116] R B4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0117] R B5 is H, optionally substituted C1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0118] v2 is 0, 1, 2, 3, or 4;

[0119] Each R B6 Independently is A 2 , halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, mercapto, cyano or optionally substituted amino;

[0120] R B7 and R B8 are each independently H, halogen, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 6 -C 10 Aryl;

[0121] R B9 is H or optionally substituted C 1 -C 6 alkyl; and

[0122] A 2 is the bond between the degradable moiety and the linker;

[0123] Where R B1 , R B3 and R B6 One and only one of them is A 2 ,

[0124] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the degradation moiety has the structure of Formula C:

[0126]

[0127] in

[0128] L 4 Yes, N(R B1 )(R B2 ),

[0129] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0130] R B2 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0131] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0132] R B4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C6 -C 10 Aryl;

[0133] R B5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0134] v2 is 0, 1, 2, 3, or 4;

[0135] Each R B6 Independently is A 2 , halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

[0136] R B7 and R B8 are each independently H, halogen, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 6 -C 10 Aryl;

[0137] R B9 is H or optionally substituted C 1 -C 6 alkyl;

[0138] R B10 is H or F; and

[0139] A 2 is the bond between the degradable moiety and the linker;

[0140] Where R B1 , R B3 and R B6 One and only one of them is A 2 ,

[0141] or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the degradation moiety has the structure of Formula C3:

[0143]

[0144] In some embodiments, the degradation moiety has the structure of Formula C4:

[0145]

[0146] In some embodiments, the degradation moiety has the structure of Formula C1:

[0147]

[0148] In some embodiments, the degradation moiety is

[0149]

[0150] In some embodiments, the degradation moiety is

[0151]

[0152] In some embodiments, the degradation moiety is

[0153]

[0154] In some embodiments, the degradation moiety is

[0155]

[0156] In some embodiments, the degradation moiety is

[0157]

[0158] In some embodiments, the degradation moiety is

[0159]

[0160] In some embodiments, the degradation moiety has the structure of Formula C2:

[0161]

[0162] In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0163] In some embodiments, RB9 Bonded to the (S)-stereocenter.

[0164] 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 C 1 -C 6 In some embodiments, R B7 In some embodiments, R B3 is an optionally substituted C 1 -C 6 In some embodiments, R B3 In some embodiments, R B8 is H. In some embodiments, R B2 It's H.

[0165] In some embodiments, the degradation moiety is

[0166]

[0167] In some embodiments, the degradation moiety has the structure of formula Ca2:

[0168]

[0169] In some embodiments, the degradation moiety has the structure of Formula Cb2:

[0170]

[0171] In some embodiments, the degradation moiety has the structure of Formula Cc2:

[0172]

[0173] In some embodiments, the degradation moiety has the structure of formula Cd2:

[0174]

[0175] In some embodiments, the degradation moiety has the structure of formula Ce2:

[0176]

[0177] In some embodiments, the degradation moiety has the structure of Formula Cf2:

[0178]

[0179] In some embodiments, RB9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0180] In some embodiments, R B9 Bonded to the (S)-stereocenter.

[0181] 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 C 1 -C 6 In some embodiments, R B7 In some embodiments, R B3 is an optionally substituted C 1 -C 6 In some embodiments, R B3 In some embodiments, R B3 is an optionally substituted C 3 -C 10 In some embodiments, R B3 In some embodiments, R B3 In some embodiments, R B3 is fluoro-2-methylpropane. In some embodiments, R B8 is H. In some embodiments, R B2 It's H.

[0182] In some embodiments, the degradation moiety is

[0183]

[0184] In some embodiments, the degradation moiety is

[0185]

[0186] In some embodiments, the degradation moiety is

[0187]

[0188] In some embodiments, the degradation moiety is

[0189]

[0190] In some embodiments, the degradation moiety is

[0191]

[0192] In some embodiments, the degradation moiety is

[0193]

[0194] In some embodiments, the degradation moiety is

[0195]

[0196] In some embodiments, the degradation moiety is

[0197]

[0198] In some embodiments, the degradation moiety is

[0199]

[0200] In some embodiments, the degradation moiety has the structure of Formula C5:

[0201]

[0202] in

[0203] L 4 Yes-N(R B1 )(R B2 ),

[0204] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0205] R B2 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0206] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0207] R B5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0208] v2 is 0, 1, 2, 3, or 4;

[0209] Each R B6 Independently is A 2 , halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, mercapto, cyano, or optionally substituted amino;

[0210] R B7 and R B8 are each independently H, halogen, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 6 -C 10 Aryl;

[0211] R B9 is H or optionally substituted C 1 -C 6 alkyl;

[0212] R B11is H, alcohol, boronic acid, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0213] and

[0214] A 2 is the bond between the degradable moiety and the linker;

[0215] Where R B1 , R B3 and R B6 One and only one of them is A 2 ,

[0216] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, R B11 It's boric acid.

[0218] In some embodiments, the degradation moiety has the structure of Formula C6:

[0219]

[0220] In some embodiments, the degradation moiety has the structure of Formula C1:

[0221]

[0222] In some embodiments, the degradation moiety has the structure of Formula C8:

[0223]

[0224] In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0225] In some embodiments, R B9 Bonded to the (S)-stereocenter.

[0226] In some embodiments, v2 is 0. In some embodiments, R B5 is H. In some embodiments, R B7 is an optionally substituted C 1 -C 6 In some embodiments, R B7 In some embodiments, R B3 is an optionally substituted C 1 -C 6 In some embodiments, R B3 In some embodiments, R B8 is H. In some embodiments, R B2 It's H.

[0227] In some embodiments, the degradation moiety is

[0228]

[0229] In some embodiments, the degradation moiety has the structure of Formula D:

[0230]

[0231] in

[0232] L 4 Yes-N(R B1 )(R B2 ),

[0233] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0234] R B2 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0235] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0236] R B4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0237] R B5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0238] v2 is 0, 1, 2, 3, or 4;

[0239] Each R B6 Independently is A 2 , halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2-C 6 heteroalkenyl, hydroxy, mercapto, cyano, or optionally substituted amino;

[0240] R B9 is H or optionally substituted C 1 -C 6 Alkyl; and

[0241] A 2 is the bond between the degradable moiety and the linker;

[0242] Where R B1 , R B3 and R B6 One and only one of them is A 2 ,

[0243] or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the degradation moiety has the structure of Formula D3:

[0245]

[0246] In some embodiments, the degradation moiety has the structure of Formula D1:

[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 has the structure of Formula D2:

[0255]

[0256] In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0257] In some embodiments, R B9 Bonded to the (S)-stereocenter. In some embodiments, RB9 It's H.

[0258] In some embodiments, v2 is 0. In some embodiments, v2 is 1. In some embodiments, v2 is 2. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C 1 -C 6 In some embodiments, R B3 In some embodiments, R B6 is H. In some embodiments, R B6 is halogen. 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 C 1 -C 6 In some embodiments, R B6 is an optionally substituted C 3 -C 6 In some embodiments, R B6 In some embodiments, R B6 It is 3-methoxy-1-propanoxy.

[0259] In some embodiments, the degradation moiety is

[0260]

[0261] In some embodiments, the degradation moiety is

[0262]

[0263] In some embodiments, the degradation moiety is

[0264]

[0265] In some embodiments, the degradation moiety is

[0266]

[0267] In some embodiments, the degradation moiety is

[0268]

[0269] In some embodiments, the degradation moiety is

[0270]

[0271] In some embodiments, the degradation moiety is

[0272]

[0273] In some embodiments, the degradation moiety is

[0274]

[0275] In some embodiments, the degradation moiety is

[0276]

[0277] In some embodiments, the degradation moiety is

[0278]

[0279] In some embodiments, the degradation moiety is

[0280]

[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 is

[0286]

[0287] In some embodiments, the degradation moiety is

[0288]

[0289] In some embodiments, the degradation moiety is

[0290]

[0291] In some embodiments, the degradation moiety is

[0292]

[0293] In some embodiments, the degradation moiety is

[0294]

[0295] In some embodiments, the degradation moiety is

[0296]

[0297] In some embodiments, the degradation moiety is

[0298]

[0299] In some embodiments, the degradation moiety is

[0300]

[0301] In some embodiments, the degradation moiety is

[0302]

[0303] In some embodiments, the degradation moiety is

[0304]

[0305] In some embodiments, the degradation moiety is

[0306]

[0307] In some embodiments, the degradation moiety is

[0308]

[0309] In some embodiments, the degradation moiety has the structure of Formula Da:

[0310]

[0311] in

[0312] L 4 Yes-N(R B1 )(R B2 ),

[0313] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0314] R B2 is H, optionally substituted C 1 -C6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0315] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0316] R B4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0317] R B5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0318] X 1 and X 2 are each independently C, N or O.

[0319] v2 is 0, 1, 2, 3, or 4;

[0320] Each R B6 Independently is A 2 , halogen, optionally substituted C 1 -C6 Alkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, mercapto, cyano, or optionally substituted amino;

[0321] R B9 is H or optionally substituted C 1 -C 6 Alkyl; and

[0322] A 2 is the bond between the degradable moiety and the linker;

[0323] Where R B1 , R B3 and R B6 One and only one of them is A 2 ,

[0324] or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the degradation moiety has the structure of formula Da3:

[0326]

[0327] In some embodiments, the degradation moiety has the structure of formula Da1:

[0328]

[0329] In some embodiments, the degradation moiety has the structure of formula Da2:

[0330]

[0331] In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0332] In some embodiments, R B9 Bonded to the (S)-stereocenter.

[0333] 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 C 1 -C 6 In some embodiments, R B3 In some embodiments, R B2 is H. In some embodiments, X 1 is C. In some embodiments, X 2 It is N.

[0334] In some embodiments, the degradation moiety is

[0335]

[0336] In some embodiments, the degradation moiety has the structure of Formula E:

[0337]

[0338] in

[0339] L 4 Yes-N(R B1 )(R B2 ),

[0340] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0341] R B2 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0342] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0343] R B4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0344] R B5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0345] R B9 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Alkynyl, optionally substituted C 3 -C 10 Carbocyclic group, or optionally substituted C 2 -C 10 Heterocyclic group;

[0346] B 10 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Alkynyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 10heterocyclyl, optionally substituted amino or cyano; and

[0347] A 2 is the bond between the degradable moiety and the linker;

[0348] Where R B1 , R B3 and R B6 One and only one of them is A 2 ,

[0349] or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the degradation moiety has the structure of Formula E3:

[0351]

[0352] In some embodiments, the degradation moiety has the structure of Formula E1:

[0353]

[0354] In some embodiments, the degradation moiety is

[0355]

[0356] In some embodiments, the degradation moiety is

[0357]

[0358] In some embodiments, the degradation moiety has the structure of Formula E2:

[0359]

[0360] In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0361] In some embodiments, R B9 Bonded to the (S)-stereocenter.

[0362] 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 C 1 -C 6 In some embodiments, R B3In some embodiments, R B2 is H. In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 In some embodiments, R B9 is H. In some embodiments, R B9 is an optionally substituted C 3 -C 6 In some embodiments, R 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 an optionally substituted C 3 -C 10 In some embodiments, R B10 is an optionally substituted C 1 -C 6 In some embodiments, R B10 It's methyl.

[0363] In some embodiments, the degradation moiety is

[0364]

[0365] In some embodiments, the degradation moiety is

[0366]

[0367] In some embodiments, the degradation moiety is

[0368]

[0369] In some embodiments, the degradation moiety is

[0370]

[0371] In some embodiments, the degradation moiety is

[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 is

[0380]

[0381] In some embodiments, the degradation moiety has the structure of Formula F:

[0382]

[0383] in

[0384] L 4 Yes-N(R B1 )(R B2 ),

[0385] R B1 It is H, A 2 , optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0386] R B2 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0387] R B3 Yes A 2 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3-C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0388] R B4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 6 -C 10 Aryl, optionally substituted C 1 -C 6 Alkyl C 3 -C 10 Carbocyclic group, or optionally substituted C 1 -C 6 Alkyl C 6 -C 10 Aryl;

[0389] R B5 is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

[0390] A 2 is the bond between the degradable moiety and the linker;

[0391] Where R B1 or R B3 One and only one of them is A2,

[0392] or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the degradation moiety has the structure of Formula F3:

[0394]

[0395] In some embodiments, the degradation moiety has the structure of Formula F1:

[0396]

[0397] In some embodiments, the degradation moiety is

[0398]

[0399] In some embodiments, the degradation moiety is

[0400]

[0401] In some embodiments, the degradation moiety has the structure of Formula F2:

[0402]

[0403] In some embodiments, R B9 is an optionally substituted C 1 -C 6 In some embodiments, R B9 It's methyl.

[0404] In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B3 is an optionally substituted C 1 -C 6 In some embodiments, R B3 In some embodiments, R B2 It's H.

[0405] In some embodiments, the degradation moiety is

[0406]

[0407] In some embodiments, the linker has the structure of Formula II:

[0408] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 ,

[0409] Formula II

[0410] or a pharmaceutically acceptable salt thereof,

[0411] in

[0412] A 1 is the bond between the linker and the ring system A;

[0413] A 2 is the bond between the degradable moiety and the linker;

[0414] B 1 , B2 , B 3 and B 4 are each independently an optionally substituted C 1 -C 4 Alkyl, optionally substituted C 6 -C 10 Aryl, optionally substituted C 6 -C 10 Aryl C 1 - 4 Alkyl, optionally substituted C 1 -C 4 Heteroalkyl, optionally substituted C 3 -C 10 Cycloalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 8 Heterocyclic group, optionally substituted C 2 -C 6 Heteroaryl, optionally substituted C 6-12 Aryl, O, S, S(O) 2 or NR N ;

[0415] 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;

[0416] C 1 and C 2 are each independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl;

[0417] f, g, h, i, j and k are each independently 0 or 1; and

[0418] 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 C 2 -C 10 Polyethylene glycol, optionally substituted C 3 -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 .

[0419] In some embodiments, B 1 , B 2 , B 3 and B 4 are each independently an optionally substituted C 1 -C 2 Alkyl, optionally substituted C 1 -C 3 Heteroalkyl, optionally substituted C 2 -C 10 Heterocyclic group, 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 Heterocyclic group, optionally substituted C 6-12 Aryl, optionally substituted C 2 -C 10 Polyethylene glycol, or optionally substituted C 1-10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connect to-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 chemical bonds.

[0420] In some embodiments, B 1 , B 2 , B3 and B 4 are each independently an optionally substituted C 1 -C 2 Alkyl, optionally substituted C 1 -C 3 Heteroalkyl, optionally substituted C 2 -C 10 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl, optionally substituted C 3 -C 10 Carbocyclic group, O or NR N .

[0421] In some embodiments, B 1 and B 4 Each independently is

[0422] O.

[0423]

[0424]

[0425] In some embodiments, B 1 yes

[0426]

[0427]

[0428]

[0429] In some embodiments, B 4 yes

[0430]

[0431]

[0432] In some embodiments, C 1 yes

[0433] In some embodiments, B 2 is an optionally substituted C 1 -C 4 alkyl.

[0434] In some embodiments, D is optionally substituted C 1 -C 10 alkyl.

[0435] 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.

[0436] 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 .

[0437] 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 Heterocyclic group, optionally substituted C 2-6 Heteroaryl, optionally substituted C 6-12 Aryl, optionally substituted C 2 -C 10 Polyethylene glycol, or optionally substituted C 1-10 In some embodiments, D is an optionally substituted C 3 -C 10 cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 1. In some embodiments, D is an optionally substituted C 3 -C 10 cycloalkyl, f is 1, g is 0, h is 0, i is 0, j is 0, and k is 0. In some embodiments, D is an optionally substituted C 3 -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 C 3 -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 C 3 -C 10carbocyclyl, 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 C 3 -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 C 3 -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 C 3 -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:

[0438]

[0439]

[0440]

[0441] In some embodiments, the linker has the following structure:

[0442]

[0443]

[0444]

[0445] In some embodiments, the linker has the structure of Formula III:

[0446] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 ,

[0447] Formula III

[0448] in

[0449] A 1 is the bond between the linker and the ring system A;

[0450] A 2 is the bond between the degradable moiety and the linker;

[0451] B 1 , B 2 , B 3 and B 4 are each independently an optionally substituted ethynyl, an optionally substituted C 6 -C 10 Aryl, optionally substituted C 3 -C 10 Cycloalkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 2 -C 10 Heterocyclic group, optionally substituted C 2 -C 9 Heteroaryl, O, S, S(O) 2 or NR N ;

[0452] 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;

[0453] C 1 and C 2 are each independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl; and

[0454] f, g, h, i, j and k are each independently 0 or 1.

[0455] In some embodiments, 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 C 2 -C 10 Heterocyclic group, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 6 -C 10 Aryl, or optionally substituted C 3 -C 10 Cycloalkyl.

[0456] In some embodiments, at least one L 1 is an optionally substituted C 2 -C 10In some embodiments, the optionally substituted C 2 -C 10 Heterocyclyl is a 4-, 5- or 6-membered monocyclic heterocyclyl. In some embodiments, a 4-, 5- or 6-membered monocyclic heterocyclyl is:

[0457]

[0458] In some embodiments, the optionally substituted C 2 -C 10 The heterocyclic group is a spirocyclic heterocyclic group. In some embodiments, the spirocyclic heterocyclic group is:

[0459]

[0460]

[0461] In some embodiments, the optionally substituted C 2 -C 10 The heterocyclyl group is a bridged heterocyclyl group. In some embodiments, the bridged heterocyclyl group is:

[0462]

[0463] In some embodiments, the optionally substituted C 2 -C 10 The heterocyclyl group is a fused bicyclic heterocyclyl group. In some embodiments, the fused bicyclic heterocyclyl group is:

[0464]

[0465] In some embodiments, at least one L 1 is an optionally substituted C 2 -C 9 In some embodiments, the linker is -(L 1 ) q -(optionally substituted C 2 -C 9 Heteroaryl)-(L 1 ) q -, wherein each q is independently 0 or 1. In some embodiments, the optionally substituted C 2 -C 9 Heteroaryl is a 6-membered monocyclic heteroaryl. In some embodiments, the 6-membered monocyclic heteroaryl is:

[0466]

[0467] In some embodiments, at least one L 1 is an optionally substituted C 2 -C9 In some embodiments, the linker is:

[0468]

[0469] In some embodiments, at least one L 1 is an optionally substituted C 6 -C 10 In some embodiments, the optionally substituted C 6 -C 10 Aryl is a 6-membered monocyclic aryl. In some embodiments, the 6-membered monocyclic aryl is an optionally substituted phenyl.

[0470] In some embodiments, at least one L 1 is an optionally substituted C 3 -C 10 In some embodiments, the optionally substituted C 3 -C 10 Cycloalkyl is a monocyclic cycloalkyl. In some embodiments, the 6-membered monocyclic cycloalkyl is:

[0471]

[0472] In some embodiments, the optionally substituted C 3 -C 10 Cycloalkyl is a bridged cycloalkyl. In some embodiments, the bridged cycloalkyl is:

[0473]

[0474] In some embodiments, at least one L 1 It is ethynyl.

[0475] In some embodiments, one and only one L 1 is O. In some embodiments, one and only one L 1 YesNR N In some embodiments, R N is an optionally substituted C 1 -C 4 In some embodiments, R N It's H.

[0476] In some embodiments, the linker has the following structure:

[0477] A 1 -(B 1 ) f -(B 2 ) h -(B 3 )i -(B 4 ) k -A 2 ,

[0478] Among them B 1 , B 2 , B 3 and B 4 are each independently an optionally substituted ethynyl, an optionally substituted C 6 -C 10 Aryl, optionally substituted C 3 -C 10 Cycloalkyl, optionally substituted C 2 -C 10 Heterocyclic group, optionally substituted C 2 -C 9 Heteroaryl, O, or NR N .

[0479] In some embodiments, at least one of f, h, i, and k is 1.

[0480] In some embodiments, B 1 , B 2 , B 3 and B 4 are each independently O, ethynyl, optionally substituted C 2 -C 9 Heteroaryl, optionally substituted C 2 -C 10 Heterocyclic group, optionally substituted C 3 -C 10 Cycloalkyl, or optionally substituted C 6 -C 10 In some embodiments, B 1 , B 2 , B 3 and B 4 are each independently an optionally substituted C 2 -C 9 Heteroaryl or optionally substituted C 2 -C 10 In some embodiments, B 1 and B 4 Each independently is

[0481] O.

[0482]

[0483]

[0484] In some embodiments, B 1yes:

[0485]

[0486]

[0487] In some embodiments, B 4 yes:

[0488] O.

[0489]

[0490] In some embodiments, B 2 YesNR N In some embodiments, B 2 is NH. In some embodiments, B 2 is an optionally substituted C 2 -C 9 In some embodiments, B 2 yes:

[0491]

[0492] 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.

[0493] In some embodiments, the linker has the structure

[0494]

[0495]

[0496] In some embodiments, the shortest chain of atoms connecting two valences of a linker is 2 to 10 atoms long. In some embodiments, the shortest chain of atoms connecting two valences of a linker is 6 atoms long.

[0497] In some embodiments, the linker has any of compounds 1-121 in Table 1 (e.g., having a BRG1 IC of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30). 50 For BRM IC50 The linker structure in any of the compounds (e.g., any of the compounds having a ratio of BRM IC of ++ or better (e.g., +++ or ++++(e.g., ++++))). In some embodiments, the linker has the linker structure in any of Compounds 1-121 in Table 1 50 The linker structure in any of the compounds (e.g., any of the compounds having a ratio of BRM IC of ++ or better (e.g., +++ or ++++(e.g., ++++))). In some embodiments, the linker has the linker structure in any of Compounds 1-121 in Table 1 50 And having a BRG1 IC of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) 50 To BRMIC 50 The linker structure in any of the compounds having a ratio of)

[0498] In one aspect, the invention features compounds selected from Compounds 1-121 in Table 1 and pharmaceutically acceptable salts thereof. In some embodiments, the compound has a BRG1 IC of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) 50 To BRM IC 50 Any of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof having a ratio of. In some embodiments, the compound has a BRM IC of ++ or better (e.g., +++ or ++++(e.g., ++++)) as visible in Table 15 50 Any of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof having a ratio of. In some embodiments, the compound has a BRM IC of ++ or better (e.g., +++ or ++++(e.g., ++++)) as visible in Table 15 50 And having a BRG1 IC of at least 5 (e.g., at least 7, 10, 15, 20, 25, or 30) 50 To BRM IC 50 Any of Compounds 1-121 in Table 1 or a pharmaceutically acceptable salt thereof having a ratio of

[0499] Table 1. Compounds of the Invention

[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] In some embodiments, the compound has a BRG1IC of at least 5 50 For BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 7. 50 For BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 10. 50 For BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 15. 50 For BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 20. 50 About BRMIC 50 In some embodiments, the compound has a BRG1 IC of at least 25. 50 For BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 30. 50 For BRM IC 50 ratio.

[0538] In one aspect, the invention features a pharmaceutical composition including any of the foregoing compounds and a pharmaceutically acceptable excipient.

[0539] In another aspect, the invention features a method of reducing the activity of a BAF complex in a cell, the method comprising contacting the cell with an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0540] In some embodiments, the cell is a cancer cell.

[0541] In another aspect, the invention features a method of treating a BAF complex-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0542] In some embodiments, the BAF complex-associated disorder is cancer or a viral infection.

[0543] In a further aspect, the invention features a method of inhibiting BRM, the method comprising contacting a 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.

[0544] In some embodiments, the cell is a cancer cell.

[0545] In another aspect, the invention features a method of inhibiting BRG1, the method comprising contacting a cell with an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0546] In some embodiments, the cell is a cancer cell.

[0547] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method comprising contacting a cell with an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0548] In some embodiments, the cell is a cancer cell.

[0549] 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 comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0550] 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, such as a BRG1 loss-of-function cancer (e.g., it has been determined that the cancer includes cancer cells with a BRG1 loss-of-function).

[0551] In another aspect, the invention features a method of inducing apoptosis in a cell, the method comprising contacting the cell with an effective amount of any of the aforementioned compounds (eg, a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0552] In some embodiments, the cell is a cancer cell.

[0553] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0554] 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, 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.

[0555] 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.

[0556] In some embodiments, the cancer is non-small cell lung cancer.In some embodiments, the cancer is soft tissue sarcoma.

[0557] In some embodiments of any of the foregoing methods, the cancer is a resistant cancer or has responded to a 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, demuximab, fortabulin, or PDL1 inhibitors) did not respond.

[0558] In some embodiments of any of the foregoing methods, the cancer has or has been determined to have a BRG1 mutation. In some embodiments of any of the foregoing methods, the BRG1 mutation is homozygous. In some embodiments of any of the foregoing methods, the cancer does not have or has been determined to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have or has been determined to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has or has been determined to have a KRAS mutation. In some embodiments of any of the foregoing methods, the BRG1 mutation is in the ATPase catalytic domain of the protein. In some embodiments of any of the foregoing methods, the BRG1 mutation is a deletion at the C-terminus of BRG1.

[0559] On the other hand, the present disclosure provides a method for treating a disorder associated with BAF (e.g., cancer or viral infection) in a subject in need thereof. The method comprises contacting a cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound), or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a viral infection, which is a retroviridae such as a lentivirus (e.g., human immunodeficiency virus (HIV)) and a delta retrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), a hepatoviridae (e.g., hepatitis B virus (HBV)), a flaviviridae (e.g., hepatitis C virus (HCV)), adenoviridae (e.g., human adenovirus), herpesviridae (e.g., human cytomegalovirus (HCMV), epidermal growth factor receptor (EGFR)), leukemia virus (EGFR) or leukemia virus (EGFR)). In some embodiments, the disorder is infection with a virus of the family of Herpes simplex virus (e.g., 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, HPVE1)), 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 disorder is Coffin-Siris syndrome, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0560] In another aspect, the present disclosure provides a method for treating a viral infection in a subject in need thereof. The method comprises administering to the subject an effective amount of any 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 one of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is a retroviridae such as a lentivirus (e.g., human immunodeficiency virus (HIV)) and a delta retrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), a hepatoviridae (e.g., hepatitis B virus (HBV)), a 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), a papillomaviridae (e.g., human papillomavirus (HPV, HPV- E1)), infection with a virus of the Parvoviridae family (e.g., Parvovirus B19), the Polyomaviridae family (e.g., JC virus and BK virus), the Paramyxoviridae family (e.g., measles virus), or the Togaviridae family (e.g., Rubella virus).

[0561] In some embodiments of any of the above 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 times greater than the level and / or activity of BRG1, and / or the binding of the compound to BRM is at least 10 times greater than the binding of the compound to BRG1. For example, in some embodiments, the IC of a BRM selective compound is 50 or IP 50 IC for 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 an activity against BRM and BRG1 within 10 times (e.g., less than 5 times, less than 2 times)). In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRM. In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRG1. For example, in some embodiments, the IC of the BRM / BRG1 dual inhibitor compound against BRM is greater than that of the BRM / BRG1 dual inhibitor compound. 50 or IP 50 In the IC of BRG1 50 or IP 50Within 10 times of.

[0562] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a blood 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.

[0563] In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a blood 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.

[0564] In another aspect, the invention features a method of inhibiting metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematological cancer in a subject, the method comprising administering an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0565] 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 a hematological cancer in a subject, the method comprising administering an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0566] In another aspect, the invention features a method of reducing the level and / or activity of BRG1 and / or BRM in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer cell, the method comprising contacting the cell with an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0567] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer cell is in a subject.

[0568] In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) compared to a reference. 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%) 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%).

[0569] In some embodiments, an effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours or more). In some embodiments, an effective amount of the compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days or more).

[0570] In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and / or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%).

[0571] In some embodiments, an 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%) compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more). In some embodiments, an effective amount of the compound reduces the level and / or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0572] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein, and / or the cell or subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein and / or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein and / or the cell or subject has been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a blood cancer, such as multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic 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's sarcoma). In some embodiments, the cancer is renal cell carcinoma (e.g., microphthalmia transcription factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., cancer has spread to the liver). The metastatic cancer may 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, the migratory cancer is a cell migration cancer. In yet other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer may be a cancer that spreads via surface seeding in the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, the metastatic cancer may be a cancer that spreads via the lymphatic system, or a cancer that spreads through the bloodstream. 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 the metastatic colonization of cancer to the liver.

[0573] In some embodiments, the cancer contains a mutation in GNAQ. In some embodiments, the cancer contains a mutation in GNA11. In some embodiments, the cancer contains a mutation in PLCB4. In some embodiments, the cancer contains a mutation in CYSLTR2. In some embodiments, the cancer contains a mutation in BAP1. In some embodiments, the cancer contains a mutation in SF3B1. In some embodiments, the cancer contains a mutation in EIF1AX. In some embodiments, the cancer contains a TFE3 translocation. In some embodiments, the cancer contains a TFEB translocation. In some embodiments, the cancer contains a MITF translocation. In some embodiments, the cancer contains an EZH2 mutation. In some embodiments, the cancer contains a SUZ12 mutation. In some embodiments, the cancer contains an EED mutation.

[0574] 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 anti-neoplastic 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.

[0575] In some embodiments, the compounds of the invention are used in combination with another anticancer therapy for the treatment of 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 invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or simultaneously with the administration of the compounds of the invention.

[0576] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other, and each is administered in an amount that together is effective to treat the subject.

[0577] In some embodiments, the subject or cancer has and / or has been identified as having a BRG1 loss-of-function mutation.

[0578] 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 chemotherapeutic or cytotoxic agents, such as by genetic markers, or may be resistant to chemotherapeutic or cytotoxic agents, such as cancer that has not responded to chemotherapeutic or cytotoxic agents). In some embodiments, the cancer has not responded to one or more chemotherapeutic agents. In some embodiments, the cancer is resistant to or has not responded to the following agents: dacarbazine, temozolomide, cisplatin, trosufant, 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., sotrastaurin or IDE196).

[0579] In some embodiments, the cancer is resistant to 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 to or unresponsive to a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, bimetinib, or trametinib) and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0580] In one aspect, the present invention provides the use of any of the aforementioned compounds (e.g., BRM / BRG1 dual inhibitor compounds or BRM selective compounds) or pharmaceutically acceptable salts thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament. In some embodiments, the use is as described in the methods described herein.

[0581] Chemical terms

[0582] The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0583] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in the particular chemical moiety. As will be appreciated, other atoms (such as H atoms) or substituents described herein may be present as needed to satisfy the valence of the atoms. For example, unsubstituted C 2 Alkyl groups have the formula -CH 2 CH 3 When used for groups defined herein, references to the number of carbon atoms include the divalent carbons in acetal and ketal groups, but exclude the carbonyl carbon in acyl, ester, carbonate or carbamate groups. References to the number of oxygen, nitrogen or sulfur atoms in a heteroaryl group include only those atoms that form part of a heterocyclic ring.

[0584] The term "acyl" as used herein represents H or an alkyl group connected to a parent molecular group through a carbonyl group as defined herein, such as formyl (i.e., formaldehyde), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbons.

[0585] The term "alkyl" used herein refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms (eg, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0586] Alkylene is a divalent alkyl group. The term "alkenyl" as used herein, alone or in combination with other groups, refers to a straight or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms, such as 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms.

[0587] The term "alkynyl" as used herein, alone or in combination with other groups, refers to a straight or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0588] The term "amino" as used herein refers to -N(R N1 ) 2 , where each R N1 H, OH, NO independently 2 、N(R N2 ) 2 、SO 2 OR N2 、SO 2 R N2 , SOR N2 , N-protecting group, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other acyl described herein), wherein these listed R N1 Each of the groups may be optionally substituted; or both R N1 to form an alkylene or heteroalkylene group, and wherein each R N2 is independently H, alkyl or aryl. The amino group of the present invention can be an unsubstituted amino group (i.e., -NH 2 ) or substituted amino (i.e. -N(R N1 ) 2 ).

[0589] The term "aryl" as used herein refers to an aromatic mono- or polycarbocyclic group of 6 to 12 carbon atoms having at least one aromatic ring. In the case of polycyclics, the aryl contains 2 or 3 rings. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl and 1H-indenyl.

[0590] The term "aralkyl" as used herein 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 C 1 -C 6 Alkyl C 6 -C 10 Aryl, C 1 -C 10 Alkyl C 6 -C 10 Aryl, or C 1 -C 20 Alkyl C 6 -C 10 In some embodiments, the alkyl and aryl groups are each further substituted with 1, 2, 3, or 4 valence-allowed substituents as defined herein for the corresponding groups.

[0591] The term "azido" as used herein represents -N 3 Group.

[0592] 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 cycloalkyl.

[0593] The term "cyano" as used herein represents a -CN group.

[0594] The term "carbocyclyl" as used herein refers to a non-aromatic C 3 -C 12 Monocyclic, bicyclic or tricyclic structures. Carbocyclic structures include cycloalkyl and unsaturated carbocyclic groups.

[0595] The term "cycloalkyl" as used herein refers to a saturated, non-aromatic and monovalent monocyclic, bicyclic or tricyclic group having 3 to 10, preferably 3 to 6 carbon atoms. The cycloalkyl group may be fully saturated or contain one or more double or triple bonds, provided that no ring is aromatic. The term is further exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl. The term "CH 2 "-cycloalkyl" refers to cycloalkyl-CH 2 - groups (e.g. cyclopropylmethyl and cyclobutylmethyl).

[0596] As used herein, the term "halo" refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) group.

[0597] The term "heteroalkyl" as used herein refers to an alkyl as defined herein, wherein one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen or sulfur. In some embodiments, the heteroalkyl is further replaced by 1, 2, 3 or 4 substituents as described herein for the alkyl. The example of heteroalkyl is "alkoxy", which refers to alkyl-O- (such as methoxy and ethoxy) as used herein. Heteroalkylene is a divalent heteroalkyl. The term "heteroalkenyl" as used herein refers to an alkenyl as defined herein, wherein one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen or sulfur. In some embodiments, the heteroalkenyl is further replaced by 1, 2, 3 or 4 substituents as described herein for the alkenyl as allowed by valence. The example of heteroalkenyl is "alkenyloxy", which refers to alkenyl-O- as used herein. Heteroalkenylene is a divalent heteroalkenyl. The term "heteroalkynyl" as used herein refers to an alkynyl as defined herein, wherein one or more of the constituent carbon atoms have 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 valences allow. An example of a heteroalkynyl is "alkynyloxy," which as used herein refers to alkynyl O. A heteroalkynylene is a divalent heteroalkynyl group.

[0598] The term "heteroaryl" used herein refers to a monocyclic, bicyclic or tricyclic group of 5 to 12 atoms having at least one aromatic ring and containing 1, 2 or 3 ring atoms selected from nitrogen, oxygen and sulphur and all the other ring atoms being carbon. One or two ring carbon atoms of heteroaryl can be replaced by a carbonyl group. Examples of heteroaryl are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl and thiazolyl.

[0599] The term "heteroarylalkyl" as used herein refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C 1 -C 6 Alkyl C 2 -C 9 Heteroaryl, C 1 -C 10 Alkyl C 2 -C 9 Heteroaryl, or C 1 -C 20 Alkyl C 2 -C 9 In some embodiments, the alkyl and heteroaryl groups are each further substituted with 1, 2, 3, or 4 substituents as defined herein for the corresponding groups, as valency permits.

[0600] 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 include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl and 1,3-dioxanyl.

[0601] The term "heterocyclylalkyl" as used herein refers to an alkyl group substituted with a heterocyclyl group. Unsubstituted heterocyclylalkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C 1 -C 6 Alkyl C 2 -C 9 Heterocyclic group, C 1 -C 10 Alkyl C 2 -C 9 Heterocyclic group, or C 1 -C 20 Alkyl C 2 -C 9 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.

[0602] The term "hydroxyalkyl" as used herein represents an alkyl group substituted with an -OH group.

[0603] The term "hydroxy" as used herein represents an -OH group.

[0604] The term "N-protecting group" as used herein represents 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, aroyl 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 benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,

[0063] Examples of the present invention include aryloxycarbonyl, cyclopentyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cyclopentyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, 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-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0605] The term "nitro" as used herein refers to -NO 2 Group.

[0606] As used herein, the term "oxo" represents a divalent oxygen atom (e.g., the structure of oxo can be shown as =O). 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, sulfur can be substituted with one or two oxo groups (e.g., -SO- or -SO- in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group). 2 -).

[0607] The term "mercapto" as used herein represents a -SH group.

[0608] The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic radical (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclic radical can be substituted or unsubstituted. When substituted, unless otherwise indicated, there will be 1, 2, 3, 4, or 5 substituents where valence permits. The 1 to 5 substituents are each independently selected from acyl, alkyl (e.g., unsubstituted and substituted, wherein the substituent includes any group described herein, such as aryl, halogen, hydroxyl), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyclic radical (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxy, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclic radical, amino (e.g., NH 2 or mono- or di-alkylamino), azido, cyano, nitro, thiol, and oxo. Each substituent is unsubstituted or substituted with one or more unsubstituted substituents as defined herein for each corresponding group. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxy, heteroaryl, heterocyclyl, amino (e.g., NH 2 In some embodiments, the substituents are substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 6

[0609] Compounds of the present invention may have one or more asymmetric carbon atoms, and may exist in the form of an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, or a mixture of diastereomeric racemates. Optically active forms may be obtained, for example, by splitting racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). That is, some disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are stereoisomer pairs whose mirror images are non-superimposable, most commonly because they contain asymmetrically substituted carbon atoms as chiral centers. "Enantiomers" refer to one of a pair of molecules that are mirror images and non-superimposable. Diastereomers are stereoisomers that are not related 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. The enantiomers of a compound can be prepared, for example, by separating enantiomers from a racemate using one or more well-known techniques and methods (such as chiral chromatography and separation methods based thereon). One 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; i.e., they do not rotate the plane of polarized light. "Geometric isomer" refers to an isomer with different orientations 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 are located on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" indicate configurations relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric tension barrier to rotation is high enough to separate the conformers. The compounds of the present invention can be prepared as single isomers by isomer-specific synthesis or resolution from an isomeric mixture. Conventional resolution techniques include forming salts of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming salts of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each isomer of the isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving isomeric mixtures of the starting material or final product using various 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% pure by weight. The optical purity percentage is the ratio of the weight of an enantiomer 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 to the weight of all diastereomers. 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 mole percent pure 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 mole percent pure. 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 mole percent pure. The percent purity by mole fraction is the ratio of the number of moles of enantiomer to the number of moles of enantiomer plus the number of moles of its optical isomers. Similarly, the percent purity by mole fraction is the ratio of the number of moles of diastereomers to the number of moles of diastereomers plus the number of moles of its isomers. When a disclosed compound is named or depicted by a structure without indicating stereochemistry and the compound has at least one chiral center, it is understood that the name or structure encompasses enantiomers of the compound that do not contain the corresponding optical isomers, racemic mixtures of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by a structure without indicating stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses diastereomers that do not contain other diastereomers, a number of diastereomers that do not contain other diastereomer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, mixtures of diastereomers in which one diastereomer is enriched relative to other diastereomers, or mixtures of diastereomers in which one or more diastereomers are enriched relative to other diastereomers. The present invention encompasses all of these forms.

[0610] Compounds of the present disclosure also include all isotopes of atoms that occur in intermediates or final compounds. "Isotopes" refer to atoms with the same atomic number but different mass numbers due to different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0611] 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. Because of their ease of preparation and detectability, tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes may be useful. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H is replaced, or one or more carbon atoms are 13 C- or 14 C-enriched carbon substitution. Positron-emitting isotopes such as 15 O. 13 N. 11 C and 18F can be used for 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, following procedures similar to those disclosed for the compounds of the present invention described herein, isotope-labeled compounds can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art to which the present invention belongs. Methods and materials for the present disclosure are described herein; other suitable methods and materials known in the art can also be used. The materials, methods and embodiments are exemplary only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, this specification (including definitions) shall prevail.

[0612] definition

[0613] In this application, unless the context clearly indicates otherwise, (i) the term "a" or "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 components or steps listed itemized, whether presented alone or together with one or more additional components or steps.

[0614] As used herein, the terms "about" and "approximately" refer to values ​​within 10% above or below the value described. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0615] The term "administering" as used herein refers to administering a composition (e.g., a compound or a formulation comprising a compound described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any appropriate route. 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, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

[0616] As used herein, the term "BAF complex" refers to a BRG1- or HRBM-associated factor complex in human cells.

[0617] As used herein, the term "BAF complex-associated disorder" refers to a disorder caused or affected by the activity level of the BAF complex.

[0618] As used herein, the term "BRG1 loss-of-function mutation" refers to a mutation in BRG1 that causes the protein to have reduced activity (e.g., a reduction in BRG1 activity of at least 1%, e.g., a reduction 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.

[0619] As used herein, the term "BRG1 loss-of-function disorder" refers to a disorder (e.g., cancer) that exhibits reduced BRG1 activity (e.g., at least 1% reduced BRG1 activity, e.g., 2%, 5%, 10%, 25%, 50% or 100% reduced BRG1 activity).

[0620] The term "cancer" refers to disorders caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias and lymphomas.

[0621] "Combination therapy" or "combined administration" as used herein refers to the administration of two (or more) different agents or treatments to a subject as part of a determined treatment regimen for a specific disease or condition. The treatment regimen defines the dosage and cycle of each agent so that the effects of a single agent on the subject overlap. In some embodiments, the delivery of two or more agents is simultaneous or concurrent, and the agent can be co-formulated. In some embodiments, two or more agents are not co-formulated and are sequentially administered as part of a prescribed 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 disorder than when a single agent or treatment is delivered or observed in the absence of other agents or treatments. The effects of the two treatments can be partially cumulative, completely cumulative, or greater than cumulative (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption by mucosal tissues. 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.

[0622] "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 a determination or test on a sample, or "analyzing a sample," as the term is 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 a physical entity or value). The method for measuring protein levels generally includes, but is not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption / ionization time of flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS) and flow cytometry, as well as determinations based on protein properties (including but not limited to enzyme activity or interactions with other protein partners). Methods of measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0623] "Reducing the activity of the BAF complex" refers to reducing the level of activity associated with the BAF complex or an associated 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.

[0624] As used herein, the term "degrader" refers to a small molecule compound comprising a degradation 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 reduction of at least 5% in protein levels, e.g., in a cell or subject.

[0625] The term "degradation moiety" as used herein refers to a moiety whose binding causes degradation of a protein (eg, BRG1 and / or BRM). In one example, the moiety binds a protease or ubiquitin ligase that metabolizes the protein (eg, BRG1 and / or BRM).

[0626] "Modulating the activity of a BAF complex" refers to changing the activity level associated with a BAF complex (e.g., GBAF) or an associated downstream effect. The activity level of a 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.

[0627] "Reducing the activity of BRG1 and / or BRM" refers to reducing the activity level associated with BRG1 and / or BRM or the associated downstream effects. A non-limiting example of inhibiting the activity of BRG1 and / or BRM is reducing the level of 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.

[0628] "Decreasing the level of BRG1 and / or BRM" refers to decreasing the level of BRG1 and / or BRM in a cell or a subject. The level of BRG1 and / or BRM can be measured using any method known in the art.

[0629] "Level" refers to the level of a protein or mRNA encoding the protein compared to a reference. The reference may be any available reference as defined herein. "Reduced level" or "increased level" of a protein refers to a reduction or increase in the level of a protein compared to a reference (e.g., a reduction 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 reduction or increase of more than about 1% compared to a reference). The level of a protein may be expressed as a percentage of mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or relative to the total protein or mRNA in the sample.

[0630] The term "inhibit BRM" as used herein refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain domain (bromodomain) of a protein. BRM inhibition can be determined using methods known in the art, such as BRM ATPase assays, Nano DSF assays, or BRM luciferase cell assays.

[0631] The term "pharmaceutical composition" as used herein represents a composition containing a compound described herein, which is formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, such as a human. Typically, a pharmaceutical composition is manufactured or sold under the approval of a 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, capsules, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a non-particulate plug and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0632] As used herein, "pharmaceutically acceptable excipients" refer to any ingredients other than the compounds described herein (e.g., vehicles capable of suspending or dissolving the active compounds) and have substantially non-toxic and non-inflammatory properties in patients. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film formers or coatings, flavoring agents, fragrances, glidants (flow promoters), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and water of hydration.

[0633] The term "pharmaceutically acceptable salt" as used herein refers to any pharmaceutically acceptable salt of a compound (e.g., any compound of Formula I). ​​Pharmaceutically acceptable salts of any compound described herein may include salts that are suitable for contact with human and animal tissues without undue toxicity, irritation, allergic response, and are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. 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. The salts may be prepared in situ during the final separation and purification of the compounds described herein, or separately prepared by reacting the free base group with a suitable organic acid.

[0634] The compounds of the present invention may have ionizable groups so that they can be prepared into 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. Often, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing appropriate salts are well known in the art. Salts may be prepared from pharmaceutically acceptable nontoxic acids and bases, including inorganic and organic acids and bases.

[0635] "Reference" refers to any available 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 a 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 (such as a cell or tissue) from a subject without a disease; a sample from a subject diagnosed with a disease but not yet treated with the compounds of the present invention; a sample from a subject treated with the compounds of the present invention; or a sample of a purified protein or RNA (such as any described herein) at a known normal concentration. "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, such as a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("X to Y"), a high threshold ("not higher than X"), or a low threshold ("not lower than X"). A subject having a measured value within a normal control value for a particular biomarker is often referred to as being "within normal limits" for that biomarker. A normal reference standard or level can be a value or number from: a normal subject without a disease or disorder (e.g., cancer); a subject that 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.

[0636] The term "subject" as used herein refers to any organism to which a composition according to the invention may be administered, e.g., for experimental, diagnostic, preventive and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be seeking or in need of treatment, requiring treatment, being treated, will be treated in the future, or may be a person or animal under the care of a trained professional for a particular disease or condition.

[0637] As used herein, the terms "treat," "treated," or "treating" refer to therapeutic treatment or any measure thereof intended to alleviate (lessen) an undesirable 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 condition, disorder, or disease; stable state (i.e., not worsening) of the condition, disorder, or disease; delayed or slowed onset of the progression of the condition, disorder, or disease; improvement or remission (whether partial or complete) of the condition, disorder, or disease state; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or amelioration or improvement of the condition, disorder, or disease. Treatment includes inducing a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The compounds of the invention may also be used for "prophylactic treatment" or "prevention" of disorders, for example, in subjects at increased risk of developing the disorder.

[0638] The details of one or more embodiments of the invention are set forth in the description that follows. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0640] 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.

[0641] The compound of formula I is:

[0642]

[0643] in

[0644] Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl group containing at least one N;

[0645] m is 0, 1, 2 or 3;

[0646] k is 0, 1, or 2;

[0647] Each R 1 are independently halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 2 -C 9 Heterocyclic group, or optionally substituted C 3 -C8 Cycloalkyl;

[0648] Each X is independently a halogen;

[0649] L is a linker; and

[0650] B is the degradation part.

[0651] In some embodiments, the compound has the structure of any one of Compounds 1-121 in Table 1, or a pharmaceutically acceptable salt thereof.

[0652] Other embodiments are described herein, as well as exemplary methods for synthesizing or producing these compounds.

[0653] Drug Use

[0654] The compounds described herein are useful in the methods of the 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 BRG1 loss-of-function mutations.

[0655] One aspect of the invention relates to methods for treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer). In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of the following: (a) reduced tumor size, (b) reduced tumor growth rate, (c) increased tumor cell death, (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced metastasis rate, (g) reduced tumor recurrence, (h) improved subject survival, (i) improved subject progression-free survival.

[0656] Treating 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. The size of a tumor can be measured by any reproducible measurement means. For example, the size of a tumor can be measured as a tumor diameter.

[0657] Treating 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 visible under a specified magnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

[0658] Treatment of cancer can result in a reduction in 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 reproducible measurement means. For example, the number of metastatic nodules can be measured by counting metastatic nodules visible to the naked eye or visible at a specified magnification (e.g., 2×, 10×, or 50×).

[0659] Compared to a population of untreated subjects, treating cancer can result in an increase in the average survival time of a population of subjects treated according to the present invention. For example, the average survival time increases by more than 30 days (more than 60 days, 90 days or 120 days). The increase in the average survival time of a population can be measured by any reproducible means. For example, the increase in the average survival time of a population can be measured by calculating the average survival time after the population begins to be treated with the compound of the present invention. For example, the increase in the average survival time of a population can also be measured by calculating the average survival time after the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0660] Treatment of cancer can also result in a reduction in mortality in 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 mortality in the treated subject population can be measured by any reproducible means, such as by calculating the average number of disease-related deaths per unit time after the population begins treatment with a pharmaceutically acceptable salt of the present invention. For example, the reduction in population mortality can also be measured by calculating the average number of disease-related deaths per unit time after the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0661] Exemplary cancers that may 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-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancers, thymic tumors, adrenocortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0662] Combination preparations and their uses

[0663] The compounds of the 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 cancer described herein.

[0664] Combination therapy

[0665] The compounds of the present invention can be used alone, or in combination with additional therapeutic agents (e.g., 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 based on drug combinations and permutations, or the dose can be inferred by isoradiometric 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.

[0666] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound that can be used to treat 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, ureas substituted with anthracenediones, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folinic acid (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. 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 benzodepa, carboquinone, metodepa, and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; caproic acid glycosides (especially bratacin and bratacinone); camptothecins (including the synthetic analog topotecan); bryostatin ; cal1ystatin; CC-1065 (including its synthetic analogs adolesin, cardzelesin and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); soft coral alcohol; water banana alkaloids; stoloniferin; sponge statin; nitrogen mustards such as chlorambucil, naphthyl nitrogen mustard, clofosamide, estramustine, ifosfamide, dichloromethyl diethylamine, dichloromethyl diethylamine Amine oxide hydrochloride, melphalan, new nitrogen mustard, phenacetin, prednimustine, trofosfamide, uracil nitrogen mustard; nitrosoureas such as carmustine, chlorozotocin, 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: 183-184). 6 (1994)); danemycins, including danemycin A; bisphosphonates, such as clodronate; esperamicins; and the neocarcinogens and related chromoprotein enediyne antibiotic chromophores), aclarubicin, actinomycin, anthramycin, azaserine, bleomycin, actinomycin C, carabicin, carminomycin, carmophorin, chromomycin, dactinomycin, daunorubicin, detopicin, 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, nogamycin, oliveromycin, peplomycin, porfiromycin, puromycin, triferon-doxorubicin, rhodorubicin, streptomycin, streptozotocin, tuberculin, Ubenimex, chlortetracycline, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylfolate, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, etoprin Norcibine, floxuridine; androgens such as caprotestosterone, drostanolone propionate, cyclothiocarb, melastane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; amustine (bestrabucil); bisantrene; edatrexate; defosfamide; colcemid; dexamethasone azquinone; eflornithine; elliptinium acetate; epothilone; etoglucagon; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansines such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidanmol; nitraerine; pentostatin; methamine nitrogen mustard; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; methylbenzylhydrazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizobactin; sizofuran; spirogermanamine; tricholomanic acid; triazoline quinone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucosporin A, baculosporin A, and serpentin); urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; piperobroman; cytosine arabinoside; 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; Noxol; Epipodophyllotoxin; 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 may be used in a mixture to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al., (1999) Proc ASCO 18: 233a and Douillard et al., (2000) Lancet 355: 1041-7.

[0667] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine used in cancer treatment (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 that is important for cancer. Such agents include Rituxan (rituximab); Zenipax (daclizumab); Sulelimab (basiliximab); Synagis (palivizumab); Remicade (infliximab); Herceptin (trastuzumab); Mylotarg (gemtuzumab ozogamicin); Campath (alemtuzumab); Zevalin (ibritumomab tiuxetan); Humira (adalimumab); Xolair (omalizumab); Bexar (tositumomab-I-131); Raptiva (efalizumab); Erbitux (cetuximab); Avastin (bevacizumab); Tesaburi (natalizumab); and Ativan (tocilizumab) ; Vectibix (panitumumab); Lusitide (ranibizumab); Sulire (eculizumab); Cimzia (pecilizumab); Simponi (golimumab); Ilaris (canakinumab); Cidano (ustekinumab); Arzerra (ofatumumab); Proli (denosumab); Numax (motuzumab); ABThrax (ranibizumab); Belimumab; Yervoy (ipilimumab); Ansari (brentuximab); Perjeta (pertuzumab); Herceptin (enmetuzumab); and Gazyva (otuzumab). Antibody-drug conjugates are also included.

[0668] The second agent can be a non-drug therapeutic agent. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and / or surgical removal of tumor tissue.

[0669] The second agent can be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of PD-1 (e.g., nivolumab / Pembrolizumab / In some embodiments, the checkpoint inhibitor 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 checkpoint inhibitor 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 checkpoint inhibitor is an inhibitor of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof (e.g., an inhibitory antibody or a small molecule inhibitor).

[0670] In any combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent may 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 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, at most 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 days, 1-14 days, 1-21 days, or 1-30 days before or after the second therapeutic agent.

[0671] Pharmaceutical composition

[0672] The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biocompatible form suitable for in vivo administration. Thus, in one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention mixed with a suitable diluent, carrier or excipient.

[0673] The compound of the present invention can be used in the form of free alkali, in the form of salt, solvate and as prodrug.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, the compound described 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 the pharmaceutical composition is formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, epithelial, nasal, intrapulmonary, intrathecal, rectal and topical administration modes.Parenteral administration can be carried out by continuous infusion in the selected time period.

[0674] The compounds of the present invention can be administered orally, for example with an inert diluent or with an assimilable 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 directly admixed with food in the diet. For oral therapeutic administration, the compounds of the present invention can be admixed 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 containing or not containing alcohol, and in oils. Under normal storage and use conditions, these preparations can contain preservatives to prevent the growth of microorganisms. Conventional procedures and ingredients for selecting and preparing suitable preparations are described in, for example, Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, the form must be sterile and must be a fluid to the extent that it can be easily applied via a syringe. Compositions for nasal administration can be conveniently formulated into aerosols, drops, gels, and powders. Aerosol preparations typically include solutions or fine suspensions of active substances in physiologically acceptable aqueous or non-aqueous solvents, and are typically present in a sterile form in a single dose or multiple dose amount in a sealed container, which can be in the form of a cartridge, or refilled for use with an atomizing device. Alternatively, the sealed container can be a unit dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is intended to be discarded after use. When the dosage form comprises 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 take the form of a pump atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, gum arabic, gum 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 as intratumoral injections. Intratumoral injections are injections directly into the tumor vasculature, and are particularly contemplated for discrete, solid, accessible tumors. Local, regional or systemic administration may also be appropriate. By administering one or more injections to the tumor, for example, at intervals of about 1 cm, the compounds described herein can be advantageously contacted.In the case of surgical intervention, the invention can be used prior to surgery, such as to allow resection of an inoperable tumor. Continuous administration can also be applied where appropriate, for example, by implanting a catheter into a tumor or tumor vasculature.

[0675] dose

[0676] The dosage of the compound of the present invention and / or the composition comprising the compound of the present invention can be different according to many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health and weight of the recipient; the nature and extent of the 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. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention can be initially administered at a suitable dosage, which can be adjusted as needed according to the clinical response. In general, when the compound of the present invention is administered to a person at a daily dosage of, for example, 0.05 mg to 3000 mg (measured in solid form), satisfactory results can be obtained. The dosage range includes, for example, 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.

[0677] 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 an exemplary, non-limiting embodiment, the 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

[0678] The following abbreviations are used throughout the examples below.

[0679] Ac Acetyl

[0680] ACN or MeCN Acetonitrile

[0681] AcOH Acetic acid

[0682] Ac 2 O Acetic anhydride

[0683] aq. water-based

[0684] Boc tert-Butyloxycarbonyl

[0685] Bu or n-Bu Butyl

[0686] CDI 1,1'-Carbonyldiimidazole

[0687] DCE or 1,2-DCE 1,2-dichloroethane

[0688] DCM Dichloromethane

[0689] DIAD Diisopropyl azodicarboxylate

[0690] DIPEA or DIEA NN-Diisopropylethylamine

[0691] DMAP 4-(dimethylamino)pyridine

[0692] DMB 2,4-dimethoxybenzyl

[0693] DME 1,2-dimethoxyethane

[0694] DMF NN-Dimethylformamide

[0695] DMSO Dimethyl sulfoxide

[0696] EA or EtOAc Ethyl acetate

[0697] EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0698] equiV equivalent

[0699] Et3N or TEA Triethylamine

[0700] EtOH

[0701] FA Formic acid

[0702] h or hr hour

[0703] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0704] HOAt 1-Hydroxy-7-azabenzotriazole

[0705] HOBt or HOBT 1-Hydroxybenzotriazole hydrate

[0706] iPr Isopropyl

[0707] MeOH Methanol

[0708] Me4t-BuXphos Di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane

[0709] min

[0710] MTBE tert-butyl methyl ether

[0711] n-BuLi n-butyllithium

[0712] NMP 1-Methyl-2-pyrrolidone

[0713] OAc acetate

[0714] Pd / C Palladium Carbon

[0715] PDC Pyridinium Dichromate

[0716] PdCl 2 (dtbpf) or dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)

[0717] Pd(dtbpf)Cl 2

[0718] PdCl 2 (dPPf) or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0719] Pd(dppf)C1 2

[0720] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)

[0721] Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0)

[0722] Pd(PPh 3 ) 2 Cl 2 Dichlorobis(triphenylphosphine)palladium(II)

[0723] PE Petroleum Ether

[0724] PPh 3 Triphenylphosphine

[0725] Pr n-propyl

[0726] Py Pyridine

[0727] rac racemic

[0728] Rf retention factor

[0729] rt or rt room temperature

[0730] sat. saturated

[0731] SFC Supercritical Fluid Chromatography

[0732] t-Bu tert-butyl

[0733] tBuXphos-Pd-G3 [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium; di-tert-butyl or tBuXphosPd G3-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane

[0734] or t-BuXphos-Pd

[0735] (gen 3)

[0736] TFA Trifluoroacetic acid

[0737] Tf 2 O Trifluoromethanesulfonic anhydride

[0738] THF Tetrahydrofuran

[0739] TLC Thin layer chromatography

[0740] Xantphos-Pd-G3 [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane

[0741] XPhos Pd G3 (2-dicyclohexylphosphino-2,4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[0742] Example 1. Preparation of compounds

[0743] Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1).

[0744]

[0745] Step 1: Preparation of 2-(3-bromoisoxazol-5-yl)acetic acid.

[0746]

[0747] 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 heated to anhydrous Na 2 SO 4 Drying on ice and concentration under reduced pressure gave 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.

[0748] Step 2: Preparation of methyl 2-(3-bromoisoxazol-5-yl)acetate.

[0749]

[0750] 2-(3-bromoisoxazol-5-yl)acetic acid (28 g, 135 mmol) and concentrated H 2 SO 4 A solution of (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 concentrated over anhydrous MgSO 4 The residue was purified by flash chromatography on silica gel (EtOAc / petroleum ether) to afford 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.

[0751] Step 3: Preparation of methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate.

[0752]

[0753] To a stirred solution of methyl 2-(3-bromoisoxazol-5-yl)acetate (23.4 g, 106 mmol) and KOtBu (17.8 g, 159 mmol) in THF (210 mL) was added 2-iodopropane (13.8 mL, 137 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 hours and then quenched with water / ice. The resulting solution was extracted several times with EtOAc. The combined organic layers were washed with brine and concentrated in anhydrous Na 2 SO 4The residue was purified by flash chromatography on silica gel (EtOAc / petroleum ether) to afford methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (16.7 g, 60%) as a clear oil.

[0754] Step 4: Preparation of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid.

[0755]

[0756] 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 several times with EtOAc. The combined organic layers were washed with brine and heated in anhydrous MgSO 4 The residue was purified by flash chromatography on silica gel (EtOAc / petroleum ether) to afford 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (8.8 g, 70%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =200.15.

[0757] Step 5: Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid.

[0758]

[0759] 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 h. The resulting mixture was concentrated under reduced pressure to afford crude 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (8.16 g, quantitative).

[0760] Step 6: Preparation of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate.

[0761]

[0762] 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 SOCl 2(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 heated in anhydrous Na 2 SO 4 The residue was purified by flash chromatography on silica gel (MeOH / DCM) to afford methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (7.79 g, 89%) as a clear oil. LCMS (ESI) m / z: [M+H] + =200.15.

[0763] Step 7: Preparation of methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate.

[0764]

[0765] 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid methyl ester (7.79 g, 39.1 mmol) was added to a solution of DMF (90 mL) with 2-bromo-1,1-diethoxyethane (8.77 mL, 58.6 mmol) and potassium carbonate (10.8 g, 78.2 mmol). The reactant was stirred overnight at 70 ° C. The reaction mixture was cooled and water was subsequently added to the mixture. The resulting mixture was extracted several times with EtOAc. The combined organic layers were washed with brine and concentrated in anhydrous MgSO 4 The solvent was removed under reduced pressure and the resulting residue was purified by silica gel flash chromatography (EtOAc / heptane) to provide methyl 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoate (7.8 g, 63%) as a colorless oil. LCMS (ESI) m / z: [MC 2 H 5 O] + =270.30.

[0766] Step 8: Preparation of 2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid.

[0767]

[0768] 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 concentrated in MgSO4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (DCM / MeOH) to afford 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.

[0769] Step 9: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate.

[0770]

[0771] 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 and concentrated in anhydrous Na 2 SO 4 The residue was purified by flash chromatography on silica gel (MeOH / DCM) to afford 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.

[0772] Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride.

[0773]

[0774] 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 ether to provide (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.

[0775] Step 11: Preparation of (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2)

[0776]

[0777] To a solution of 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butyric 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 h, 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 mmmm 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 the addition of water and extracted several times with EtOAc. The combined organic layers were washed with brine and concentrated over anhydrous MgSO 4The residue was purified by flash chromatography on silica gel (DCM / MeOH) to afford (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 diastereoisomers was separated by chiral SFC chromatography to afford (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.

[0778] (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 Peak 1: (2.2 g, 19%). LCMS (ESI) m / z [M+H] + =615.4.

[0779] (2S,4R)-1-((R)-2-(3-(2,2-diethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-2) Peak 2: (2.5 g, 21%). LCMS (ESI) m / z [M+H]+ = 615.4.

[0780] Step 12: Preparation of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1).

[0781]

[0782] At room temperature, H 2 SO 4To a stirred solution of 4-nitropropene (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-2, 300 mg, 0.499 mmol) in portions. The resulting mixture was stirred at 50° C. for 8 hours. The resulting mixture was diluted with water and then washed with saturated NaHCO 3 The aqueous solution was neutralized to pH 7. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed twice with brine and concentrated in anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-1, 256 mg, 97.3%) as a white solid. LCMS (ESI) m / z: [M+H] + =541.

[0783] The following intermediates in Table 2 were prepared in a similar manner as described in the preparation of intermediate 1-1 starting from methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate and the appropriate alkyl bromide.

[0784] Table 2.

[0785]

[0786] Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (I-5) and

[0787] (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)

[0788]

[0789] Step 1: Preparation of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate.

[0790]

[0791] To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (100.00 mg, 0.502 mmol, 1.00 equiv) in MeCN (0.50 mL) at room temperature was added perfluorobutanesulfonyl fluoride (303.29 mg, 1.004 mmol, 2.00 equiv) and K 2 CO 3 (208.13 mg, 1.506 mmol, 3.00 equiv). The resulting mixture was stirred for 3 h and then carefully quenched with water at 0 °C. The resulting mixture was extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous 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 (2 / 1) to afford methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate (217 mg) as a white solid. LCMS (ESI) m / z: [M+H] + = 482.

[0792] Step 2: Preparation of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate.

[0793]

[0794] To a stirred solution of methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)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 cooled to room temperature. 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 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.

[0795] Step 3: Preparation of 2-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,2-oxazol-5-yl]-3-methylbutanoic acid.

[0796]

[0797] To a stirred solution of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperazine-1-carboxylate (54.00 mg, 0.147 mmol, 1.00 equiv) in MeOH (0.80 mL) was added THF (0.80 mL) and H 2 O (0.80 mL), followed by the addition of LiOH. 2 O (18.50 mg, 0.441 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 6 with HCl (1 M, aqueous solution) and then extracted with EA (2×50 mL). The combined organic layers were washed with brine (50 mL) and heated to anhydrous Na 2 SO 4 The filtrate was concentrated under reduced pressure. This provided 2-[3-[4-(tert-butoxycarbonyl)piperazine-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.

[0798] 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.

[0799]

[0800] 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 directly 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 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.

[0801] 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.

[0802]

[0803] Tert-butyl 4-(5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)piperazine-1-carboxylate (73 mg) was purified by SFC using the following conditions: column, CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; mobile phase, MeOH.

[0804] This provides:

[0805] 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.

[0806] 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.

[0807] 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-5) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-(piperazin-1-yl)-1,2-oxazol-5-yl]butyryl]pyrrolidine-2-carboxamide (I-4).

[0808]

[0809] 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 (1.50 mL, 26.276 mmol, 473.57 equiv) in 1,4-dioxane. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This afforded I-5 (45 mg, crude product) as a yellow oil. LCMS (ESI) m / z: [M+H]+=567.

[0810] I-4 was prepared according to the same protocol as I-5 and obtained as a yellow oil. LCMS (ESI) m / z: [M+H] + =567.

[0811] The following intermediates in Table 3 were prepared in a similar manner as described in the preparation of intermediate 1-5 starting from methyl 3-methyl-2-[3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl]butanoate and the appropriate amine.

[0812] Table 3.

[0813]

[0814]

[0815] Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate.

[0816]

[0817] Step 1: Preparation of (E)-N-[(2-chloropyrimidin-5-yl)methylene]hydroxylamine.

[0818]

[0819] 2-Chloropyrimidine-5-carboxaldehyde (5 g, 35.078 mmol, 1 eq.) and NH 2To a stirred solution of OH.HCl (4.93 g, 70.945 mmol, 2.02 equiv) in EtOH (250 mL) was added NaOAc (14.48 g, 176.512 mmol, 5.03 equiv). 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 heated to anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide (E)-N-[(2-chloropyrimidin-5-yl)methylene]hydroxylamine (4.6 g, crude product) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =158.

[0820] Step 2: Preparation of (Z)-2-chloro-N-hydroxypyrimidine-5-carbamidoyl chloride.

[0821]

[0822] 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 h. The mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with water (3×300 mL), brine (1×300 mL), and the organic phase was added to anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give (Z)-2-chloro-N-hydroxypyrimidine-5-carbimidoyl chloride (4.8 g, crude product) as a yellow solid. LCMS (ESI) m / z: [M+H] + =192.

[0823] Step 3: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate.

[0824]

[0825] A solution of (Z)-2-chloro-N-hydroxypyrimidine-5-carbimidoyl chloride (4.8 g, 25.00 mmol, 1 eq.) in EtOAc (80 mL) was stirred at 0 °C under a dry nitrogen atmosphere with NaHCO 3(3 g, 35.712 mmol, 1.43 equiv) for 30 min, followed by the addition of but-3-ynoic acid methyl ester (2.02 g, 20.591 mmol, 0.82 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (1 x 400 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 2-[3-(2-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.

[0826] Step 4: Preparation of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid.

[0827]

[0828] A solution of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (3 g, 11.828 mmol, 1 eq.) and NaOMe (1.92 g, 35.484 mmol, 3.00 eq.) in MeOH (50 mL) was stirred at room temperature under an atmosphere of dry nitrogen for 1 hour. The mixture was acidified to pH 6 with HCl (aqueous solution). The residue was dissolved in EtOAc (300 mL). The resulting mixture was washed with water (2×300 mL). The combined organic layers were washed with brine (1×300 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.5 g, crude product) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =236.

[0829] Step 5: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate

[0830]

[0831] A solution of [3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetic acid (2.4 g, 10.204 mmol, 1 equiv) and (trimethylsilyl)diazomethane (2.33 g, 20.408 mmol, 2 equiv) in DCM (20 mL) and MeOH (5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to afford 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.

[0832] Step 6: Preparation of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutyrate.

[0833]

[0834] A solution of methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]acetate (2.5 g, 10.031 mmol, 1 equiv) in THF (20 mL) was treated with t-BuOK (1.2 g, 10.694 mmol, 1.07 equiv) at 0 °C under a dry nitrogen atmosphere for 30 minutes, followed by the dropwise addition of 2-iodopropane (1.5 g, 8.824 mmol, 0.88 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 12 hours. The mixture was acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na 2 SO 4 2SO4. 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 afford methyl 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutyrate (310 mg, 10.08%) as a yellow oil. LCMS (ESI) m / z: [M+H] + = 292.

[0835] Step 7: Preparation of methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutyrate.

[0836]

[0837] 2-[3-(2-methoxypyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid methyl ester (200 mg, 0.687 mmol, 1 equivalent) and POCl 3 A solution of 1,4-dihydro-1,4-dihydro-2-nitropropene (1.9 mL, 20.61 mmol, 30 equiv) in DMF (1.5 mL) was stirred at 60 °C under a dry nitrogen atmosphere for 3 h. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine (2 x 100 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (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.

[0838] Preparation of 2-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(2-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)acetic acid (I-10)

[0839]

[0840] 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-butyl alcohol (2 mL) was added NaClO dropwise at 0 °C. 2 (50.19 mg, 0.550 mmol, 10.00 equiv) and NaH 2 PO 4 (78.77 mg, 0.550 mmol, 10.00 equiv) in water (2.00 mL). The mixture was stirred at 0 °C for 0.5 h, then warmed to room temperature and stirred for 1.5 h. The reaction was quenched by addition of saturated Na 2 S 2 O 3 The solution was quenched with a mixture of saline and CHCl 3 (20 mL × 3) extraction. The combined organic extracts were added to 2 SO4 Dry on ice, filter, concentrate in vacuo, and purify by silica gel chromatography (PE / EtOAc=1:1 to 1:3). This provides intermediate I-10 (15.80 mg, 49.93%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =557.

[0841] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1).

[0842] Preparation of 2-(6-(azetidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5)

[0843]

[0844] Step 1: Preparation of tert-butyl 3-[2-(4-amino-6-chloropyridazin-3-yl)ethynyl]azetidine-1-carboxylate (Intermediate 2)

[0845]

[0846] 3,6-dichloropyridazin-4-amine (2.87 g, 17.501 mmol, 1.00 equiv), Et 3 To a stirred solution of N (8.85 g, 87.505 mmol, 5 eq.) and tert-butyl 3-ethynylazetidine-1-carboxylate (3.49 g, 19.251 mmol, 1.1 eq.) in ACN (45 mL) was added Pd(PPh 3 ) 2 Cl 2 (2.46 g, 3.500 mmol, 0.2 eq) and CuI (0.67 g, 3.500 mmol, 0.2 eq). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 2 hours. After concentration under reduced pressure, the residue was purified by flash chromatography using the following conditions: column, silica gel; mobile phase, EA in PE, 10% to 50% gradient in 25 minutes; detector, UV 254 nm. This gave intermediate 2 (2.87 g, 53.11%) as a brownish yellow solid. LCMS (ESI) m / z [M+H] + =309.

[0847] Step 2: Preparation of tert-butyl 3-{3-chloro-5H-pyrrolo[3,2-c]pyridazin-6-yl}azetidine-1-carboxylate (Intermediate 3)

[0848]

[0849] Intermediate 2 (2.82 g, 9.133 mmol, 1.00 equiv) and K 2 CO 3 A solution of (3.79 g, 27.399 mmol, 3.00 equiv) in DMF (20 mL) was stirred at 60 °C for 2 h. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH 3 CN, 0% to 100% gradient in 25 minutes; detector, UV 254 nm. This gave intermediate 3 as a yellow solid (1.27 g, 45.10%). LCMS (ESI) m / z: [M+H] + =309.

[0850] Step 3: Preparation of tert-butyl 3-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carboxylate (Intermediate 4)

[0851]

[0852] Intermediate 3 (500 mg, 1.619 mmol, 1 eq), 2-hydroxyphenylboronic acid (670.06 mg, 4.857 mmol, 3 eq), XPhos Pd G3 (274.14 mg, 0.324 mmol, 0.2 eq) and Cs 2 CO 3 (1582.83 mg, 4.857 mmol, 3 eq.) in dioxane (5 mL) and H 2 The mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The resulting mixture was cooled to room temperature and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×30 mL) and then washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide intermediate 4 (702 mg) as a brown solid. LCMS (ESI) m / z: [M+H] + =367.

[0853] Step 4: Preparation of 2-(6-(azetidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5)

[0854]

[0855] A mixture of intermediate 4 (700 mg, 1.910 mmol, 1 eq) and TFA (1.00 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to provide intermediate 5 (150 mg, 29.48%) as a yellow solid. LCMS (ESI) m / z [M+H] + =267.

[0856] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl}azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1).

[0857]

[0858] Intermediate 5 (12.31 mg, 0.046 mmol, 1 eq), (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 (25 mg, 0.046 mmol, 1.00 eq) and NaOAc (3.79 mg, 0.046 mmol, 1.0 eq) were dissolved in DCM (1 mL) and CHCl. 3 The solution in OH (1 mL) was stirred at room temperature for 20 min. To the above mixture was added NaBH 3 CN (8.72 mg, 0.138 mmol, 3.0 equiv) and AcOH (catalytic). The resulting mixture was stirred at room temperature for 2 hours. 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, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3 CN; Flow rate: 25 mL / min; Gradient: 37% B to 43% B in 7 min; Detector, UV 254 / 220 nm. This gave compound 1 (11 mg, 29.50%) as a yellow solid. 1HNMR (300MHz, DMSO-d6) δ14.47 (brs, 1H), 12.05 (brs, 1H), 8.98 (s, 1H), 8.42 (d, J = 7.7Hz, 1H), 8.25 (d, J = 0.9Hz, 1H), 8.04 (dt, J = 8.3, 2.6Hz, 1H), 7. 48-7.40(m, 2H), 7.40-7.26(m, 3H), 7.01-6.92(m, 2H), 6.84(s, 1H), 6.09( s, 1H), 5.10 (d, J=3.5Hz, 1H), 4.92 (q, J=7.0Hz, 1H), 4.37 (t, J=7.9Hz, 1H), 4.28(brs, 1H), 4.17(t, J=5.4Hz, 2H), 3.89(q, J=7.2Hz, 1H), 3.78-3.62(m , 4H), 3.48-3.39 (m, 3H), 2.86 (t, J=5.4Hz, 2H), 2.45 (d, J=2.2Hz, 3H), 2.3 0-2.18 (m, 1H), 2.03 (t, J=9.8Hz, 1H), 1.78 (ddd, J=12.7, 8.1, 4.7Hz, 1H), 1.37 (d, J=7.0Hz, 3H), 0.96 (d, J=6.4Hz, 3H), 0.81 (dd, J=13.7, 6.7Hz, 3H). LCMS (ESI) m / z: [M+H]+=791.30.

[0859] The compounds in Table 4 were prepared using procedures analogous to those used above for the preparation of Compound 1 using the appropriate amine and aldehyde (or ketone).

[0860] Table 4.

[0861]

[0862]

[0863] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{3-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carbonyl}piperidin-1-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 6).

[0864]

[0865] To a stirred solution of 1-{5-[(2R)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl}piperidine-4-carboxylic acid (22.90 mg, 0.038 mmol, 1.00 equiv) in DMF (1.00 mL) was added PyBOP (58.62 mg, 0.114 mmol, 3.00 equiv) and DIEA (24.27 mg, 0.190 mmol, 5.00 equiv) at room temperature. To the above mixture was added Intermediate 5 (10.00 mg, 0.038 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by Prep-HPLC using the following conditions: column, Kinetex EVO C18 column, 21.2*150, 5 μm; mobile phase, water (10 mmol / L NH 4 HCO 3 ) and MeOH (55% MeOH up to 77% in 7 min); detector, UV 254 / 220 nm. This gave compound 6 (8.0 mg, 24.11%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ14.39 (s, 1H), 12.24 (s, 1H), 8.99 (s, 1H), 8.41 (d, J=7.7Hz, 1H), 8.29 (s, 1H), 8.07 (dd, J=8.4, 1.7Hz, 1H), 7.49-7.41 (m, 2H), 7.41-7.34(m, 2H), 7.34-7.28(m, 1H), 7.03-6.93(m, 3H), 6.16(s, 1H ), 5.11 (d, J = 3.7Hz, 1H), 4.97-4.86 (m, 1H), 4.66 (t, J = 8.5Hz, 1H), 4.48- 4.24(m, 4H), 4.23-4.12(m, 1H), 4.12-4.03(m, 1H), 3.76-3.62(m, 3H), 3 .58(d, J=10.0Hz, 1H), 3.50-3.39(m, 2H), 2.91-2.75(m, 2H), 2.46(s, 3H) , 2.30-2.11(m, 1H), 2.08-1.97(m, 1H), 1.85-1.66(m, 3H), 1.66-1.50(m, 2H), 1.38 (d, J=7.0Hz, 3H), 0.96 (t, J=6.7Hz, 3H), 0.82 (d, J=6.7Hz, 3H). LCMS (ESI) m / z: [M+H] + =858.20.

[0866] Using procedures analogous to those used above for the preparation of compound 6, the compounds in Table 5 were prepared using the appropriate amines and carboxylic acids.

[0867] Table 5.

[0868]

[0869] Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8).

[0870] Preparation of 2-(6-(azetidin-3-yl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 7)

[0871]

[0872] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (Intermediate 2)

[0873]

[0874] To a stirred mixture of 4-bromo-6-chloropyridazin-3-amine (10 g, 47.975 mmol, 1.00 equiv) and CuI (10.96 g, 57.570 mmol, 1.2 equiv) in THF (450 mL) was added CH 2 i 2 (15.42 g, 57.570 mmol, 1.2 eq) and t-BuONO (5.94 g, 57.570 mmol, 1.2 eq). The resulting mixture was stirred at 60 °C for 15 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography using the following conditions: column, silica gel; mobile phase, EtOAc in PE, 0% to 30% gradient in 20 minutes; detector, UV 254 nm. This gave intermediate 2 (6.9 g, 45.04%) as a yellow solid. LCMS (ESI) m / z [M+H] + =319.

[0875] Step 2: Preparation of tert-butyl 3-((4-bromo-6-chloropyridazin-3-yl)ethynyl)azetidine-1-carboxylate (Intermediate 3)

[0876]

[0877] To a stirred mixture of intermediate 2 (1.6 g, 5.011 mmol, 1.00 equiv) and tert-butyl 3-ethynylazetidine-1-carboxylate (1.36 g, 7.517 mmol, 1.50 equiv) in toluene (10 mL) was added CuI (0.19 g, 1.002 mmol, 0.2 equiv) and Pd(PPh 3 ) 2 Cl 2 (0.70 g, 1.002 mmol, 0.2 eq.). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography using the following conditions: column, silica gel; mobile phase, EtOAc in PE, 0% to 40% gradient in 10 minutes; detector, UV 254 nm. This gave intermediate 3 as a yellow solid (786 mg, 42.09%). LCMS (ESI) m / z: [M+H] + =372.

[0878] Step 3: Preparation of tert-butyl 3-((6-chloro-4-(methylamino)pyridazin-3-yl)ethynyl)azetidine-1-carboxylate (Intermediate 4)

[0879]

[0880] To a stirred mixture of intermediate 3 (786 mg, 2.109 mmol, 1.00 equiv) and DIEA (0.82 g, 6.327 mmol, 3 equiv) in NMP (13 mL) was added methylamine hydrochloride (0.21 g, 3.163 mmol, 1.5 equiv). The resulting mixture was stirred at 100 °C for 2 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave intermediate 4 (598 mg, 87.83%) as a yellow solid. LCMS (ESI) m / z [M+H] + =323.

[0881] Step 4: Preparation of tert-butyl 3-(3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 5)

[0882]

[0883] To a stirred mixture of intermediate 4 (420 mg, 0.620 mmol, 1.00 equiv) in DMF (2 mL) was added K 2 CO 3(256.90 mg, 1.860 mmol, 3 eq.). The resulting mixture was stirred at 60°C for 2 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave intermediate 5 (164 mg, 39.05%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =323.

[0884] Step 5: Preparation of tert-butyl 3-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 6)

[0885]

[0886] Intermediate 5 (80 mg, 0.248 mmol, 1.00 equiv) and 2-hydroxyphenylboronic acid (102.55 mg, 0.744 mmol, 3 equiv) were dissolved in dioxane (3.33 mL) and H 2 To the stirred solution in O (0.67 mL) was added Cs 2 CO 3 (242.25 mg, 0.744 mmol, 3 eq.) and XPhos Pd G3 (41.96 mg, 0.050 mmol, 0.20 eq.). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave intermediate 6 (74.2 mg, 78.69%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =381.

[0887] Step 6: Preparation of 2-(6-(azetidin-3-yl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 7)

[0888]

[0889] A mixture of intermediate 6 (74.8 mg, 0.197 mmol, 1.00 equiv) in TFA (1.5 mL) and DCM (0.5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to provide intermediate 7. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =281.

[0890] Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8).

[0891]

[0892] To a stirred mixture 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 (26 mg, 0.048 mmol, 1.00 equiv) and Intermediate 7 (18.74 mg, 0.067 mmol, 1.39 equiv) in DCM (1 mL) and MeOH (1 mL) was added AcOH (catalytic). The mixture was stirred at room temperature for 2 h. To the mixture was added NaBH 3 CN (9.07 mg, 0.144 mmol, 3 equivalents). The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by Prep-HPLC using the following conditions: column, XBridge Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase, water (10 mmol / L NH 4 HCO 3 ) and CH 3 CN (34% CH in 8 minutes 3 CN up to 55%). This gave compound 8 (21.8 mg, 55.69%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ14.62 (s, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 8.42 (d, J = 7.6Hz, 1H), 8.21-8.12 (m, 1H), 7.48-7.41 (m, 2H), 7.40-7.28 (m, 3H), 7.04-6.91 (m, 3H), 6.10 (s, 1H), 5.10 (d, J=3.7Hz, 1H), 4.92 (t, J=7.1Hz, 1H), 4.38 (t, J=7.8Hz, 1H), 4.29 (s, 1H), 4.16 (t, J=5.3H z, 2H), 4.02 (t, J=7.6Hz, 1H), 3.84 (t, J=7.2Hz, 2H), 3.79-3.69 (m, 5H), 3.69-3.63 (m, 1H), 3.50-3.37 (m, 2H), 2.84 (t, J=5.5Hz, 2H), 2.4 9-2.43 (m, 3H), 2.29-2.19 (m, 1H), 2.06-1.97 (m, 1H), 1.86-1.74 (m, 1H), 1.50-1.34 (m, 3H), 0.96 (d, J=6.4Hz, 3H), 0.81 (d, J=6.7Hz, 3H). LCMS(ESI)m / z:[M+H] + =805.34.

[0893] Using procedures analogous to those used above for the preparation of compound 8, the compounds in Table 6 were prepared using the appropriate amine and aldehyde (or ketone).

[0894] Table 6.

[0895]

[0896]

[0897] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(4-{3-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]azetidine-1-carbonyl}piperidin-1-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 13).

[0898]

[0899] To a stirred mixture of 1-{5-[(2R)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl}piperidine-4-carboxylic acid (20 mg, 0.033 mmol, 1 eq) and Intermediate 7 (11.95 mg, 0.043 mmol, 1.3 eq) in DMF (1 mL) was added PyBOP (34.14 mg, 0.066 mmol, 2 eq) and DIEA (12.72 mg, 0.099 mmol, 3 eq). The resulting mixture was stirred at room temperature for 1.5 hours. The mixture was purified by Prep-HPLC using the following conditions: column, SunFire Prep C188 OBD column, 19*150 mm, 5 μm; mobile phase, water (0.1% NH 4 HCO 3 ) and CH 3 CN (13% CH in 7 minutes 3 CN up to 47%). This gave compound 13 (15.3 mg, 52.04%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ14.56 (s, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 8.40 (d, J=7 .7Hz, 1H), 8.21-8.14(m, 1H), 7.50-7.41(m, 2H), 7.40-7.29(m, 3H), 7.14(s, 1 H), 7.03-6.95 (m, 2H), 6.16 (s, 1H), 5.11 (d, J=3.8Hz, 1H), 4.91 (t, J=7.3Hz, 1H), 4.74 (t, J=8.6Hz, 1H), 4.52 (t, J=7.4Hz, 1H), 4.43-4.33 (m, 2H), 4.31-4. 26 (m, 2H), 4.15-4.07 (m, 1H), 3.77 (s, 3H), 3.75-3.63 (m, 3H), 3.58 (d, J=9.9 Hz, 1H), 3.44 (d, J=10.9Hz, 1H), 2.82 (q, J=11.0Hz, 2H), 2.46 (d, J=1.7Hz, 3H) , 2.24-2.20(m, 2H), 2.04-1.97(m, 1H), 1.86-1.64(m, 3H), 1.56(t, J=12.8Hz , 2H), 1.38 (d, J=7.0Hz, 3H), 1.00-0.92 (m, 3H), 0.82 (dd, J=15.2, 6.7Hz, 3H). LCMS(ESI)m / z:[M+H]+ =872.38.

[0900] Using procedures analogous to those used above for the preparation of compound 13, the compounds in Table 7 were prepared using the appropriate amines and carboxylic acids.

[0901] Table 7.

[0902]

[0903] Preparation of (2S,4R)-1-((R)-2-(3-(2-(3-(5-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14)

[0904]

[0905] Step 1: Preparation of tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 2).

[0906]

[0907] To tert-butyl 3-{3-chloro-5H-pyrrolo[3,2-e]pyridazin-6-yl}azetidine-1-carboxylate (500.00 mg, 1.619 mmol, 1 eq.) and 2-(methoxymethoxy)phenylboronic acid (442.03 mg, 2.429 mmol, 1.5 eq.) in dioxane (10.00 mL) and H 2 Cs was added to the solution in O (2.00 mL) 2 CO 3 (1055.22 mg, 3.238 mmol, 2.0 equiv) and XPhos Pd G3 (137.07 mg, 0.162 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. 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, CH 3 CN, 0% to 100% gradient in 25 minutes; detector, UV 254 nm. This gave Intermediate 2 (390 mg, 53.39%) as a tan solid. LCMS (ESI) m / z: [M+H] + =411.5.

[0908] Step 2: Preparation of tert-butyl 3-(5-(difluoromethyl)-3-(2-(methoxymethoxy)phenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 3).

[0909]

[0910] Intermediate 2 (120.00 mg, 0.292 mmol, 1 eq.) and (bromodifluoromethyl)trimethylsilane (29.69 mg, 0.146 mmol, 0.5 eq.) were reacted in CH 3 To the stirred mixture in CN (5.00 mL) was added t-BuOK (98.41 mg, 0.876 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with MeOH at room temperature. The resulting mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave intermediate 3 (16 mg, 10.34%) as a brown oil. LCMS (ESI) m / z: [M+H] + =461.5.

[0911] Step 3: Preparation of 2-(6-(azetidin-3-yl)-5-(difluoromethyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 4).

[0912]

[0913] To a stirred solution of intermediate 3 (24.00 mg, 0.052 mmol, 1 eq.) in DCM (1.00 mL) was added TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 minutes; detector, UV 254 nm. This gave intermediate 4 (12 mg, 71.33%) as a yellow-green oil. LCMS (ESI) m / z: [M+H] + =317.3.

[0914] Step 4: Preparation of (2S,4R)-1-((R)-2-(3-(2-(3-(5-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14).

[0915]

[0916] To a stirred mixture of intermediate 4 (10.00 mg, 0.032 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 (17.09 mg, 0.032 mmol, 1.0 eq) in MeOH (1.00 mL) and DCM (1.00 mL) was added AcOH (catalytic) and NaBH 3 CN (5.96 mg, 0.096 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1.00 mL) and purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3 CN; Flow rate: 25 mL / min; Gradient: 38% B to 60% B in 7 min; Detector, UV 254 / 220 nm. This gave compound 14 (6.9 mg, 23.72%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ13.47 (s, 1H), 8.98 (d, J = 1.7Hz, 1H), 8.69 (s, 1H), 8.41 (d, J = 7.7Hz, 1H), 8.19-8.00 (m, 2H), 7.47-7.42 (m, 2H), 7.40-7.31 ( m, 3H), 7.24 (s, 1H), 7.06-6.97 (m, 2H), 6.08 (d, J=10.5Hz, 1H), 5.10 (d, J =3.7Hz, 1H), 4.91 (t, J = 7.1Hz, 1H), 4.37 (t, J = 7.9Hz, 1H), 4.28 (s, 1H), 4. 22-4.11 (m, 2H), 4.05 (t, J=7.4Hz, 1H), 3.80 (t, J=7.2Hz, 2H), 3.74-3.60 (m, 2H), 3.49-3.37 (m, 3H), 2.84 (t, J = 5.3Hz, 2H), 2.45 (d, J = 3.0Hz, 3H), 2 .26-2.19 (m, 1H), 2.03 (t, J=9.9Hz, 1H), 1.78 (ddd, J=12.7, 7.9, 4.7Hz, 1H ), 1.45-1.36 (m, 3H), 0.96 (d, J=6.5Hz, 3H), 0.81 (dd, J=13.8, 6.6Hz, 3H). LCMS (ESI) m / z: [M+H] + =841.3.

[0917] Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, formic acid (Compound 16).

[0918]

[0919] Step 1: Preparation of tert-butyl 3-((6-chloro-4-(oxetan-3-ylamino)pyridazin-3-yl)ethynyl)azetidine-1-carboxylate (Intermediate 2)

[0920]

[0921] A mixture of tert-butyl 3-((4-bromo-6-chloropyridazin-3-yl)ethynyl)azetidine-1-carboxylate (350 mg, 0.939 mmol, 1 eq.), oxetane-3-amine (102.98 mg, 1.408 mmol, 1.5 eq.) and DIEA (364.16 mg, 2.817 mmol, 3.0 eq.) in NMP (4 mL) was stirred at 100 °C under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to provide intermediate 2 (300 mg, 87.55%) as a yellow solid. LCMS (ESI) m / z [M+H] + =365.

[0922] Step 2: Preparation of tert-butyl 3-(3-chloro-5-(oxetane-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 3)

[0923]

[0924] Intermediate 2 (170 mg, 0.466 mmol, 1 eq.) and K 2 CO 3 A mixture of (193.20 mg, 1.398 mmol, 3 eq.) in DMF (3 mL) was stirred at 60 °C under nitrogen overnight. 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 in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This gave intermediate 3 (150 mg, 88.24%) as a white solid. LCMS (ESI) m / z [M+H] + =365.

[0925] Step 3: Preparation of tert-butyl 3-(3-(2-hydroxyphenyl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidine-1-carboxylate (Intermediate 4)

[0926]

[0927] Intermediate 3 (145 mg, 0.397 mmol, 1 eq.), 2-hydroxyphenylboronic acid (191.87 mg, 1.389 mmol, 3.5 eq.), XPhos Pd G3 (33.64 mg, 0.040 mmol, 0.1 eq.) and Cs 2 CO 3 (388.49 mg, 1.191 mmol, 3 eq.) in dioxane (2.5 mL) and H2 The solution in 4% 4-(2-[ ...4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4-(2-4- + =423.

[0928] Step 4: Preparation of 2-(6-(azetidin-3-yl)-5-(oxetane-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5)

[0929]

[0930] A solution of intermediate 4 (150 mg, 0.355 mmol, 1 eq.) in TFA (1 mL) and DCM (4 mL) was stirred at 0 °C under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. This gave intermediate 5 (330 mg, crude) as a black solid. LCMS (ESI) m / z [M+H] + =323.

[0931] Step 5: Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(3-(3-(2-hydroxyphenyl)-5-(oxetan-3-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, formic acid (Compound 16).

[0932]

[0933] To a stirred solution of intermediate 5 (13.88 mg, 0.230 mmol, 5 equiv) and (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 (25 mg, 0.046 mmol, 1.00 equiv) in MeOH (1 mL) and DCM (1 mL) were added AcOH (one drop) and NaBH 3CN (7.26 mg, 0.115 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was purified by Prep-HPLC. This gave compound 16 (5.8 mg, 14.68%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 13.89 (brs, 1H), 8.98 (s, 1H), 8.64 (s, 1H), 8.42 (d, J = 7.5Hz, 1H), 8.29 (FA salt, 1H), 7.98 (d, J = 7.3Hz, 1H), 7.44 (d, J = 8.0Hz, 2H), 7.34 (dd, J=15.9, 7.6Hz, 3H), 7.05-6.97 (m, 3H), 6.09 (s, 1H), 5.54 (s, 1H), 5.18-5.05 (m, 5H), 4.92 (d, J=7.2Hz, 1H), 4.37 (t, J= 7.6Hz, 1H), 4.28 (s, 1H), 4.15 (d, J=5.3Hz, 2H), 3.98 (s, 1H), 3.80 (t, J=7.4Hz, 3H), 3.65 (d, J=9.8Hz, 2H), 2.82 (s, 2H), 2.45 (d, J=2.4Hz, 2H ), 2.25 (s, 3H), 2.03 (s, 1H), 1.45 (d, J=6.8Hz, 1H), 1.38 (d, J=6.9Hz, 1H), 1.15 (s, 3H), 0.96 (d, J=6.6Hz, 3H), 0.81 (dd, J=13.6, 6.7Hz, 3H). LCMS(ESI)m / z[M+H] + =847.40.

[0934] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 17)

[0935] Preparation of 2-[6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 5)

[0936]

[0937] Step 1: Preparation of tert-butyl 4-[(4-amino-6-chloropyridazin-3-yl)ethynyl]piperidine-1-carboxylate (Intermediate 2)

[0938]

[0939] To a stirred mixture of 3,6-dichloropyridazin-4-amine (2 g, 12.196 mmol, 1 eq.) and tert-butyl 4-ethynylpiperidine-1-carboxylate (3.06 g, 14.635 mmol, 1.2 eq.) in toluene (30 mL) at room temperature under nitrogen atmosphere were added CuI (0.46 g, 2.439 mmol, 0.2 eq.) and Pd(PPh 3 ) 2 Cl 2 (0.86 g, 1.220 mmol, 0.1 eq.) To the above mixture was added Et 3 N (6.17 g, 60.980 mmol, 5.0 equiv). The resulting mixture was stirred at 80 °C for another 3 hours. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×30 mL) and then washed with anhydrous Na 2 SO 4 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, MeOH in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This gave intermediate 2 (2.1 g, 51.12%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =337.

[0940] Step 2: Preparation of tert-butyl 4-{3-chloro-5H-pyrrolo[3,2-c]pyridazin-6-yl}piperidine-1-carboxylate (Intermediate 3)

[0941]

[0942] Intermediate 2 (1 g, 2.969 mmol, 1 eq.) and K 2 CO 3 A mixture of (2.05 g, 14.845 mmol, 5.0 equiv) in DMF (5 mL) was stirred at 60 °C under nitrogen atmosphere for 24 hours. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×30 mL) and then washed with anhydrous Na 2 SO 4After 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, 10% to 50% gradient in 10 minutes; detector, UV 254nm. This gave intermediate 3 (433mg, 43.30%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =337.

[0943] Step 3: Preparation of tert-butyl 4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 4)

[0944]

[0945] To a stirred mixture of intermediate 3 (200 mg, 0.594 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (204.75 mg, 1.485 mmol, 2.5 eq.) in dioxane (5 mL) at room temperature under nitrogen atmosphere were added XPhosPd G3 (100.52 mg, 0.119 mmol, 0.2 eq.) and Cs 2 CO 3 (773.87 mg, 2.376 mmol, 4.0 equiv.) To the above mixture was added H dropwise at room temperature. 2 O (0.5 mL). The resulting mixture was stirred at 80 ° C for another 3 hours. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×30 mL) and then washed with anhydrous Na 2 SO 4 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, 10% to 50% gradient in 10 minutes; detector, UV 254nm. This gave intermediate 4 (130mg, 55.50%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =395.

[0946] Step 4: Preparation of 2-[6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 5)

[0947]

[0948] A mixture of intermediate 4 (50 mg, 0.127 mmol, 1 eq.) and TFA (0.24 mL) in DCM (2 mL) was stirred at room temperature for 1 hour. 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] + =295.

[0949] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 17)

[0950]

[0951] A mixture 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 (20 mg, 0.037 mmol, 1 eq) and Intermediate 5 (13.07 mg, 0.044 mmol, 1.2 eq) in DMF (0.6 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. To the above mixture was added NaBH(OAc) portionwise over 1 minute at room temperature. 3 (23.52 mg, 0.111 mmol, 3.0 equivalents). The resulting mixture was stirred at room temperature for another 2 hours. The mixture was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3CN; flow rate: 25 mL / min; gradient: 42% B to 55% B in 7 minutes; detector, UV 254 / 220 nm. This gave compound 17 (7.1 mg, 23.43%) as a white solid. 1H NMR (400MHz, methanol-d4) δ8.85(d, J=13.5Hz, 1H), 8.18-8.10(m, 1H), 7.95-7.88(m, 1H), 7.46-7.27(m, 5H), 7.03-6.94(m, 2H), 6.65(d , J=3.9Hz, 1H), 6.01 (d, J=24.1Hz, 1H), 5.05-5.00 (m, 1H), 4.60-4.51 (m, 1H), 4.44-4.39 (m, 3H), 3.84 (dd, J=10.8, 4.2Hz, 1H), 3.7 7-3.66 (m, 1H), 3.62 (d, J=10.9Hz, 1H), 3.17 (d, J=11.5Hz, 2H), 2.93-2.85 (m, 3H), 2.48 (s, 3H), 2.36 (t, J=11.8Hz, 3H), 2.14 (d, J= 13.1Hz, 3H), 1.95 (ddt, J=12.7, 8.9, 4.3Hz, 3H), 1.55 (dd, J=31.9, 7.0Hz, 3H), 1.06 (d, J=6.6Hz, 3H), 0.91 (dd, J=9.2, 6.6Hz, 3H). LCMS(ESI)m / z:[M+H] + =819.40.

[0952] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 18) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 19).

[0953]

[0954] Step 1: Preparation of methyl 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 6)

[0955]

[0956] To a stirred solution of intermediate 5 (500 mg, 1.70 mmol, 1 eq.) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (503 mg, 1.70 mmol, 1.00 eq.) in DMSO (5 mL) was added DIEA (1.09 g, 8.50 mmol, 5.00 eq.). The resulting mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), 0% to 100% gradient in 40 minutes; detector, UV 254 nm. This gave intermediate 6 (200 mg, 42.54%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =554.

[0957] Step 2: Preparation of 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 7)

[0958]

[0959] A solution of intermediate 6 (200 mg, 0.361 mmol, 1 eq) and LiOH (86.52 mg, 3.610 mmol, 10 eq) in MeOH (6 mL) and H2O (1.5 mL) was stirred at 40°C for 2 hours. The mixture was acidified to pH 6 with HCl (aq). The precipitated solid was collected by filtration and washed with water (3 x 2 mL). This gave intermediate 7 (102 mg, 52.33%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =540.

[0960] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1 8) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 19).

[0961]

[0962] To a stirred solution of intermediate 7 (68 mg, 0.126 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (45.94 mg, 0.139 mmol, 1.1 eq) in DMF (2 mL) was added PyBOP (131.16 mg, 0.252 mmol, 2 eq) and DIEA (48.86 mg, 0.378 mmol, 3 eq). The resulting mixture was stirred at room temperature for 2 hours. 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 NH4HCO3), gradient 10% to 80% in 10 minutes; detector, UV 254 nm. The residue was then purified by chiral 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: 20% B to 50% B in 15 minutes; detector, UV 254 / 220 nm. This gave:

[0963] Compound 18 (27.3 mg, 24.79%) as off-white solid. NMR (400MHz, DMSO-d6) δ14.49 (s, 1H), 12.07 (s, 1H), 8.92 (d, J = 56.8Hz, 3H), 8.44 (d, J = 7.7Hz, 1H), 8.23 ​​(s, 1H), 8.05 (dd, J = 8.5, 1.7Hz, 1H), 7.49-7. 34 (m, 4H), 7.30 (td, J=7.6, 1.6Hz, 1H), 7.00-6.91 (m, 3H), 6.75 (d, J=2.4H z, 1H), 5.11 (d, J=3.6Hz, 1H), 4.91 (t, J=9.7Hz, 3H), 4.39 (t, J=7.9Hz, 1H), 4.30 (s, 1H), 3.85 (d, J=9.8Hz, 1H), 3.76 (dd, J=10.4, 4.4Hz, 1H), 3.51 (d, J=10.6Hz, 1H), 3.17(t, J=12.5Hz, 3H), 2.45(d, J=6.6Hz, 3H), 2.36-2.30(m , 1H), 2.17 (d, J=12.7Hz, 2H), 2.04 (t, J=10.6Hz, 1H), 1.85-1.70 (m, 3H), 1 .45-1.36 (m, 3H), 1.02 (dd, J=6.7, 4.2Hz, 3H), 0.85 (dd, J=8.8, 5.9Hz, 3H). LCMS (ESI) m / z: [M+H]+=853.35.

[0964] Compound 19 (13.5 mg, 12.52%) was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.49 (d, J = 3.8 Hz, 1H), 12.06 (s, 1H), 8.98 (d, J = 18.7 Hz, 1H), 8.83 (d, J = 18.0 Hz, 2H), 8.29 (d, J = 7.9 Hz, 1H), 8.23 ​​(s, 1H), 8.09-8.02 (m, 1H), 7.53-7.41 (m, 1H), 7.40-7.26 (m, 4H), 7.00-6.91 (m, 3H), 6.75 (s, 1H), 5.14 (d, J = 3.6 Hz, 1H), 5.05-4.81 (m, 3H) , 4.45 (t, J=7.7Hz, 1H), 4.29 (s, 1H), 3.95 (d, J=9.0Hz, 1H), 3.64-3.58 (m, 2H), 3.17 (t, J=12.4Hz, 3H), 2.41 (s, 3H), 2.36-2.29 (m, 1H), 2. 16 (d, J=12.5Hz, 2H), 2.11-2.02 (m, 1H), 1.78 (dd, J=16.5, 8.9Hz, 3H), 1.34 (d, J=7.0Hz, 3H), 1.01 (d, J=6.6Hz, 2H), 0.87 (t, J=6.4Hz, 4H). LCMS(ESI)m / z:[M+H] + =853.35.

[0965] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 20)

[0966] Preparation of 2-(5-methyl-6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 4).

[0967]

[0968] Step 1: Preparation of tert-butyl 4-(3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 2).

[0969]

[0970] To intermediate 1 (380 mg, 1.128 mmol, 1 eq) and Cs 2 CO 3 To a stirred mixture of 1.1 g, 3.384 mmol, 3 eq. was added MeI (240.20 mg, 1.692 mmol, 1.5 eq.) in DMF (4 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH 3 CN, 0% to 50% gradient in 20 min; detector, UV 254 nm. This afforded intermediate 2 (196 mg, 49.52%) as a yellow-green solid. LCMS (ESI) m / z [M+H] + = 351.

[0971] Step 2: Preparation of tert-butyl 4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidine-1-carboxylate (Intermediate 3).

[0972]

[0973] Intermediate 2 (180 mg, 0.513 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (212.29 mg, 1.539 mmol, 3 eq.) were dissolved in dioxane (4.17 mL) and H 2 To the stirred mixture in 2% O (0.83 mL) were added XPhos Pd G3 (87.1 mg, 0.103 mmol, 0.2 eq) and Cs 2 CO 3 (501.48 mg, 1.539 mmol, 3 eq.). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 1.5 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH 3 CN, 0% to 60% gradient in 23 minutes; detector, UV 254 nm. This gave intermediate 3 as a yellow-green solid (112 mg, 53.44%). LCMS (ESI) m / z: [M+H] + =409.

[0974] Step 3: Preparation of 2-(5-methyl-6-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 4).

[0975]

[0976] A mixture of intermediate 3 (112 mg, 0.274 mmol, 1 eq.) in TFA (3 mL) and DCM (1 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This gave intermediate 4 (159 mg, crude) as a brownish yellow solid. LCMS (ESI) m / z: [M+H]+=309.

[0977] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 20).

[0978]

[0979] A mixture of intermediate 4 (15 mg, 0.049 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 (31.56 mg, 0.059 mmol, 1.2 eq) in DMF (0.5 mL) was stirred at room temperature for 1 hour. To the above mixture was added NaBH(OAc) in portions at room temperature. 3 (30.93 mg, 0.147 mmol, 3 equivalents). The resulting mixture was stirred at room temperature for another 2 hours. The mixture was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3CN; flow rate: 25 mL / min; gradient: 45% B to 70% B in 7 minutes; detector, UV 254 / 220 nm. This gave compound 20 (12.6 mg, 31.10%) as a white solid. 1H NMR (400MHz, methanol-d4) δ8.85 (d, J=15.2Hz, 1H), 8.36-8.29 (m, 1H), 8.03 (d, J=8.2Hz, 1H), 7.48-7.34 (m, 4H), 7.34-7.26 (m, 1H), 7 .03-6.94 (m, 2H), 6.70 (d, J=3.6Hz, 1H), 6.04 (s, 1H), 5.04-5.00 (m, 1H), 4.54-4.50 (m, 1H), 4.44-4.38 (m, 3H), 3.88 (s, 2H), 3. 86-3.82 (m, 1H), 3.70-3.61 (m, 2H), 3.35 (s, 1H), 3.21-3.19 (d, J=11.1Hz, 2H), 3.02-2.95 (m, 1H), 2.90-2.87 (m, 2H), 2.48-2.4 5 (m, 3H), 2.42-2.34 (m, 3H), 2.20-2.08 (m, 3H), 2.01-1.84 (m, 3H), 1.60-1.52 (m, 3H), 1.06 (d, J=6.5Hz, 3H), 0.93-0.89 (m, 3H). LCMS (ESI) m / z: [M+H]+=833.3.

[0980] Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 21) and (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 22).

[0981]

[0982] Step 1: Preparation of methyl 2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 5)

[0983]

[0984] A solution of intermediate 4 (100 mg, 0.324 mmol, 1 eq), 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid methyl ester (86.80 mg, 0.324 mmol, 1 eq) and DIEA (209 mg, 1.62 mmol, 5 eq) in DMF (2 mL) was stirred at 120 ° C for 2 hours. The resulting mixture was cooled to room temperature and then diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (50 mL) and then washed with anhydrous Na 2 SO 4 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, CH 3 CN, 0% to 50% gradient in 30 min; detector, UV 254 nm. This afforded intermediate 5 (98 mg, 53.24%). LCMS (ESI) m / z: [M+H]+=568.

[0985] Step 2: Preparation of 2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 6)

[0986]

[0987] Intermediate 5 (95 mg, 0.167 mmol, 1 eq.) and LiOH (8.02 mg, 0.334 mmol, 2 eq.) were reacted in H 2 A solution of 1% O (1 mL) and MeOH (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and then washed with anhydrous Na 2 SO 4 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, CH 3CN (0.1% FA), gradient 10% to 50% in 25 min; detector, UV 254 nm. This afforded intermediate 6 (76 mg, 82.03%). LCMS (ESI) m / z: [M+H]+=554.

[0988] Step 3: Preparation of (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 2 1) and (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(3-(2-hydroxyphenyl)-5-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)piperidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 22).

[0989]

[0990] A solution of intermediate 6 (76 mg, 0.153 mmol, 1 eq) in DMF (1 mL) was treated with (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (96.08 mg, 0.289 mmol, 1.9 eq), PyBOP (142.4 mg, 0.274 mmol, 1.8 eq) and DIEA (49.96 mg, 0.386 mmol, 2.5 eq) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3 CN; Flow rate: 25 mL / min; Gradient: 46% B to 63% B in 7 minutes, then 63% B; Detector, UV 254 / 220 nm. The residue was then purified by chiral HPLC using the following conditions: Column, CHIRALPAK ID-3, 4.6*50 mm, 3 μm; Mobile phase A: MtBE (0.1% DIEA), Mobile phase B: MeOH; Flow rate: 1.67 mL / min; Gradient: 20% B to 50% B. This gave:

[0991] Compound 21 (10.3 mg, 6.07%) as white solid. 1 H NMR (300MHz, DMSO-d6) δ14.70 (s, 1H), 9.06 (s, 1H), 8.92 (d, J=2.3Hz, 2H), 8.68 (s, 1H), 8.51-8.41 (m, 1H), 8.23-8.07 (m, 1H), 7.55-7.32 (m, 5H), 6.92 (s, 2H), 6.85 (s, 1H), 5.19 (d, J=3.6Hz, 1H), 5.02-4.82 (m, 3H), 4.52-4.21 (m, 2H), 4.99 (s, 3H), 3.88-3 .85 (m, 1H), 3.80-3.70 (m, 1H), 3.58-3.45 (m, 1H), 3.23 (d, J = 12.4Hz, 2H), 2.53 (d, J = 5.0Hz, 3H), 2.41-2.23 (m, 1H), 2.22-2.0 9 (m, 2H), 2.11 (t, J=10.6Hz, 1H), 1.93-1.65 (m, 3H), 1.56-1.53 ​​(m, 1H), 1.41-1.35 (m, 3H), 1.15 (s, 1H), 1.09 (d, J=6.4Hz, 3H). LCMS(ESI)m / z: [M+H]+=867.3

[0992] Compound 22 (7.9 mg, 4.66%) as white solid. 1H NMR (300MHz, DMSO-d6) δ14.70 (s, 1H), 9.06-8.91 (m, 1H), 8.90 (d, J = 14.5Hz, 2H), 8.69 (s, 1H), 8.38-8.06 (m, 2H), 7.59-7.4 5(m, 1H), 7.43-7.28(m, 4H), 7.06-6.95(m, 2H), 6.85(s, 1H), 5.21(s, 1H), 5.03-4.80(m, 3H), 4.7-3.48(m, 1H), 4.37(s, 1H) , 4.03 (s, 4H), 3.70-3.60 (s, 1H), 3.57-3.50 (m, 1H) 3.23-3.15 (m, 2H), 2.42-2.39 (m, 3H), 2.23-2.01 (m, 3H), 1.91-1.65 (m, 3H), 1.52-1.48 (m, 1H), 1.45-1.41 (m, 1H), 1.41-1.31 (m, 2H), 1.28-1.21 (m, 1H), 1.09 (d, J=6.6Hz, 3H), 0.91-0.81 (m, 4H). LCMS (ESI) m / z: [M+H]+=867.3.

[0993] Preparation of (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 23) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 24).

[0994]

[0995] Step 1: Preparation of 3,6-dichloro-N-ethylpyridazin-4-amine (Intermediate 2).

[0996]

[0997] To a stirred mixture of 4-bromo-3,6-dichloropyridazine (10 g, 43.885 mmol, 1 eq) and ethylamine hydrochloride (4.29 g, 52.662 mmol, 1.2 eq) in NMP (100 mL) was added DIEA (17.02 g, 131.655 mmol, 3 eq) dropwise at room temperature. After stirring at 100 °C for 1 hour, the mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (500 mL) and subsequently washed with water (3 x 300 mL). The organic layer was washed with anhydrous Na 2 SO 4 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]+=192.

[0998] Step 2: Preparation of tert-butyl 4-([6-chloro-4-(ethylamino)pyridazin-3-yl]ethynyl)piperidine-1-carboxylate (Intermediate 3).

[0999]

[1000] Intermediate 2 (8.7 g, 45.303 mmol, 1 eq.) and tert-butyl 4-ethynylpiperidine-1-carboxylate (11.38 g, 54.364 mmol, 1.2 eq.) were reacted in CH 3 Et 3 N (13.75 g, 135.909 mmol, 3 eq.), Pd(PPh 3 ) 2 Cl 2 (6.36 g, 9.061 mmol, 0.2 eq) and CuI (1.73 g, 9.061 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 silica gel column chromatography eluted with PE / EA (3:7) to provide intermediate 3 (13.4 g, 72.96%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=365.

[1001] Step 3: Preparation of tert-butyl 4-{3-chloro-5-ethylpyrrolo[3,2-c]pyridazin-6-yl}piperidine-1-carboxylate (Intermediate 4).

[1002]

[1003] To a stirred mixture of intermediate 3 (14 g, 38.370 mmol, 1 eq) in DMF (100 mL) was added K 2 CO 3(10.61 g, 76.740 mmol, 2 eq.). After stirring at 60 °C for 3 h, the mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (500 mL) and then washed with water (3×300 mL). The organic layer was concentrated to anhydrous Na 2 SO 4 The product was dried over medium. After filtration, the filtrate was concentrated under reduced pressure. EA (100 mL) was added to the residue and the mixture was stirred at 0°C for 30 minutes. The precipitated solid was collected by filtration and washed with EtOAc (3×20 mL) to provide intermediate 4 (10 g, 67.86%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=365.

[1004] Step 4: Preparation of tert-butyl 4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 5).

[1005]

[1006] Intermediate 4 (5 g, 13.704 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (5.67 g, 41.112 mmol, 3 eq.) were dissolved in dioxane (50 mL) and H 2 Cs was added to the solution in O (10 mL) 2 CO 3 (13.39 g, 41.112 mmol, 3 eq) and XPhos Pd G3 (2.32 g, 2.741 mmol, 0.2 eq). After stirring at 100 °C under nitrogen atmosphere for 3 hours, the mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were stirred in anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (50 mL). This gave Intermediate 5 (2.9 g, 47.58%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=423.

[1007] Step 5: Preparation of 2-[5-ethyl-6-(piperidin-4-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 6).

[1008]

[1009] To a stirred mixture of intermediate 5 (2.9 g, 6.863 mmol, 1 eq.) in DCM (10 mL) was added TFA (3.00 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This gave intermediate 6 (2.4 g, 97.61%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=323.

[1010] Step 6: Preparation of methyl 2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 7)

[1011]

[1012] To a stirred mixture of intermediate 6 (322 mg, 0.999 mmol, 1 eq.) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (295.34 mg, 0.999 mmol, 1 eq.) in DMSO (3 mL) was added DIEA (645.41 mg, 4.995 mmol, 5 eq.) dropwise. The resulting mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and the product was precipitated by the addition of water (10 mL). The precipitated solid was collected by filtration and washed with water (3 x 10 mL). This gave intermediate 7 (210 mg, 34.34%) as an off-white solid. LCMS (ESI) m / z: [M+H]+=582.

[1013] Step 7: Preparation of 2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 8)

[1014]

[1015] Intermediate 7 (210 mg, 0.361 mmol, 1 eq) was dissolved in MeOH (4 mL) and H 2 To the stirred mixture in 4% 4-nitropropene (1 mL) was added LiOH (86.47 mg, 3.610 mmol, 10 equiv). After stirring at 40°C for 2 h, the mixture was cooled to room temperature. The mixture was acidified to pH 6 with 4M HCl (aq). The precipitated solid was collected by filtration and washed with water (3 x 10 mL). This gave intermediate 8 (174 mg, 78.35%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=568.

[1016] Step 8: Preparation of (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 23) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-ethyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 24)

[1017]

[1018] To a stirred mixture of intermediate 8 (150 mg, 0.264 mmol, 1 eq) 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 eq) in DMF (4 mL) was added DIEA (102.46 mg, 0.792 mmol, 3 eq) and PyBOP (274.56 mg, 0.528 mmol, 2.0 eq) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH 4 HCO 3 ), 0% to 100% gradient in 30 minutes; detector, UV 254nm. The obtained residue (80mg) was then purified by chiral HPLC using the following conditions: column, CHIRALPAK ID-3, 4.6*50mm, 3μm; mobile phase A: MtBE (0.1% DIEA), mobile phase B: MeOH; flow rate: 1.67mL / min. This gave:

[1019] Compound 23 (36.7 mg, 15.21%) as a white solid. NMR (400MHz, DMSO-d6) δ14.57 (s, 1H), 8.99 (s, 1H), 8.84 (s, 2H), 8.61 (s, 1H), 8.43 (d, J = 7.6Hz, 1H), 8.23-8.16 (m, 1H), 7.45 (d, J = 8.3Hz, 2H ), 7.41-7.35 (m, 2H), 7.32 (td, J=7.6, 1.6Hz, 1H), 6.98 (t, J=7.6Hz, 2H), 6.93 (s, 1H), 6.87-6.80 (m, 1H), 5.11 (d, J=3.6Hz, 1H), 4.99-4.90 (m , 3H), 4.50-4.35 (m, 3H), 4.31 (s, 1H), 3.85 (d, J=9.7Hz, 1H), 3.80-3.58 (m, 1H), 3.51 (d, J=10.7Hz, 1H), 3.31-3.27 (m, 1H), 3.20 (t, J=12.7H z, 2H), 2.48-2.42 (m, 3H), 2.39-2.27 (m, 1H), 2.17-1.97 (m, 3H), 1.86- 1.71 (m, 3H), 1.52-1.33 (m, 6H), 1.06-0.99 (m, 3H), 0.89-0.81 (m, 3H). LCMS (ESI) m / z: [M+H]+=881.35.

[1020] Compound 24 (20.4 mg, 8.53%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.02-8.94 (m, 1H), 8.86-8.78 (m, 2H), 8.61 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.23-8.16 (m, 1H), 7.53-7.41 (m, 1H), 7.40-7.27 (m, 4H), 6.98 (t, J = 7.7 Hz, 2H), 6.93 (s, 1H), 6.86-6.81 (m, 1H), 5.14 (s, 1H), 4.96-4.82 (m, 3H), 4. 49-4.41 (m, 3H), 4.30 (s, 1H), 3.95 (d, J=9.0Hz, 1H), 3.67-3.40 (m, 2H), 3.31-3.26 (m, 1H), 3.19 (t, J=12.7Hz, 2H), 2.47 (s, 1H), 2 .41 (s, 2H), 2.40-2.32 (m, 1H), 2.14-2.02 (m, 3H), 2.00-1.71 (m, 3H), 1.52-1.29 (m, 6H), 1.02 (d, J=6.6Hz, 3H), 0.91-0.79 (m, 3H). LCMS (ESI) m / z: [M+H]+=881.45.

[1021] Preparation of (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 25) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 26).

[1022]

[1023] Step 1: Preparation of 3,6-dichloro-N-cyclopropylpyridazin-4-amine (Intermediate 2).

[1024]

[1025] To a stirred mixture of 4-bromo-3,6-dichloropyridazine (6 g, 26.331 mmol, 1 eq.) and DIEA (10.21 g, 78.993 mmol, 3 eq.) in NMP (50 mL) was added aminocyclopropane (2.26 g, 39.496 mmol, 1.5 eq.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and then washed with 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 (5:1) to afford Intermediate 2 (3.4 g, 63.28%) as an off-white solid. LCMS (ESI) m / z: [M+H]+=204.

[1026] Step 2: Preparation of tert-butyl 4-([6-chloro-4-(cyclopropylamino)pyridazin-3-yl]ethynyl)piperidine-1-carboxylate (Intermediate 3).

[1027]

[1028] Intermediate 2 (1.7 g, 8.331 mmol, 1 eq.) and tert-butyl 4-ethynylpiperidine-1-carboxylate (2.62 g, 12.496 mmol, 1.5 eq.) were reacted in CH 3 To the stirred mixture in CN (85 mL) was added Pd(PPh 3 ) 2 Cl 2 (1.17 g, 1.666 mmol, 0.2 eq), CuI (0.32 g, 1.666 mmol, 0.2 eq) and Et 3 N (2.53 g, 24.993 mmol, 3 eq.). The resulting mixture was stirred at 60 °C for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (2:1) to provide Intermediate 3 (506 mg, 16.11%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=377.

[1029] Step 3: Preparation of tert-butyl 4-{3-chloro-5-cyclopropylpyrrolo[3,2-c]pyridazin-6-yl}piperidine-1-carboxylate (Intermediate 4).

[1030]

[1031] Intermediate 3 (500 mg, 1.327 mmol, 1 eq) and K were reacted at 60 °C under nitrogen atmosphere. 2 CO 3 A mixture of (733.40 mg, 5.308 mmol, 4 eq.) in DMF (10 mL) was stirred for 3 h. After cooling to room temperature, the mixture was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine (2×100 mL) and then washed with 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 (2:1) to afford Intermediate 4 (413 mg, 80.95%) as a red solid. LCMS (ESI) m / z: [M+H]+=377.

[1032] Step 4: Preparation of tert-butyl 4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 5).

[1033]

[1034] Intermediate 4 (413 mg, 1.096 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (755.73 mg, 5.480 mmol, 5 eq.) were prepared in dioxane (10 mL) and H2O under nitrogen atmosphere at room temperature. 2 XPhos Pd G3 (139.13 mg, 0.164 mmol, 0.15 equiv) and Cs 2 Co 3 (1071.11 mg, 3.288 mmol, 3 eq.). The resulting mixture was stirred at 100°C for 1.5 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH 4 HCO 3 ), gradient 5% to 95% in 35 minutes; detector, UV 254 nm. This gave intermediate 5 (296 mg, 60.30%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=435.

[1035] Step 5: Preparation of 2-[5-cyclopropyl-6-(piperidin-4-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 6).

[1036]

[1037] A mixture of intermediate 5 (296 mg, 0.681 mmol, 1 eq.) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was concentrated under reduced pressure. This gave intermediate 6 (186 mg, 81.65%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=335.

[1038] Step 6: Preparation of methyl 2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 7)

[1039]

[1040] To a stirred mixture of intermediate 6 (186 mg, 0.556 mmol, 1 eq.) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (164.47 mg, 0.556 mmol, 1 eq.) in DMSO (3 mL) was added DIEA (581.28 μL, 3.336 mmol, 6 eq.) dropwise at 100 °C under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 hour. After cooling to room temperature, the product was precipitated by adding water (20 mL). The precipitated solid was collected by filtration. This gave intermediate 7 (175 mg, 46.64%) as a brown solid. LCMS (ESI) m / z: [M+H]+=594.

[1041] Step 7: Preparation of 2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 8)

[1042]

[1043] Intermediate 7 (175 mg, 0.295 mmol, 1 eq.) and LiOH.H 2 O (123.68 mg, 2.950 mmol, 10 equiv) in MeOH (4 mL) and H 2 The mixture in 4% 4-(4-(4-hydroxy-1-nitropropene)-2-yl)-2-nitropropene (1 mL) was stirred for 1 hour. After cooling to room temperature, the mixture was acidified to pH 5 with HCl (aq). The precipitated solid was collected by filtration and washed with EtOAc (2×50 mL). This gave intermediate 8 (126 mg, 73.74%) as an off-white solid. LCMS (ESI) m / z: [M+H]+=580.

[1044] Step 8: Preparation of (2S,4R)-1-[(2R)-2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 2 5) and (2S,4R)-1-[(2S)-2-[3-(2-{4-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 26).

[1045]

[1046] To a stirred mixture of intermediate 8 (126 mg, 0.217 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (72.04 mg, 0.217 mmol, 1 eq) in DMF (2.5 mL) was added PyBOP (226.24 mg, 0.434 mmol, 2 eq) and DIEA (84.28 mg, 0.651 mmol, 3 eq) at room temperature under nitrogen atmosphere. 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, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH 4 HCO 3 +0.1% NH 3 .H 2 O) and CH 3 CN (maintain 2% CH 3 CN, up to 46% in 1 minute and then up to 68% in 6.5 minutes); detector, UV 254 nm. The obtained residue (82 mg) was then purified by chiral HPLC using the following conditions: column, CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase, MtBE (10 mM NH 3 -MeOH) and MeOH (hold 50% MeOH for 30 min); detector, UV 254 nm This gave:

[1047] Compound 25 (52 mg, 40.69%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.31 (s, 1H), 8.99 (s, 1H), 8.85 (d, J = 2.9 Hz, 2H), 8.44 (d, J = 7.7 Hz, 1H), 8.35 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7. 38 (d, J=8.3Hz, 2H), 7.32 (td, J=7.6, 1.5Hz, 1H), 6.99 (t, J=8.2Hz, 2H), 6.93 (s , 1H), 6.82 (d, J=3.3Hz, 1H), 5.12 (d, J=3.6Hz, 1H), 5.02-4.87 (m, 3H), 4.39 (t, J =7.9Hz, 1H), 4.31 (s, 1H), 3.85 (d, J = 9.7Hz, 1H), 3.76 (dd, J = 10.3, 4.2Hz, 1H), 3.59-3.42(m, 3H), 3.18(t, J=12.7Hz, 2H), 2.45(d, J=6.6Hz, 3H), 2.40-2.29(m , 1H), 2.21 (d, J=12.7Hz, 2H), 2.11-1.87 (m, 1H), 1.85-1.64 (m, 3H), 1.49 (d, J= 6.9Hz, 5H), 1.17 (d, J=3.6Hz, 2H), 1.02 (t, J=5.4Hz, 3H), 0.85 (t, J=7.4Hz, 3H). LCMS (ESI) m / z: [M+H]+=893.30.

[1048] Compound 26 (35.6 mg, 29.10%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.31 (d, J = 4.1 Hz, 1H), 8.98 (d, J = 15.0 Hz, 1H), 8.83 (d, J = 19.3 Hz, 2H), 8.35 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.14 (dd, J = 8.1, 1.6 Hz, 1H), 7 .53-7.42(m, 2H), 7.40-7.26(m, 4H), 7.04-6.91(m, 3H), 6.82(d, J=3.2Hz, 1H), 5 .15 (dd, J=3.6, 1.4Hz, 1H), 5.08-4.83 (m, 3H), 4.51 (dt, J=51.6, 7.4Hz, 1H), 4.29 (d, J=7.5Hz, 1H), 3.95 (d, J=9.0Hz, 1H), 3.67-3.41 (m, 4H), 3.17 (t, J=12.7Hz, 2 H), 2.44 (d, J=24.0Hz, 3H), 2.39-2.31 (m, 1H), 2.21 (d, J=12.7Hz, 2H), 2.12-1.90 (m, 1H), 1.75 (ddt, J=35.8, 14.3, 8.3Hz, 3H), 1.49 (d, J=6.9Hz, 1H), 1.35 (dd, J= 6.9, 3.5Hz, 4H), 1.18 (q, J=3.7Hz, 2H), 1.02 (d, J=6.5Hz, 2H), 0.92-0.77 (m, 4H). LCMS (ESI) m / z: [M+H]+=893.30.

[1049] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 27)

[1050] Preparation of 2-(5-methyl-6-(piperazin-1-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 8)

[1051]

[1052] Step 1: Preparation of 4-bromo-6-chloro-3-iodopyridazine (Intermediate 2)

[1053]

[1054] To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (10 g, 47.975 mmol, 1 eq.) and CuI (18.27 g, 95.950 mmol, 2.0 eq.) in THF (50 mL) was added t-BuONO (9.89 g, 95.950 mmol, 2.0 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure and then purified by silica gel column chromatography eluted with PE / EA (1:1) to provide intermediate 2 (6.0 g, 39.17%) as a yellow solid. LCMS (ESI) m / z [M+H] + = 319.

[1055] Step 2: Preparation of 6-chloro-3-iodo-N-methylpyridazin-4-amine (Intermediate 3)

[1056]

[1057] A mixture of intermediate 2 (2.00 g, 6.263 mmol, 1.00 equiv), methylamine hydrochloride (0.63 g, 9.395 mmol, 1.50 equiv) and DIEA (2.43 g, 18.789 mmol, 3.00 equiv) in NMP (10 mL) was stirred at 100° C. for 3 hours. After cooling to room temperature, the mixture 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 100% gradient in 40 minutes; detector, UV 254 nm. This gave intermediate 3 (1.1 g, 65.17%) as a brown solid. LCMS (ESI) m / z [M+H] + = 270.

[1058] Step 3: Preparation of tert-butyl 6-amino-3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazine-7-carboxylate (Intermediate 4)

[1059]

[1060] Intermediate 3 (1.00 g, 3.711 mmol, 1.00 equiv), tert-butyl 2-cyanoacetate (1.57 g, 11.133 mmol, 3.00 equiv), CuI (0.14 g, 0.742 mmol, 0.20 equiv) and Cs 2 CO 3 A mixture of 4-(3.63 g, 11.133 mmol, 3.00 equiv) in dioxane (15 mL) was stirred for 4 hours. After cooling to room temperature, the resulting mixture was diluted with EtOAc (100 mL), washed with brine (3×100 mL) and then heated in anhydrous Na2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to afford Intermediate 4 (980 mg, 93.40%) as a brown solid. LCMS (ESI) m / z [M+H] + = 283.

[1061] Step 4: Preparation of tert-butyl 6-bromo-3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazine-7-carboxylate (Intermediate 5)

[1062]

[1063] Intermediate 4 (900.0 mg, 3.183 mmol, 1.00 equiv), t-BuONO (656.5 mg, 6.366 mmol, 2.00 equiv) and CuBr were reacted at room temperature. 2 A mixture of (1066.4 mg, 4.774 mmol, 1.50 equiv) in ACN (10 mL) was stirred for 3 hours. The mixture 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 100% gradient in 40 minutes; detector, UV 254 nm. This gave intermediate 5 (220 mg, 18.94%) as a brown solid. LCMS (ESI) m / z [M+H] + = 346.

[1064] Step 5: Preparation of tert-butyl 3-chloro-5-methyl-6-(piperazin-1-yl)pyrrolo[3,2-c]pyridazine-7-carboxylate (Intermediate 6)

[1065]

[1066] A solution of intermediate 5 (220 mg, 0.635 mmol, 1 eq), DIEA (246.11 mg, 1.905 mmol, 3.0 eq) and piperazine (218.69 mg, 2.540 mmol, 4 eq) in DMSO (4 mL) was stirred for 2 h at 120° C. under nitrogen atmosphere. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH 4 HCO 3 ), gradient 0% to 50% in 40 minutes; detector, UV 254 nm. This gave intermediate 6 (200 mg, 89.56%) as a yellow oil. LCMS (ESI) m / z [M+H] + = 352.

[1067] Step 6: Preparation of 1-{3-chloro-5-methylpyrrolo[3,2-c]pyridazin-6-yl}piperazine (Intermediate 7)

[1068]

[1069] A solution of intermediate 6 (200 mg, 0.568 mmol, 1 eq.) in HFIP (4 mL) was stirred at 100 °C under nitrogen for 12 hours. The resulting mixture was concentrated under reduced pressure. This gave intermediate 7 (150 mg, 104.83%) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + = 252.

[1070] Step 7: Preparation of 2-[5-methyl-6-(piperazin-1-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 8)

[1071]

[1072] Intermediate 7 (150 mg, 0.596 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (246.58 mg, 1.788 mmol, 3.0 eq.) were dissolved in dioxane (5 mL) and H 2 Cs was added to the solution in O (1 mL) 2 CO 3 (582.47 mg, 1.788 mmol, 3.0 equiv) and XPhos Pd G3 (100.88 mg, 0.119 mmol, 0.2 equiv). After stirring at 90 °C under nitrogen atmosphere for 2 hours, the mixture was cooled to room temperature. The mixture 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 in 50 minutes; detector, UV 254 nm. This gave intermediate 8 (75 mg, 40.68%) as a yellow solid. LCMS (ESI) m / z [M+H] + = 310.

[1073] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 27)

[1074]

[1075] A mixture of intermediate 8 (15 mg, 0.048 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 (26.21 mg, 0.048 mmol, 1.0 eq) in MeOH (1 mL) and DCM (1 mL) was stirred at room temperature for 1 h. NaBH 3 CN (15.23 mg, 0.240 mmol, 5.0 equiv) and AcOH (catalytic). 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, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: CH 3 CN; flow rate: 25 mL / min; gradient: 42% B to 55% B in 7 minutes, then 55% B; detector, UV 254 / 220 nm. This gave compound 27 (16.4 mg, 40.03%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.17 (d, J = 12.3 Hz, 1H), 8.04-7.96 (m, 1H), 7.40-7.24 (m, 5H), 7.01-6.93 (m, 2H), 6.21-6.15 (m, 1H), 6.04 (s, 1H), 5.03 (d, J = 7.0 Hz, 1H), 4.51 (t, J = 8.2 Hz, 1H), 4.46-4.37 (m, 3H), 3.84 (dd, J = 10.9, 4.1 Hz, 1H), 3.77-3.65(m, 3H), 3.65-3.52(m, 2H), 3.52-3.47(m, 1H), 3.34(s, 3H), 2.92(t, J=5.5Hz, 2H), 2.84(d, J=5.0Hz, 4H) , 2.46-2.32(m, 4H), 2.22-2.13(m, 1H), 2.00-1.87(m, 1H), 1.59-1.52(m, 3H), 1.06(d, J=6.5Hz, 3H), 0.95-0.87(m, 3H). LCMS (ESI) m / z: [M+H]+=834.3.

[1076] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 28) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 29).

[1077]

[1078] Step 1: Preparation of methyl 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (Intermediate 9)

[1079]

[1080] A solution of intermediate 8 (75 mg, 0.242 mmol, 1 eq.), methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (86.03 mg, 0.290 mmol, 1.2 eq.) and DIEA (94.00 mg, 0.726 mmol, 3.0 eq.) in DMSO (3 mL) was stirred at 100° C. under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture 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 in 40 minutes; detector, UV 254 nm. This gave intermediate 9 (70 mg, 50.78%) as a yellow solid. LCMS (ESI) m / z[M+H]+=569.

[1081] Step 2: Preparation of 2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (Intermediate 10)

[1082]

[1083] To a stirred solution of intermediate 9 (80.00 mg, 0.140 mmol, 1.00 equiv) in MeOH (5.00 mL) and H2O (5.00 mL) was added LiOH.H2O (29.40 mg, 0.700 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH 3 with HCl (1 M). 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, ACN in H2O (0.1% FA), 0% to 100% gradient in 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 10 (78 mg, 99.11%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=555.

[1084] Step 3: Preparation of (2S,4R)-4-hydroxy-1-[2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 12)

[1085]

[1086] To a stirred solution of intermediate 10 (78.00 mg, 0.140 mmol, 1.00 equiv) in DMF (5.00 mL) was added PyBOP (218.40 mg, 0.420 mmol, 3.00 equiv) and DIEA (90.30 mg, 0.700 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 (46.48 mg, 0.140 mmol, 1.00 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, ACN (10 mmol / L NH4HCO3) in H2O, gradient from 0% to 100% in 30 minutes; detector, UV 254 / 220 nm. This gave intermediate 12 (120 mg, 98.36%) as a white solid. LCMS (ESI) m / z: [M+H]+=868.

[1087] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 2 8) and (2S,4R)-4-hydroxy-1-[(2S)-2-[3-(2-{4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperazin-1-yl}pyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 29).

[1088]

[1089] Intermediate 12 (120 mg) was purified by chiral HPLC using the following conditions: column, CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 20% B to 50% B in 16 minutes; detector, UV 254 / 220 nm. This gave:

[1090] Compound 28 (35.40 mg, 29.50%) as a white solid. NMR (400MHz, DMSO-d6) δ14.82 (s, 1H), 8.99 (s, 1H), 8.89 (d, J = 3.9Hz, 2H), 8.44 (d, J = 10.4Hz, 2H), 8.15 (dd, J = 8.9, 1.6Hz, 1H), 7.47-7.42 (m , 2H), 7.41-7.35(m, 2H), 7.34-7.26(m, 1H), 7.02-6.92(m, 3H), 6.33( s, 1H), 5.23-5.01 (m, 1H), 5.01-4.69 (m, 1H), 4.39 (t, J=7.9Hz, 1H), 3. 35-3.25 (m, 1H), 4.08 (t, J=5.1Hz, 4H), 3.86 (d, J=9.7Hz, 1H), 3.80 (s, 3H), 3.79-3.72 (m, 1H), 3.69-3.47 (m, 1H), 3.32-3.26 (m, 4H), 2.45 (d , J=6.6Hz, 3H), 2.39-2.18 (m, 1H), 2.09-1.99 (m, 1H), 1.86-1.75 (m, 1H), 1.39 (d, J=7.0Hz, 3H), 1.02 (d, J=6.6Hz, 3H), 0.85 (d, J=6.6Hz, 3H). LCMS (ESI) m / z: [M+H]+=868.25.

[1091] Compound 29 (18.00 mg, 15.00%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.83 (s, 1H), 9.01-8.94 (m, 1H), 8.89 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.18-8.12 (m, 1H), 7.52-7.41 (m, 1H), 7.40-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.01-6.93 (m, 3H), 6.33 (d, J = 0.8 Hz, 1H), 5.14 (d, J = 3.7 Hz, 1H), 4.98-4.83 (m, 1H), 4.45 (t, J = 7.7Hz, 1H), 4.35-4.22 (m, 1H), 4.12-4.03 (m, 4H), 3.96 (d, J = 8.9Hz, 1H), 3.80 (d, J = 1.7Hz, 3H), 3.68-3.57 (m, 2H), 3. 31-3.26 (m, 4H), 2.41 (s, 3H), 2.23-1.87 (m, 2H), 1.84-1.75 (m, 1H), 1.34 (d, J=7.0Hz, 3H), 1.02 (d, J=6.6Hz, 3H), 0.86 (t, J=6.6Hz, 3H). LCMS (ESI) m / z: [M+H]+=868.25.

[1092] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-hydroxy-4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 30)

[1093]

[1094] Step 1: Preparation of tert-butyl 4-([6-chloro-4-(methylamino)pyridazin-3-yl]ethynyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 2)

[1095]

[1096] To a solution of Intermediate 1 (3.3 g, 12.246 mmol, 1 eq.), tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (2.76 g, 12.246 mmol, 1 eq.) and CuI (0.47 g, 2.449 mmol, 0.2 eq.) in toluene (30 mL) was added TEA (3.72 g, 36.738 mmol, 3 eq.). The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was filtered and the filter cake was washed with DCM (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to provide Intermediate 2 (3.5 g, 77.91%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=367.

[1097] Step 2: Preparation of tert-butyl 4-{3-chloro-5-methylpyrrolo[3,2-c]pyridazin-6-yl}-4-hydroxypiperidine-1-carboxylate (Intermediate 3)

[1098]

[1099] A mixture of intermediate 2 (3.5 g, 9.541 mmol, 1 eq.) and KCO (2.64 g, 19.082 mmol, 2 eq.) in DMF (30 mL) was stirred at 60° C. for 16 h. After cooling to room temperature, the mixture was purified by reverse phase flash C18 chromatography with an elution gradient of 0% to 57% ACN in H2O to provide intermediate 3 (2.80 g, 80.00%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=367.

[1100] Step 3: Preparation of tert-butyl 4-hydroxy-4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidine-1-carboxylate (Intermediate 4)

[1101]

[1102] To a solution of intermediate 3 (2.80 g, 7.633 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (1.58 g, 11.450 mmol, 1.5 eq.) in 1,4-dioxane (3.2 mL) and H2O (0.8 mL) was added XPhos Pd G3 (0.65 g, 0.763 mmol, 0.1 eq.) and K2CO3 (2.11 g, 15.266 mmol, 2 eq.). The resulting mixture was stirred at 80°C under nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL) and washed with water (3×150 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to provide intermediate 4 (788 mg, 24.32%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=425.

[1103] Step 4: Preparation of 4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-4-ol (Intermediate 5)

[1104]

[1105] A solution of intermediate 4 (788 mg, 1.856 mmol, 1 eq.) in TFA (1.5 mL) and DCM (4.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash C18 chromatography with an elution gradient of 0% to 35% ACN in H2O to provide intermediate 5 (374 mg, 62.11%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=325.

[1106] Step 5: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{4-hydroxy-4-[3-(2-hydroxyphenyl)-5-methylpyrrolo[3,2-c]pyridazin-6-yl]piperidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 30)

[1107]

[1108] A solution of intermediate 5 (20 mg, 0.062 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 (33.33 mg, 0.062 mmol, 1 eq) in MeOH (0.8 mL) and DCM (0.8 mL) was stirred at room temperature for 30 minutes. NaBH3CN (15.50 mg, 0.248 mmol, 4 eq) and AcOH (0.37 mg, 0.006 mmol, 0.1 eq) were then added and the mixture was stirred at room temperature for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 25 mL / min; gradient: 36% B to 50% B in 7 minutes, then 50% B; detector, UV 254 / 220 nm. This gave compound 30 (11.6 mg, 22.16%) as a white solid. 1HNMR (300MHz, DMSO-d6) δ14.63 (s, 1H), 9.07 (s, 1H), 8.65 (s, 1H), 8.50 (d, J=7.5Hz, 1H), 8.27 (d, J =8.0Hz, 1H), 7.60-7.34(m, 7H), 7.11-6.91(m, 4H), 6.19(s, 1H), 5.58(s, 1H), 5.18(d, J=3.7Hz, 1H), 5.03-4.95(s, 1H), 4.42(s, 1H), 4.48-4.42(m, 3H), 4.18(s, 3H), 3.82-3.68(m, 1H), 2.88-2.76(m, 5 H), 2.34 (s, 2H), 2.20-2.05 (m, 6H), 1.45 (d, J=6.9Hz, 3H), 1.03 (d, J=6.5Hz, 3H), 0.94-0.82 (m, 5H). LCMS (ESI) m / z: [M+H]+=849.10.

[1109] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 31)

[1110]

[1111] Step 1: Preparation of tert-butyl 3-{3-chloropyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 2)

[1112]

[1113] A mixture of 3-chloro-5H-pyrrolo[3,2-c]pyridazine (200 mg, 1.302 mmol, 1.00 equiv), tert-butyl 3-iodoazetidine-1-carboxylate (737.41 mg, 2.604 mmol, 2.0 equiv) and CsCO (1.273 g, 3.906 mmol, 3 equiv) in DMF (4 mL) was stirred at 90° C. under nitrogen atmosphere for 12 hours. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 40 minutes; detector, UV 254 nm. This gave intermediate 2 (120 mg, 29.84%) as a yellow oil. LCMS (ESI) m / z[M+H]+=309.

[1114] Step 2: Preparation of tert-butyl 3-[3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidine-1-carboxylate (Intermediate 3)

[1115]

[1116] To a solution of intermediate 2 (120 mg, 0.389 mmol, 1.00 eq) and 2-hydroxyphenylboronic acid (160.81 mg, 1.167 mmol, 3.0 eq) in dioxane (5 mL) and H2O (1 mL) was added Cs2CO3 (379.88 mg, 1.167 mmol, 3.0 eq) and XPhos Pd G3 (65.79 mg, 0.078 mmol, 0.2 eq). After stirring at 100°C under nitrogen atmosphere for 2 hours, the resulting mixture was cooled to room temperature and then diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:) to give intermediate 3 (100 mg, 70.22%) as a yellow oil.LCMS (ESI) m / z: [M+H]+=367.

[1117] Step 3: Preparation of 2-[5-(azetidin-3-yl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 4).

[1118]

[1119] A solution of intermediate 3 (40 mg, 0.109 mmol, 1.00 equiv) and TFA (1 mL) in DCM (4 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, Kinetex EVO C18, 21.2*150, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 25 mL / min; gradient: 14% B to 32% B in 6 minutes, then 32% B; detector, UV 254 / 220 nm. This gave intermediate 4 (16.5 mg, 56.36%) as a white solid. LCMS (ESI) m / z: [M+H]+=267.

[1120] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-[3-(2-{3-[3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidin-1-yl}ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 31)

[1121]

[1122] A 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 (40.60 mg, 0.075 mmol, 1.0 eq) and intermediate 4 (20 mg, 0.075 mmol, 1 eq) in CHOH (1 mL) and DCM (1 mL) was stirred at room temperature for 10 minutes. AcOH (catalytic) and NaBHCN (14.16 mg, 0.225 mmol, 3.0 eq) were added to the above mixture. The resulting mixture was stirred for another 4 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep C18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 25 mL / min; gradient: 28% B to 57% B in 7 minutes; detector, UV 254 / 220 nm. This gave compound 31 (19.6 mg, 31.84%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ14.43 (s, 1H), 9.06 (s, 1H), 8.84 (s, 1H), 8.53-8.43 (m, 2H), 8.20 (d, J=8.3Hz, 1H), 7.56-7.35 (m, 5H), 7.14 (t, J=3.9Hz , 1H), 7.11-7.01 (m, 2H), 6.17 (s, 1H), 5.51 (t, J=6.6Hz, 1H), 5.18 (d, J=3.6Hz, 1H), 4.98 (t, J=7.2Hz, 1H), 4.44 (t, J=8.0Hz, 1H), 4.36 (brs, 1H) , 4.29 (t, J=5.3Hz, 2H), 3.95 (t, J=7.4Hz, 2H), 3.82-3.69 (m, 2H), 3.63 (t, J=6.9Hz, 2H), 3.57-3.48 (m, 1H), 3.04 (t, J=5.4Hz, 2H), 2.53 (d, J=2 .8Hz, 3H), 2.37-2.24 (m, 1H), 2.17-2.04 (m, 1H), 1.92-1.78 (m, 1H), 1.48 (dd, J=21.3, 7.0Hz, 3H), 1.03 (d, J=6.4Hz, 3H), 0.87 (d, J=6.7Hz, 3H). LCMS (ESI) m / z: [M+H]+=791.00.

[1123] Preparation of (2S,4R)-1-((R)-2-(3-(2-(3-(7-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 32)

[1124]

[1125] Step 1: Preparation of tert-butyl 3-{7-bromo-3-chloropyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 2)

[1126]

[1127] A solution of Intermediate 1 (927.0 mg, 3.002 mmol, 1.00 equiv) and NBS (534.3 mg, 3.002 mmol, 1.00 equiv) in DMF (10 mL) 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, ACN in water, 0% to 100% gradient in 40 minutes; detector, UV 254 nm. This gave Intermediate 2 (752.0 mg, 64.4%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=387.

[1128] Step 2: Preparation of tert-butyl 3-{3-chloro-7-vinylpyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 3)

[1129]

[1130] To a stirred mixture of intermediate 2 (752.0 mg, 1.940 mmol, 1.00 equiv), Cs2CO3 (1.26 g, 3.880 mmol, 2.00 equiv) and Pd(dppf)Cl2 (212.9 mg, 0.291 mmol, 0.15 equiv) in 1,4-dioxane (10 mL) and H2O (2 mL) was added potassium (vinyl)trifluoroborate (155.91 mg, 1.164 mmol, 0.6 equiv). The resulting mixture was stirred at 60°C under 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, ACN in water, 0% to 100% gradient in 40 minutes; detector, UV 254 nm. This gave intermediate 3 (453 mg, 69.70%) as a brown solid. LCMS (ESI) m / z: [M+H]+=335.

[1131] Step 3: Preparation of tert-butyl 3-{3-chloro-7-formylpyrrolo[3,2-c]pyridazin-5-yl}azetidine-1-carboxylate (Intermediate 4)

[1132]

[1133] A solution of intermediate 3 (453.0 mg, 1.353 mmol, 1.00 equiv), NaIO4 (2315.24 mg, 10.824 mmol, 8 equiv), K2OsO4·2H2O (49.8 mg, 0.135 mmol, 0.10 equiv) and 2,6-lutidine (289.9 mg, 2.706 mmol, 2.00 equiv) in 1,4-dioxane (8 mL) and H2O (8 mL) was stirred at 0°C for 2 h. The resulting mixture was extracted with EA (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 40 minutes; detector, UV 254 nm. This gave intermediate 4 (142.0 mg, 31.1%) as a brown solid. LCMS (ESI) m / z: [M+H]+=337.

[1134] Step 4: Preparation of tert-butyl 3-[3-chloro-7-(difluoromethyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidine-1-carboxylate (Intermediate 5)

[1135]

[1136] A solution of intermediate 4 (142.0 mg, 0.422 mmol, 1.00 equiv) and DAST (1 mL, 15.22 equiv) in DCM (5 mL) was stirred for 3 hours at 0°C under a nitrogen atmosphere. The reaction was quenched with NH4Cl at 0°C. The resulting mixture was extracted with EA (3×10 mL). The combined organic layers were washed with brine (3×4 mL) and then dried over anhydrous 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, 0% to 100% gradient in 10 minutes; detector, UV 254 nm. This gave intermediate 5 (15.0 mg, 9.9%) as a light yellow solid. LCMS (ESI) m / z: [M+H]+=359.

[1137] Step 5: Preparation of tert-butyl 3-[7-(difluoromethyl)-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-5-yl]azetidine-1-carboxylate (Intermediate 6)

[1138]

[1139] To a stirred mixture of intermediate 5 (15.0 mg, 0.044 mmol, 1.00 equiv), Cs2CO3 (35.6 mg, 0.110 mmol, 2.50 equiv) and 2-hydroxyphenylboronic acid (7.2 mg, 0.053 mmol, 1.20 equiv) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added XPhos Pd G3 (7.4 mg, 0.009 mmol, 0.2 equiv). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE 1:1) to afford intermediate 6 (10 mg, 54.50%) as a light yellow solid. LCMS (ESI) m / z: [M+H]+=417.

[1140] Step 6: Preparation of 2-[5-(azetidin-3-yl)-7-(difluoromethyl)pyrrolo[3,2-c]pyridazin-3-yl]phenol (Intermediate 7)

[1141]

[1142] A solution of Intermediate 6 (10.0 mg, 0.024 mmol, 1.00 equiv) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure to provide Intermediate 7 (12 mg, crude) as a light yellow solid. LCMS (ESI) m / z: [M+H]+=317.

[1143] Step 7: Preparation of (2S,4R)-1-((R)-2-(3-(2-(3-(7-(difluoromethyl)-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5-yl)azetidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 32)

[1144]

[1145] A solution of intermediate 7 (8 mg, 0.015 mmol, 1 eq), (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 (9.36 mg, 0.030 mmol, 2 eq) and AcOH (4.44 mg, 0.075 mmol, 5 eq) in DCM (0.5 mL) and MeOH (0.5 mL) was stirred for 30 minutes at room temperature under a nitrogen atmosphere. NaBH3CN (2.32 mg, 0.037 mmol, 2.5 eq) was subsequently added at room temperature. The resulting mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC. This gave compound 32 (4.7 mg, 36.18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.89 (s, 1H), 8.99 (s, 1H), 8.85 (s, 1H), 8.79-8.73 (m, 1H), 8.42 (d, J = 7.5 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.49-7.32 (m, 6H), 7.02 (d, J = 8.0 Hz, 2H), 6.10 (s, 1H), 5.45 (t, J = 6.6 Hz, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.92 (t, J = 7.2 Hz, 1H), 4. 43-4.18 (m, 4H), 3.87 (t, J=7.5Hz, 2H), 3.72-3.56 (m, 4H), 3.49-3.39 (m, 1H), 2.97 (t, J=5.4Hz, 2H), 2.46 (d, J=2.8Hz, 3H), 2.37 -2.24 (m, 1H), 2.17-2.04 (m, 1H), 1.92-1.78 (m, 1H), 1.41 (dd, J=22.1, 6.8Hz, 3H), 0.96 (d, J=6.4Hz, 3H), 0.80 (d, J=6.8Hz, 3H). LCMS (ESI) m / z[M+H]+=841.2.

[1146] Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(1R,5S,6S)-6-[3-(2-hydroxyphenyl)-6-methylpyrrolo[3,2-c]pyridazin-5-yl]-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 33)

[1147]

[1148] Step 1: Preparation of 4-bromo-6-chloro-3-[3-(trimethylsilyl)prop-1-yn-1-yl]pyridazine (Intermediate 2)

[1149]

[1150] A mixture of Intermediate 1 (5 g, 15.658 mmol, 1 eq.), trimethyl(prop-2-yn-1-yl)silane (1.76 g, 15.658 mmol, 1 eq.), Pd(dppf)Cl2.CH2Cl2 (1.27 g, 1.566 mmol, 0.1 eq.), CuI (596.42 mg, 3.132 mmol, 0.2 eq.) and Et3N (3.17 g, 31.316 mmol, 2 eq.) in toluene (20 mL) was stirred overnight at room temperature under nitrogen atmosphere. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave Intermediate 2 (827.5 mg, 17.40%) as a brown oil. LCMS (ESI) m / z [M+H]+=303.

[1151] Step 2: Preparation of (1R,5S,6S)-6-{3-chloro-6-methylpyrrolo[3,2-c]pyridazin-5-yl}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate 3)

[1152]

[1153] A mixture of intermediate 2 (400 mg, 1.317 mmol, 1 eq.), (1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (391 mg, 1.975 mmol, 1.5 eq.) and K2CO3 (546.16 mg, 3.951 mmol, 3 eq.) in DMF (5 mL) was stirred at 100°C under nitrogen atmosphere for 1 hour. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave intermediate 3 (159 mg, 34.60%) as a brown solid. LCMS (ESI) m / z: [M+H]+=349.

[1154] Step 3: Preparation of (1R, 5S, 6S)-6-[3-(2-hydroxyphenyl)-6-methylpyrrolo[3,2-c]pyridazin-5-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate 4)

[1155]

[1156] A mixture of intermediate 3 (65 mg, 0.186 mmol, 1 eq.), 2-hydroxyphenylboronic acid (77.10 mg, 0.558 mmol, 3 eq.), XPhos Pd G3 (31.55 mg, 0.037 mmol, 0.2 eq.) and Cs2CO3 (182.14 mg, 0.558 mmol, 3 eq.) in dioxane (3 mL) and H2O (0.6 mL) was stirred at 80°C under nitrogen atmosphere for 1 hour. After cooling to room temperature and concentrating under reduced pressure, the mixture was purified by Prep-TLC (PE / EA 1:1) to afford intermediate 4 (63 mg, 83.18%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=407.

[1157] Step 4: Preparation of 2-{5-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-6-methylpyrrolo[3,2-c]pyridazin-3-yl}phenol (Intermediate 5)

[1158]

[1159] A mixture of intermediate 4 (63 mg, 0.155 mmol, 1 eq.) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford intermediate 5 (76.4 mg, TFA salt) as a yellow solid. LCMS (ESI) m / z: [M+H]+=307.

[1160] Step 5: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-2-(3-{2-[(1R,5S,6S)-6-[3-(2-hydroxyphenyl)-6-methylpyrrolo[3,2-c]pyridazin-5-yl]-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 33)

[1161]

[1162] A mixture of Intermediate 5 (20 mg, 0.065 mmol, 1.76 equiv), (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 (20 mg, 0.037 mmol, 1.00 equiv) and AcOH (8.00 mg, 0.133 mmol, 3.60 equiv) in MeOH (1 mL) and DCM (1 mL) was stirred at room temperature for 30 min. To the above mixture was added NaBH3CN (11.62 mg, 0.185 mmol, 5 equiv). The resulting mixture was stirred at room temperature for another 2 h. The mixture was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 25 mL / min; gradient: 48% B to 73% B in 7 minutes; detector, UV 254 / 220 nm. This gave compound 33 (17.0 mg, 54.03%) as a white solid. 1HNMR (300MHz, DMSO-d6) δ14.51 (s, 1H), 9.06 (s, 1H), 8.48 (d, J=7.4Hz, 1H), 8.33 (s, 1H), 8.26 (d, J=8.0Hz, 1H), 7.56 -7.47 (m, 2H), 7.47-7.35 (m, 3H), 7.11-7.00 (m, 2H), 6.81 (s, 1H), 6.19 (s, 1H), 5.18 (d, J=3.5Hz, 1H), 5.03-4.95 (m, 1 H), 4.49-4.22(m, 4H), 3.81-3.68(m, 2H), 3.63-3.50(m, 4H), 2.98-2.92(m, 2H), 2.72-2.62(m, 5H), 2.56-2.49(m, 3H) , 2.35-2.29 (m, 4H), 2.09 (s, 1H), 1.85 (s, 1H), 1.49 (dd, J=24.9, 6.9Hz, 3H), 1.02 (d, J=6.7Hz, 3H), 0.90-0.82 (m, 3H). LCMS (ESI) m / z: [M+H]+=831.50.

[1163] Preparation of (2S,4R)-1-((R)-2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34) and (2S,4R)-1-((S)-2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35).

[1164]

[1165] Step 1: Preparation of tert-butyl 3-(3-chloro-5-cyclopropyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 2)

[1166]

[1167] To a solution of intermediate 1 (3 g, 14.702 mmol, 1 eq.) in toluene (20 mL) was added tert-butyl 3-ethynylpyrrolidine-1-carboxylate (3.44 g, 17.642 mmol, 1.2 eq.), CuI (0.56 g, 2.940 mmol, 0.2 eq.), Pd(PPh3)2Cl2 (2.06 g, 2.940 mmol, 0.2 eq.) and TEA (4.46 g, 44.106 mmol, 3 eq.) under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL) and subsequently washed with brine (2×200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash C18 chromatography with elution gradient 0% to 35% CH3CN in water (0.05% FA) to afford intermediate 2 (2.18 g, 40.86%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=363.

[1168] Step 2: Preparation of tert-butyl 3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 3)

[1169]

[1170] To a solution of intermediate 2 (2.5 g, 6.890 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (1.43 g, 10.335 mmol, 1.5 eq.) in dioxane (16 mL) and H2O (4 mL) was added XPhos Pd G3 (583.19 mg, 0.689 mmol, 0.1 eq.) and Cs2CO3 (4.49 g, 13.780 mmol, 2 eq.) under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL) and subsequently washed with brine (2×200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash C18 chromatography with elution gradient 0% to 65% CH3CN in water (0.05% FA) to afford intermediate 3 (1.5 g, 51.77%) as a yellow oil. LCMS (ESI) m / z: [M+H]+=421.

[1171] Step 3: Preparation of (S)-tert-butyl 3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 4a) and (R)-tert-butyl 3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidine-1-carboxylate (Intermediate 4b)

[1172]

[1173] Intermediate 3 was purified by SFC-Prep-HPLC using the following conditions: column, CHIRALPAK AS-H, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 65 mL / min; gradient: isocratic 35% B; column temperature: 35°C; back pressure: 100 bar; detector, UV 254 nm; RT1=7.67 minutes; RT2=10.01 minutes; sample solvent: MeOH / DCM 1: 1. This gave intermediate 4a (first peak) (797 mg) as a yellow solid and intermediate 4b (second peak) (639 mg) as a yellow solid.

[1174] Step 4: Preparation of (S)-2-(5-cyclopropyl-6-(pyrrolidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 5)

[1175]

[1176] A solution of intermediate 4a (250 mg, 0.595 mmol, 1 eq) in DCM (3 mL) and TFA (1 mL) was stirred at 25°C for 1 hour. The resulting mixture was concentrated under reduced pressure to afford intermediate 5 (300 mg, TFA salt) as a brown oil. LCMS (ESI) m / z: [M+H]+=321.

[1177] Step 5: Preparation of methyl 2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoate (Intermediate 6)

[1178]

[1179] To a solution of intermediate 5 (300 mg, 0.936 mmol, 1 eq.) and methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (276.89 mg, 0.936 mmol, 1 eq.) in DMSO (2 mL) was added DIEA (363.06 mg, 2.808 mmol, 3 eq.). The resulting solution was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was purified by reverse phase flash C18 chromatography with an elution gradient of 0% to 60% CH3CN in water (0.05% FA) to obtain intermediate 6 (265 mg, 48.82%) as a purple solid. LCMS (ESI) m / z: [M+H]+=580.

[1180] Step 6: Preparation of 2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 7)

[1181]

[1182] To a solution of intermediate 6 (265 mg, 0.457 mmol, 1 eq.) in MeOH (4 mL) and H2O (1 mL) was added LiOH (54.75 mg, 2.285 mmol, 5 eq.). The resulting solution was stirred at room temperature for 2 hours. The mixture was acidified to pH 6 with HCl (1 M). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 7 (214 mg, crude) as a brown solid. LCMS (ESI) m / z: [M+H]+=566.

[1183] Step 7: Preparation of (2S,4R)-1-(2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 8)

[1184]

[1185] To a solution of intermediate 7 (214 mg, 0.378 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (125.39 mg, 0.378 mmol, 1.0 eq) in DMF (2 mL) was added PyBOP (393.77 mg, 0.756 mmol, 2 eq) and DIEA (244.49 mg, 1.890 mmol, 5 eq) at room temperature. The resulting solution was stirred at room temperature for 2 hours. Without additional post-treatment, the reaction solution was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 2% B for 1 minute, 2% B to 40% B in 1.5 minutes, 40% B to 60% B in 9 minutes; detector, UV 254 / 220 nm. This gave intermediate 8 (182 mg, 54.72%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=879.

[1186] Step 8: Preparation of (2S,4R)-1-((R)-2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34) and (2S,4R)-1-((S)-2-(3-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35)

[1187]

[1188] Intermediate 8 was purified by chiral Prep-HPLC using the following conditions: column, CHIRALPAK IA-3, 4.6*50 mm, 3 μm; mobile phase A: MtBE (0.1% DIEA), mobile phase B: EtOH; flow rate: 1 mL / min. This gave:

[1189] Compound 34 (57.9 mg, 17.36%) as a white solid. NMR (400MHz, DMSO-d6) δ14.23 (s, 1H), 8.99 (d, J=2.0Hz, 1H), 8.86 (s, 2H), 8. 44 (d, J=7.7Hz, 1H), 8.37 (s, 1H), 8.15 (d, J=7.8Hz, 1H), 7.45 (d, J=8.2Hz, 2H ), 7.41-7.29 (m, 3H), 7.00 (t, J=7.9Hz, 2H), 6.92 (d, J=10.4Hz, 2H), 5.12 (s, 1H), 4.94 (h, J=6.9Hz, 1H), 4.39 (t, J=7.9Hz, 1H), 4.29 (dd, J=10.9, 6.9Hz, 2 H), 4.13 (p, J=7.8Hz, 1H), 3.94-3.81 (m, 2H), 3.74 (td, J=11.8, 5.4Hz, 2H), 3 .54-3.44(m, 2H), 2.69-2.58(m, 2H), 2.52(d, J=6.9Hz, 3H), 2.45(d, J=7.0Hz , 2H), 2.10-1.99 (m, 1H), 1.80 (ddd, J=12.8, 8.0, 4.7Hz, 1H), 1.50-1.28 (m, 5 H), 1.21 (p, J=6.8, 6.2Hz, 2H), 1.01 (d, J=6.2Hz, 3H), 0.85 (t, J=7.2Hz, 3H). LCMS (ESI) m / z: [M+H]+=879.25.

[1190] Compound 35 (43.9 mg, 13.11%) as a white solid. NMR (400MHz, DMSO-d6) δ14.23 (d, J=6.2Hz, 1H), 8.95 (s, 1H), 8.81 (s, 2H), 8.37 (s, 1H), 8.27 (d, J=7.9Hz, 1H), 8.16 (d, J=7.9Hz, 1H), 7.52-7.41 (m , 1H), 7.38-7.29 (m, 2H), 7.28 (d, J=8.1Hz, 2H), 7.04-6.96 (m, 2H), 6.92- 6.86 (m, 2H), 5.14 (d, J=3.6Hz, 1H), 4.88 (t, J=7.3Hz, 1H), 4.64 (t, J=7.7 Hz, 1H), 4.28 (t, J=9.2Hz, 3H), 3.94 (t, J=7.8Hz, 2H), 3.82 (d, J=9.0Hz, 2 H), 3.75(s, 2H), 2.65(s, 2H), 2.52(dt, J=19.2, 10.3Hz, 3H), 2.50-2.28( m, 1H), 1.80 (dt, J=12.7, 6.2Hz, 1H), 1.49 (d, J=6.9Hz, 1H), 1.34 (dd, J=7 .3, 3.6Hz, 4H), 1.21 (s, 2H), 1.12 (d, J=6.6Hz, 2H), 0.87 (t, J=6.4Hz, 4H). LCMS (ESI) m / z: [M+H]+=879.25.

[1191] Preparation of (2S,4R)-1-((R)-2-(3-(2-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36) and (2S,4R)-1-((S)-2-(3-(2-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37).

[1192]

[1193] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

[1194]

[1195] A solution of compound 1 (350 mg, 1.092 mmol, 1 eq.) (prepared from intermediate 4b, second peak, using a procedure similar to that used above for preparing intermediate 5 from 4a, first peak), methyl 2-[3-(2-chloropyrimidin-5-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (323.04 mg, 1.092 mmol, 1 eq.) and DIEA (423.57 mg, 3.276 mmol, 3 eq.) in DMSO (3 mL) was stirred for 3 hours at 100°C. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN (0.05% FA) in water, 0% to 60% gradient in 30 minutes. This gave intermediate 2 (218 mg, 34.43%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=580.

[1196] Step 2: Preparation of 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-5-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

[1197]

[1198] A solution of intermediate 2 (218 mg, 0.376 mmol, 1 eq.) and LiOH (45.04 mg, 1.880 mmol, 5 eq.) in MeOH (4 mL) and H2O (2 mL) was stirred at room temperature for 4 hours. The mixture was acidified to pH 6 with HCl (1 M). The resulting mixture was extracted with EA (2×200 mL). The combined organic layers were washed with brine (200 mL) and subsequently dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave intermediate 3 (230 mg, crude) as a brown solid. LCMS (ESI) m / z: [M+H]+=566.

[1199] Step 3: Preparation of (2S,4R)-1-(2-(3-(2-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 4)

[1200]

[1201] A solution of Intermediate 3 (230 mg, 0.407 mmol, 1 eq), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (269.53 mg, 0.814 mmol, 2 eq), PyBOP (423.21 mg, 0.814 mmol, 2 eq) and DIEA (262.77 mg, 2.035 mmol, 5 eq) in DMF (3 mL) was stirred at room temperature for 2 h. Without additional post-treatment, the reaction solution was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 2% B 1 minute, 2% B to 38% B in 1.5 minutes, 38% B to 60% B in 8 minutes, 60% B; detector, UV 254 / 220 nm. This gave intermediate 4 (200 mg, 56.02%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=879.

[1202] Step 4: Preparation of (2S,4R)-1-((R)-2-(3-(2-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36) and (2S,4R)-1-((S)-2-(3-(2-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37)

[1203]

[1204] Intermediate 4 (200 mg) was purified by chiral Prep-HPLC using the following conditions: column, CHIRAL ART Amylose-SA, 3*25 cm, 5 μm; mobile phase, MtBE (0.5% 2M NH3-MeOH) / EtOH (50% EtOH for 52 minutes). This gave:

[1205] Compound 36 (82.8 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.24 (d, J = 3.7 Hz, 1H), 8.99 (d, J = 1.5 Hz, 1H), 8.86 (s, 2H), 8.44 (d, J = 7.7 Hz, 1H), 8.37 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.48-7.43 (m , 2H), 7.41-7.29 (m, 3H), 7.02 (t, J=7.7Hz, 2H), 7.00-6.89 (m, 2H), 5.12 (d, J= 3.6Hz, 1H), 4.94 (q, J=6.8Hz, 1H), 4.39 (t, J=7.9Hz, 1H), 4.29 (t, J=9.3Hz, 2H) , 4.13 (p, J=7.8Hz, 1H), 3.94-3.83 (m, 2H), 3.81-3.58 (m, 3H), 3.54-3.44 (m, 2 H), 2.62 (s, 1H), 2.45 (d, J=6.5Hz, 3H), 2.38-2.26 (m, 2H), 2.10-1.99 (m, 1H), 1.80 (dd, J=12.6, 4.7Hz, 1H), 1.49 (d, J=7.0Hz, 3H), 1.36 (dd, J=19.3, 7.2Hz, 2H), 1.19 (d, J=6.5Hz, 2H), 1.02 (dd, J=6.6, 4.0Hz, 3H), 0.85 (t, J=7.2Hz, 3H). LCMS (ESI) m / z: [M+H]+=879.25.

[1206] Compound 37 (47.3 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.24 (d, J = 6.1 Hz, 1H), 8.98 (d, J = 16.9 Hz, 1H), 8.86 (s, 2H), 8.37 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.65-7.58 (m , 1H), 7.52-7.41(m, 2H), 7.38-7.25(m, 2H), 7.04-6.95(m, 2H), 6.88-6.75(m, 2 H), 5.14 (d, J=3.6Hz, 2H), 5.08-4.93 (m, 1H), 4.88 (p, J=7.0Hz, 2H), 4.44 (t, J= 7.8Hz, 1H), 4.32-4.23(m, 1H), 4.14(p, J=7.5Hz, 1H), 3.81-3.69(m, 2H), 3.63( s, 1H), 3.57-3.44 (m, 2H), 2.63 (s, 1H), 2.47 (s, 1H), 2.40 (s, 2H), 2.35 (d, J=6. 6Hz, 2H), 2.12-2.02(m, 1H), 1.85-1.73(m, 1H), 1.49(d, J=7.0Hz, 1H), 1.34(d, J=7.1Hz, 4H), 1.20 (d, J=9.0Hz, 2H), 1.01 (d, J=6.6Hz, 2H), 0.91-0.78 (m, 4H). LCMS (ESI) m / z: [M+H]+=879.25.

[1207] Using procedures analogous to those used above for the preparation of compound 37, the compounds in Table 8 were prepared using the appropriate amines.

[1208] Table 8.

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219] Preparation of methyl 2-(3-(6-fluoro-5-methylpyridin-3-yl)isoxazol-5-yl)-3-methylbutanoate (I-11)

[1220]

[1221] Step 1: Preparation of (Z)-N-[(6-fluoro-5-methylpyridin-3-yl)methylene]hydroxylamine (Intermediate 2)

[1222]

[1223] To a solution of 6-chloro-5-methylpyridine-3-carboxaldehyde (2.0 g, 12.855 mmol, 1 eq.), hydroxylamine hydrochloride (1.79 g, 25.710 mmol, 2 eq.) in methanol (15 mL) was added Na2CO3 (4.09 g, 38.565 mmol, 3 eq.) and water (15 mL). The resulting solution was stirred at 25 ° C for 2 hours. The desired product can be detected by LCMS. The mixture was diluted with ethyl acetate (500 mL) and washed with water (500 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 2 (2.1 g, crude) as a white solid. LCMS (ESI) m / z: [M+H]+=155

[1224] Step 2: Preparation of (E)-6-fluoro-N-hydroxy-2-methylpyridine-3-carboimidoyl chloride (Intermediate 3)

[1225]

[1226] To a solution of intermediate 2 (2.1 g, 14.272 mmol, 1 eq.) in ethyl acetate (20 mL) was added NCS (2.86 g, 21.408 mmol, 1.5 eq.). The resulting solution was stirred at 25 °C overnight. The mixture was diluted with ethyl acetate (500 mL) and washed with water (300 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 3 (3.6 g, crude) as a white solid. LCMS (ESI) m / z: [M+H]+=189.

[1227] Step 3: Preparation of methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]acetate (Intermediate 4)

[1228]

[1229] To a solution of intermediate 3 (3.6 g, 19.089 mmol, 1 eq.) in ethyl acetate (14 mL) was added but-3-ynoic acid methyl ester (3.75 g, 38.178 mmol, 2 eq.) and NaHCO3 (4.81 g, 57.267 mmol, 3 eq.) at 0°C. The resulting solution was stirred overnight at 25°C. The mixture was diluted with ethyl acetate (500 mL) and washed with water (500 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 0% to 100% gradient in 30 minutes to obtain intermediate 4 (2.5 g, 52.34%) as a white solid. LCMS (ESI) m / z: [M+H]+=251.

[1230] Step 4: Preparation of methyl 2-[3-(6-fluoro-5-methylpyridin-3-yl)-1,2-oxazol-5-yl]-3-methylbutanoate (I-11)

[1231]

[1232] To a solution of intermediate 4 (500 mg, 1.998 mmol, 1 eq.), 2-iodopropane (679.35 mg, 3.996 mmol, 2 eq.) in THF (5 mL) was added Cs2CO3 (1302.08 mg, 3.996 mmol, 2 eq.). The resulting solution was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 0 to 60% acetonitrile in water to obtain I-11 (288 mg, 49.31%) as a white solid. LCMS (ESI) m / z: [M+H]+=293.

[1233] The following intermediates in Table 9 were prepared starting from the appropriate aldehyde in a similar manner as described in the preparation of intermediate 1-11.

[1234] Table 9.

[1235]

[1236] Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 110)

[1237]

[1238] Step 1: Preparation of methyl 2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

[1239]

[1240] To a solution of 2-{5-cyclopropyl-6-[(3S)-pyrrolidin-3-yl]pyrrolo[3,2-c]pyridazin-3-yl}phenol (200 mg, 0.624 mmol, 1 eq) and I-11 (182.47 mg, 0.624 mmol, 1 eq) in DMSO (5 mL) was added DIEA (242.04 mg, 1.872 mmol, 3 eq). The resulting solution was stirred at 120 °C for 2 h. Without additional workup, the mixture was purified by flash C18 chromatography with an elution gradient of 0 to 60% acetonitrile in water to afford intermediate 2 (110 mg, 19.46%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=593.

[1241] Step 2: Preparation of 2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

[1242]

[1243] To a solution of intermediate 2 (100 mg, 0.169 mmol, 1 eq.) in methanol (4 mL) was added LiOH (20.20 mg, 0.845 mmol, 5 eq.) and water (1 mL). The resulting solution was stirred at 25 ° C for 2 hours. The mixture was acidified to pH 6 with HCl (aqueous solution, 1 mol / L). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 3 (140 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H]+=579.

[1244] Step 3: Preparation of (2S,4R)-1-[2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4)

[1245]

[1246] To a solution of intermediate 3 (130 mg, 0.225 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (74.46 mg, 0.225 mmol, 1 eq) in DMF (2 mL) was added DIEA (145.18 mg, 1.125 mmol, 5 eq) and PyBOP (233.82 mg, 0.450 mmol, 2 eq). The resulting solution was stirred at 25 °C for 2 h. Without additional work-up, the crude reaction solution was purified by HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 2% B in 1 min, 2% B to 44% B in 1.5 min, 44% B to 61% B, 61% B in 8.5 min; wavelength: 254 / 220 nm; RT1 (min): 9.75; number of runs: 0) to obtain intermediate 4 (65 mg, 32.43%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=892.

[1247] Step 4: Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[(3S)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]-5-methylpyridin-3-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 110)

[1248]

[1249] Intermediate 4 (65 mg) was purified by chiral HPLC using the following conditions: (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 2% B in 1 minute, 2% B to 44% B in 1.5 minutes, 44% B to 61% B, 61% B in 8.5 minutes; wavelength: 254 / 220 nm; RT1 (min): 9.75; number of runs: 0). Compound 110-001 (second peak) (21.8 mg, 10.10%) was obtained as a white solid. NMR (400MHz, DMSO-d6) δ14.24 (s, 1H), 8.98 (d, J = 2.0Hz, 1H), 8.48-8.38 (m, 1H), 8.35 ( s, 1H), 8.15 (d, J=7.5Hz, 1H), 7.86-7.80 (m, 1H), 7.78-7.65 (m, 1H), 7.48-7.45 (m, 2H), 7.41-7.28 (m, 2H), 7.25-7.05 (m, 1H), 6.99 (t, J=7.6Hz, 2H), 6.91 (d, J=5.8Hz, 1H), 6. 85 (s, 1H), 5.10 (d, J=3.6Hz, 1H), 4.92 (q, J=7.1Hz, 1H), 4.39 (t, J=7.9Hz, 1H), 4.30 (s, 1H), 4.20 (dd, J=10.2, 7.1Hz, 1H), 4.02 (p, J=7.6Hz, 1H), 3.89-3.79 (m, 4H), 3.76 (dd, J=10.6, 4.4Hz, 1H), 3.53-3.43 (m, 2H), 2.59-2.52 (m, 1H), 2.48-2.41 (m, 6H), 2.39-2.2 1 (m, 2H), 2.09-1.99 (m, 1H), 1.95-1.80 (m, 1H), 1.44 (dd, J=39.2, 7.0Hz, 3H), 1.36-1. 30 (m, 2H), 1.26-1.16 (m, 2H), 1.01 (dd, J=6.6, 3.9Hz, 3H), 0.85 (dd, J=9.9, 6.7Hz, 3H). LCMS (ESI) m / z: [M+H]+=892.20.

[1250] Using procedures analogous to those described above for the preparation of compound 110, the compounds in Table 10 were prepared using the appropriate amines.

[1251] Table 10.

[1252]

[1253] Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 116)

[1254]

[1255] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

[1256]

[1257] To a stirred solution of intermediate 1 (240 mg, 0.749 mmol, 1 eq.) in DMSO (1 mL) was added 1-12 (443.03 mg, 1.498 mmol, 2 eq.) and DIEA (484.08 mg, 3.745 mmol, 5 eq.) at room temperature. The resulting mixture was stirred at 120 °C for 2 hours. The desired product can be detected by LCMS. The crude product was purified by flash C18 chromatography with an elution gradient of 0 to 60% ACN in H2O to obtain intermediate 2 (133 mg, 30.63%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=580.

[1258] Step 2: Preparation of 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

[1259]

[1260] To a solution of intermediate 2 (128 mg, 0.221 mmol, 1 eq.) in MeOH (4 mL) was added H2O (1 mL) and LiOH (26.44 mg, 1.105 mmol, 5 eq.), and the resulting solution was stirred at 25 ° C for 2 hours. The desired product can be detected by LCMS. The mixture was acidified to pH 5 with 1M HCl (aqueous solution) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with H2O (150 mL×3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 3 (126 mg, thick) as a yellow solid. LCMS (ESI) m / z: [M+H]+=566.

[1261] Step 3: Preparation of (2S,4R)-1-[2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4).

[1262]

[1263] To a stirred solution of intermediate 3 (126 mg, 0.223 mmol, 1 eq) and ((2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (147.66 mg, 0.446 mmol, 2 eq) in DMF (2.8 mL) were added PyBOP (231.85 mg, 0.446 mmol, 2 eq) and DIEA (143.95 mg, 1.115 mmol, 5 eq). The resulting mixture was stirred at room temperature for 2 hours. The desired product can be detected by LCMS. The mixture was purified by Prep-HPLC using the following conditions: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 65% B in 8 minutes; wavelength: 254 / 220 nm; RT1 (min): 9.15 to provide intermediate 4 (66 mg, 33.71%) as a white solid. LCMS (ESI) m / z: [M+H]+=879.

[1264] Step 4: Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyrimidin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 116).

[1265]

[1266] Intermediate 4 (66 mg) was purified by chiral Prep-HPLC using the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: Hex: MtBE = 1: 1 (0.5% 2M NH3-MEOH), mobile phase B: MeOH-HPLC; flow rate: 20 mL / min; gradient: 50% B to 50% B in 25 minutes; wavelength: 262 / 218 nm; RT1 (minute): 8.46; RT2 (minute): 15.24; sample solvent: EtOH: DCM = 1: 1-HPLC; injection volume: 0.5 mL; number of runs: 3. This gave compound 116 (16.8 mg, 25.45%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ14.25 (s, 1H), 8.98-8.89 (m, 1H), 8.55 (d, J = 4.9Hz, 1H), 8.40 (d, J = 16.0Hz, 2H), 8.15 (d, J = 7.5Hz, 1H), 7. 48-7.33 (m, 5H), 7.28-7.22 (m, 1H), 7.05-6.89 (m, 4H), 5.09-5.01 (m, 1H), 4.91 (s, 1H), 4.38-4.29 (m, 3H), 4.13 (d, J=8.1Hz, 1H), 3.92-3.81(m, 2H), 3.74-3.56(m, 3H), 3.48-3.2(m, 2H), 2.62-2.56(m, 1H), 2.45-2.39(m, 3H), 2.32-2.21(m, 2H), 2.11-2.01(m, 1 H), 1.78-1.71 (m, 1H), 1.47-1.41 (m, 1H), 1.35 (d, J=6.7Hz, 4H), 1.21-1.12 (m, 2H), 0.95 (d, J=6.4Hz, 3H), 0.83 (t, J=7.3Hz, 3H). LCMS (ESI) m / z: [M+H]+=878.37.

[1267] Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 82)

[1268]

[1269] Step 1: Preparation of methyl 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

[1270]

[1271] I-13 (87 mg, 0.313 mmol, 1 eq.) and 2-{5-cyclopropyl-6-[(3R)-pyrrolidin-3-yl]pyrrolo[3,2-c]pyridazine-3-yl}phenol (100.17 mg, 0.313 mmol, 1 eq.) and DMSO (3 mL, 42.237 mmol, 135.10 eq.) and DIEA (323.25 mg, 2.504 mmol, 8 eq.) were added to an 8 mL vial at room temperature. The final reaction mixture was at 120 ° C for 1 hour. The reaction was monitored by LCMS. The desired product can be detected by LCMS. This gave intermediate 2 (140 mg, 77.39%) as a yellow solid. LCMS (ESI) m / z[M+H]+=579.

[1272] Step 2: Preparation of 2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

[1273]

[1274] Intermediate 2 (130 mg, 0.225 mmol, 1 eq.) and LiOH (53.80 mg, 2.250 mmol, 10 eq.) and THF (1.6 mL, 19.748 mmol, 87.91 eq.) and H2O (0.4 mL, 22.204 mmol, 98.84 eq.) were added to an 8 mL vial at room temperature. The final reaction mixture was at room temperature for 1 hour. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The mixture was neutralized to pH 6 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3×10 mL). The resulting mixture was concentrated under reduced pressure. This gave intermediate 3 (60 mg, 47.30%) as a yellow solid. LCMS (ESI) m / z[M+H]+=565.

[1275] Step 3: Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 4)

[1276]

[1277] To an 8 mL vial was added intermediate 3 (55 mg, 0.097 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (32.28 mg, 0.097 mmol, 1 eq) and PyBOP (76.04 mg, 0.146 mmol, 1.5 eq) and DMF (3 mL, 38.765 mmol, 397.97 eq) and DIEA (37.77 mg, 0.291 mmol, 3 eq) at room temperature. The final reaction mixture was left at room temperature for 1 hour. The reaction was monitored by LCMS. The desired product can 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), gradient 10% to 50% in 10 minutes; detector, UV 254 nm. This gave intermediate 4 (57 mg, 66.64%) as a white solid. LCMS (ESI) m / z [M+H] + = 878.

[1278] Step 4: Preparation of (2S,4R)-1-[(2R)-2-(3-{2-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-4-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 82).

[1279]

[1280] Intermediate 4 (57 mg) was purified using chiral Prep-HPLC using the following conditions: column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 16 minutes; wavelength: 264 / 244 nm; RT1 (minute): 6.25; RT2 (minute): 10.5; sample solvent: MeOH:DCM=2:1; injection volume: 1 mL; this gave compound 82 (17.1 mg, 19.73%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ14.26 (s, 1H), 8.98 (d, J = 2.3Hz, 1H), 8.43 (d, J = 7.7Hz, 1H), 8.37 (s, 1H), 8.22 (d, J = 5.2Hz, 1H), 8.16 (dd, J = 8.0, 1.7Hz, 1H), 7 .47-7.40 (m, 2H), 7.40-7.29 (m, 3H), 7.12-6.94 (m, 5H), 6.91 (d, J=4.2Hz, 1H), 5.11 (d, J=3.6Hz, 1H), 5.06-4.86 (m, 1H), 4.39 (t, J=7.9Hz, 1H), 4.30 ( s, 1H), 4.21-4.05 (m, 2H), 3.89 (d, J=9.7Hz, 1H), 3.85-3.71 (m, 2H), 3.73- 3.58(m, 2H), 3.55-3.44(m, 2H), 2.70-2.57(m, 1H), 2.45(d, J=8.4Hz, 3H), 2 .40-2.29(m, 2H), 2.04(t, J=10.5Hz, 1H), 1.86-1.70(m, 1H), 1.57-1.28(m, 5H), 1.27-1.15 (m, 2H), 1.02 (dd, J=6.6, 2.7Hz, 3H), 0.85 (t, J=7.6Hz, 3H). LCMS (ESI) m / z[M+H]+=878.07.

[1281] Using procedures analogous to those described above for the preparation of compound 82, the compounds in Table 11 were prepared using the appropriate amines.

[1282] Table 11.

[1283]

[1284] Preparation of (2S,4R)-1-((R)-2-(3-(4-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyridin-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 91)

[1285]

[1286] Step 1: Preparation of methyl 2-(3-{4-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 2)

[1287]

[1288] To a stirred solution of I-14 (200.0 mg, 0.590 mmol, 1 eq) and 2-{5-cyclopropyl-6-[(3R)-pyrrolidin-3-yl]pyrrolo[3,2-c]pyridazin-3-yl}phenol (188.9 mg, 0.590 mmol, 1 eq) in 1,4-dioxane (5 mL) was added CsCO (576.3 mg, 1.770 mmol, 3 eq) and Pd-PEPPSI-IPentCl-methylpyridine (o-methylpyridine) (24.0 mg, 0.029 mmol, 0.05 eq). The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere for 2 hours. The mixture was concentrated under vacuum and 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), 30% to 70% gradient in 30 minutes; detector, UV 254 nm. This gave intermediate 2 (210.0 mg, 61.5%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=579.

[1289] Step 2: Preparation of 2-(3-{4-[(3R)-3-[5-cyclopropyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]pyrrolidin-1-yl]pyridin-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 3)

[1290]

[1291] To a stirred solution of intermediate 2 (210.0 mg, 0.363 mmol, 1 eq.) in THF (5 mL) and H2O (5 mL) was added LiOH (86.9 mg, 3.630 mmol, 10 eq.). The resulting mixture was stirred at room temperature for 1 hour. The mixture was neutralized to pH 7 with 1N HCl, and the precipitated solid was collected by filtration and washed with water (3×1 mL). This gave intermediate 3 (180.0 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z[M+H]+=565.

[1292] Step 3: Preparation of (2S,4R)-1-((R)-2-(3-(4-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)*5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyridin-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 4)

[1293]

[1294] To a stirred solution of intermediate 3 (100.0 mg, 0.177 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (70.4 mg, 0.212 mmol, 1.2 eq) in DMF (5 mL) was added PyBOP (184.3 mg, 0.354 mmol, 2 eq) and DIEA (137.3 mg, 1.062 mmol, 6 eq) and the resulting solution was stirred at room temperature for 2 hours. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 30% to 100% gradient over 35 minutes; detector, UV 254 nm. This gave intermediate 4 (78.0 mg, 50.1%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=878.

[1295] Step 4: Preparation of (2S,4R)-1-((R)-2-(3-(4-((R)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyridin-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 91)

[1296]

[1297] Intermediate 4 (78.0 mg) was separated by chiral Prep-HPLC using the following conditions: column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 16 minutes; wavelength: 264 / 244 nm; RT1 (minute): 6.25; RT2 (minute): 10.5; sample solvent: MeOH:DCM=2:1; injection volume: 1 mL; number of runs: 3, to provide 91-001 (second peak) (17.6 mg, 34.9%) as a white solid. NMR (400MHz, DMSO-d6) δ14.23 (s, 1H), 9.01-8.96 (m, 1H), 8.44 (d, J = 7.7Hz, 1H), 8.37 (s, 1H), 8.26 (d, J = 5.8Hz, 1H), 8.19-8.12 (m, 1H), 7.4 8-7.29(m, 5H), 7.19-7.12(m, 1H), 7.04-6.90(m, 3H), 6.84(s, 1H), 6. 72-6.66(m, 1H), 5.11(d, J=3.7Hz, 1H), 4.99-4.87(m, 1H), 4.43-4.34( m, 1H), 4.32-4.27 (m, 1H), 4.19-4.08 (m, 1H), 4.08-3.99 (m, 1H), 3.92-3.84 (m, 1H), 3.79-3.47 (m, 6H), 2.70-2.60 (m, 1H), 2.38-2.25 (m, 5H ), 2.10-1.98 (m, 1H), 1.84-1.73 (m, 1H), 1.49 (d, J=6.9Hz, 1H), 1.42-1.31 (m, 4H), 1.24-1.19 (m, 2H), 1.05-0.91 (m, 3H), 0.89-0.79 (m, 3H). LCMS (ESI) m / z: [M+H]+=878.35.

[1298] Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 105)

[1299]

[1300] Step 1: 3,6-dichloro-N-cyclobutylpyridazin-4-amine (Intermediate 2)

[1301]

[1302] 4-bromo-3,6-dichloropyridazine (10 g, 43.885 mmol, 1 eq.) and cyclobutylamine (3.43 g, 48.273 mmol, 1.1 eq.) and NMP (88 mL, 912.552 mmol, 20.79 eq.) and DIEA (11.34 g, 87.770 mmol, 2 eq.) were added to a 250 mL round bottom flask at room temperature. The final reaction mixture was at 100 ° C for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (50 × mL). The combined organic layer was washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to afford Intermediate 2 (8.8893 g, 92.88%) as a light red solid. LCMS (ESI) m / z [M+H]+=218.

[1303] Step 2: Preparation of tert-butyl 6-{2-[6-chloro-4-(cyclobutylamino)pyridazin-3-yl]ethynyl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 3)

[1304]

[1305] A mixture of intermediate 3 (1.7935 g, 8.224 mmol, 1 eq.) and tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (2.00 g, 9.046 mmol, 1.1 eq.) and CuI (0.31 g, 1.645 mmol, 0.2 eq.) and dichloropalladium; bis(triphenylphosphine) (1.15 g, 1.645 mmol, 0.2 eq.) and Et3N (2.50 g, 24.672 mmol, 3 eq.) in toluene was stirred at 60° C. under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with MeOH (50 mL). The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to provide intermediate 3 (1.2 g, 36.21%) as a yellow solid. LCMS (ESI) m / z [M+H] + = 403

[1306] Step 3: Preparation of tert-butyl 6-{3-chloro-5-cyclobutylpyrrolo[3,2-c]pyridazin-6-yl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 4)

[1307]

[1308] To an 8 mL vial was added intermediate 3 (40 mg, 0.099 mmol, 1 eq.) and K2CO3 (41.16 mg, 0.297 mmol, 3 eq.) and DMF (1 mL, 12.922 mmol, 130.16 eq.) at room temperature. The final reaction mixture was at 100°C for 1 hour. The reaction was monitored by LCMS. The desired product can 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 (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This gave intermediate 4 (384 mg, 34.91%) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 403

[1309] Step 4: Preparation of tert-butyl 6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 5)

[1310]

[1311] A solution of 4 (354 mg, 0.879 mmol, 1 eq.) and 2-hydroxyphenylboronic acid (363.55 mg, 2.637 mmol, 3 eq.) and XPhos Pd G3 (148.74 mg, 0.176 mmol, 0.2 eq.) and Cs2CO3 (858.78 mg, 2.637 mmol, 3 eq.) in dioxane (2.5 mL, 29.510 mmol, 33.59 eq.) and H2O (0.5 mL, 27.755 mmol, 31.59 eq.) was stirred at room temperature under nitrogen atmosphere for 1 h. 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, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave intermediate 5 (337 mg, 83.28%) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 461

[1312] Step 5: Preparation of 2-(6-{2-azaspiro[3.3]hept-6-yl}-5-cyclobutylpyrrolo[3,2-c]pyridazin-3-yl)phenol (Intermediate 6)

[1313]

[1314] To an 8 mL vial was added intermediate 5 (50 mg, 0.109 mmol, 1 eq) and TFA (0.5 mL, 6.732 mmol, 62.01 eq) and DCM (1 mL, 15.731 mmol, 144.90 eq) at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting oil was dried under vacuum. This gave intermediate 6 (417 mg, 92.83%) as a brown solid. LCMS (ESI) m / z [M+H] + = 361

[1315] Step 6: Preparation of methyl 2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoate (Intermediate 7)

[1316]

[1317] To an 8 mL vial was added intermediate 6 (405 mg, 1.124 mmol, 1 eq) and methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazol-5-yl}butanoate (540.76 mg, 1.124 mmol, 1 eq) and DMF (7 mL, 90.451 mmol, 80.50 eq) and DIEA (726.08 mg, 5.620 mmol, 5 eq) at room temperature. The final reaction mixture was at 120 ° C for 2 hours. The reaction was monitored by LCMS. The residue / crude product was purified by reverse phase flash chromatography using the following conditions (MeCN / water) to provide intermediate 7 (85 mg, 13.97%) as a brown solid. LCMS (ESI) m / z[M+H]+=542.

[1318] Step 7: Preparation of 2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoic acid (Intermediate 8)

[1319]

[1320] Intermediate 7 (8 mg, 0.015 mmol, 1 eq.) and LiOH (3.54 mg, 0.150 mmol, 10 eq.) and MeOH (0.9 mL, 22.229 mmol, 1505.04 eq.) and H2O (0.3 mL, 16.653 mmol, 1127.50 eq.) were added to an 8 mL vial at room temperature. The final reaction mixture was at 40°C for 1 hour. The reaction was monitored by LCMS. The mixture / residue was acidified to pH 6 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (1×3 mL). The resulting mixture was concentrated under reduced pressure. This gave Intermediate 8 (120 mg, 159.99%) as a yellow solid. LCMS (ESI) m / z [M+H]+ ==528.

[1321] Step 8: Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Intermediate 9)

[1322]

[1323] To a stirred solution / mixture of intermediate 8 (26 mg, 0.049 mmol, 1 eq) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (16.33 mg, 0.049 mmol, 1 eq) and PyBOP (38.47 mg, 0.074 mmol, 1.5 eq) in DMF was added DIEA (15.92 mg, 0.122 mmol, 2.5 eq) dropwise at room temperature under nitrogen atmosphere. The final reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The residual product was purified by reverse phase flash chromatography using the following conditions (MeCN / water (0.1% FA)) to provide intermediate 9 (8.7 mg, 20.09%) as a white solid. LCMS (ESI) m / z [M+H] + = 841.

[1324] Step 9: Preparation of (2S,4R)-1-[(2R)-2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 105-001)

[1325]

[1326] Intermediate 9 (26 mg) was purified by chiral Prep-HPLC using the following conditions (NB-Prep Chiral HPLC-02): column, CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase, MtBE (10 mM NH3-MeOH) and MeOH (maintaining 30% MeOH in 16 minutes). The resulting mixture was concentrated under reduced pressure to provide compound 105 (8.7 mg, 20.09%) as a white solid. 1HNMR (400MHz, DMSO-d6) δ14.16 (s, 1H), 8.99 (d, J=2.8Hz, 1H), 8.46-8.41 (m, 2H), 8.25-8.05 (m, 1H), 7.51-7.41 (m, 2H), 7.37 (d, J=8.3Hz, 2H), 7.33- 7.31(m, 1H), 7.12-6.92(m, 2H), 6.87(s, 1H), 5.81(d, J=43.6Hz, 1H), 5.10( d, J=3.5Hz, 1H), 4.97-4.86 (m, 2H), 4.37 (t, J=7.8Hz, 1H), 4.29 (s, 1H), 4.0 3(s, 2H), 3.84(s, 2H), 3.79-3.67(m, 2H), 3.59(d, J=9.7Hz, 1H), 3.53-3.39 (m, 2H), 2.88 (td, J=9.8, 2.6Hz, 2H), 2.84-2.75 (m, 2H), 2.52 (s, 1H), 2.49- 2.44(m, 5H), 2.36-2.12(m, 1H), 2.04(q, J=7.2Hz, 2H), 1.85(dt, J=22.3, 10 .7Hz, 2H), 1.60-1.16 (m, 3H), 0.95 (d, J=6.4Hz, 3H), 0.80 (t, J=7.4Hz, 3H). LCMS (ESI) m / z[M+H]+=841.04.

[1327] The compounds in Table 12 were prepared using procedures analogous to those described above for the preparation of compound 105 using the appropriate amines and alkynes.

[1328] Table 12.

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340]

[1341]

[1342] Preparation of (2S,4R)-1-[2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-phenylethyl]pyrrolidine-2-carboxamide (Compound 49)

[1343]

[1344] Step 1: Preparation of (2S,4R)-1-[2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-phenylethyl]pyrrolidine-2-carboxamide (Compound 49)

[1345]

[1346] To a stirred solution of (2S,4R)-1-[2-(3-{6-[5-cyclobutyl-3-(2-hydroxyphenyl)pyrrolo[3,2-c]pyridazin-6-yl]-2-azaspiro[3.3]hept-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (40 mg, 0.062 mmol, 1 eq), (S)-α-phenylethylamine (15.13 mg, 0.124 mmol, 2 eq) and T3P (59.59 mg, 0.186 mmol, 3 eq) in DCE (3 mL) was added DIEA (24.21 mg, 0.186 mmol, 3 eq). The resulting solution was stirred at 40 °C for 8 hours. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 36% B to 56% B in 8 minutes; wavelength: 254 nm / 220 nm nm; RT1 (min): 9.95) to provide compound 49 (14.8 mg, 30.21%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ14.16 (d, J=3.1Hz, 1H), 8.42 (s, 1H), 8.33 (d, J=7.9Hz, 2H), 7.38-7.17 (m, 6H), 6.99 (t, J=7.4Hz, 2H), 6.87 (s, 1H), 5.92-5.83 (m, 1H), 5.08 (d, J=3.6Hz, 1H), 4.91 (dt, J=19.6, 9.7Hz, 2H), 4.45 -4.30 (m, 2H), 4.27 (s, 2H), 3.95 (d, J = 4.9Hz, 2H), 3.87-3.64 (m, 2H), 3.66-3.35 (m, 4H), 2.90 (d, J = 10.6Hz, 5H), 2.46 (t, J=11.8Hz, 1H), 2.19-1.81 (m, 5H), 1.46-1.29 (m, 3H), 0.95 (d, J=6.4Hz, 3H), 0.86-0.71 (m, 3H). LCMS (ESI) m / z: [M+H]+=744.35.

[1347] Using procedures analogous to those described above for the preparation of compound 49, the compounds in Table 13 were prepared using the appropriate amines.

[1348] Table 13.

[1349]

[1350]

[1351]

[1352]

[1353]

[1354]

[1355]

[1356] Preparation of (2S,4R)-1-((R)-2-(4-(2-((S)-3-(5-cyclopropyl-3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyrrolidin-1-yl)pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hyd...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: Formula I in Ring system A is a 5- to 9-membered heterocyclyl or heteroaryl group containing at least one N; m is 0, 1, 2, or 3; k is 0, 1, or 2; Each R 1 are independently halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 2 -C 9 Heterocyclic group, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted CH 2 -C 3 -C 8 Cycloalkyl; Each X is independently a halogen; L is a linker; and B is the degradation part.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IA: Formula IA Where R 2 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl, optionally substituted C 2 -C 9 A heterocyclic group or a bond to -LB.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof having the formula IB: IB 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IC: IC 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 It's H.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted C1-C6 alkyl group.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 It is an optionally substituted C3-C8 cycloalkyl group.

8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 It is an optionally substituted C2-C9 heterocyclic group.

9. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H, CH3, 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 2 It is H, CH3, 11. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula ID: Formula ID 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein m is 1.

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

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted C1-C6 alkyl group.

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

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

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

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

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

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

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula IE, Formula IF, Formula IG, Formula IH or Formula II:

22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula IJ, Formula IK, Formula IL, Formula IM or Formula IN:

23. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula IO, Formula IP, Formula IQ, Formula IR or Formula IS:

24. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula IT, Formula IU, Formula IV or Formula IW:

25. The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the degradation portion B has a structure of formula A-1: in Y 1 yes R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A6 is H or optionally substituted C1-C6 alkyl; and R A7 is H or optionally substituted C1-C6 alkyl; or R A6 and R A7 Together with the carbon atoms to which they are each bound, they form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl; or R A6 and R A7 Combined together with the carbon atoms to which they are each bound to form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl; 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 is independently H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 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, 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 the carbon atoms to which they are attached to form and is an optionally substituted C6-C10 aryl group, an optionally substituted C3-C10 carbocyclyl group, an optionally substituted C2-C9 heteroaryl group, or a C2-C9 heterocyclyl group, any of which is optionally replaced 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 It is the bond between the degradable part and the linker.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the degradation portion has the following structure:

27. 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: Formula C in L 4 Yes-N(R B1 )(R B2 ), R B1 It is 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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkylC3-C10 carbocyclyl, or optionally substituted C1-C6 alkylC6-C10 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 is A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 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, hydroxyl, thiol, cyano, or optionally substituted amino; R B7 and R B8 Each is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl; R B9 is H or 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.

28. 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 Yes-N(R B1 )(R B2 ), R B1 It is 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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkylC3-C10 carbocyclyl, or optionally substituted C1-C6 alkylC6-C10 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 is A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 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, hydroxyl, thiol, or optionally substituted amino; R B7 and R B8 Each is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 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.

29. The compound of any one of claims 27-28 or a pharmaceutically acceptable salt thereof, wherein the degradation portion is 30. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 31. The compound of any one of claims 27-28 or a pharmaceutically acceptable salt thereof, wherein the degradation portion is 32. The compound of any one of claims 27 or a pharmaceutically acceptable salt thereof, wherein the degradation portion is 33. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 34. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 35. 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: Formula C5 in L 4 Yes-N(R B1 )(R B2 ), R B1 It is 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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 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 is A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 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, hydroxyl, thiol, cyano, or optionally substituted amino; R B7 and R B8 Each is independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl; R B9 is H or optionally substituted C1-C6 alkyl; R B11 is H, alcohol, boronic acid, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 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.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 37. 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: Formula D in L 4 Yes-N(R B1 )(R B2 ), R B1 It is 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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkylC3-C10 carbocyclyl, or optionally substituted C1-C6 alkylC6-C10 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 is A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 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, hydroxyl, 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.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 39. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 40. 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: Style in L 4 Yes-N(R B1 )(R B2 ), R B1 It is H, A 2 , optionally substituted Cl-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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkylC3-C10 carbocyclyl, or optionally substituted C1-C6 alkylC6-C10 aryl; R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; X 1 and X 2 are each independently C, N or O. v2 is 0, 1, 2, 3, or 4; Each R B6 Independently is A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 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, hydroxyl, 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.

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 42. 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: Formula E in L 4 Yes-N(R B1 )(R B2 ), R B1 It is 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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkylC3-C10 carbocyclyl, or optionally substituted C1-C6 alkylC6-C10 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-C10 carbocyclyl, or optionally substituted C2-C10 heterocyclyl; B 10 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted amino or cyano; 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.

43. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 44. 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 Yes-N(R B1 )(R B2 ), R B1 It is 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 Yes A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl; R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkylC3-C10 carbocyclyl, or optionally substituted C1-C6 alkylC6-C10 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.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 46. ​​The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein the degraded portion is 47. The compound of any one of claims 1 to 46, 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 independently represents optionally substituted C1-C4 alkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 arylC1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-12 aryl, O, S, S(O) 2 or NR N ; Each R N is independently H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl; C 1 and C 2 are each independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D is an optionally substituted C1-10 alkyl, an optionally substituted C2-10 alkenyl, an optionally substituted C2-10 alkynyl, an optionally substituted C2-10 heterocyclyl, an optionally substituted C2-6 heteroaryl, an optionally substituted C6-12 aryl, an optionally substituted C2-C10 polyethylene glycol, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C3-C10 carbocyclyl, or an optionally substituted C1-10 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 .

48. The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein A1 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 is independently an optionally substituted C1-C4 alkyl, an optionally substituted C6-C10 aryl, an optionally substituted C6-C10 arylC1-4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C2-C8 heterocyclyl, an optionally substituted C2-C6 heteroaryl, an optionally substituted C612 aryl, O, S, S(O) 2 or NR N ; Each R N is independently H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl; C 1 and C 2 are each independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D is an optionally substituted C1-10 alkyl, an optionally substituted C2-10 alkenyl, an optionally substituted C2-10 alkynyl, an optionally substituted C2-6 heterocyclyl, an optionally substituted C2-6 heteroaryl, an optionally substituted C6-12 aryl, an optionally substituted C2-C10 polyethylene glycol, or an optionally substituted C1-10 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 .

49. The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure 50. The compound of any one of claims 47-48 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure 51. 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 independently represents optionally substituted ethynyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C9 heteroaryl, O, S, S(O) 2 or NR N ; Each R N is independently H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl; C 1 and C 2 are each independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl; and f, g, h, i, j and k are each independently 0 or 1.

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure 53. A pharmaceutical composition comprising a compound according to any one of claims 1 to 52 and a pharmaceutically acceptable excipient.

54. 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 52 or a pharmaceutical composition of claim 53.

55. The method of claim 54, wherein the BAF complex-associated disorder is cancer or a viral infection.

56. 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 52 or a pharmaceutical composition of claim 53.

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

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

59. The method of any one of claims 54-58, 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.

60. The method of claim 59, 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.

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

62. The method of claim 59, wherein the cancer is a soft tissue sarcoma.

63. A method of treating a cancer selected from melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and a blood 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 52 or a pharmaceutical composition of claim 53.

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

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

66. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 65, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, 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's 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.

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

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

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

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