Heterocyclic RBM39 modulators

Abstract

Provided herein are compounds having formula (I) that modulate RMB39, and methods of using these compounds in RMB39-related disorders, such as cancer (e.g., renal cell carcinoma). # imgabs0 #

Description

Background Art

[0001] The present disclosure relates to thiazole derivatives and their use as medicaments. Specifically, the present invention relates to the use of these compounds for degrading the activity of RNA binding motif protein 39 (also known as splicing factor HCC1, CAPERα, FSAP59, RNPC2, CAPERα containing 2), and generally referred to as RBM39 (Xu et al., Cell Death Discov. [Cell Death Discovery] 7, 214 (2021)).

[0002] RBM39 (59.4 kDa protein) is an essential serine / arginine-rich RNA-binding protein found in the nuclei of all living organisms and is involved in pre-mRNA splicing, transcriptional co-regulation, and translation (Xu et al., Cell Death Discov. 7, 214 (2021)).

[0003] Several observations have led to the conclusion that RBM39 acts as a transcriptional coactivator of activator protein-1 (AP-1) and estrogen receptor alpha (ERα), where genes containing RBM39 regulate variable exons associated with a variety of biological processes, such as G2 / M transition, cellular response to DNA damage, adherens junctions, and endocytosis (Mai et al., Biochim Biophys Acta., 1859(8), 1014-1024 (2016)). RBM39 is also associated with the malignant progression of many solid and hematological cancers (Xu et al., Cell Death Discov. 7, 214 (2021)).

[0004] A number of arylsulfonamides (indisulam, tasisulam, CQS, and E7820) have been shown to act as molecular glue degraders of RBM39 by forming a ternary complex with RBM39 and the E3 ubiquitin ligase receptor DCAF15, with no detectable affinity for either species alone. These molecular glues promote the interaction of the RBM39 splicing factor and the CUL4-DCAF15 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of RBM39. In human cancer cell lines treated with arylsulfonamides, degradation of RBM39 resulted in a significant antiproliferative effect. Additionally, silencing DCAF15 in cancer cells using CRISPR-Cas9 resisted degradation of RBM39 by arylsulfonamides, highlighting RBM39 degradation as a major mechanism of anticancer effects seen with these compounds (Han et al., Science., 356(6336), (2017); Du et al., Structure., 27, 1625-1633 (2019). Furthermore, gene knockout experiments of RBM39-deficient human cancer cells injected into mice slowed the development of leukemia progression and improved overall survival (Wang et al., Cancer Cell., 35(3), 369-384 (2019)).

[0005] Arylsulfonamides have previously been shown to exhibit acceptable safety in clinical trials, with some anti-tumor efficacy seen in various cancers. However, the overall response rate remains low, which may be due to a lack of understanding of the mechanism of action and potential biomarkers of the response. Therefore, for specific patient populations, RBM39 degraders have the potential to effectively treat certain types of human cancers, and further exploration is necessary (Wang et al., Cancer Cell. [Cancer Cell], 35(3), 369-384(2019). Summary of the invention

[0006] Provided herein are compounds having formula (I) and pharmaceutically acceptable salts thereof:

[0007]

[0008] Where R N1 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 Alkyl; R N2 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 Alkyl; X 1 Yes CR 1 or N;X 2 Yes CR 3 or N;X 3Yes CR 4 or N; R 1 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 2 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 3 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 4 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 5 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NRN R N , and CO2C 1-6 Alkyl; each R N is independently H, optionally substituted by 1, 2, or 3 R 7 Substituted C 1-6 Alkyl, or C 3-10 Cycloalkyl; Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 Replace; each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR N R N ,COOH,C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , C 1-6 Alkylene-C(O)NR N R N , SO2NR N R N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 1-6 Alkylene-C 3-10 Cycloalkyl, C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl, C 1-6 Alkylene, or C 1-6 The alkoxy group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; and; each R 7 are independently OH, halo, CN, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, NH2, NH(C 1-6 alkyl), or N(C 1-6 In some cases, R N1 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 Alkyl; R N2 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 Alkyl; X 1 Yes CR 1 or N;X 2 Yes CR 3 or N;X 3 Yes CR 4 or N; R 1 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 2 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 3 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 4 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; R 5 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; each R N is independently H or optionally substituted by 1, 2, or 3 R 7 Substituted C 1-6 alkyl; Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 Replace; each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, COOH, C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 3-10 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-10 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; and each R 7 are independently OH, halo, CN, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, NH(C 1-6 alkyl), or N(C 1-6 Alkyl)2.

[0009] Also provided are compositions comprising a compound as disclosed herein and a pharmaceutically acceptable excipient. Further provided are methods for regulating RBM39 protein by contacting RBM30 protein with a compound as disclosed herein. Also provided are methods for treating a disease associated with abnormal RBM39 activity (e.g., cancer, such as renal cell carcinoma) in a subject by administering to the subject a therapeutically effective amount of a compound as disclosed herein. DETAILED DESCRIPTION

[0010] Provided herein are compounds and their uses in treating or preventing diseases and disorders (e.g., cancer) associated with abnormal RBM39 activity. Also provided are compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions comprising such compounds or pharmaceutically acceptable salts thereof for treating or preventing diseases and disorders (e.g., cancer) associated with abnormal RBM39 activity.

[0011] Compound

[0012] Provided herein are compounds having formula (I) and pharmaceutically acceptable salts thereof:

[0013]

[0014] in

[0015] R N1 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0016] R N2 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0017] X 1 Yes CR 1 or N;

[0018] X 2 Yes CR 3 or N;

[0019] X 3 Yes CR 4 or N;

[0020] R 1 It is H, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0021] R 2 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0022] R 3 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0023] R 4 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0024] R 5 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0025] Each R N is independently H, optionally substituted by 1, 2, or 3 R 7 Substituted C 1-6 Alkyl, or C 3-10 Cycloalkyl;

[0026] Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 replace;

[0027] Each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR N R N ,COOH,C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , C 1-6 Alkylene-C(O)NR N R N , SO2NR N R N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 1-6 Alkylene-C 3-10 Cycloalkyl, C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl, C 1-6 Alkylene, or C 1-6The alkoxy group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; and

[0028] Each R 7 are independently OH, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, NH(C 1-6 alkyl), or N(C 1-6 Alkyl)2.

[0029] In some cases, R N1 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0030] R N2 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0031] X 1 Yes CR 1 or N;

[0032] X 2 Yes CR 3 or N;

[0033] X 3 Yes CR 4 or N;

[0034] R 1 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0035] R 2 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0036] R 3 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0037] R 4 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0038] R 5 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0039] Each R N is independently H or optionally substituted by 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0040] Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 replace;

[0041] Each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, COOH, C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 3-10 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-10 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; and

[0042] Each R 7 are independently OH, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, NH(C 1-6 alkyl), or N(C 1-6 Alkyl)2.

[0043] In some cases, Het is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 In some cases, Het is a 5-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 In some cases, Het is optionally replaced by 1, 2, or 3 R 6 In some cases, Het is

[0044]

[0045] And R 6 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, P(O)(Me)2, or C(O)-morpholinyl. In some cases, Het is And R 6 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 In some cases, Het is optionally substituted with 1, 2, or 3 R 6 In some cases, Het is And R 6 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, P(O)(Me)2, or C(O)-morpholinyl. In some cases, Het is And R 6 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, P(O)(Me)2, or C(O)-morpholinyl.

[0046] In some cases, X 1 Yes CR 1 In some cases, X 2 Yes CR 3 In some cases, X 3 Yes CR 4 In some cases, X 1 Yes CR 1 , X 2 Yes CR 3 , and X 3 Yes CR 4 In some cases, X 1 , X 2 , and X 3 At least one of is N. In some cases, X 1 , X 2 , and X 3 One of them is N. In some cases, X 1 , X 2 , and X 3Two of them are N. In some cases, X 1 is N. In some cases, X 2 is N. In some cases, X 3 It is N.

[0047] In some cases, the compound has the structure of Formula (Ia):

[0048]

[0049] In some cases, R N1 and R N2 One is H. In some cases, R N1 is H. In some cases, R N2 is H. In some cases, R N1 and R N2 Each is H. In some cases, R N1 is optionally replaced by 1, 2, or 3 R 7 Substituted C 1-6 In some cases, R N2 is optionally replaced by 1, 2, or 3 R 7 Substituted C 1-6 alkyl.

[0050] In some cases, R 1 Is H or C 1-6 Alkyl, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, R 1 It's H.

[0051] In some cases, R 2 It is H, C 1-6 alkyl, halo, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, R 2 is H, halo, or CN. In some cases, R 2 is Cl. In some cases, R 2 It is CN.

[0052] In some cases, R 3It is H, C 1-6 Alkyl, or halogenated, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, R 3 is H. In some cases, R 3 It is C 1-6 Alkyl, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, R 3 is methyl. In some cases, R 3 is halogenated. In some cases, R 3 It's fluorine.

[0053] In some cases, R 4 It is H, C 1-6 Alkyl, or halogenated, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, R 4 It's H.

[0054] In some cases, R 5 It is H, C 1-6 Alkyl, or halogenated, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, R 5 It's H.

[0055] In some cases, each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, COOH, C(O)NR N R N, C 1-6 Alkylene-C(O)OR N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 3-5 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-5 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylene-C(O)OC 1-6 alkyl, 5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein the 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, each R 6 are independently halogenated, C 1-6 alkyl, or 5- or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein the 5- or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C1-6 The alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, at least one R 6 is halogenated. In some cases, an R 6 is halogenated. In some cases, at least one R 6 is chlorine or bromine. In some cases, an R 6 is chlorine or bromine. In some cases, R 6 is chlorine. In some cases, R 6 is bromine. In some cases, at least one R 6 It is C 1-6 alkyl, and each C 1-6 The alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 In some cases, at least one R 6 is methyl, ethyl, or isopropyl. 6 is methyl, ethyl, or isopropyl. 6 is methyl. In some cases, R 6 is ethyl. In some cases, R 6 is isopropyl. In some cases, each R 6 is independently a 5- or 6-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the 5- or 6-membered heteroaryl group may be optionally replaced by 1, 2, or 3 R 7 In some cases, at least one R 6 is pyrazolyl, pyridyl, pyridazinyl, or pyrimidinyl, each of which may be optionally substituted by 1, 2, or 3 R 7 In some cases, an R 6 is pyrazolyl, pyridyl, pyridazinyl, or pyrimidinyl, each of which may be optionally substituted by 1, 2, or 3 R 7 In some cases, R 6 is optionally replaced by 1, 2, or 3 R 7 In some cases, R 6 is optionally replaced by 1, 2, or 3 R 7 In some cases, R 6 is pyridazinyl, or optionally 1, 2, or 3 R 7In some cases, R 6 is optionally replaced by 1, 2, or 3 R 7 Substituted pyrimidinyl.

[0056] In some cases, each R 7 are independently halogenated, C 1-6 Alkyl, or C 1-6 In some cases, at least one R 7 It is C 1-6 In some cases, at least one R 7 It's methyl.

[0057] Specific compounds contemplated include the compounds in Table A below, or pharmaceutically acceptable salts thereof. Compounds having a chiral center without indicating a specific stereoisomerism indicate a mixture of stereocenters at that chiral center.

[0058] Table A

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] Unless otherwise indicated, the structures depicted herein are also meant to include all isomeric (e.g., enantiomers, diastereomers, cis-trans, conformation, and rotation) forms of the structure. For example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in the present disclosure unless only one isomer is specifically indicated. Therefore, single stereochemical isomers of the compounds of the present invention as well as enantiomers, diastereomers, cis / trans, conformational and rotational mixtures are within the scope of the present disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomers" refer to compounds with different chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein may exist as single stereoisomers or mixtures of stereoisomers. Unless otherwise discussed, the stereochemistry of the compounds shown herein indicates relative stereochemistry rather than absolute. As indicated herein, a single stereoisomer, diastereomer or enantiomer refers to a compound that is at least greater than 50% of the indicated stereoisomer, diastereomer or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer or enantiomer.

[0087] Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0088] Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, or with 13 C- or 14 Compounds having the structures of the present invention are within the scope of the present disclosure, wherein the carbon is replaced by a C-enriched carbon. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterated analogs, may also be useful therapeutically.

[0089] The compounds of the present disclosure are defined herein by their chemical structure and / or chemical name. When a compound is referred to by both a chemical structure and a chemical name, and the chemical structure conflicts with the chemical name, the chemical structure determines the identity of the compound.

[0090] The compounds disclosed herein can be used as modulators of RBM39, such as inhibitors of RBM39. These compounds can also be used to treat or prevent diseases and disorders associated with abnormal RBM39 activity in patients, such as cancer.

[0091] definition

[0092] As used herein, the term "alkyl" refers to straight chain and branched chain saturated hydrocarbon groups containing from one to thirty carbon atoms, for example, from one to twenty carbon atoms or from one to ten carbon atoms. n Means an alkyl group with "n" carbon atoms. For example, a C6 alkyl group refers to an alkyl group with 6 carbon atoms. C1-C6 alkyl groups refer to alkyl groups with a plurality of carbon atoms covering the entire range (e.g., 1 to 6 carbon atoms), and all subgroups (e.g., 1 to 6, 2 to 6, 1 to 5, 3 to 6, 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl) and tert-butyl (1,1-dimethylethyl). Unless otherwise indicated, alkyl groups may be unsubstituted alkyl groups or substituted alkyl groups.

[0093] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more halogen atoms.

[0094] As used herein, the term "alkylene" refers to an alkyl group having a substituent. For example, the term "alkylene halo" refers to an alkyl group substituted with a halogen group. For example, an alkylene group can be -CH2CH2- or -CH2-. The term C n It means an alkylene group having "n" carbon atoms. For example, C 1-6 Alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range and all subgroups as previously described for "alkyl." Unless otherwise specified, an alkylene group may be unsubstituted or substituted.

[0095] As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing three to ten carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms). n It means a cycloalkyl group having "n" carbon atoms. For example, C5 cycloalkyl refers to a cycloalkyl group having 5 carbon atoms in the ring. 10 Cycloalkyl refers to a group having carbon atoms that encompasses the entire range (e.g., 3 to 10), as well as all subgroups (e.g., 1-10, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5 In some embodiments, cycloalkyl includes cycloalkyl, cycloalkyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified, cycloalkyl can be unsubstituted cycloalkyl or substituted cycloalkyl. Cycloalkyl described herein can be separated or fused to another cycloalkyl, heterocycloalkyl, aryl and / or heteroaryl. When cycloalkyl is fused to another cycloalkyl, unless otherwise specified, each cycloalkyl can contain three to eight carbon atoms. Unless otherwise specified, a cycloalkyl group can be unsubstituted or substituted.

[0096] As used herein, the term "heterocycloalkyl" is similarly defined as cycloalkyl, except that the ring contains one to three heteroatoms independently selected from oxygen, nitrogen and sulfur. In particular, the term "heterocycloalkyl" refers to a ring containing a total of 5 or 6 atoms, wherein 1, 2 or 3 ring atoms are heteroatoms independently selected from the group consisting of: oxygen, nitrogen and sulfur, and the remaining atoms in the ring are carbon atoms. Non-limiting examples of heterocycloalkyl include piperidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, etc.

[0097] Cycloalkyl and heterocycloalkyl can be saturated or partially unsaturated ring systems, which are optionally substituted by, for example, one to three groups independently selected from: alkyl, alkylene OH, C (O) NH2, NH2, oxo (= O), aryl, alkylene halo, halo, and OH. Heterocycloalkyl can alternatively be further substituted by alkyl (e.g., methyl or ethyl), alkylene-OH, alkylene aryl, and alkylene heteroaryl N-. Heterocycloalkyl described herein can be separated or fused to another heterocycloalkyl, cycloalkyl, aryl, and / or heteroaryl. When heterocycloalkyl is fused to another heterocycloalkyl, each heterocycloalkyl can contain three to twelve total ring atoms and one to three heteroatoms. Unless otherwise indicated, heterocycloalkyl can be unsubstituted or substituted.

[0098] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring having 5 to 12 total ring atoms and containing one to four heteroatoms selected from nitrogen, oxygen and sulfur atoms in the aromatic ring. In particular, the heteroaryl groups described herein contain a total of 5 or 6 ring atoms and contain 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the aromatic ring. Unless otherwise indicated, the heteroaryl group may be unsubstituted or substituted with one or more, and in particular one to three, substituents as described herein. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyridinyl, pyrrolyl, oxazolyl, triazinyl, triazolyl, thiazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyrimidinyl, thiazolyl, thiadiazolyl, 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 6H-furo[2,3-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, 1H-indolyl, 2H-isoindolyl, indazolyl, 1H-indazolyl, benzimidazolyl, 7-azaindolyl, 5-azaindolyl, 6-azaindolyl, 1 , 2-benzisoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzo[c][1,2,5]thiadiazolyl, 1,2-benzisothiazol-3(2H)-onyl, adeninyl, carbamimidyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthaloyl, quinazolinyl, cinnolinyl, 1,8-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, 2H-chromen-2-onyl, 2H-benzo[e][1,2]oxazinyl, quinolin-2(1H)-onyl, and isoquinolin-1(2H)-onyl.

[0099] As used herein, the term "alkoxy" or "alkoxyl" as used herein refers to an "-O-alkyl" group. An alkoxy (alkoxy or alkoxyl) group can be unsubstituted or substituted.

[0100] As used herein, the term "therapeutically effective amount" means an amount of a compound or combination of therapeutically active compounds that improves, reduces or eliminates one or more symptoms of a particular disease or condition (e.g., cancer), or prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0101] As used herein, the terms "patient" and "subject" are used interchangeably and refer to animals such as dogs, cats, cows, horses, and sheep (eg, non-human animals) and humans. A specific patient or subject is a mammal (eg, a human).

[0102] As used herein, the term "pharmaceutically acceptable" means that the substance mentioned (such as the compound of the present disclosure or a formulation containing the compound) or a specific excipient is safe and suitable for administration to a patient or subject. The term "pharmaceutically acceptable excipient" refers to a medium that does not interfere with the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0103] As used herein, the term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient other than the active pharmaceutical ingredient (API).

[0104] Pharmaceutically acceptable salts

[0105] The compounds described herein may exist in free form or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest because they can be used to administer the compounds described below for medical purposes. Pharmaceutically unacceptable salts may be used in manufacturing processes, for separation and purification purposes, and in some cases, for separation of stereoisomeric forms of the compounds of the present disclosure or their intermediates.

[0106] As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio.

[0107] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0108] When the compounds described herein contain a basic group or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid, and 2) isolating the salt so formed. In practice, the acid addition salt may be the more convenient form for use, and use of the salt is equivalent to use of the free base form.

[0109] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with an amino group formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts with an amino group formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy -ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0110] When the compounds described herein contain a carboxyl group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base, and 2) isolating the salt so formed. In practice, the use of base addition salts may be more convenient, and the use of the salt form is inherently equivalent to the use of the free acid form. Salts derived from appropriate bases include alkali metals (such as sodium, lithium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium and N + (C1-4 The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization.

[0111] Base addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. Sodium salts and potassium salts are generally preferred. Other pharmaceutically acceptable salts include nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates) when appropriate. Suitable inorganic base addition salts are prepared from metal bases, including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, etc. Suitable amine base addition salts are prepared from amines, which are often used in pharmaceutical chemistry due to their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietinamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, etc.

[0112] Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0113] It should be understood that the compounds disclosed herein may exist as mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of compounds in free form and pharmaceutically acceptable salts are also contemplated.

[0114] Drug formulations, dosing and routes of administration

[0115] Further provided are pharmaceutical formulations (alternatively referred to herein as compositions) comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0116] The compounds described herein can be administered to a subject individually or as part of a pharmaceutically acceptable composition or formulation in a therapeutically effective amount. In addition, these compounds can be administered once, multiple times, or delivered substantially uniformly over a period of time. It should also be noted that the dosage of the compound can vary over time.

[0117] The specific administration regimen for a particular subject will depend in part on the compound, the amount of the compound administered, the route of administration, and the cause and extent of any side effects. The amount of the compound administered to a subject (e.g., a mammal, such as a human) according to the disclosure should be sufficient to affect the desired response within a reasonable time frame. The dosage typically depends on the route, time, and frequency of administration. Therefore, the clinician adjusts the dosage and changes the route of administration to obtain the best therapeutic effect, and conventional range-finding techniques are known to those of ordinary skill in the art.

[0118] Purely by way of illustration, the method includes administering, for example, about 0.1 mg / kg to about 100 mg / kg or more of the compound, depending on the above factors. In other embodiments, the dosage range is from 1 mg / kg to about 100 mg / kg; or 5 mg / kg to about 100 mg / kg; or 10 mg / kg to about 100 mg / kg. Some conditions require long-term treatment, which may or may not require the administration of lower doses of the compound in multiple administrations. If necessary, the dose of the compound is administered as two, three, four, five, six or more sub-doses, which are optionally administered separately at appropriate intervals throughout the day in a unit dosage form. The treatment period will depend on the specific condition and type of pain, and may last from one day to several months.

[0119] Suitable methods for administering physiologically acceptable compositions (such as pharmaceutical compositions comprising compounds disclosed herein) are well known in the art. Although more than one approach can be used to administer the compound, a specific approach can provide a more immediate and more effective response than another approach. Depending on the circumstances, the pharmaceutical composition comprising the compound is administered or instilled into the body cavity, absorbed, ingested, inhaled and / or introduced into the circulation by the skin or mucous membrane. For example, in some cases, it is desirable to be oral, by intravenous injection, intraperitoneal, intracerebral (in the brain parenchyma), intraventricular, intramuscular, intraocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local, sublingual, urethral, ​​vaginal or rectal means, by a sustained release system or by an implant device to deliver a pharmaceutical composition comprising a medicament. If necessary, by intrathecal administration, intracerebral (in the brain parenchyma) administration, intraventricular administration or intraarterial or intravenous administration, the compound is locally administered to the area of ​​interest. Alternatively, the composition is administered locally via an implanted membrane, sponge or other suitable material onto which the desired compound has been absorbed or encapsulated. Where an implant device is used, in one aspect, the device is implanted in any suitable tissue or organ and the desired compound is delivered via diffusion, timed release bolus or continuous administration.

[0120] In order to facilitate administration, in many aspects, the compound is formulated into a physiologically acceptable composition comprising a carrier (e.g., a vehicle, an adjuvant or a diluent). The specific carrier used is only subject to physical-chemical considerations (such as solubility and lack of reactivity with the compound) and the restriction of the route of administration. Physiologically acceptable carriers are well known in the art. Illustrative drug forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the temporary preparation of sterile injectable solutions or dispersions (e.g., see U.S. Patent No. 5,466,468). Injectable formulations are further described in, for example, Pharmaceutics and Pharmacy Practice [Pharmacy and Pharmacy Practice], JB Lippincott Co., Philadelphia. [JB Lippincott Company, Philadelphia] Pa., Banker and Chalmers edited, pp. 238-250 (1982), and ASHP Handbook on Injectable Drugs [ASHP injectable drug manual], Toissel, 4th edition, pp. 622-630 (1986)). In one aspect, a pharmaceutical composition comprising the compound is placed in a container together with packaging material that provides instructions for use of such pharmaceutical compositions. Typically, such instructions include a tangible expression describing the concentration of the agent, and in certain embodiments, the relative amounts of excipient ingredients or diluents (e.g., water, saline, or PBS) that may be required to reconstruct the pharmaceutical composition.

[0121] Compositions suitable for parenteral injection can include physiologically acceptable aseptic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstruction in aseptic injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by using coatings (such as lecithin), by maintaining the required particle size in the case of dispersions and by using a surfactant.

[0122] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Microbial contamination can be prevented by adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It can also be desirable to include isotonic agents, such as sugar, sodium chloride, etc. The prolonged absorption of injectable pharmaceutical compositions can be achieved by using delayed absorption agents (e.g., aluminum monostearate and gelatin).

[0123] Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, such as starch, lactose, sucrose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retardants, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage form may also include a buffering agent.Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0124] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art. Solid dosage forms may also contain opacifiers. In addition, solid dosage forms may be embedding compositions so that they release one or more active compounds in a delayed manner in a specific part of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound may also be in a microencapsulated form optionally with one or more excipients.

[0125] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, or mixtures of these substances, etc.

[0126] In addition to such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics. In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures of these substances.

[0127] Compositions for rectal administration are preferably suppositories which can be prepared by mixing a compound of the disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredients.

[0128] The composition used in the method of the present invention can be formulated into micelles or liposomes. Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes. Such formulations can facilitate intracellular delivery because the lipid bilayer of liposomes and micelles is known to fuse with the plasma membrane of the cell and deliver the entrapped contents into the intracellular compartment.

[0129] When formulated, the solution will be administered in a manner compatible with the dosage formulation and in such an amount as to be therapeutically effective. These formulations are easily administered in a variety of dosage forms (e.g., injectable solutions, drug release capsules, etc.). For parenteral administration in aqueous solutions, for example, if necessary, the solution should be appropriately buffered and the liquid diluent first made isotonic with sufficient saline or glucose. These specific aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.

[0130] The frequency of administration will depend on the pharmacokinetic parameters and route of administration of the medicament. The optimal pharmaceutical formulation will be determined by those skilled in the art according to the route of administration and the desired dosage. See, for example, Remington's Pharmaceutical Sciences, 18th edition (1990) Mack Publishing Co., Easton, PA, pp. 1435-1712, which is incorporated herein by reference. Such formulations may affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered medicament. Depending on the route of administration, a suitable dosage can be calculated based on body weight, body surface area, or organ size. Those of ordinary skill in the art can routinely further refine the calculations required to determine the appropriate therapeutic dose without excessive experimentation, especially based on the dosage information and determination disclosed herein, and the pharmacokinetic data observed in animal or human clinical trials.

[0131] The precise dose to be used depends on several factors, including the host (whether in veterinary or human medicine), the nature and severity of the condition (e.g., disease or disorder) being treated, the mode of administration, and the specific active substance used. These compounds can be administered by any conventional route, particularly enteral administration, and in one aspect, orally in the form of tablets or capsules. The compounds administered can be in free form or in the form of a pharmaceutically acceptable salt (as the case may be), for use as a medicament, particularly for the preventive or curative treatment of the disease of interest. These measures will slow the rate of progression of the disease state and help the body reverse the direction of progress in a natural manner.

[0132] It should be understood that the pharmaceutical compositions and methods of treatment of the present invention are useful in the fields of human medicine and veterinary medicine. Thus, in one aspect, the subject to be treated is a mammal. In another aspect, the mammal is a human.

[0133] In jurisdictions that prohibit patenting of methods performed on humans, "administering" a composition to a human subject shall be limited to prescribing a controlled substance, which the human subject will self-administer by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patenting of methods performed on humans, "administering" a composition includes methods performed on humans and the foregoing activities.

[0134] How to use

[0135] The compounds described herein can modulate RBM39. In some embodiments, these compounds inhibit RBM39. In various embodiments, these compounds induce RBM39 degradation, i.e., these compounds are RBM39 degraders.

[0136] As used herein, the term "RBM39 degrader" refers to a compound having the ability to induce degradation of the RBM39 protein by forming a complex between the RBM39 protein and any part of the E3 ubiquitin ligase complex.

[0137] Although RBM39 has been implicated in the malignant progression of many solid and hematological cancers, there remains a great need and opportunity to find improved approaches to modulate the activity of this protein. For example, RBM39 is essential for colorectal cancer cell survival in vitro and in vivo (Owa et al., Journal of Medicinal Chemistry., 42(19), 3789-3799 (1999); Han et al., Science., 356(6336), (2017); Ozawa et al., Eur J Cancer, 37(17), 2275-2282 (2001); Sillars-Hardebol et al., Gut., (61), 1568-1575 (2012); Uehara et al., Nat Chem Biol., 13, 675-680 (2017)) and has been implicated in breast cancer progression, where it mediates VEGF alternative splicing (Mercier et al., Am J Chem Biol., 13, 675-680 (2017)). Pathol. [American Journal of Clinical Pathology] 174(4), 1172-1190 (2009)), and is also upregulated in human non-small cell lung cancer (NSCLC) tissue compared with normal lung tissue, promoting proliferation and migration (Chai et al., Tumor Biol. [Tumor Biology], 35, 6311-6317 (2014)). RBM39 protein is required for the maintenance of acute myeloid leukemia (AML) through missplicing of HOXA9 target genes, and is required for the survival of neuroblastoma cells in vitro and in vivo (Wang et al., Cancer Cell. [Cancer Cell], 35(3), 369-384 (2019); Singh et al., Sci Adv. [Science Progress], 7(47), (2021)). RBM39 is an emerging cancer target (Yuewei et al., 2021). Other cancers showing promising therapeutic potential are neuroblastoma with MYC-N amplification and tumors with KRAS mutations, as highlighted in this article.

[0138] The compounds disclosed herein are particularly useful for treating or preventing diseases or disorders caused by aberrant RBM39 activity.

[0139] As used herein, "abnormal RBM39 activity" refers to RBM39 activity associated with malignant progression in cancer. This RBM39-related malignant progression is associated with a variety of cancers (Xu et al., Cell Death Discov. [Cell Death Discovery] 7, 214 (2021)). An example of abnormal RBM39 activity is RBM39-induced splicing of proteins encoded by KRAS oncogenes (such as KRAS4A).

[0140] Considering the importance of the biological effects of RBM39, the compounds disclosed herein can be used for a variety of applications in a variety of environments. For example and most simply, the active agent disclosed herein can be used to induce the degradation of RBM39 in cells. In this regard, the disclosure provides a method for inducing RBM39 degradation in cells. The method includes contacting the cell with a compound of the disclosure or a pharmaceutically acceptable salt thereof in an amount that effectively induces degradation. In some aspects, the cell is part of an in vitro or ex vivo cell culture or an in vitro or ex vivo tissue sample. In some aspects, the cell is a cell in vivo. In certain embodiments, the method is intended for research purposes, and in other embodiments, the method is intended for therapeutic purposes.

[0141] As shown herein, compounds that induce RBM39 degradation increase tumor cell death. Therefore, the present disclosure provides a method for increasing tumor cell death in a subject. The method includes administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in an amount effective to increase tumor cell death.

[0142] In accordance with the foregoing, the present disclosure further provides methods for treating cancer in a subject. These methods include administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof in an amount effective to treat the cancer in the subject.

[0143] As used herein, the term "treatment" and words related thereto do not necessarily mean 100% or complete treatment. On the contrary, there are different degrees of treatment, and those of ordinary skill in the art believe that these treatments have potential benefits or therapeutic effects. In this regard, the methods of treating cancer disclosed herein can provide any amount or any level of cancer treatment. In addition, the treatment provided by the methods of the present disclosure can include treating one or more conditions or symptoms of the cancer being treated. Moreover, the treatment provided by the methods of the present disclosure can cover slowing the progression of cancer. For example, these methods can treat cancer by reducing tumor or cancer growth, reducing the metastasis of tumor cells, increasing cell death of tumor or cancer cells, etc.

[0144] The cancer that can be treated by the method disclosed herein can be any cancer, such as any malignant growth or tumor caused by abnormal and uncontrolled cell division, which can spread to other parts of the body through the lymphatic system or bloodstream. In some embodiments, cancer is a cancer in which RBM39 is expressed by cells of the cancer. In some aspects, cancer is a cancer in which RBM39 protein is overexpressed, a gene encoding RBM39 is amplified, and / or an RBM39 mutant protein (e.g., truncated RBM39, point mutation RBM39) is expressed.

[0145] Neuroblastoma is the most common pediatric solid tumor, and despite the use of multimodal therapy, high-risk cases have a poor prognosis. Neuroblastoma is a MYC-driven cancer characterized by dysregulated splicing and spliceosome dependency, requiring the splicing factor RBM39 for survival. Shivendra et al. (see “Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma models” 2021) showed that aberrant alternative pre-mRNA splicing plays a key role in MYC-driven cancers and that targeting the dysregulated spliceosome may represent an effective therapeutic strategy in these cancers. Genetic loss or indisulam-mediated degradation of RBM39 induced dramatic genome-wide splicing abnormalities and cell death in neuroblastoma, leading to remarkable responses in multiple high-risk disease models without overt toxicity. Anke Nijhuis et al. (2022, see “Indisulam targets RNA splicing and metabolism to serve as atherapeutic strategy for high-risk neuroblastoma”) also demonstrated that neuroblastoma lines are exquisitely sensitive to indisulam. RNAseq and proteomic analyses highlighted significant disruptions to the cell cycle, metabolome, and mitochondrial function in vitro and in vivo. Their work also demonstrated complete tumor regression with no recurrence following xenograft and Th-MYCN transgenic models of neuroblastoma treated with indisulam.

[0146] The KRAS oncogene, which is mutated in many cancers, encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. Wei-Ching Chen et al. (2021) recently demonstrated that the coordinated regulation of KRAS4A and KRAS4B isoforms through splicing control is critical for the development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells and responds to hypoxia, while the major KRAS4B is induced by ER stress. The splicing of KRAS4A is controlled by the DCAF15 / RBM39 pathway. They experimentally demonstrated that deletion of KRAS4A using indisulam or pharmacological inhibition of RBM39 led to the suppression of cancer stem cells. Therefore, sulfonamides targeting KRAS4A splicing may have the potential to inhibit human tumors expressing minor KRAS4A isoforms. Minor KRAS4A expression can be used as a biomarker of sensitivity to these drugs (see Wei-Ching Chen et al., “Targeting KRAS4A splicing through the RBM39 / DCAF15 pathway inhibits cancer stem cells,” Nature Communications 12:4288, (2021)).

[0147] Puvvula et al. (2021, “Inhibiting an RBM39 / MLL1 epigenomic regulatory complex with dominant-negative peptides disrupts cancer cell transcription and proliferation”) demonstrated that a pathological complex between RBM39 and MLL1 regulates tumor formation, H3K4me3, and the expression of tumor suppressor genes and oncogenes in breast cancer cells. They demonstrated the therapeutic potential of RBM39 RRM3-derived peptides that disrupt the RBM39 / MLL1 complex, reduce H3K4me3 and cancer hallmarks in multiple breast cancer subtypes, and are nontoxic to normal cells.

[0148] In some aspects, the cancer is a cancer selected from the group consisting of acute lymphocytic carcinoma, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, anal cancer, anal canal cancer, or anorectal cancer, eye cancer, intrahepatic bile duct cancer, joint cancer, cervical cancer, gallbladder cancer, or pleural cancer, nasal cancer, nasal cavity cancer, or middle ear cancer, oral cancer, vulvar cancer, leukemia (e.g., chronic lymphocytic leukemia), chronic myeloid cancer, colon cancer, Esophageal cancer, cervical cancer, gastrointestinal carcinoid tumors, Hodgkin's lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, peritoneal, omental and mesenteric cancer, pharyngeal cancer, prostate cancer, rectal cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, gastric cancer, testicular cancer, thyroid cancer, ureteral cancer, and bladder cancer. In particular aspects, the cancer is selected from the group consisting of head and neck cancer, ovarian cancer, cervical cancer, bladder cancer and esophageal cancer, pancreatic cancer, gastrointestinal cancer, gastric cancer, breast cancer, endometrial cancer and colorectal cancer, hepatocellular carcinoma, glioblastoma, bladder cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), bronchioloalveolar carcinoma. In particular aspects, the cancer is osimertinib-resistant cancer. In some cases, the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, kidney cancer, leukemia, or breast cancer. In some cases, the cancer is melanoma, colon cancer, kidney cancer, leukemia, or breast cancer. In some cases, the cancer is kidney cancer. In some cases, the cancer is renal cell carcinoma.

[0149] Also provided herein is the use of a compound disclosed herein in the preparation of a medicament for modulating RBM39 or for treating or preventing a disease or disorder associated with aberrant RBM39 activity.

[0150] The disclosure herein will be more easily understood by reference to the following examples.

[0151] In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are merely examples and should not be taken as limiting the scope of the invention.

[0152] As used herein, the term "treatment" or "treating" disease or disorder refers to a method of reducing, delaying or improving such a disorder before or after the occurrence of such a disorder. Treatment can be directed to one or more effects or symptoms of a disease and / or underlying pathology. Treatment is intended to obtain beneficial or desired results, including but not limited to therapeutic benefits and / or preventive benefits. Therapeutic benefit means eradicating or improving the underlying disorder being treated. In addition, the therapeutic benefit is achieved by eradicating or alleviating one or more physiological symptoms associated with the underlying disorder, so that improvements are observed in the patient, although the patient may still be afflicted with the underlying disorder. For preventive benefits, drug compounds and / or compositions can be administered to patients at risk of developing a specific disease, or to patients reporting one or more physiological symptoms of the disease, even if the disease may not have been diagnosed. Treatment can be any reduction, and can be, but is not limited to, complete ablation of the disease or disease symptoms. Compared to an equivalent untreated control, this reduction or prevention degree is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100%, as measured by any standard technique.

[0153] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and / or a preventive benefit as described herein. A preventive effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0154] Synthesis of the compounds disclosed herein

[0155] The compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds known in the literature or from readily prepared intermediates, by adopting standard synthetic methods and procedures known to those skilled in the art or in view of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the synthetic schemes as described in the Examples section, with modifications to specific desired substituents.

[0156] Standard synthetic methods and procedures for the preparation of organic molecules and for the transformation and manipulation of functional groups can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or more sources, the following classical literature is useful and is a recognized reference textbook for organic synthesis known to those skilled in the art: such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999. The following description of synthetic methods is designed to illustrate, but not to limit, the general procedures for preparing the compounds of the present disclosure.

[0157] The synthetic methods disclosed herein can tolerate a variety of functional groups; therefore, various substituted starting materials can be used. These methods generally provide the desired final compound at the end or near the end of the entire process, but in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.

[0158] Example

[0159] The present disclosure can be further understood in view of the following non-limiting examples.

[0160] Example 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0161]

[0162] in

[0163] R N1 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0164] R N2 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl;

[0165] X 1 Yes CR 1 or N;

[0166] X 2 Yes CR3 or N;

[0167] X 3 Yes CR 4 or N;

[0168] R 1 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0169] R 2 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0170] R 3 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0171] R 4 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0172] R 5 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl;

[0173] Each R N is independently H, optionally substituted by 1, 2, or 3 R 7 Substituted C 1-6 Alkyl, or C 3-10 Cycloalkyl;

[0174] Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 replace;

[0175] Each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR N R N ,COOH,C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , C 1-6 Alkylene-C(O)NR N R N , SO2NR N R N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 1-6 Alkylene-C 3-10 Cycloalkyl, C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl, C6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl, C 1-6 Alkylene, or C 1-6 The alkoxy group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; and

[0176] Each R 7 are independently OH, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, NH(C 1-6 alkyl), or N(C 1-6 Alkyl)2.

[0177] Embodiment 2. The compound or salt as described in Embodiment 1, wherein Het is a 5-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 replace.

[0178] Embodiment 3. The compound or salt as described in Embodiment 2, wherein Het is optionally replaced by 1, 2, or 3 R 6 Substituted thiazolyl.

[0179] Embodiment 4. The compound or salt of Embodiment 1 or 2, wherein Het is

[0180] And R 6 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, P(O)(Me)2, or C(O)-morpholinyl.

[0181] Embodiment 5. A compound or salt as described in any one of Embodiments 1 to 4, wherein X 1 Yes CR 1 , X 2 Yes CR 3 , and X 3 Yes CR 4 .

[0182] Embodiment 6. A compound or salt as described in any one of Embodiments 1 to 4, wherein X1 , X 2 , and X 3 One of them is N.

[0183] Embodiment 7. The compound or salt as described in Embodiment 6, wherein X 1 It is N.

[0184] Embodiment 8. The compound or salt as described in Embodiment 6, wherein X 3 It is N.

[0185] Embodiment 9. The compound or salt as described in Embodiment 1, which has the structure of Formula (Ia):

[0186]

[0187] Embodiment 10. A compound or salt as described in any one of Embodiments 1 to 9, wherein R N1 It's H.

[0188] Embodiment 11. A compound or salt as described in any one of Embodiments 1 to 10, wherein R N2 It's H.

[0189] Embodiment 12. A compound or salt as described in any one of Embodiments 1 to 6 and 8 to 11, wherein R 1 Is H or C 1-6 alkyl, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0190] Embodiment 13. The compound or salt as described in Embodiment 12, wherein R 1 It's H.

[0191] Embodiment 14. A compound or salt as described in any one of Embodiments 1 to 13, wherein R 2 It is H, C 1-6 alkyl, halo, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0192] Embodiment 15. The compound or salt as described in Embodiment 14, wherein R 2 is H, halo, or CN.

[0193] Embodiment 16. The compound or salt as described in Embodiment 15, wherein R 2 It is Cl.

[0194] Embodiment 17. The compound or salt as described in Embodiment 16, wherein R 2 It is CN.

[0195] Embodiment 18. A compound or salt as described in any one of Embodiments 1 to 17, wherein R 3 It is H, C 1-6 alkyl, or halogenated, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0196] Embodiment 19. The compound or salt as described in Embodiment 18, wherein R 3 It's H.

[0197] Embodiment 20. The compound or salt of Embodiment 18, wherein R 3 It is C 1-6 alkyl, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0198] Embodiment 21. The compound or salt as described in Embodiment 20, wherein R 3 It's methyl.

[0199] Embodiment 22. The compound or salt as described in Embodiment 18, wherein R 3 It is halogenated.

[0200] Embodiment 23. The compound or salt as described in Embodiment 22, wherein R 3 It's fluorine.

[0201] Embodiment 24. A compound or salt as described in any one of Embodiments 1 to 7 and 9 to 23, wherein R 4 It's H.

[0202] Embodiment 25. A compound or salt as described in any one of Embodiments 1 to 24, wherein R 5 It's H.

[0203] Embodiment 26. The compound or salt as described in Embodiment 1, wherein X 1 It is CH, R 2 is H or CN, X 2 is CH or CMe, X 3 It is CH, R 5 is H, and Het is thiazolyl, imidazolyl, isoxazolyl, 1,2,4-triazolyl, or oxazolyl, and Het is unsubstituted or substituted with 1 or 2 R 6 replace.

[0204] Embodiment 27. The compound or salt of Embodiment 26, wherein Het is replaced by 1 R 6 replace.

[0205] Embodiment 28. The compound or salt of Embodiment 26, wherein Het is replaced by 2 R 6 replace.

[0206] Embodiment 29. A compound or salt as described in any one of Embodiments 1 to 28, wherein each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, COOH, C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 3-5 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein C 3-5 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0207] Embodiment 30. The compound or salt of Embodiment 29, wherein each R6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylene-C(O)OC 1-6 alkyl, 5-membered or 6-membered heterocycloalkyl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), C 6-10 aryl, or 5-membered or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein the 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0208] Embodiment 31. A compound or salt as described in Embodiment 30, wherein each R 6 are independently halogenated, C 1-6 alkyl, or 5- or 6-membered heteroaryl (containing 1, 2, or 3 ring heteroatoms selected from O, S, and N), wherein the 5- or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 The alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

[0209] Embodiment 32. The compound or salt of Embodiment 30, wherein at least one R 6 It is halogenated.

[0210] Embodiment 33. The compound or salt of Embodiment 32, wherein at least one R 6 It is chlorine or bromine.

[0211] Embodiment 34. The compound or salt of Embodiment 30, wherein at least one R 6 It is C 1-6 alkyl, and each C 1-6 The alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NRN R N , and CO2C 1-6 alkyl.

[0212] Embodiment 35. The compound or salt of Embodiment 34, wherein at least one R 6 It is methyl, ethyl, or isopropyl.

[0213] Embodiment 36. The compound or salt of Embodiment 30, wherein each R 6 is independently a 5- or 6-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the 5- or 6-membered heteroaryl group may be optionally replaced by 1, 2, or 3 R 7 replace.

[0214] Embodiment 37. The compound or salt of Embodiment 36, wherein at least one R 6 is pyrazolyl, pyridyl, pyridazinyl, or pyrimidinyl, each of which may be optionally substituted by 1, 2, or 3 R 7 replace.

[0215] Embodiment 38. A compound or salt as described in any one of Embodiments 1 to 37, wherein each R 7 are independently halogenated, C 1-6 Alkyl, or C 1-6 Halogenated alkyl.

[0216] Embodiment 39. The compound or salt of Embodiment 38, wherein at least one R 7 It is C 1-6 alkyl.

[0217] Embodiment 40. The compound or salt of Embodiment 39, wherein at least one R 7 It's methyl.

[0218] Embodiment 41. A compound listed in Table A, or a pharmaceutically acceptable salt thereof.

[0219] Embodiment 42. A pharmaceutical composition comprising a compound or salt as described in any one of Embodiments 1 to 41 and a pharmaceutically acceptable excipient.

[0220] Embodiment 43. A method for regulating RBM39 protein, the method comprising contacting the RBM39 protein with a compound or salt as described in any one of Embodiments 1 to 41 or a pharmaceutical composition as described in Embodiment 42.

[0221] Example 44. A method as described in Example 43, wherein regulating the RBM39 protein includes degrading the RBM39 protein.

[0222] Embodiment 45. The method of embodiment 43 or 44, wherein contacting the compound or salt comprises administering to a subject.

[0223] Embodiment 46. The method of embodiment 45, wherein the subject is human.

[0224] Embodiment 47. A method for treating a disease associated with abnormal RBM39 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or salt as described in any one of Embodiments 1 to 41 or a pharmaceutical composition as described in Embodiment 42.

[0225] Embodiment 48. The method of embodiment 47, wherein the disease is cancer.

[0226] Embodiment 49. The method of embodiment 48, wherein the cancer is renal cell carcinoma.

[0227] Examples

[0228] Example 1

[0229] General Method A

[0230]

[0231] Synthesis of 2-(Benzylthio)-5-bromothiazole. To a stirred suspension of benzylthiol (0.62 g, 5.03 mmol) and K2CO3 (1.39 g, 10.07 mmol) in DMF (10 mL) was added compound 2-bromo-5-chlorothiazole (1.0 g, 5.03 mmol) at room temperature and stirred for 16 h. The reaction progress was monitored by TLC and LCMS. (SM and R of the product) f Values ​​were 0.3 and 0.5 respectively; TLC system: 20% EtOAc and petroleum ether). After the reaction was completed, RM was quenched by adding ice-cold water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (3X 30 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography (using 100-200 silica and eluted with 15% EtOAc in petroleum ether) to provide the product.

[0232]

[0233] Synthesis of 5-bromothiazole-2-sulfonyl chloride. At 0°C, N-chlorosuccinimide (0.55 g, 4.13 mmol) was added to a stirred solution of 2-(benzylthio)-5-chlorothiazole (0.5 g, 2.06 mmol) in acetic acid: water (3: 1) (10 mL), and stirred at room temperature for 2 h. After 2 h, the reaction mass was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with saturated NaHCO aqueous solution (2 × 20 mL), brine (15 mL), dried over NaSO and concentrated under reduced pressure to give the title compound, which was used in the next step without any further purification.

[0234]

[0235] Synthesis of 5-bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide. Crude 5-chlorothiazole-2-sulfonyl chloride was added to a stirred solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (1 eq.) and pyridine (5 eq.) in DMF (7.0 mL) at 0 °C and allowed to stir at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC / achiral SFC method to obtain the corresponding final compound.

[0236] LCMS: 369.16 [M+H]+ ion present. 1 H-NMR (400MHz, DMSO-d6): δ12.11(s,1H),11.00(s,1H),8.21-8.16(m,3H),7.68-7.59(m,2H),6.75(s,2H),2.56(s,3H)

[0237] Example 2

[0238] General Method B

[0239]

[0240]

[0241] Synthesis of the preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(morpholine-4-yl)-1,3-thiazole-2-sulfonamide. To a solution of 5-bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide (300 mg, 0.755 mmol, 1.00 equiv) in DMF (6 mL) was added morpholine (98.7 mg, 1.13 mmol, 1.50 equiv) and K2CO3 (209 mg, 1.51 mmol, 2.00 equiv), and the resulting mixture was stirred at 60 ° C under a nitrogen atmosphere for 48 h. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography to provide the title compound.

[0242] LCMS(ES)m / z:[M+H] + :404, 1 H NMR(300MHz,DMSO-d6,ppm)δ11.99(s,1H),10.35(bs,1H),8.18(s,1H),7.27(s,1H),6.85(d,J =7.8Hz, 1H), 6.75 (d, J = 7.7Hz, 1H), 3.70 (t, J = 4.9Hz, 4H), 3.16 (t, J = 4.9Hz, 4H), 2.59 (s, 3H).

[0243] General Method C

[0244]

[0245] Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(pyridin-3-yl)-1,3-thiazole-2-sulfonamide. To a solution of 5-bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide (150 mg, 0.378 mmol, 1 eq) and pyridin-3-ylboronic acid (185 mg, 1.51 mmol, 4 eq) in dioxane (2.4 mL) and H2O (0.6 mL) was added Na2CO3 (200 mg, 1.89 mmol, 5 eq) and Pd(dppf)Cl2 (27.6 mg, 0.0380 mmol, 0.1 eq). After stirring at 80 °C under a nitrogen atmosphere for 4 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to provide the title compound.

[0246] LCMS(ES)m / z:[M+H]+:396.0,1H NMR(300MHz,DMSO-d6,ppm)δ12.13(s,1H),10.86(s,1H),9.03-8.93(m,1H),8.69-8.60(m,2H),8.26 -8.14(m,2H),7.51(dd,J=8.2,4.8Hz,1H),6.85(d,J=7.9Hz,1H),6.75(d,J=7.8Hz,1H),2.60(s,3H).

[0247] General Method D

[0248]

[0249] Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(pyridin-2-yl)-1,3-thiazole-2-sulfonamide. To a solution of 5-bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-2-sulfonamide and 4-(tributylstannyl)pyridine (741 mg, 2.01 mmol, 4 equivalents) in DMF (5 mL) was added CuI (28.8 mg, 0.151 mmol, 0.3 equivalents) and Pd(PPh3)4 (116 mg, 0.101 mmol, 0.2 equivalents) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C under microwave irradiation for 5 min. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography to provide the title compound.

[0250] LCMS (ES) m / z): [M+H] + :396.0, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.13(d,J=3.2Hz,1H),10.82(s,1H),8.77(s,1H),8.59(dt,J=4.8,1.5Hz,1H),8.23(d,J=3.0Hz,1H),8.17 -8.07(m,1H),7.96(td,J=7.8,1.7Hz,1H),7.43(ddd,J=7.5,4.9,1.1Hz,1H),6.85(d,J=7.8Hz,1H),6.74(d,J=7.7Hz,1H),2.59(s,3H).

[0251] General Program E

[0252]

[0253] Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(2-hydroxyethyl)thiazole-2-sulfonamide. To a solution of methyl 2-(2-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)thiazol-5-yl)acetate (0.38 mmol, 1.00 equiv) in MeOH (3 mL) was added NaBH4 (11.5 mmol, 30 equiv) at 0°C and the resulting mixture was stirred at room temperature for another 3 days. The residue was purified by preparative HPLC / achiral SFC method to give the corresponding final compound.

[0254] LCMS: (LCMS (ES) m / z): [M+1] + :363, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.05(d,J=3.2Hz,1H),10.63(s,1H),8.20(d,J=3.0Hz,1H),7.85(s,1H),6.84(d,J=7 .8Hz, 1H), 6.72 (d, J = 7.7Hz, 1H), 5.01 (t, J = 5.0Hz, 1H), 3.59 (q, J = 5.6Hz, 2H), 3.00 (t, J = 6.0Hz, 2H), 2.60 (s, 3H).

[0255] General Program F

[0256]

[0257] The synthesis of 2-ethyl-1H-imidazole-4-sulfonyl chloride.To 2-ethyl-1H-imidazole (20g, 208mmol, 1 equivalent) in CHCl (1600mL) solution in add chlorosulfonic acid (80mL), and the gained mixture is stirred overnight under nitrogen atmosphere under reflux.In the above mixture, add SOCl (600mL) and the gained mixture is stirred for 2h at 100 ℃ and then concentrated under reduced pressure.The above mixture is poured into ice water.Gained mixture DCM (4x 150mL) is extracted, through anhydrous Na SO Dry.After filtration, the filtrate is concentrated under reduced pressure to provide title compound, it is used for next step without any further purification.

[0258]

[0259] Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-2-ethyl-1H-imidazole-4-sulfonamide. 2-ethyl-1H-imidazole-4-sulfonyl chloride (49.0mmol, 1.2 equivalents) in DCM (20mL) was added dropwise to a solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (40.8mmol, 1 equivalent) and pyridine (122mmol, 3 equivalents) in DCM (100mL) at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to provide the title compound.

[0260] LCMS (LCMS (ES) m / z): [M+1] + :330, 1 H NMR (400MHz, DMSO-d6, ppm) δ12.41 (s, 1H), 12.16-12.11 (m, 1H), 9.77 (s, 1H), 8.20 (d, J = 3.0Hz, 1 H), 7.55 (d, J = 1.7Hz, 1H), 6.81 (s, 2H), 2.65 (q, J = 7.6Hz, 2H), 2.57 (s, 3H), 1.20 (t, J = 7.6Hz, 3H).

[0261] General Program G

[0262]

[0263] Synthesis of ethyl 2-mercaptothiazole-4-formate.To a stirred solution of ethyl 2-bromo-1,3-thiazole-4-formate (2.5 g, 10.590 mmol, 1 equivalent) in EtOH (50.00 mL) at 80 °C, a mixture of NaSH (2.97 g, 53.0 mmol, 5 equivalents) in EtOH (25 mL) was added dropwise. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and acidified to pH 3 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (3 x 5 mL) to provide the title compound, which was used in the next step without any further purification.

[0264]

[0265] Synthesis of ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate. To a solution of ethyl 2-sulfanyl-1,3-thiazole-4-carboxylate (1.40 g, 7.40 mmol, 1 eq) in concentrated HCl (14 mL) was added dropwise NaClO (14.3 mL, 192 mmol, 26 eq, 10% wt in water) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and at room temperature for 15 min. The precipitated solid was collected by filtration and washed with water (3 x 5 mL) to provide the title compound, which was used in the next step without any further purification.

[0266]

[0267] Synthesis of ethyl 2-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)thiazole-4-carboxylate. A solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (0.83 g, 4.85 mmol, 1 eq) and pyridine (1.15 g, 14.5 mmol, 3 eq) in DCM (25 mL) was treated with ethyl 2-(chlorosulfonyl)-1,3-thiazole-4-carboxylate (1.24 g, 4.85 mmol, 1 eq) (146-2) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The residue was concentrated under vacuum and purified by silica gel chromatography to provide the title compound.

[0268]

[0269] Synthesis of 2-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)thiazole-4-carboxylic acid.To 2-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-1,3-thiazole-4-carboxylic acid ethyl ester (200mg, 0.51mmol, 1 equivalent) in THF (2mL) at room temperature, 1M LiOH (2mL, 2.00mmol, 3.90 equivalent) in water was added dropwise and the resulting mixture was stirred at room temperature for 30min.The resulting mixture was washed with DCM (1x 10mL), and the water layer was acidified to pH 3 with 1M HCl.The precipitated solid was collected by filtration and washed with water (3x 3mL).The material was purified on reverse phase chromatography to provide the title compound.

[0270] LCMS: (LCMS (ES) m / z): [M+1] + :363, 1H NMR(300MHz,DMSO-d6,ppm)13.56(s,1H),12.18(d,J=3.1Hz,1H),10.91(s,1H),8.71(s,1 H), 8.22 (d, J = 3.1Hz, 1H), 6.85 (dd, J = 7.7, 1.0Hz, 1H), 6.64 (d, J = 7.7Hz, 1H), 2.60 (s, 3H).

[0271]

[0272] Synthesis of 2-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)thiazole-4-carboxamide. To a solution of 2-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-1,3-thiazole-4-carboxylic acid (0.41 mmol, 1 eq) in DMF was added DIEA (2.07 mmol, 5.00 eq), ammonium chloride (5 eq) and HATU (0.62 mmol, 1.5 eq) and the resulting mixture was stirred at room temperature for another 1 h. The crude material was purified by reverse phase chromatography to provide the title compound.

[0273] LCMS (LCMS (ES) m / z): [M+1] + :362, 1 H NMR (400MHz, DMSO-d6, ppm) δ12.12(d,J=3.0Hz,1H),10.86(s,1H),8.55(s,1H),8.21(d,J=3. 2Hz, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 6.87 (d, J = 7.8Hz, 1H), 6.75 (d, J = 7.7Hz, 1H), 2.61 (s, 3H).

[0274] General Procedure H

[0275]

[0276] Preparation of 2-ethyl-1H-imidazole-4-sulfonic acid. To a solution of 2-ethyl-1H-imidazole (2g, 20.8mmol, 1 equivalent) in CHCl (16.0mL), HSO was added Cl (8mL) and the resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and diluted with Et at room temperature O (200mL) and EtOH (20mL), and the resulting mixture was stirred at room temperature for 0.5h. The resulting mixture was filtered, the filter cake was washed with Et O, and dried under vacuum to give a crude product, which was used without further purification.

[0277] Preparation of 2-ethyl-1-(2-methoxy-2-oxoethyl)imidazole-4-sulfonic acid. To a solution of 2-ethyl-1H-imidazole-4-sulfonic acid (3.30 g, 18.7 mmol, 1 eq.) in DMF (66.0 mL) was added methyl 2-bromoacetate (3.44 g, 22.4 mmol, 1.2 eq.) and KCO (7.77 g, 56.1 mmol, 3 eq.) and the resulting mixture was stirred at 80° C. under nitrogen atmosphere overnight. The reaction mixture was diluted with MeOH, filtered, acidified with HCl in MeOH (4 M, 40 mL), and concentrated under vacuum to give the crude product, which was used without further purification.

[0278] Preparation of 2-[4-(chlorosulfonyl)-2-ethylimidazol-1-yl]acetate. A solution of 2-ethyl-1-(2-methoxy-2-oxoethyl)imidazole-4-sulfonic acid (6.30 g, 25.3 mmol, 1 eq.) in POCl3 (126 mL) was stirred at 85 ° C for 2 h. The mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 267

[0279] Preparation of methyl 2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-2-ethylimidazol-1-yl}acetate. To a solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (0.45 g, 2.62 mmol, 1 eq) and pyridine (0.62 g, 7.88 mmol, 3 eq) in DCM (14 mL) was added dropwise at 0 ° C. 2-[4-(chlorosulfonyl)-2-ethylimidazol-1-yl]acetate (0.70 g, 2.62 mmol, 1 eq) in DCM (4 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1]+: 402

[0280] Preparation of {4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-2-ethylimidazol-1-yl}acetic acid. To a solution of methyl 2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-2-ethylimidazol-1-yl}acetate (0.50 g, 1.24 mmol, 1 eq) in MeOH (10 mL) and H2O (10 mL) was added LiOH (0.03 g, 1.24 mmol, 1 eq) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum and the crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 388, 1 H NMR (300MHz, DMSO-d6, ppm) δ13.32 (s, 1H), 12.15 (s, 1H), 9.85 (s, 1H), 8.20 (d, J = 3.1Hz, 1H), 7.63 (s, 1H), 6.81 (s, 2H), 4.83 (s, 2H), 2.59 (d, J = 7.4Hz, 5H), 1.21 (t, J = 7.5Hz, 3H).

[0281] Preparation of 2-(4-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)-2-ethyl-1H-imidazol-1-yl)-N-cyclopropylacetamide. To a solution of {4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-2-ethylimidazol-1-yl}acetic acid (150 mg, 0.38 mmol, 1 eq) and aminocyclopropane (111 mg, 1.93 mmol, 5 eq) in THF (3 mL) was added T3P (185 mg, 0.58 mmol, 1.50 eq) and DIPEA (251 mg, 1.93 mmol, 5 eq) and the resulting mixture was stirred at room temperature overnight. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 426, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.18(s,1H),9.85(s,1H),8.34(d,J=4.1Hz,1H),8.20(d,J=2.8Hz,1H),7.61(s,1H) ,6.90-6.77(m,2H),4.57(s,2H),2.69-2.51(m,6H),1.20(t,J=7.5Hz,3H),0.76-0.58(m,2H),0.47-0.35(m,2H).

[0282] General Program I

[0283]

[0284] Preparation of 7-(2-amino-1,3-thiazol-5-ylsulfonylamino)-3-indolecarbonitrile. A solution of tert-butyl N-{5-[(3-cyano-1H-indol-7-yl)sulfamoyl]-1,3-thiazol-2-yl}carbamate (200 mg, 0.48 mmol, 1 equivalent) in TFA (4 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to provide the title compound. LCMS (ES) m / z: [M+1] +: 320, 1 H NMR (400MHz, DMSO-d6, ppm) δ11.87(d,J=3.1Hz,1H),10.01(s,1H),8.22(d,J=3.1Hz,1H),7. 85(s,2H),7.47(d,J=7.9Hz,1H),7.30(s,1H),7.18(t,J=7.8Hz,1H),7.02(d,J=7.7Hz,1H).

[0285] General Program N

[0286] Preparation of methyl 2-((5-(chlorosulfonyl)thiazol-2-yl)oxy)acetate

[0287]

[0288] Preparation of methyl 2-[(5-bromo-1,3-thiazol-2-yl)oxy]acetate. To a solution of methyl 2-hydroxyacetate (1.11 g, 12.3 mmol, 1.5 eq.) in THF (40 mL) was added NaH (0.41 g, 17.2 mmol, 2.1 eq.) and 2,5-dibromo-1,3-thiazole (2 g, 8.23 ​​mmol, 1 eq.) at 0 °C and the resulting mixture was stirred at 65 °C for 3 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :252

[0289] Preparation of methyl 2-{[5-(benzylsulfanyl)-1,3-thiazol-2-yl]oxy}acetate. To a solution of methyl 2-[(5-bromo-1,3-thiazol-2-yl)oxy]acetate (400 mg, 1.58 mmol, 1.0 eq) in dioxane (8 mL) was added XantPhos (91.8 mg, 0.159 mmol, 0.1 eq), Pd2(dba)3 (72.6 mg, 0.079 mmol, 0.05 eq), benzyl mercaptan (236 mg, 1.90 mmol, 1.2 eq) and DIPEA (615 mg, 4.76 mmol, 3 eq) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :296

[0290] Preparation of methyl 2-((5-(chlorosulfonyl)thiazol-2-yl)oxy)acetate. To a solution of methyl 2-{[5-(benzylsulfanyl)-1,3-thiazol-2-yl]oxy}acetate (420 mg, 1.42 mmol, 1.0 equiv) in DCM (3 mL) and H2O (7 mL) was added 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (363 mg, 1.56 mmol, 1.1 equiv) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :272

[0291] General Program J

[0292] Preparation of methyl 2-((5-(N-(3-cyano-1H-indol-7-yl)sulfamoyl)thiazol-2-yl)oxy)acetate and N-(3-cyano-1H-indol-7-yl)-2-(2-hydroxy-2-methylpropoxy)thiazole-5-sulfonamide

[0293]

[0294] Preparation of methyl 2-((5-(N-(3-cyano-1H-indol-7-yl)sulfamoyl)thiazol-2-yl)oxy)acetate Methyl 2-((5-(chlorosulfonyl)thiazol-2-yl)oxy)acetate and 7-amino-1H-indole-3-carbonitrile (150 mg, 0.954 mmol, 1 eq) were reacted in the presence of pyridine in dichloromethane solution at 0 °C for 1 h to form a sulfonamide intermediate. The intermediate was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to provide the title compound. LCMS (ES, m / z): [M+1] + :393, 1 H NMR (400MHz, DMSO-d6, ppm) δ12 (s, 1H), 10.41 (s, 1H), 8.22 (d, J = 3.0Hz, 1H), 7.60-7 .48(m,2H),7.17(t,J=7.8Hz,1H),6.94(d,J=7.6Hz,1H),5.12(s,2H),3.69(s,3H).

[0295] Preparation of N-(3-cyano-1H-indol-7-yl)-2-(2-hydroxy-2-methylpropoxy)thiazole-5-sulfonamide The sulfonamide intermediate from above was reacted with MeMgCl in THF at 0°C for 2h to provide the desired compound. The compound was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254nm. The resulting mixture was concentrated under reduced pressure to provide the title compound.

[0296] LCMS (ES, m / z): [M+1] + :391, 1 H NMR (400MHz, DMSO-d6, ppm) δ11.99(d,J=3.1Hz,1H),10.38(s,1H),8.22(d,J=3.1Hz,1H),7.60-7.4 8(m,2H),7.18(t,J=7.8Hz,1H),6.96(dd,J=7.7,1.0Hz,1H),4.81(s,1H),4.18(s,2H),1.14(s,6H).

[0297] Preparation of N-(3-cyano-1H-indol-7-yl)-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydrothiazole-5-sulfonamide

[0298]

[0299] Methyl 2-(5-(chlorosulfonyl)-2-oxothiazol-3(2H)-yl)acetate and 7-amino-1H-indole-3-carbonitrile (100 mg, 0.636 mmol, 1 eq.) were reacted in a similar manner as described above. The intermediate was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to provide the desired compound. LCMS (ES, m / z): [M+1] + :391, 1 H NMR (400MHz, DMSO-d6, ppm) δ11.99 (s, 1H), 10.32 (s, 1H), 8.22 (d, J = 2.8Hz, 1H), 7.56-7.44 ( m, 2H), 7.18 (t, J = 7.8Hz, 1H), 7.03 (d, J = 7.5Hz, 1H), 4.67 (s, 1H), 3.57 (s, 2H), 0.96 (s, 6H).

[0300] Preparation of intermediate sulfonyl chloride

[0301] Preparation of 5-(2-hydroxy-2-methylpropyl)-1,3-thiazole-2-sulfonyl chloride

[0302]

[0303] Preparation of methyl 2-(2-bromo-1,3-thiazol-5-yl)acetate. To a solution of methyl 2-(2-amino-1,3-thiazol-5-yl)acetate (700 mg, 4.06 mmol, 1 eq.) and CuBr2 (998 mg, 4.47 mmol, 1.1 eq.) in MeCN (35 mL) was added dropwise t-BuONO (628 mg, 6.09 mmol, 1.5 eq.) at -10 °C and the resulting mixture was stirred at room temperature for 30 min. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1]+: 236

[0304] Preparation of methyl 2-[2-(benzylsulfanyl)-1,3-thiazol-5-yl]acetate. To a solution of methyl 2-(2-bromo-1,3-thiazol-5-yl)acetate (356 mg, 1.50 mmol, 1 eq.) and benzyl mercaptan (224 mg, 1.81 mmol, 1.2 eq.) in dioxane (7 mL) was added DIPEA (584 mg, 4.52 mmol, 3 eq.), XantPhos (87.3 mg, 0.15 mmol, 0.1 eq.) and Pd2(dba)3 (69.0 mg, 0.07 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :280

[0305] Preparation of 1-[2-(benzylsulfanyl)-1,3-thiazol-5-yl]-2-methylpropan-2-ol. To a solution of methyl 2-[2-(benzylsulfanyl)-1,3-thiazol-5-yl]acetate (400 mg, 1.43 mmol, 1 eq.) in THF (8 mL) was added dropwise CH3MgCl (1.5 mL, 4.29 mmol, 3.0 eq.) at 0°C and the resulting mixture was stirred at 0°C under nitrogen atmosphere for 30 min. The reaction was quenched with saturated NH4Cl and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :280

[0306] Preparation of 5-(2-hydroxy-2-methylpropyl)-1,3-thiazole-2-sulfonyl chloride. To a solution of 1-[2-(benzylsulfanyl)-1,3-thiazol-5-yl]-2-methylpropan-2-ol (202 mg, 0.72 mmol, 1 eq) in AcOH (2 mL) and H2O (2 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (285 mg, 1.44 mmol, 2 eq) and the resulting mixture was stirred at 40 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification.

[0307] Preparation of oxazole-5-sulfonyl chloride

[0308]

[0309] Preparation of 2-(triisopropylsilyl)oxazole. To a solution of oxazole (1.0 g, 14.4 mmol, 1.0 equiv) in Et2O (20 mL) was added n-BuLi (12.5 mL, 132 mmol, 1.1 equiv, 2.5 M) dropwise at -78 °C and the resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 h. Triisopropylsilyl trifluoromethanesulfonate (4.44 g, 14.4 mmol, 1.0 equiv) was added to the mixture at -78 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :226

[0310] Preparation of oxazole-5-sulfonyl chloride. To a solution of 2-(triisopropylsilyl)oxazole (2.0 g, 8.87 mmol, 1.0 equiv) in THF (40 mL) was added n-BuLi (4.2 mL, 9.76 mmol, 1.1 equiv, 2.5 M) dropwise at -78 ° C and the resulting mixture was stirred at -78 ° C under a nitrogen atmosphere for 1 h. SO2 and SO2Cl2 (2.39 g, 17.7 mmol, 2.0 equiv) were added dropwise to the mixture at -40 ° C in 3 min and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :168

[0311] Preparation of 2-fluorothiazole-5-sulfonyl chloride

[0312]

[0313] Preparation of 5-(benzylsulfanyl)-1,3-thiazole-2-amine. To a solution of 5-bromo-1,3-thiazole-2-amine (30.0 g, 167 mmol, 1.0 eq.) and benzyl mercaptan (25.0 g, 201 mmol, 1.2 eq.) in DMF (300 mL) was added K2CO3 (34.7 g, 251 mmol, 1.5 eq.) and the resulting mixture was stirred at room temperature for 3 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] +:223.

[0314] Preparation of 5-(benzylsulfanyl)-2-fluoro-1,3-thiazole. A solution of 5-(benzylsulfanyl)-1,3-thiazole-2-amine (10.0 g, 45.0 mmol, 1.0 eq.) in pyridine hydrofluoride (100 mL) was stirred at 0 °C under a nitrogen atmosphere for 1 h. To the mixture was added NaNO2 (3.7 g, 54.0 mmol, 1.2 eq.) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :226.

[0315] Preparation of 2-fluorothiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-2-fluoro-1,3-thiazole (900 mg, 4.0 mmol, 1.0 eq.) in AcOH (9 mL) and H2O (4.5 mL) was added NCS (1600 mg, 12.0 mmol, 3.0 eq.) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :202.

[0316] Preparation of 2-substituted 1,3-oxazole-4-sulfonyl chloride

[0317]

[0318] Preparation of propanecarbonyl isothiocyanate. To a solution of propionyl chloride (6.0 g, 64.9 mmol, 1.0 eq.) in acetone (60 mL) was added potassium thiocyanate (6.3 g, 64.8 mmol, 1.0 eq.) and the resulting mixture was stirred at 50 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure to give a crude product which was not further purified. LCMS (ES, m / z): [M+1] + :116.

[0319] Preparation of 4-(benzylsulfanyl)-2-ethyl-1,3-oxazole. To a solution of propanecarbonyl isothiocyanate (313-1) (7.3 g, 63.4 mmol, 1.0 equiv) in DCM (73 mL) was added TMS-CHN2 (7.2 g, 63.4 mmol, 1.0 equiv) and the resulting mixture was stirred at 0 ° C under a nitrogen atmosphere for 1 h. DBU (19.3 g, 126 mmol, 2.0 equiv) and BnBr (10.8 g, 63.4 mmol, 1.0 equiv) were added to the mixture and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :220.

[0320] Preparation of 2-ethyl-1,3-oxazole-4-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)-2-ethyl-1,3-oxazole (1.3 g, 5.9 mmol, 1.0 eq.) in AcOH (13 mL) and H2O (6.5 mL) was added NCS (2.8 g, 20.7 mmol, 3.5 eq.) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :196.

[0321] Preparation of 5-methylisoxazole-3-sulfonyl chloride

[0322]

[0323] Preparation of 2-benzyl-5-methyl-1,2-oxazol-3-one. To a solution of 3-hydroxy-5-methylisoxazole (10.0 g, 101 mmol, 1 eq.) in acetone (200 mL) was added benzyl bromide (19.0 g, 111 mmol, 1.1 eq.) and K2CO3 (20.9 g, 151 mmol, 1.5 eq.) and the resulting mixture was stirred at 60 ° C under a nitrogen atmosphere for 4 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M-Cl]+: 190

[0324] Preparation of 2-benzyl-3-chloro-5-methyl-1,2-oxazol-2-ium chloride. To a solution of 2-benzyl-1,2-oxazol-3-one (7.20 g, 41.1 mmol, 1 eq) in toluene (216 mL) and triphosgene (12.2 g, 41.1 mmol, 1 eq) was added DMF (1.20 g, 10% BTC wt) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. The precipitated solid was collected by filtration and washed with toluene. The filter cake was dried under vacuum to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :208

[0325] Preparation of 2-benzyl-5-methyl-1,2-oxazole-3-thione. To a solution of benzyl-3-chloro-5-methyl-1,2-oxazol-2-ium (6.80 g, 32.6 mmol, 1 eq.) in water was added dropwise NaSH (3.65 g, 65.2 mmol, 2.0 eq.) in H2O (10 mL) at 0 °C and the resulting mixture was stirred at room temperature overnight. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :206

[0326] Preparation of 3-(benzylsulfanyl)-5-methyl-1,2-oxazole. To a solution of 2-benzyl-5-methyl-1,2-oxazole-3-thione (4.40 g, 21.4 mmol, 1 eq) in MeCN (110 mL) was added benzyl bromide (3.67 g, 21.4 mmol, 1 eq) and the resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction mixture was concentrated under vacuum. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] + :206

[0327] Preparation of 5-methylisoxazole-3-sulfonyl chloride. To a solution of 3-(benzylsulfanyl)-5-methyl-1,2-oxazole (400 mg, 1.94 mmol, 1 eq.) in DCM (2 mL) and H2O (6 mL) was added trichloroisocyanuric acid (679 mg, 2.92 mmol, 1.5 eq.) and the resulting mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+aniline-Cl+1] + :239

[0328] Preparation of 1,3,4-oxadiazole-2-sulfonyl chloride

[0329]

[0330] Preparation of 2-(benzylthio)-1,3,4-oxadiazole. To a solution of N-formyl hydrazide (5 g, 83.2 mmol, 1 eq.) and KOH (5.14 g, 91.5 mmol, 1.1 eq.) in EtOH (100 mL) was added dropwise CS2 (6.97 g, 91.5 mmol, 1.1 eq.) at 0 °C, and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 5 h. Benzyl bromide (4.98 g, 29.1 mmol, 0.35 eq.) was added to the mixture and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :193.

[0331] Preparation of 1,3,4-oxadiazole-2-sulfonyl chloride. To a solution of 2-(benzylsulfanyl)-1,3,4-oxadiazole (500 mg, 2.60 mmol, 1 eq.) in H2O (15 mL) and DCM (5 mL) was added trichloro-1,3,5-triazine-2,4,6-trione (906 mg, 3.90 mmol, 1.5 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification.

[0332] Preparation of Isoxazole-4-sulfonyl chloride

[0333]

[0334] Preparation of 2-(benzylsulfanyl)malonaldehyde. To a solution of 2-chloromalonaldehyde (8 g, 75.1 mmol, 1 eq.) in DMF (160 mL) was added benzyl mercaptan (11.2 g, 90.1 mmol, 1.2 eq.) and K2CO3 (31.1 g, 225 mmol, 3 eq.) and the resulting mixture was stirred at 60 °C under nitrogen atmosphere for 3 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :195

[0335] Preparation of 4-(benzylsulfanyl)-1,2-oxazole. To a solution of 2-(benzylsulfanyl)malonaldehyde (2.50 g, 12.9 mmol, 1 eq.) in EtOH (50 mL) was added NH2OH.HCl (0.89 g, 12.9 mmol, 1 eq.) and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction mixture was quenched with water and extracted with DCM. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :192

[0336] Preparation of 1,2-oxazole-4-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)-1,2-oxazole (1.50 g, 7.84 mmol, 1 eq.) in DCM (30 mL) and H2O (90 mL) was added trichloroisocyanuric acid (2.73 g, 11.8 mmol, 1.5 eq.) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+aniline-Cl+1] + :225

[0337] Preparation of 1,2,5-oxadiazole-3-sulfonyl chloride

[0338]

[0339] Preparation of (1E,2E)-N-hydroxy-2-(hydroxyimino)iminoethyl chloride. To a solution of NH2OH.HCl (28.3 g, 407 mmol, 3 eq.) in H2O (300 mL) was added NaHCO3 (17.1 g, 203 mmol, 1.5 eq.) and 2,2,2-trichloroacetaldehyde (20.0 g, 135 mmol, 1 eq.) in H2O (300 mL) and the resulting mixture was stirred at 0°C for 4 h. To the mixture was added NaOH (21.7 g, 542 mmol, 4 eq.) in H2O (200 mL) and the resulting mixture was stirred at 0°C for 5 h. The reaction mixture was quenched with H2SO4 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 123

[0340] Preparation of (E)-N-[(2E)-2-(benzylsulfanyl)-2-(hydroxyimino)ethylidene]hydroxylamine. To a solution of (1E,2E)-N-hydroxy-2-(hydroxyimino)ethanecarbodiimide chloride (3 g, 24.4 mmol, 1 eq) in MeCN (60 mL) was added benzyl mercaptan (3.7 g, 29.3 mmol, 1.2 eq) and K2CO3 (10.1 g, 73.4 mmol, 3 eq) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 211

[0341] Preparation of 3-(benzylsulfanyl)-1,2,5-oxadiazole. To a solution of (E)-N-[(2E)-2-(benzylsulfanyl)-2-(hydroxyimino)ethylidene]hydroxylamine (2 g, 9.51 mmol, 1 eq) in THF (20 mL) was added SOCl2 (11.3 g, 95.1 mmol, 10 eq) and the resulting mixture was stirred at 50 °C overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 193

[0342] Preparation of 1,2,5-oxadiazole-3-sulfonyl chloride. To a solution of 3-(benzylsulfanyl)-1,2,5-oxadiazole (1.20 g, 6.24 mmol, 1 eq.) in DCM (7 mL) and H2O (22 mL) was added trichloroisocyanuric acid (1.45 g, 6.24 mmol, 1 eq.) and the resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 169

[0343] Preparation of 3-cyclopropylisothiazole-5-sulfonyl chloride

[0344]

[0345] Preparation of 5-(benzylsulfanyl)-3-cyclopropyl-1,2-thiazole. To a solution of 5-(benzylsulfanyl)-3-bromo-1,2-thiazole (400 mg, 1.39 mmol, 1 eq.) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (704 mg, 4.19 mmol, 3 eq.) in dioxane (3 mL) and H2O (1 mL) was added K3PO4 (889 mg, 4.19 mmol, 3 eq.) and Pd(dtbpf)Cl2 (273 mg, 0.419 mmol, 0.3 eq.) and the resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :248

[0346] Preparation of 3-cyclopropyl-1,2-thiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-3-cyclopropyl-1,2-thiazole (120 mg, 0.485 mmol, 1 eq.) in DCM (1.8 mL) and H2O (0.6 mL) was added 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (169 mg, 0.728 mmol, 1.5 eq.) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :224

[0347] Preparation of 3-(difluoromethyl)isothiazole-5-sulfonyl chloride

[0348]

[0349] Preparation of 5-(benzylsulfanyl)-1,2-thiazole-3-carboxaldehyde. To a solution of 5-bromo-1,2-thiazole-3-carboxaldehyde (500 mg, 2.60 mmol, 1 eq.) in DMF (10 mL) was added benzyl mercaptan (388 mg, 3.12 mmol, 1.2 eq.), K2CO3 (1.07 g, 7.80 mmol, 3 eq.) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :236

[0350] Preparation of 5-(benzylsulfanyl)-3-(difluoromethyl)-1,2-thiazole. To a solution of 5-(benzylsulfanyl)-1,2-thiazole-3-carbaldehyde (300 mg, 1.27 mmol, 1 eq) in DCM (6 mL) was added DAST (226.0 mg, 1.40 mmol, 1.1 eq) dropwise at -78 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :258

[0351] Preparation of 3-(difluoromethyl)isothiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-3-(difluoromethyl)-1,2-thiazole (240 mg, 0.933 mmol, 1 eq.) in DCM (1.5 mL) and H2O (4.5 mL) was added 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (238 mg, 1.02 mmol, 1.1 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :234

[0352] Preparation of 5-sulfamoylthiophene-2-sulfonyl chloride

[0353]

[0354] Preparation of 5-bromothiophene-2-sulfonamide. To a solution of 5-bromothiophene-2-sulfonyl chloride (500 mg, 1.91 mmol, 1 eq.) in THF (10 mL) was added NH3.H2O (100 mg, 2.86 mmol, 1.5 eq.) dropwise at 0°C and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was used without further purification. LCMS (ES, m / z): [M+1]+: 242.

[0355] Preparation of 5-(benzylsulfanyl)thiophene-2-sulfonamide. To a solution of 5-bromothiophene-2-sulfonamide (460 mg, 1.90 mmol, 1 eq.) in dioxane (10 mL) was added DIPEA (736 mg, 5.70 mmol, 3 eq.), benzyl mercaptan (283 mg, 2.28 mmol, 1.2 eq.), XantPhos (109 mg, 0.19 mmol, 0.1 eq.) and Pd2(dba)3 (86.9 mg, 0.09 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 286.

[0356] Preparation of 5-sulfamoylthiophene-2-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)thiophene-2-sulfonamide (320 mg, 1.12 mmol, 1 eq.) in AcOH (4 mL) and water (2 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (331 mg, 1.68 mmol, 1.5 eq.) at 0 ° C. and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 262.

[0357] Preparation of 5-sulfamoylthiophene-3-sulfonyl chloride

[0358]

[0359] Preparation of 4-bromothiophene-2-sulfonamide. To a solution of 4-bromothiophene-2-sulfonyl chloride (800 mg, 3.06 mmol, 1 eq.) in THF (16 mL) was added NH3.H2O (78.1 mg, 4.59 mmol, 1.5 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give a crude product which was used without further purification. LCMS (ES, m / z): [M+1] + :242

[0360] Preparation of 4-(benzylsulfanyl)thiophene-2-sulfonamide. To a solution of 4-bromothiophene-2-sulfonamide (796 mg, 3.28 mmol, 1 eq) in dioxane (15 mL) was added benzyl mercaptan (490 mg, 3.94 mmol, 1.2 eq), Pd2(dba)3 (150 mg, 0.16 mmol, 0.05 eq), XantPhos (190 mg, 0.33 mmol, 0.1 eq) and DIPEA (1.27 g, 9.86 mmol, 3 eq) and the resulting mixture was stirred at 100 °C for 1 h. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :286

[0361] Preparation of 5-sulfamoylthiophene-3-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)thiophene-2-sulfonamide (835 mg, 2.92 mmol, 1 eq.) in H2O (0.4 mL), AcOH (0.5 mL) and MeCN (12.5 mL) was added DCDMH (864 mg, 4.38 mmol, 1.2 eq.) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :262

[0362] Preparation of 2-sulfamoylthiazole-5-sulfonyl chloride

[0363]

[0364] Preparation of 2-(benzylsulfanyl)-5-bromo-1,3-thiazole. To a solution of 2,5-dibromo-1,3-thiazole (4.1 g, 16.8 mmol, 1 eq.) and K2CO3 (4.67 g, 33.7 mmol, 2 eq.) in DMF (82 mL) was added benzyl mercaptan (2.52 g, 20.2 mmol, 1.2 eq.) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was diluted with and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1]+: 286

[0365] Preparation of 5-bromo-1,3-thiazole-2-sulfonyl chloride. To a solution of 2-(benzylsulfanyl)-5-bromo-1,3-thiazole (2.5 g, 8.73 mmol, 1 eq.) in DCM (12.5 mL) and H2O (37.5 mL) was added trichloroisocyanuric acid (3.04 g, 13.1 mmol, 1.5 eq.) at 0°C and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was filtered and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 262

[0366] Preparation of 5-bromo-1,3-thiazole-2-sulfonamide. To a solution of 5-bromo-1,3-thiazole-2-sulfonyl chloride (1.71 g, 6.53 mmol, 1 eq.) in THF (30 mL) was added NH3.H2O (0.92 g, 26.1 mmol, 4 eq.) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 243

[0367] Preparation of 5-(benzylsulfanyl)-1,3-thiazole-2-sulfonamide. To a solution of 5-bromo-1,3-thiazole-2-sulfonamide (0.8 g, 3.29 mmol, 1 eq.) in dioxane (16 mL) was added benzyl mercaptan (0.49 g, 3.94 mmol, 1.2 eq.), DIPEA (1.28 g, 9.87 mmol, 3 eq.), Xantphos (0.19 g, 0.329 mmol, 0.1 eq.) and Pd2(dba)3 (0.15 g, 0.165 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 287

[0368] Preparation of 2-sulfamoyl-1,3-thiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-1,3-thiazole-2-sulfonamide (740 mg, 2.58 mmol, 1 eq.) in DCM (12 mL) and H2O (38 mL) was added trichloroisocyanuric acid (898 mg, 3.87 mmol, 1.5 eq.) at 0°C and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 263

[0369] Preparation of 4-sulfamoylthiophene-2-sulfonyl chloride

[0370]

[0371] Preparation of 4-(benzylsulfanyl)-2-chlorothiophene. To a solution of 4-bromo-2-chlorothiophene (200 mg, 1.03 mmol, 1 eq.) in dioxane (4 mL) was added benzyl mercaptan (151 mg, 1.21 mmol, 1.2 eq.), DIPEA (392 mg, 3.04 mmol, 3 eq.), XantPhos (58.6 mg, 0.101 mmol, 0.1 eq.) and Pd2(dba)3 (46.4 mg, 0.051 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :241

[0372] Preparation of 5-chlorothiophene-3-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)-2-chlorothiophene (180 mg, 0.748 mmol, 1 eq.) in AcOH (3 mL) and H2O (1 mL) was added NCS (300 mg, 2.24 mmol, 3 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :217

[0373] Preparation of 5-chlorothiophene-3-sulfonamide. To a solution of 5-chlorothiophene-3-sulfonyl chloride in THF (10 mL) was added NH3.H2O (10 mL) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :198

[0374] Preparation of 5-(benzylsulfanyl)thiophene-3-sulfonamide. To a solution of 5-chlorothiophene-3-sulfonamide (100 mg, 0.50 mmol, 1 eq.) in dioxane (2 mL) was added benzyl mercaptan (75.4 mg, 0.607 mmol, 1.2 eq.), DIPEA (196 mg, 1.52 mmol, 3 eq.), XantPhos (29.3 mg, 0.051 mmol, 0.1 eq.) and Pd2(dba)3 (23.2 mg, 0.025 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :286

[0375] Preparation of sulfamoylthiophene-2-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)thiophene-3-sulfonamide (55 mg, 0.19 mmol, 1 eq.) in AcOH (1 mL) and H2O (0.1 mL) was added NCS (77.2 mg, 0.58 mmol, 3 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :262

[0376] Preparation of 2-(2-hydroxy-2-methylpropyl)thiazole-5-sulfonyl chloride

[0377]

[0378] Preparation of 1-(5-bromo-1,3-thiazol-2-yl)-2-methylpropan-2-ol. To a solution of 5-bromo-2-methyl-1,3-thiazole (10.0 g, 56.2 mmol, 1 eq.) in THF (100 mL) was added LiHMDS (73.0 mL, 73.0 mmol, 1.3 eq.) and the resulting mixture was stirred at -60 ° C for 30 min under a nitrogen atmosphere. Acetone (3.91 g, 67.4 mmol, 1.2 eq.) was added dropwise to the mixture at -60 ° C and the resulting mixture was stirred at 0 ° C for 1 h under a nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES) m / z: [M+1] + :236

[0379] Preparation of 1-[5-(benzylsulfanyl)-1,3-thiazol-2-yl]-2-methylpropan-2-ol. To a solution of 1-(5-bromo-1,3-thiazol-2-yl)-2-methylpropan-2-ol (120 mg, 0.51 mmol, 1 eq) in dioxane (3 mL) was added benzyl mercaptan (75.7 mg, 0.61 mmol, 1.2 eq), DIPEA (197 mg, 1.52 mmol, 3.00 eq), XantPhos (29.4 mg, 0.05 mmol, 0.10 eq) and Pd2(dba)3 (23.3 mg, 0.03 mmol, 0.05) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS(ES)m / z:[M+1] + :280

[0380] Preparation of 2-(2-hydroxy-2-methylpropyl)-1,3-thiazole-5-sulfonyl chloride. To a solution of 1-[5-(benzylsulfanyl)-1,3-thiazol-2-yl]-2-methylpropan-2-ol (114 mg, 0.41 mmol, 1 eq.) in AcOH (1 mL) and H2O (1 mL) was added NCS (196.2 mg, 1.23 mmol, 3.0 eq.) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with DCM. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: [M+Aniline-Cl+1] + :313

[0381] Preparation of tert-butyl (5-(chlorosulfonyl)thiazol-2-yl)carbamate

[0382]

[0383] Preparation of tert-butyl (5-(chlorosulfonyl)thiazol-2-yl)carbamate. To a solution of tert-butyl N-(5-bromo-1,3-thiazol-2-yl)carbamate (1 g, 3.58 mmol, 1 eq.) in toluene (20 mL) was added iPrMgCl.LiCl (9 mL, 6.44 mmol, 1.8 eq.) at -20 °C and the resulting mixture was stirred at room temperature for 1 h. SO2Cl2 (1.21 g, 8.96 mmol, 2.5 eq.) was added to the mixture and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :299

[0384] Preparation of tert-butyl (2-(chlorosulfonyl)thiazol-4-yl)carbamate

[0385]

[0386] Preparation of tert-butyl (2-(chlorosulfonyl)thiazole-4-yl)carbamate. To a solution of tert-butyl N-(2-bromo-1,3-thiazole-4-yl)carbamate (600 mg, 2.14 mmol, 1 eq.) in toluene (12 mL) was added dropwise iPrMgCl.LiCl (2.98 mL, 3.86 mmol, 1.8 eq., 1.3 M in THF) at -20 °C and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. SO2Cl2 (725 mg, 5.37 mmol, 2.5 eq.) was added to the mixture and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The reaction mixture was quenched with saturated NH4Cl and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :299

[0387] Preparation of 2-((dimethylamino)methyl)thiazole-5-sulfonyl chloride

[0388]

[0389]

[0390] Preparation of 1-(5-bromothiazol-2-yl)-N,N-dimethylmethanamine. To a solution of 5-bromo-1,3-thiazole-2-carbaldehyde (400 mg, 2.0 mmol, 1.0 eq.) in MeOH (8 mL) was added dimethylamine (2 M in MeOH) (375 mg) and AcOH (0.5 mL) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. NaBH3CN (392 mg, 6.24 mmol, 3 eq.) was added to the mixture and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 9 with saturated NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :221

[0391] Preparation of 1-(5-(Benzylthio)thiazol-2-yl)-N,N-dimethylmethanamine. To a solution of 1-(5-bromothiazol-2-yl)-N,N-dimethylmethanamine (300 mg, 1.35 mmol, 1.0 eq.) in dioxane (6 mL) was added DIPEA (526 mg, 4.07 mmol, 3 eq.), benzyl mercaptan (202 mg, 1.63 mmol, 1.2 eq.), XantPhos (78.5 mg, 0.136 mmol, 0.10 eq.) and Pd2(dba)3 (62.1 mg, 0.06 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was concentrated under vacuum. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :265

[0392] Preparation of 2-((dimethylamino)methyl)thiazole-5-sulfonyl chloride. To a solution of 1-(5-(benzylthio)thiazol-2-yl)-N,N-dimethylmethanamine (200 mg, 0.75 mmol, 1.0 eq) in AcOH (4 mL) and H2O (0.4 mL) was added NCS (303 mg, 2.26 mmol, 3 eq) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO and concentrated under reduced pressure to give the product, which was used without further purification.

[0393] Preparation of 2-(1,1-difluoroethyl)thiazole-5-sulfonyl chloride

[0394]

[0395]

[0396] Preparation of 1-(5-(benzylthio)thiazol-2-yl)ethan-1-one. To a solution of 1-(5-bromo-1,3-thiazol-2-yl)ethanone (500 mg, 2.42 mmol, 1.0 eq.) in dioxane (10 mL) was added DIPEA (940 mg, 7.27 mmol, 3 eq.), benzyl mercaptan (331 mg, 2.66 mmol, 1.1.0 eq.), XantPhos (140 mg, 0.24 mmol, 0.10 eq.) and Pd2(dba)3 (111 mg, 0.12 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :249

[0397] Preparation of 5-(benzylthio)-2-(1,1-difluoroethyl)thiazole. To a solution of 1-(5-(benzylthio)thiazol-2-yl)ethan-1-one (475 mg, 1.90 mmol, 1.0 equiv) in DCM (3 mL) was added DAST (2.4 mL) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 24 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :272

[0398] Preparation of 2-(1,1-difluoroethyl)thiazole-5-sulfonyl chloride. To a solution of 5-(benzylthio)-2-(1,1-difluoroethyl)thiazole (435 mg, 1.60 mmol, 1.0 eq.) in MeCN (4.3 mL), AcOH (0.3 mL), H2O (0.2 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (473 mg, 2.40 mmol, 1.5 eq.) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :247

[0399] Preparation of 2-(3-hydroxyoxetane-3-yl)thiazole-5-sulfonyl chloride and 5-(3-hydroxyoxetane-3-yl)thiazole-2-sulfonyl chloride

[0400]

[0401] Preparation of 3-(5-bromo-1,3-thiazol-2-yl)oxetane-3-ol and 3-(2-bromothiazol-5-yl)oxetane-3-ol. To a solution of 2,5-dibromo-1,3-thiazole (3 g, 12.3 mmol, 1.0 equiv) in Et2O (150 mL) was added n-BuLi (7.4 mL, 18.4 mmol, 1.5 equiv, 2.5 M in hexane) at -100 ° C and the resulting mixture was stirred at -100 ° C for 1 h. To the solution was added oxetane-3-one (1.36 g, 18.4 mmol, 1.5 equiv) in Et2O (10 mL) and the resulting mixture was stirred at -100 ° C for 3 h. The reaction mixture was quenched with MeOH and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :236

[0402]

[0403] Preparation of 3-(5-(benzylthio)thiazol-2-yl)oxetane-3-ol. To a solution of 3-(5-bromo-1,3-thiazol-2-yl)oxetane-3-ol (750 mg, 3.17 mmol, 1.0 eq.) in dioxane (15 mL) was added DIPEA (1.23 g, 9.5 mmol, 3 eq.), XantPhos (183 mg, 0.31 mmol, 0.10 eq.), Pd2(dba)3 (145 mg, 0.15 mmol, 0.05 eq.) and benzyl mercaptan (473 mg, 3.81 mmol, 1.2 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :280

[0404] Preparation of 2-(3-hydroxyoxetane-3-yl)-1,3-thiazole-5-sulfonyl chloride. To a solution of 3-(5-(benzylthio)thiazol-2-yl)oxetane-3-ol (800 mg, 2.86 mmol, 1.0 equiv) in DCM (5 mL) and H2O (15 mL) was added trichloroisocyanuric acid (732 mg, 3.15 mmol, 1.1.0 equiv) at 0 ° C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification.

[0405] Preparation of 5-(3-hydroxyoxetane-3-yl)thiazole-2-sulfonyl chloride

[0406]

[0407] Preparation of 3-(2-(benzylthio)thiazol-5-yl)oxetane-3-ol. To a solution of 3-(2-bromo-1,3-thiazol-5-yl)oxetane-3-ol (1 g, 4.23 mmol, 1.0 equiv) in dioxane (20 mL) was added XantPhos (0.25 g, 0.42 mmol, 0.10 equiv), Pd2(dba)3 (0.19 g, 0.21 mmol, 0.05 equiv), DIPEA (1.64 g, 12.7 mmol, 3 equiv) and benzyl mercaptan (0.63 g, 5.08 mmol, 1.2 equiv) and the resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :280

[0408] Preparation of 5-(3-hydroxyoxetane-3-yl)-1,3-thiazole-2-sulfonyl chloride. To a solution of 3-[2-(benzylsulfanyl)-1,3-thiazole-5-yl]oxetane-3-ol (1.05 g, 3.75 mmol, 1.0 equiv) in DCM (6.3 mL) and H2O (18.9 mL) was added trichloroisocyanuric acid (0.96 g, 4.13 mmol, 1.1.0 equiv) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification.

[0409] Preparation of intermediates indole and indazole

[0410] Preparation of 7-amino-4-methyl-1H-indole-3-carbonitrile

[0411]

[0412] Preparation of 7-bromo-4-methyl-1H-indole. Vinylmagnesium bromide (1.39L, 1.39mol, 1M, 3 equivalents) was added to a solution of 1-bromo-4-methyl-2-nitrobenzene (100g, 462mmol, 1 equivalent) in THF (2L) at -45°C and the resulting mixture was stirred for 1h at -45°C. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product.

[0413] Preparation of 7-bromo-4-methyl-1H-indole-3-carboxaldehyde. To a solution of POCl3 (26.7 mL, 286 mmol, 1.1 equivalents) in DMF (250 mL) was added 7-bromo-4-methyl-1H-indole (50 g, 238 mmol, 1 equivalent) in DMF (250 mL) at 0 ° C and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with water, and the precipitated solid was collected by filtration and washed with water to give a crude product, which was used without further purification. LCMS (ES, m / z): 239.9 [M+1].

[0414] Preparation of (E)-7-bromo-4-methyl-1H-indole-3-carbaldehyde oxime. To a solution of 7-bromo-4-methyl-1H-indole-3-carbaldehyde (52g, 218mmol, 1 equivalent) in EtOH (1L), NaCO (46.3g, 437mmol, 2 equivalents) and NHOH.HCl (30.3g, 437mmol, 2 equivalents) in H2O (130mL) were added and the resulting mixture was stirred at room temperature for 4h. The reaction mixture was quenched with water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): 255.0 [M+2H] + .

[0415] Preparation of 7-amino-1H-indole-3-carbonitrile. To a solution of (E)-7-bromo-4-methyl-1H-indole-3-carbaldehyde oxime (51 g, 201 mmol, 1 eq.) in THF (50 mL) was added pyridine (33 mL, 403 mmol, 2 eq.) and TFAA (143 mL, 403 mmol, 2 eq.) at 0 ° C. and the resulting mixture was stirred at 65 ° C. for 16 h. The reaction mixture was concentrated, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): 232.9 [MH] -

[0416] Preparation of 7-amino-4-methyl-1H-indole-3-carbonitrile. To a solution of 7-bromo-4-methyl-1H-indole-3-carbonitrile (25g, 106mmol, 1 equivalent) in DMSO (125mL), K2CO3 (36.7g, 266mmol, 2.5 equivalents), CuI (4.05g, 22mmol, 0.2 equivalents), L-co-peptide (2.45g, 22mmol, 0.2 equivalents) and NH4OH aqueous solution (500mL) were added and the resulting mixture was stirred at 120°C for 3h. The reaction mixture was filtered and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): 169.9 [MH] +

[0417] Preparation of 7-amino-1H-indole-3-carbonitrile

[0418]

[0419] Preparation of 7-nitro-1H-indole-3-carboxaldehyde. To a solution of POCl3 (34.6 mL, 320 mmol, 1.1 eq.) in DMF (50 mL) was added 7-nitro-1H-indole (50 g, 308 mmol, 1 eq.) in DMF (500 mL) at 0 °C and the resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): 190.98 [M+1] + .

[0420] Preparation of (E)-7-nitro-1H-indole-3-carbaldehyde oxime. To a solution of 7-nitro-1H-indole-3-carbaldehyde (60 g, 315 mmol, 1 eq.) in EtOH (1 L) was added NaCO (100 g, 945 mmol, 3 eq.), NHOH.HCl (54.7 g, 687 mmol, 2.5 eq.) in H2O (240 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): 205.98 [M+1] + .

[0421] Preparation of 7-nitro-1H-indole-3-carbonitrile. To a solution of (E)-7-nitro-1H-indole-3-carbaldehyde oxime (60 g, 292 mmol, 1 eq.) in THF (1.2 L) was added pyridine (70 mL, 877 mmol, 3 eq.) and TFAA (143 mL, 1024 mmol, 3.5 eq.) and the resulting mixture was stirred at 65 ° C for 16 h. The reaction mixture was concentrated, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS (ES, m / z): 185.97 [MH] - .

[0422] Preparation of 7-amino-1H-indole-3-carbonitrile. Iron powder (37.24g, 667mmol, 3 equivalents) and NH4Cl (71.4g, 1336mmol, 5 equivalents) were added to a solution of 7-nitro-1H-indole-3-carbonitrile (50g, 267mmol, 1 equivalent) in EtOH (500mL) and H2O (500mL) at 0°C and the resulting mixture was stirred at room temperature for 16h. The reaction mixture was filtered and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): 157.98 [M+1] + .

[0423] Preparation of 7-amino-4-(trifluoromethyl)-1H-indole-3-carbonitrile

[0424]

[0425] Preparation of 2,2,2-trifluoro-N-[2-nitro-4-(trifluoromethyl)phenyl]acetamide. To a solution of 2-nitro-4-(trifluoromethyl)aniline (13.5 g, 65.5 mmol, 1 eq) (SM1) and Et3N (19.9 g, 196 mmol, 3 eq) in DCM (270 mL) was added dropwise TFAA (27.5 g, 131 mmol, 2 eq) at 0 °C under a nitrogen atmosphere and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide a crude product, which was used without further purification.

[0426] Preparation of 2,2,2-trifluoro-N-[4-(trifluoromethyl)-1H-indol-7-yl]acetamide. To a solution of 2,2,2-trifluoro-N-[2-nitro-4-(trifluoromethyl)phenyl]acetamide (22.7 g, 75.13 mmol, 1 eq.) in THF (450 mL) was added dropwise vinylmagnesium bromide (451 mL, 451 mmol, 6 eq., 1 M in THF) at -40 °C under a nitrogen atmosphere and the resulting mixture was stirred for 1 h at -40 °C. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] + :297

[0427] Preparation of N-[3-cyano-4-(trifluoromethyl)-1H-indol-7-yl]-2,2,2-trifluoroacetamide. To a solution of 2,2,2-trifluoro-N-[4-(trifluoromethyl)-1H-indol-7-yl]acetamide (3.70 g, 12.5 mmol, 1 eq) in DMF (75 mL) was added dropwise chlorosulfonyl isocyanate (5.30 g, 37.5 mmol, 3 eq) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with water and the precipitated solid was collected by filtration and washed with water to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :322

[0428] Preparation of 7-amino-4-(trifluoromethyl)-1H-indole-3-carbonitrile. To a solution of N-[3-cyano-4-(trifluoromethyl)-1H-indol-7-yl]-2,2,2-trifluoroacetamide (4.30 g, 13.4 mmol, 1 eq.) in MeOH (50 mL) was added NH3(g) in MeOH (50.0 mL, 3 M) and the resulting mixture was stirred at 50 ° C for 9 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] + :226

[0429] Preparation of 3-(Trifluoromethyl)-1H-indol-7-amine analogs

[0430]

[0431] Preparation of 3-iodo-4-methyl-7-nitro-1H-indole. To a solution of 4-methyl-7-nitro-1H-indole (650 mg, 3.70 mmol, 1 eq.) in DMF (10 mL) was added NIS (875 mg, 3.88 mmol, 1.05 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and the precipitated solid was collected by filtration and washed with water and dried under vacuum to give the product, which was used without further purification.

[0432] Preparation of 4-methyl-7-nitro-3-(trifluoromethyl)-1H-indole. To a solution of 3-iodo-4-methyl-7-nitro-1H-indole (940 mg, 3.12 mmol, 1 eq) and methyl 2,2-difluoro-2-sulfoacetate (3 g, 15.6 mmol, 5 eq) in DMF (20 mL) was added CuI (118 mg, 0.62 mmol, 0.2 eq) and the resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature and the precipitated solid was collected by filtration, washed with water and dried under vacuum to give the product.

[0433] Preparation of 4-methyl-3-(trifluoromethyl)-1H-indole-7-amine. To a solution of 4-methyl-7-nitro-3-(trifluoromethyl)-1H-indole (476 mg, 1.95 mmol, 1 equivalent) in EtOAc (50 mL) was added Pd / C (10% wt) and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The precipitated solid was collected by filtration, washed with water and dried under vacuum to give the product.

[0434] Preparation of 3-chloro-1H-indol-7-amine analogs

[0435]

[0436] Preparation of 3-chloro-4-fluoro-7-nitro-1H-indole. To a solution of 4-fluoro-7-nitro-1H-indole (1 g, 5.55 mmol, 1 eq) in DMF (20 mL) was added dropwise NCS (815 mg, 6.10 mmol, 1.1 eq) in DMF (1 mL) at 0 °C and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and the precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the product, which was used without further purification.

[0437] The preparation of the fluoro-1H-indole-7-amine of 3-chloro-4-.At room temperature, add and Raney nickel (440mg, 5.12mmol, 1 equivalent) and hydrazine hydrate (330mg, 10.2mmol, 2 equivalents) to the solution of 3-chloro-4-fluoro-7-nitro-1H-indole (1.1g, 5.12mmol, 1 equivalent) in EtOH (55mL) and the gained mixture is stirred at room temperature for 30min.Collect the precipitated solid by filtering, wash with EtOH, and dry under vacuum to provide product, it is used without further purification.

[0438] Preparation of 7-amino-1H-indole-3-carbonitrile analogs

[0439]

[0440] Preparation of 4-fluoro-3-iodo-7-nitro-1H-indole.To a solution of 4-fluoro-7-nitro-1H-indole (1 g, 5.55 mmol, 1 equivalent) in DMF (20 mL), add NIS (1.4 g, 6.10 mmol, 1.1 equivalents) and the resulting mixture was stirred at room temperature for 8 h. The reaction was quenched with water and the precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the product, which was used without further purification.

[0441] Preparation of 4-fluoro-7-nitro-1H-indole-3-carbonitrile.To a solution of 4-fluoro-3-iodo-7-nitro-1H-indole (1.5g, 4.90mmol, 1 equivalent) in DMF (20mL), Zn(CN)2(345mg, 2.94mmol, 0.6 equivalent) and Pd(PPh3)4(566mg, 0.49mmol, 0.1 equivalent) were added, and the resulting mixture was stirred for 1h at 100°C under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product.

[0442] Preparation of 7-amino-4-fluoro-1H-indole-3-carbonitrile. A solution of 4-fluoro-7-nitro-1H-indole-3-carbonitrile (308 mg, 1.5 mmol, 1 equivalent) and Pd / C (10% wt) in EtOAc (10 mL V) was stirred at room temperature under a hydrogen atmosphere for 1 h. The resulting mixture was filtered and concentrated under reduced pressure to give the product, which was used without further purification.

[0443] Preparation of 7-amino-1H-indazole-3-carbonitrile analogs

[0444]

[0445] Preparation of 3-iodo-7-nitro-1H-indazole. To a solution of 7-nitroindazole (4 g, 24 mmol, 1 eq.) in DMF (80 mL) was added NIS (6.6 g, 29 mmol, 1.2 eq.) and the resulting mixture was stirred at 80 ° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with water and the precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :290

[0446] Preparation of 7-nitro-1H-indazole-3-carbonitrile. To a solution of 3-iodo-7-nitro-1H-indazole (4.2 g, 14.5 mmol, 1 eq.) in DMF (80 mL) was added Zn(CN)2 (1.02 g, 8.71 mmol, 0.6 eq.) and XantPhos-Pd-G4 (1.29 g, 1.45 mmol, 0.1 eq.) and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction was quenched with water and the precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :189

[0447] Preparation of 7-amino-1H-indazole-3-carbonitrile. To a solution of 7-nitro-1H-indazole-3-carbonitrile (2.8 g, 14.8 mmol, 1 equivalent) in EtOH (70 mL) and H2O (14 mL), NH4Cl (7.96 g, 148 mmol, 10 equivalents) and Fe (8.31 g, 148 mmol, 10 equivalents) were added and the resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 1 h. The resulting mixture was filtered, and the solid was washed with EtOH and concentrated under reduced pressure. The crude residue was dissolved in water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product. LCMS (ES, m / z): [M+1] + :159

[0448] Preparation of 3-chloro-1H-indazol-7-amine

[0449]

[0450] Preparation of 3-chloro-1H-indazole-7-amine. To a solution of 3-chloro-7-nitro-1H-indazole (1 g, 5.06 mmol, 1 eq.) in MeOH (10 mL) and EtOAc (10 mL) was added Pd / C (0.20 g, 20% wt) at room temperature under a hydrogen atmosphere and the resulting mixture was stirred at room temperature for 4 h. The resulting mixture was filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :168

[0451] Preparation of 7-amino-4-ethyl-1H-indole-3-carbonitrile

[0452]

[0453] Preparation of N-(4-bromo-3-cyano-1H-indol-7-yl)-2,2,2-trifluoroacetamide. Chlorosulfonyl isocyanate (3.50 g, 24.4 mmol, 3 equivalents) was added dropwise to a solution of N-(4-bromo-1H-indol-7-yl)-2,2,2-trifluoroacetamide (2.50 g, 8.14 mmol, 1) in DMF (50 mL) at 0 ° C and the resulting mixture was stirred at 0 ° C for 1 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :332

[0454] Preparation of N-(3-cyano-4-ethyl-1H-indol-7-yl)-2,2,2-trifluoroacetamide. To a solution of N-(4-bromo-3-cyano-1H-indol-7-yl)-2,2,2-trifluoroacetamide (1 g, 3 mmol, 1 eq.) in THF (20 mL) was added diethylzinc (1.12 g, 9 mmol, 3 eq.) and Pd(dppf)Cl2 (0.11 g, 0.15 mmol, 0.05 eq.) and the resulting mixture was stirred at 70 °C under nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :282

[0455] Preparation of 7-amino-4-ethyl-1H-indole-3-carbonitrile. To a solution of N-(3-cyano-4-ethyl-1H-indol-7-yl)-2,2,2-trifluoroacetamide (750 mg, 2.7 mmol, 1 eq.) in MeOH (5 mL) was added NH3(g) in MeOH (7.5 mL) at room temperature and the resulting mixture was stirred at room temperature for 3 days. The resulting mixture was concentrated under vacuum to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :186

[0456] Preparation of 7-amino-4-methoxy-1H-indole-3-carbonitrile

[0457]

[0458] Preparation of 4-methoxy-7-nitro-1H-indole-3-carbonitrile. To a solution of 4-methoxy-7-nitro-1H-indole (500 mg, 2.6 mmol, 1 eq.) in ACN (10 mL) and DMF (5 mL) was added dropwise chlorosulfonyl isocyanate (1.10 g, 7.81 mmol, 3 eq.) at 0 ° C and the resulting mixture was stirred at 0 ° C under a nitrogen atmosphere for 3 h. The reaction was quenched with water, and the precipitated solid was collected by filtration and washed with water to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :218.

[0459] Preparation of 7-amino-4-methoxy-1H-indole-3-carbonitrile. To a solution of 4-methoxy-7-nitro-1H-indole-3-carbonitrile (450 mg, 2.1 mmol, 1 eq.) in MeOH (100 mL) was added Raney nickel (500 mg, 100% wt) and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The residue was concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :188

[0460] Preparation of 7-amino-4-methoxy-1H-indole-3-carbonitrile

[0461]

[0462] Preparation of 7-bromo-5-methoxy-1H-indole. Vinylmagnesium bromide (57.3mL, 172mmol, 4 equivalents, 3M in THF) was added dropwise to a solution of 2-bromo-4-methoxy-1-nitrobenzene (10g, 43mmol, 1 equivalent) in THF (200mL) at -78°C under a nitrogen atmosphere and the resulting mixture was stirred for 1h at -78°C. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product. LCMS: (ES, m / z): [M+1] + :226

[0463] Preparation of 7-bromo-5-methoxy-1H-indole-3-carbonitrile. Chlorosulfonyl isocyanate (6.26 g, 44.2 mmol, 2 eq.) was added dropwise to a solution of 7-bromo-5-methoxy-1H-indole (5 g, 22.1 mmol, 1 eq.) in DMF (100 mL) at 0 ° C under a nitrogen atmosphere and the resulting mixture was stirred at 0 ° C for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :251

[0464] Preparation of 7-((benzhydryl)amino)-5-methoxy-1H-indole-3-carbonitrile. To a solution of 7-bromo-5-methoxy-1H-indole-3-carbonitrile (2.6 g, 10.3 mmol, 1 eq.) in THF (50 mL) was added benzophenone imine (3.75 g, 20.7 mmol, 2 eq.), PEPPSI-iPr-Pd (1.01 g, 1.03 mmol, 0.1 eq.) and LiHMDS (31 mL, 31.1 mmol, 3 eq., 1 M in THF) under nitrogen atmosphere and the resulting mixture was stirred at 100 °C overnight. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :352

[0465] Preparation of 7-amino-5-methoxy-1H-indole-3-carbonitrile. To a solution of 7-((benzhydryl)amino)-5-methoxy-1H-indole-3-carbonitrile (3.5 g, 9.96 mmol, 1 eq.) in THF (35 mL) was added dropwise HCl (35 mL, 70 mmol, 7 eq., 2 M in THF) at room temperature under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :188

[0466] Preparation of 7-amino-5-methyl-1H-indole-3-carbonitrile

[0467]

[0468] Preparation of 5-bromo-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile. To a solution of 5-bromo-7-nitro-1H-indole-3-carbonitrile (4.5 g, 16.9 mmol, 1 eq.) in THF (90 mL) was added dropwise NaH (0.49 g, 20.3 mmol, 1.2 eq.) and SEM-Cl (3.67 g, 21.9 mmol, 1.3 eq.) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :396.

[0469] Preparation of 5-methyl-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)indole-3-carbonitrile. To a solution of 5-bromo-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (6.2 g, 15.6 mmol, 1 eq) in dioxane (100 mL) and H2O (25 mL) was added K3PO4 (9.96 g, 46.9 mmol, 3 eq), RuPhos-Pd-G3 (650 mg, 0.8 mmol, 0.05 eq) and trimethyl-1,3,5,2,4,6-trioxatriborinane (5.89 g, 47 mmol, 3 eq) and the resulting mixture was stirred at 80°C under nitrogen atmosphere for 3 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] + :322.

[0470] Preparation of 7-amino-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)indole-3-carbonitrile. To a solution of 5-methyl-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)indole-3-carbonitrile (3.9 g, 11.7 mmol, 1 eq) in MeOH (160 mL) was added 10% Pd / C (0.63 g, 50% wt) at room temperature and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :302.

[0471] Preparation of 7-amino-5-methyl-1H-indole-3-carbonitrile. A solution of 7-amino-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)indole-3-carbonitrile (2.5 g, 8.29 mmol, 1 eq.) in TFA (50 mL) was stirred at 40 ° C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude residue was a mixture, adjusted to pH 8 with saturated NaHCO3, and the precipitated solid was collected by filtration and washed with water to give a crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :172.

[0472] Preparation of 3,4-dichloro-1H-indol-7-amine

[0473]

[0474] Preparation of 3,4-dichloro-7-nitro-1H-indole. To a solution of 4-chloro-7-nitro-1H-indole (2 g, 10.1 mmol, 1 eq.) in DMF (40 mL) was added NCS (1.49 g, 11.1 mmol, 1.1 eq.) at 0 °C and the resulting mixture was stirred at 80 °C for 1 h. The reaction was quenched with water. The precipitated solid was collected by filtration and washed with water to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :231

[0475] Preparation of 3,4-dichloro-1H-indole-7-amine. To a solution of 3,4-dichloro-7-nitro-1H-indole (2.05 g, 8.87 mmol, 1 eq.) in MeOH (50 mL) was added Raney nickel (20% wt) and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The resulting mixture was filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :201

[0476] Preparation of 7-amino-3-chloro-1H-indole-4-carbonitrile

[0477]

[0478] Preparation of 7-nitro-1H-indole-4-carbonitrile. To a solution of 4-chloro-7-nitro-1H-indole (8.1 g, 41.2 mmol, 1 eq.) in DMF (160 mL) was added Zn(CN)2 (5.81 g, 49.4 mmol, 1.2 eq.) and XPhos-Pd-G3 (3.49 g, 4.12 mmol, 0.1 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :186

[0479] Preparation of 3-chloro-7-nitro-1H-indole-4-carbonitrile. To a solution of 7-nitro-1H-indole-4-carbonitrile (1.02 g, 5.45 mmol, 1 eq.) in DMF (10 mL) was added NCS (0.80 g, 6 mmol, 1.1 eq.) and the resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :220

[0480] - Preparation of amino-3-chloro-1H-indole-4-carbonitrile. To a solution of 3-chloro-7-nitro-1H-indole-4-carbonitrile (1.2 g, 5.4 mmol, 1 eq.) in EtOH (18 mL) and H2O (6 mL) was added NH4Cl (2.90 g, 54.2 mmol, 10 eq.), Fe (3.02 g, 54.2 mmol, 10 eq.) at room temperature and the resulting mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :192

[0481] Preparation of 7-amino-3-methyl-1H-indole-4-carbonitrile

[0482]

[0483] Preparation of 3-iodo-7-nitro-1H-indole-4-carbonitrile. To a solution of 7-nitro-1H-indole-4-carbonitrile (1 g, 5.3 mmol, 1 eq.) in DMF (25 mL) was added NIS (1.32 g, 5.88 mmol, 1.1 eq.) in portions at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give a crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :312

[0484] Preparation of 3-methyl-7-nitro-1H-indole-4-carbonitrile. To a solution of 3-iodo-7-nitro-1H-indole-4-carbonitrile (1.53 g, 4.89 mmol, 1 eq) in dioxane (24 mL) and H2O (6 mL) was added K3PO4 (3.1 g, 15 mmol, 3 eq), Pd(PPh3)4 (0.56 g, 0.48 mmol, 0.1 eq) and trimethyl-1,3,5,2,4,6-trioxatriborinane (6.14 g, 48.8 mmol, 10 eq) at room temperature and the resulting mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with water. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give a crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :200

[0485] Preparation of 7-amino-3-methyl-1H-indole-4-carbonitrile. To a solution of 3-methyl-7-nitro-1H-indole-4-carbonitrile (1.20 g, 6 mmol, 1 eq.) in MeOH (60 mL) was added Raney nickel (0.48 g, 40% wt) and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :172

[0486] Preparation of 3-amino-4H-thieno[3,2-b]pyrrole-6-carbonitrile

[0487]

[0488] Preparation of methyl 3-bromo-6-iodo-4H-thieno[3,2-b]pyrrole-5-carboxylate. To a solution of methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate (5 g, 19.2 mmol, 1.0 equiv) in DMF (100 mL) was added NIS (4.76 g, 21.1 mmol, 1.1.0 equiv) at 0 °C and the resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M-1] - :386

[0489] Preparation of methyl 3-bromo-6-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylate. To a solution of methyl 3-bromo-6-iodo-4H-thieno[3,2-b]pyrrole-5-carboxylate (7 g, 18.1 mmol, 1.0 eq) in DMF (40 mL) was added Zn(CN)2 (1.28 g, 10.8 mmol, 0.6 eq), XantPhos-Pd-G4 (1.61 g, 1.81 mmol, 0.10 eq) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was filtered and extracted with EtOAc. The combined organic layers were washed with 4% 4H-thieno[3,2-b]pyrrole, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M-1] - :285

[0490] Preparation of 3-bromo-6-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylic acid. To a solution of methyl 3-bromo-6-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylate (3.4 g, 11.9 mmol, 1.0 eq) in THF (28 mL), MeOH (14 mL) and H2O (20 mL) was added LiOH-H2O (8.01 g, 190 mmol, 16 eq) and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature, washed with EtOAc, and adjusted to pH 3 with 2M HCl(aq). The precipitated solid was collected by filtration and washed with water to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :271

[0491] Preparation of 3-bromo-4H-thieno[3,2-b]pyrrole-6-carbonitrile. To a solution of 3-bromo-6-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (744 mg, 2.74 mmol, 1.0 eq.) in quinoline (40 mL) was added Cu (34.9 mg, 0.549 mmol, 0.2 eq.) and the resulting mixture was stirred at 160 ° C under microwave irradiation for 20 min. The reaction mixture was diluted with 2M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :227

[0492] Preparation of 3-[(diphenylmethylene)amino]-4H-thieno[3,2-b]pyrrole-6-carbonitrile. To a solution of 3-bromo-4H-thieno[3,2-b]pyrrole-6-carbonitrile (300 mg, 1.32 mmol, 1.0 equiv) in THF (6 mL) was added t-BuXPhos-Pd-G3 (104 mg, 0.132 mmol, 0.10 equiv), t-BuONa (380 mg, 3.96 mmol, 3 equiv) and benzophenone imine (478 mg, 2.64 mmol, 2 equiv) and the resulting mixture was stirred at 85 °C under nitrogen atmosphere for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :328

[0493] Preparation of 3-amino-4H-thieno[3,2-b]pyrrole-6-carbonitrile. To a solution of 3-[(diphenylmethylene)amino]-4H-thieno[3,2-b]pyrrole-6-carbonitrile (1.3 g, 3.97 mmol, 1.0 eq) in THF (13 mL) was added 2.0 M HCl(aq) (13 mL, 26 mmol, 6.5 eq) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :164.

[0494] Preparation of 2-(7-amino-1H-indol-3-yl)acetonitrile

[0495]

[0496] Preparation of N,N-dimethyl-1-(7-nitro-1H-indol-3-yl)methylamine. To a solution of [(dimethylamino)methyl]dimethylamine (1.39 g, 13.6 mmol, 1.1 eq.) in AcOH (30 mL) was added 7-nitroindole (2.0 g, 12.3 mmol, 1.0 eq.) in AcOH (30 mL) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 3.5 h. The reaction mixture was quenched with NaOH and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M-1] - :220

[0497] Preparation of 2-(7-nitro-1H-indol-3-yl)acetonitrile. To a solution of N,N-dimethyl-1-(7-nitro-1H-indol-3-yl)methanamine (300 mg, 1.36 mmol, 1.0 eq.) in DMF (0.3 mL), H2O (0.3 mL) and THF (15 mL) was added MeI (485 mg, 3.42 mmol, 2.5 eq.) and the resulting mixture was stirred at 70 °C under nitrogen atmosphere for 15 min. To the mixture was added NaCN (335 mg, 6.84 mmol, 5 eq.) and the resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered, washed with THF, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M-1] - :202

[0498] Preparation of 2-(7-amino-1H-indol-3-yl)acetonitrile. To a solution of 2-(7-nitro-1H-indol-3-yl)acetonitrile (250 mg, 1.24 mmol, 1.0 equiv) in EtOH (7.5 mL) and H2O (2.5 mL) was added NH4Cl (664 mg, 12.4 mmol, 10 equiv) and Zn (812 mg, 12.4 mmol, 10 equiv) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. The reaction mixture was filtered, washed with EtOH and concentrated under reduced pressure. The residue was dissolved in water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M-1] - :172

[0499] Example 3: Preparation of specific final compounds

[0500] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(dimethylphosphoryl)thiazole-2-sulfonamide (Compound 111)

[0501]

[0502] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(dimethylphosphoryl)thiazole-2-sulfonamide. To a solution of 5-bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide (200 mg, 0.50 mmol, 1 eq) and (methylphosphonyl)methane (197 mg, 2.51 mmol, 5 eq) in DMF (10 mL) was added Pd(OAc)2 (11.3 mg, 0.05 mmol, 0.10 eq), XantPhos (29.0 mg, 0.050 mmol, 0.1 eq) and K3PO4 (160.29 mg, 0.754 mmol, 1.5 eq) and the resulting mixture was stirred under microwave irradiation at 95 °C for 1.5 min. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 395, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.13(d,J=3.1Hz,1H),10.94(s,1H),8.44(d,J=3.3Hz,1H),8.22(d ,J=3.1Hz,1H),6.86(d,J=7.8Hz,1H),6.72(d,J=7.7Hz,1H),2.61(s,3H),1.83(d,J=14.1Hz,6H).

[0503] Preparation of N-(3-cyano-1H-indol-7-yl)-2-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-imidazole-5-sulfonamide (Compound 394)

[0504]

[0505] Preparation of 2-bromo-1-methylimidazole-4-sulfonyl chloride. A solution of 2-bromo-1-methylimidazole (2 g, 12.4 mmol, 1 equivalent) in HSO3Cl (16.0 mL) was stirred overnight at 130 ° C under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :259, 1 HNMR (300MHz, DMSO-d6, ppm) δ7.76 (s, 1H), 3.69 (s, 3H).

[0506] Preparation of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-methylimidazole-4-sulfonamide.To the stirred mixture of 7-amino-1H-indole-3-carbonitrile (350mg, 2.22mmol, 1 equivalent) in THF (10mL), 2-bromo-1-methylimidazole-4-sulfonyl chloride (636mg, 2.45mmol, 1.10 equivalents) and pyridine (528mg, 6.70mmol, 3 equivalents) were added and the resulting mixture was stirred for 1h at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was used without further purification. LCMS[M+1] + :380

[0507] Preparation of 2-bromo-N-(3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-1-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-sulfonamide. To a stirred mixture of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-methylimidazole-4-sulfonamide (1 g, 2.63 mmol, 1 eq) in THF (20.0 mL) at 0°C under nitrogen atmosphere was added NaH (158 mg, 6.58 mmol, 2.50 eq) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 min. To the mixture was added SEM-Cl (965 mg, 5.79 mmol, 2.20 eq) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :N / A

[0508] Preparation of 2-(2-(benzyloxy)-2-methylpropoxy)-N-(3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-1-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-sulfonamide. To a solution of 2-(benzyloxy)-2-methylpropan-1-ol (281 mg, 1.56 mmol, 2 eq) in THF (10.0 mL) was added NaH (37.5 mg, 1.56 mmol, 2 eq) at 0 °C and the resulting mixture was stirred at 80 °C under nitrogen atmosphere for 10 min. To the mixture was added 2-bromo-N-(3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-1-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-sulfonamide (500 mg, 0.780 mmol, 1 eq) in THF (1 mL) and the resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS [M+1] + :740

[0509] Preparation of N-(3-cyano-1H-indol-7-yl)-2-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-imidazole-5-sulfonamide. To a solution of 2-(2-(benzyloxy)-2-methylpropoxy)-N-(3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-1-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-sulfonamide (200 mg, 0.33 mmol, 1 eq) in TBAF (2 mL, 1 M in THF) was added 1,2-ethylenediamine (29.6 mg, 0.49 mmol, 1.50 eq) and the resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. TFA (6 mL) was added to the crude residue and the resulting mixture was stirred at 75 °C under a nitrogen atmosphere for 0.5 h. The reaction mixture was concentrated under vacuum. The crude residue was purified by reverse phase flash chromatography to give the title compound. LCMS (ES, m / z): [M+1] + :390, 1H NMR(400MHz,DMSO-d6,ppm)δ11.92(s,1H),10.21(s,1H),8.14(s,1H),7.32(s,1H),7.16- 7(m,2H),6.91(dd,J=7.7,1.0Hz,1H),4.71(s,1H),4.05(s,2H),3.44(s,3H),1.14(s,6H).

[0510] Preparation of methyl 2-(5-(chlorosulfonyl)-2-oxothiazol-3(2H)-yl)acetate

[0511]

[0512] Preparation of 5-(benzylsulfanyl)-1,3-thiazol-2-ol. To a solution of 5-(benzylsulfanyl)-2-methoxy-1,3-thiazole (1 g, 4.21 mmol, 1 eq) in EtOAc (10 mL) was added 4M HCl (10 mL, 40 mmol, 10 eq) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :224

[0513] Preparation of methyl 2-[5-(benzylsulfanyl)-2-oxo-1,3-thiazol-3-yl]acetate. To a solution of 5-(benzylsulfanyl)-1,3-thiazol-2-ol (860 mg, 3.85 mmol, 1 eq) in acetone (20 mL) was added methyl 2-bromoacetate (706 mg, 4.62 mmol, 1.2 eq) and Cs2CO3 (1.88 g, 5.77 mmol, 1.5 eq) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :296

[0514] Preparation of methyl 2-[5-(chlorosulfonyl)-2-oxo-1,3-thiazol-3-yl]acetate. To a solution of methyl 2-[5-(benzylsulfanyl)-2-oxo-1,3-thiazol-3-yl]acetate (900 mg, 3.04 mmol, 1 eq) in DCM (5 mL) and H2O (16 mL) was added 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (778 mg, 3.35 mmol, 1.5 eq) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :272

[0515] Preparation of N-(3-cyano-1H-indol-7-yl)thiazole-5-sulfonamide (Compound 50)

[0516]

[0517] Preparation of 5-(benzylsulfanyl)-1,3-thiazole. To a solution of 5-bromo-1,3-thiazole (30 g, 184 mmol, 1 eq.) in dioxane (600 mL) was added benzyl mercaptan (27 g, 219 mmol, 1.2 eq.), DIPEA (71 g, 552 mmol, 3 eq.), XantPhos (10.6 g, 18.3 mmol, 0.10 eq.) and Pd2(dba)3 (8.37 g, 9.15 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the product (38 g, 92%). LCMS (ES, m / z): [M+1] + :208

[0518] Preparation of thiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-1,3-thiazole (30 g, 145 mmol, 1 eq.) in MeCN (300 mL), AcOH (17 mL) and H2O (13 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (43 g, 217 mmol, 1.50 eq.) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS ES, m / z: [M+Aniline+1]+ :240

[0519] Preparation of N-(3-cyano-1H-indol-7-yl)-1,3-thiazole-5-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (15g, 95.4mmol, 1 equivalent) in DCM (300mL) was added pyridine (23g, 286mmol, 3 equivalents) and 1,3-thiazole-5-sulfonyl chloride (21g, 115mmol, 1.2 equivalents) in DCM (150mL) at 0°C and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the title compound (10g, 34%). LCMS ES, m / z:[M+1] + :305, 1 H NMR-PH-ROP-2021-03-259-0:(300MHz,DMSO-d 6, ppm)δ12.01(s,1H),10.49(s,1H),9.34(d,J=0.9Hz,1H),8.27-8.18(m,2H) ,7.53(d,J=7.9Hz,1H), 7.16(t,J=7.8Hz,1H), 6.86(dd,J=7.6,1.0Hz,1H). 13 C NMR-PH-ROP-2021-03-259-0: (75MHz, DMSO-d6, ppm) δ161.28,147.82,136.7 2,135.54,131.25,129.04,122.52,122.33,119.33,117.69,116.35,85.42.

[0520] Preparation of N-(3-cyano-1H-indol-7-yl)-2-oxo-2,3-dihydrothiazole-5-sulfonamide (Compound 353)

[0521]

[0522] Preparation of N-(3-cyano-1H-indol-7-yl)-2-methoxythiazole-5-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (200 mg, 1.27 mmol, 1 eq.) and pyridine (301 mg, 3.81 mmol, 3 eq.) in DCM (4 mL) was added 2-methoxy-1,3-thiazole-5-sulfonyl chloride (326 mg, 1.52 mmol, 1.2 eq.) at 0 ° C. and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was quickly purified by reverse phase to give the product. LCMS: (ES, m / z): [M+1] + :335, 1 HNMR(300MHz,DMSO-d6,ppm)δ11.98(s,1H),10.36(s,1H),8.22(d,J=3.1Hz,1H),7 .61-7.47(m,2H),7.18(t,J=7.8Hz,1H),6.97(dd,J=7.6,1.1Hz,1H),4.06(s,3H).

[0523] Preparation of N-(3-cyano-1H-indol-7-yl)-2-oxo-2,3-dihydrothiazole-5-sulfonamide. A solution of N-(3-cyano-1H-indol-7-yl)-2-methoxy-1,3-thiazole-5-sulfonamide (150mg, 0.449mmol, 1 equivalent) in concentrated HCl (3mL) was stirred for 30min at room temperature. The reaction mixture was neutralized to pH 7 with saturated Na2CO3 and extracted with EtOAc (2x 5mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude residue was quickly purified by reverse phase to give the product. LCMS (ES, m / z): [M+1] + :319, 1 H NMR (400MHz, DMSO-d6, ppm) δ11.84-12.33 (s, 2H), 10.30 (s, 1H), 8.22 (dd, J = 3.1, 1.7 Hz,1H),7.56-7.45(m,2H),7.20(td,J=7.8,1.7Hz,1H),7.04(dt,J=7.6,1.3Hz,1H).

[0524] Preparation of N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-imidazole-4-sulfonamide (Compound 408)

[0525]

[0526] Preparation of 2-bromo-1H-imidazole-4-sulfonyl chloride. A solution of 2-bromo-1H-imidazole (8 g, 54.4 mmol, 1.0 equiv) in HSO3Cl (80 mL) was stirred at 130 ° C for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :245

[0527] Preparation of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1H-imidazole-4-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (1 g, 6.36 mmol, 1.0 equiv) and pyridine (1.51 g, 19.0 mmol, 3 equiv) in DCM (10 mL) was added 2-bromo-1H-imidazole-4-sulfonyl chloride (2.34 g, 9.54 mmol, 1.5 equiv) in DCM (10 mL) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :366

[0528] Preparation of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)imidazole-4-sulfonamide. To a solution of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1H-imidazole-4-sulfonamide (1g, 2.73mol, 1.0 equivalent) in DMF (20mL) was added KCO (1.13g, 8.19mmol, 3 equivalents) and 2,2-dimethyloxirane (0.39g, 5.46mmol, 2 equivalents) and the resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product.

[0529] . LCMS: (ES) m / z: [M+1] + :438,HNMR:(300MHz,DMSO-d 6,ppm)δ11.93(s,1H),9.64(s,1H),8.20(s,1H),7.72(s,1H),7.41(dd,J=8.0,1.0Hz,1H),7 .08(t,J=7.8Hz,1H),6.91(dd,J=7.7,1.0Hz,1H),4.83(s,1H),3.85(s,2H),0.99(s,6H).

[0530] Preparation of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-sulfonamide. To a solution of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)imidazole-4-sulfonamide (460mg, 1.05mol, 1.0 equivalent) in DCM (20mL), Et3N (318mg, 3.15mmol, 3 equivalents) and SEM-Cl (524mg, 3.15mmol, 3 equivalents) were added and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :568

[0531] Preparation of 2-(benzyloxy)-N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydroimidazole-4-sulfonamide. To a solution of benzyl alcohol (608 mg, 5.63 mmol, 5 eq.) in THF (10 mL) was added NaH (135 mg, 5.63 mmol, 5 eq.) and 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-sulfonamide (640 mg, 1.12 mmol, 1.0 eq.) in THF (10 mL) at 0°C and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :598

[0532] Preparation of N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)-2-oxo-3H-imidazole-4-sulfonamide. A solution of 2-(benzyloxy)-N-(3-cyano-1H-indol-7-yl)-1-(2-hydroxy-2-methylpropyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydroimidazole-4-sulfonamide (130 mg, 0.217 mmol, 1.0 equiv) in TFA (4 mL) was stirred at 60 ° C under a nitrogen atmosphere for 30 min. The reaction mixture was concentrated under vacuum. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :376, 1 H NMR (400MHz, DMSO-d6, ppm) δ11.97-11.92(m,1H),11.01(s,1H),9.89(s,1H),8.24(s,1H),7.47(d,J=8.0 Hz,1H),7.15(t,J=7.8Hz,1H),7.03(s,1H),6.98(d,J=7.6Hz,1H),4.64(s,1H),3.39(s,2H),0.96(s,6H).

[0533] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-2-ethyl-1H-imidazole-4-sulfonamide (Compound 8)

[0534]

[0535] Preparation of 2-ethyl-1H-imidazole-4-sulfonyl chloride. Chlorosulfonic acid (80 mL) was added to a solution of 2-ethyl-1H-imidazole (20 g, 208 mmol, 1.0 equiv) in CHCl3 (1.6 L) and the resulting mixture was stirred overnight at reflux under a nitrogen atmosphere. SOCl2 (600 mL), DMF (3 drops, catalyst) were added to the mixture and the resulting mixture was stirred for another 2 h at 100 ° C. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :195

[0536] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-2-ethyl-1H-imidazole-4-sulfonamide. To a solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (7g, 40.9mmol, 1 eq) and pyridine (7.32g, 122mmol, 3 eq) in DCM (100mL) was added 2-ethyl-1H-imidazole-4-sulfonyl chloride (9.56g, 49.0mmol, 1.2 eq) in DCM (40mL) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :330, 1 H NMR: (400MHz, DMSO-d6, ppm) δ12.41 (s, 1H), 12.16-12.11 (m, 1H), 9.77 (s, 1H), 8.20 (d, J = 3.0Hz, 1 H), 7.55 (d, J = 1.7Hz, 1H), 6.81 (s, 2H), 2.65 (q, J = 7.6Hz, 2H), 2.57 (s, 3H), 1.20 (t, J = 7.6Hz, 3H).

[0537] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-4-(trifluoromethyl)-1,3-thiazole-2-sulfonamide (Compound 12)

[0538]

[0539] Preparation of 2-(benzylsulfanyl)-4-(trifluoromethyl)-1,3-thiazole. To a solution of 2-bromo-4-(trifluoromethyl)-1,3-thiazole (15.0 g, 64.6 mmol, 1.0 eq.) in DMF (300 mL) was added benzyl mercaptan (9.64 g, 77.5 mmol, 1.2 eq.) and K2CO3 (13.4 g, 96.9 mmol, 1.5 eq.) and the resulting mixture was stirred at room temperature for another 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] + :276

[0540] Preparation of 4-(trifluoromethyl)-1,3-thiazole-2-sulfonyl chloride. To a solution of 2-(benzylsulfanyl)-4-(trifluoromethyl)-1,3-thiazole (13.0 g, 47.2 mmol, 1.00 equiv) in AcOH (260 mL) and H2O (26 mL) was added NCS (25.2 g, 188 mmol, 4.0 equiv) in portions and the resulting mixture was stirred at room temperature for another 2 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product (12 g, 87% yield), which was used without further purification. LCMS (ES, m / z): [M+1] + :252

[0541] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-4-(trifluoromethyl)-1,3-thiazole-2-sulfonamide. To a solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (7g, 40.9mmol, 1.0 equiv) in DCM (140mL) was added dropwise pyridine (16.2g, 204mmol, 5.0 equiv) and 4-(trifluoromethyl)-1,3-thiazole-2-sulfonyl chloride (11.3g, 44.9mmol, 1.1 equiv) in DCM (5mL) at 0°C and the resulting mixture was stirred at room temperature for another 1h. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :387, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.23 (d, J = 3.1Hz, 1H), 11.02 (s, 1H), 8.85 (s, 1H), 8.25(d,J=3.1Hz,1H), 6.86(d,J=7.7Hz,1H), 6.60(d,J=7.6Hz,1H), 2.61(s,3H).

[0542] Preparation of N-(3-chloro-4-fluoro-1H-indol-7-yl)-4-(trifluoromethyl)-1,3-thiazole-2-sulfonamide (Compound 159)

[0543]

[0544] Preparation of 3-chloro-4-fluoro-7-nitro-1H-indole. To a solution of 4-fluoro-7-nitro-1H-indole (1 g, 5.55 mmol, 1 eq.) in DMF (20 mL) was added NCS (815 mg, 6.10 mmol, 1.1 eq.) and the resulting mixture was stirred at 65 ° C under a nitrogen atmosphere for 3 h. The crude residue was purified by trituration with water. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :214.

[0545] Preparation of 3-chloro-4-fluoro-1H-indole-7-amine. To a solution of 3-chloro-4-fluoro-7-nitro-1H-indole (1.1 g, 5.12 mmol, 1 equivalent) in EtOH (55 mL), Raney nickel (1.1 g, 100% wt) and hydrazine hydrate (0.40 g, 10.2 mmol, 2.0 equivalents, 80% solution) were added and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was filtered, the filter cake was washed with EtOH, and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :185.

[0546] Preparation of N-(3-chloro-4-fluoro-1H-indol-7-yl)-4-(trifluoromethyl)-1,3-thiazole-2-sulfonamide. To a solution of 3-chloro-4-fluoro-1H-indol-7-amine (150 mg, 0.81 mmol, 1.0 equiv) in DCM (3 mL) was added pyridine (146 mg, 2.43 mmol, 3.0 equiv) and 4-(trifluoromethyl)-1,3-thiazole-2-sulfonyl chloride (245 mg, 0.97 mmol, 1.2 equiv) in DCM (0.5 mL) dropwise at 0 ° C and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :400, 1 H NMR (300 MHz, DMSO-d 6, ppm) δ 11.69 (s, 1H), 10.96 (s, 1H), 8.86 (s, 1H), 7.54 (d, J = 2.7Hz, 1H), 6.76 (dd, J = 10.8, 8.3Hz, 1H), 6.59 (dd, J = 8.4, 4.3Hz, 1H).

[0547] Preparation of N-(3-cyano-4-ethyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide (Compound 216)

[0548]

[0549] Preparation of N-(4-bromo-3-cyano-1H-indol-7-yl)-2,2,2-trifluoroacetamide. Chlorosulfonyl isocyanate (3.50 g, 24.4 mmol, 3.00 equiv) was added dropwise to a solution of N-(4-bromo-1H-indol-7-yl)-2,2,2-trifluoroacetamide (2.50 g, 8.14 mmol, 1.0 equiv) in DMF (50 mL) at 0 ° C and the resulting mixture was stirred at 0 ° C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :332

[0550] Preparation of N-(3-cyano-4-ethyl-1H-indol-7-yl)-2,2,2-trifluoroacetamide. To a solution of N-(4-bromo-3-cyano-1H-indol-7-yl)-2,2,2-trifluoroacetamide (1.00 g, 3.01 mmol, 1.0 equiv) in THF (20 mL) was added diethylzinc (1.12 g, 9.03 mmol, 3.0 equiv) and Pd(dppf)Cl2 (0.11 g, 0.15 mmol, 0.05 equiv) and the resulting mixture was stirred at 70 ° C under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :282

[0551] Preparation of 7-amino-4-ethyl-1H-indole-3-carbonitrile. To a solution of N-(3-cyano-4-ethyl-1H-indole-7-yl)-2,2,2-trifluoroacetamide (750 mg, 2.66 mmol, 1.0 eq.) and NH3(g) in MeOH (8 mL) was added and the resulting mixture was stirred at room temperature for 3 days. The resulting mixture was concentrated under vacuum to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :186

[0552] Preparation of N-(3-cyano-4-ethyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide. To a solution of 7-amino-4-ethyl-1H-indole-3-carbonitrile (200 mg, 1.08 mmol, 1.0 equiv) in DCM (2 mL) was added dropwise pyridine (257 mg, 3.24 mmol, 3.0 equiv) and 1,3-thiazole-2-sulfonyl chloride (238 mg, 1.29 mmol, 1.2 equiv) in DCM (2 mL) at 0 ° C. and the resulting mixture was stirred for another 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :333, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.13(d,J=3.2Hz,1H),10.74(s,1H),8.23(d,J=3.1Hz,1H),8.13(s ,2H),6.87(d,J=7.8Hz,1H),6.69(d,J=7.8Hz,1H),2.98(q,J=7.5Hz,2H),1.24(t,J=7.5Hz,3H).

[0553] Preparation of N-(3-cyano-1H-indazol-7-yl)-1,3-thiazole-5-sulfonamide (Compound 244)

[0554] Preparation of 1,3-thiazole-5-sulfonyl chloride. To a solution of 5-bromo-1,3-thiazole (1.5 g, 9.14 mmol, 1.0 equiv) in toluene (15 mL) was added iPrMgCl-LiCl (9.1 mL, 11.9 mmol, 1.3 equiv, 1.3 M in THF) dropwise at -20 ° C and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. SO2Cl2 (1.11 mL, 13.7 mmol, 1.5 equiv) in toluene (15 mL) was added dropwise to the reaction mixture at 0 ° C and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :184.

[0555] Preparation of N-(3-cyano-1H-indazole-7-yl)-1,3-thiazole-5-sulfonamide. Pyridine (225 mg, 2.84 mmol, 3.0 equivalents) and 1,3-thiazole-5-sulfonyl chloride (348 mg, 1.89 mmol, 2.0 equivalents) were added dropwise to a solution of 7-amino-1H-indazole-3-carbonitrile (150 mg, 0.94 mmol, 1.0 equivalents) in DCM (3 mL) at 0 ° C. and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :306, 1 H NMR-PH-ROP-2021-03-340-0:(400MHz,DMSO-d 6, ppm) δ14.38(s,1H),10.76(s,1H),9.38(s,1H),8.23(s,1H),7.79(d,J=8.2Hz,1H),7.30(t,J=7.8Hz,1H),6.99(d,J=7.4Hz,1H).

[0556] Preparation of N-(3-cyano-1H-indol-7-yl)-3-methyl-1,2-thiazole-5-sulfonamide (Compound 256)

[0557]

[0558] Preparation of 5-(benzylsulfanyl)-3-methyl-1,2-thiazole. To a solution of 5-bromo-3-methyl-1,2-thiazole (15 g, 84.2 mmol, 1.0 equiv) in dioxane (300 mL) was added benzyl mercaptan (12.5 g, 101 mmol, 1.2 equiv), DIPEA (32.5 g, 252 mmol, 3.0 equiv), XantPhos (4.87 g, 8.42 mmol, 0.1 equiv) and Pd2(dba)3 (3.86 g, 4.21 mmol, 0.05 equiv) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product. LCMS: (ES, m / z): [M+1] + :222

[0559] Preparation of 3-methyl-1,2-thiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-3-methyl-1,2-thiazole (18 g, 85.8 mmol, 1.0 eq) in DCM (108 mL) and H2O (324 mL) was added trichloroisocyanuric acid (29.9 g, 129 mmol, 1.5 eq) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, the filter cake was washed with DCM, and the filtrate was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification.

[0560] Preparation of N-(3-cyano-1H-indol-7-yl)-3-methyl-1,2-thiazole-5-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (9.0 g, 57.2 mmol, 1.0 equiv) in DCM (180 mL) was added pyridine (13.6 g, 172 mmol, 3.0 equiv) and 3-methyl-1,2-thiazole-5-sulfonyl chloride (12.4 g, 63.0 mmol, 1.1 equiv) at 0 ° C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1] + :319, 1 H NMR (300MHz, DMSO-d6, ppm) δ12.07 (s, 1H), 10.70 (s, 1H), 8.24 (d, J = 3.1Hz, 1H), 7 .60-7.51(m,2H),7.17(t,J=7.8Hz,1H),6.88(dd,J=7.7,1.0Hz,1H),2.44(s,3H).

[0561] Preparation of N-(3-cyano-1H-indol-7-yl)-2-cyclopropyl-1,3-oxazole-5-sulfonamide (Compound 107)

[0562]

[0563] Preparation of tert-butyl N-[2-(benzylsulfanyl)-2-oxoethyl]carbamate. To a solution of (tert-butoxycarbonyl)glycine (60 g, 0.34 mol, 1.0 equiv) in DMF (1.2 L) was added DIPEA (133 g, 1.03 mol, 3.0 equiv), benzyl mercaptan (51.0 g, 0.41 mol, 1.2 equiv) and T3P (327 g, 0.51 mol, 1.5 equiv, 50% EtOAc solution) and the resulting mixture was stirred overnight at 100 ° C under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :282

[0564] Preparation of S-benzyl 2-aminothioacetate. A solution of tert-butyl N-[2-(benzylsulfanyl)-2-oxoethyl]carbamate (200 g, 0.71 mol, 1.0 equiv) in HCl / dioxane (4 L, 4 M, 4.0 5.7 equiv) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :182

[0565] Preparation of N-[2-(Benzylsulfanyl)-2-oxoethyl]cyclopropanecarboxamide. To a solution of S-benzyl 2-aminothioacetate (98 g, 0.34 mol, 1.0 eq.) in DCM (1 L) was added Et3N (104 g, 1.03 mol, 3.0 eq.) and cyclopropanecarbonyl chloride (42.7 g, 0.41 mol, 1.2 eq.) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :250

[0566] Preparation of 5-(benzylsulfanyl)-2-cyclopropyl-1,3-oxazole. A solution of N-[2-(benzylsulfanyl)-2-oxoethyl]cyclopropanecarboxamide (22.7 g, 0.091 mol, 1.0 equiv) and POCl3 (230 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :232

[0567] Preparation of 2-cyclopropyl-1,3-oxazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-2-cyclopropyl-1,3-oxazole (20 g, 86 mmol, 1.0 eq) (450-2) in AcOH (265 mL) and H2O (135 mL) was added NCS (40.4 g, 303 mol, 3.5 eq) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :207

[0568] Preparation of N-(3-cyano-1H-indol-7-yl)-2-cyclopropyl-1,3-oxazole-5-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (8.0 g, 51 mmol, 1.0 equiv) in DCM (120 mL) was added pyridine (120 mL) and 2-cyclopropyl-1,3-oxazole-5-sulfonyl chloride (12.7 g, 611 mmol, 1.2 equiv) in DCM (20 mL) at 0 ° C. and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :329, 1 HNMR (400MHz, DMSO-d6, ppm) δ12.09(d,J=3.2Hz,1H),10.63(s,1H),8.25(d,J=3.1Hz,1H),7.60-7.51(m,2H),7.18(t, J=7.8Hz,1H),6.85(dd,J=7.6,0.9Hz,1H),2.19(tt,J=8.4,4.8Hz,1H),1.13(dt,J=8.4,3.5Hz,2H),0.98-0.89(m,2H).

[0569] Preparation of N-(3-cyano-1H-indol-7-yl)-4-(hydroxymethyl)thiophene-2-sulfonamide (Compound 306)

[0570]

[0571] Preparation of [5-(benzylsulfanyl)thiophen-3-yl]methanol. To a solution of (5-bromothiophen-3-yl)methanol (600 mg, 3.1 mmol, 1.0 eq.) in dioxane (12 mL) were added XantPhos (179 mg, 0.311 mmol, 0.1 eq.), dioxane (12 mL), DIPEA (1.20 g, 9.32 mmol, 3 eq.), benzylthiol (462 mg, 3.73 mol, 1.2 eq.) and Pd2(dba)3 (142 mg, 0.155 mmol, 0.05 eq.) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1]+: 237

[0572] Preparation of 4-(hydroxymethyl)thiophene-2-sulfonyl chloride. To a solution of [5-(benzylsulfanyl)thiophene-3-yl]methanol (500 mg, 2.1 mmol, 1.0 equiv) in AcOH (10 mL) and H2O (1 mL) was added NCS (847 mg, 6.34 mmol, 3.0 equiv) at 0°C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :213

[0573] Preparation of N-(3-cyano-1H-indol-7-yl)-4-(hydroxymethyl)thiophene-2-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (150 mg, 0.95 mmol, 1.0 equiv) in DCM (4 mL) was added pyridine (226 mg, 2.86 mmol, 3.0 equiv) and 4-(hydroxymethyl)thiophene-2-sulfonyl chloride (243 mg, 1.14 mmol, 1.2 equiv) at 0 ° C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M-1] - :332, 1HNMR (400MHz, DMSO-d6, ppm) δ11.97-11.90 (m, 1H), 10.26 (s, 1H), 8.22 (d, J = 2.7Hz, 1H), 7.64 (d, J = 1.6Hz, 1H), 7. 52-7.41(m,2H),7.14(t,J=7.8Hz,1H),6.90(dd,J=7.7,0.9Hz,1H),5.27(t,J=5.8Hz,1H),4.39(d,J=5.6Hz,2H).

[0574] Preparation of N-(3-cyano-4-fluoro-1H-indol-7-yl)-3-methyl-1,2-oxazole-5-sulfonamide (Compound 354)

[0575]

[0576] Preparation of 5-(benzylthio)-3-methylisoxazole. To a solution of 5-bromo-3-methylisoxazole (200 mg, 1.23 mmol, 1.0 equiv) in dioxane (4 mL) was added benzyl mercaptan (184 mg, 1.48 mmol, 1.2 equiv), Pd2(dba)3 (114 mg, 0.12 mmol, 0.1 equiv), XantPhos (142 mg, 0.24 mmol, 0.2 equiv) and DIPEA (319 mg, 2.40 mmol, 2.0 equiv) and the resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography to give the product. LCMS: (ES, m / z): [M+1]+: 192

[0577] Preparation of 3-methylisoxazole-5-sulfonyl chloride. To a solution of 5-(benzylthio)-3-methylisoxazole (110 mg, 0.53 mmol, 1.0 eq.) in MeCN (1.1 mL), AcOH (0.11 mL) and H2O (0.11 mL) was added NCS (85.8 mg, 0.64 mmol, 1.2 eq.) at 0°C and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :182

[0578] Preparation of N-(3-cyano-4-fluoro-1H-indol-7-yl)-3-methyl-1,2-oxazole-5-sulfonamide. To a solution of 3-methyl-1,2-oxazole-5-sulfonyl chloride (124 mg, 0.68 mmol, 2.0 equiv) in THF (1.2 mL) was added 7-amino-4-fluoro-1H-indole-3-carbonitrile (60 mg, 0.343 mmol, 1.0 equiv) and pyridine (81.3 mg, 1.03 mmol, 3.0 equiv) at 0 ° C. and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by preparative reverse phase chromatography to give the product. LCMS (ES, m / z): [M+1] + :321, 1 H NMR (300MHz, DMSO-d6, ppm) δ 12.56 (s, 1H), 11.00 (s, 1H), 8.33 (d, J = 2.9Hz, 1H), 6.97 (d, J = 9.1Hz, 2H), 6.75 (dd, J = 8.5, 4.3Hz, 1H), 2.29 (s, 3H). 19 F NMR (300MHz, DMSO-d6, ppm) δ-124.8.

[0579] Preparation of N-(3-cyano-4-methyl-1H-indazol-7-yl)-1,3-thiazole-5-sulfonamide (Compound 342)

[0580]

[0581] To a solution of 7-amino-4-methyl-1H-indazole-3-carbonitrile (300 mg, 1.74 mmol, 1.0 equiv) in THF (3 mL) and DCM (3 mL) was added pyridine (689 mg, 8.71 mmol, 5.0 equiv) and 1,3-thiazole-5-sulfonyl chloride (383 mg, 2.09 mmol, 1.2 equiv) at 0 ° C. and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography to give the product. LCMS (ES, m / z): [M+1] + :320, 1 H NMR (400MHz, DMSO-d6, ppm) δ14.36 (s, 1H), 10.60 (s, 1H), 9.38 (d, J = 0.9Hz, 1H), 8.20 ( d, J=0.9Hz, 1H), 7.02 (dd, J=7.5, 1.1Hz, 1H), 6.81 (d, J=7.5Hz, 1H), 2.68-2.64 (m, 3H).

[0582] Table B : Synthetic procedures of the compounds disclosed herein

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638] Example 3- Targeted RBM39 degradation assay

[0639] Molecular glue enhances the efficient formation of a complex between the RBM39 protein and DCAF15, a substrate recognition subunit of the E3 ubiquitin ligase complex, which is believed to lead to the subsequent ubiquitination and proteasomal degradation of the RBM39 protein. To confirm the ubiquitin- and proteasomal-dependent degradation of RBM39 by the compounds disclosed herein, OVCAR3 cells were cultured for 6 h with 1 μM of the compound and with and without 5 μM of MG132 (a proteasomal degrader) and 0.3 uM of Pevonedistat (MLN4924) class ubiquitination inhibitors. 50 μg of protein / sample was loaded per lane of SDS PAGE gel and the proteins were transferred to PVDF membranes using the iBlot2 dry blotting system high MW protocol: 10 min at 2.5 A, up to 25 V. The membranes were blocked in TBST / 5% BSA for 1 hour at room temperature with shaking at 100 rpm. The membrane was probed with rabbit antibodies (RBM39 and β-actin: 1 to 4000) diluted 1:1000 in TBST / 5% milk with shaking at 100 rpm, and probed with fluorescent secondary antibodies conjugated with 800nm ​​and anti-B-actin (CST, #3700 mouse antibody, diluted 1:4000) as loading controls. The membrane was washed with 1xTBST at room temperature for 4X5mins, incubated with linked secondary antibodies anti-rabbit IgG antibody HRP (1 to 10000 dilution) and IRDye680 anti-mouse antibody (1 to 10000 dilution), and then diluted in TBST / 5% milk for 1h at room temperature. The membrane was washed in TBST for 5min×4 times. The loading control protein and target protein bands were analyzed after rinsing the membrane once with TBS, and the band signals were quantified.

[0640] Example 4- CellTiter-Glo Assay for Evaluating the Effects of RBM39 Degraders on Cell Viability and Proliferation in Vitro:

[0641] The CellTiter-Glo assay was used to evaluate the cytotoxicity of compounds on cell proliferation in OVCAR3, SK-N-SH, SK-N-AS, Kelly, IMR32, SK-N-BE-2C cell lines. Cells were harvested into cell culture medium and counted. Cells were diluted with culture medium to the cell density listed in the table below and 50 μL of cell suspension was added to each well of a 384-well cell culture plate, except for the low concentration control cells. For the low concentration control wells, 50 μL of phosphate buffered saline was added.

[0642] serial number Cell lines Cells / well 1 SK-N-SH 4K 2 SK-N-AS 6K 3 Kelly 4K 4 IMR32 5k / 10K 5 SKNBE2C 2K 6 OVCAR3 2K / 4K / 8K

[0643] The plates were covered and incubated at room temperature for 30 minutes without shaking, then incubated overnight at 37°C and 5% CO2 for cell attachment. Test compounds were dissolved to prepare 10 mM DMSO stock solutions. Aliquots of 10 μL of the stock solution were placed in 384LDV plates and 3-fold 11-point dilutions were made by transferring 4 μL of compound into 8 μL of DMSO.

[0644] Next, transfer 50 nL of diluted compound to the cell plate at a final concentration of 10 μM. Prepare a high concentration control with 50 nL DMSO. Spin the plate at 1,000 RPM for 1 minute at room temperature.

[0645] After 72 hours of compound treatment, the plates were removed from the incubator and equilibrated at room temperature for 15 minutes. Next, 40 μL of CellTiter-Glo reagent (1:1 with culture medium) was added to each well, the plates were incubated at room temperature for 30 minutes, and then read.

[0646] Example 5- DCAF15-RBM39 complex formation assay:

[0647] The TR-FRET assay was used to evaluate the effects of the compounds disclosed herein on the interaction between RBM39 and the DCAF15 complex. The test compounds were dissolved to form a 10 mM DMSO stock solution. An aliquot of 45 μL of the stock solution was transferred to a 384pp plate and three-fold 8-point dilutions were made by transferring 15 μL of the compound solution to 30 μL of DMSO. The plate was then rotated at 1,000 RPM for 1 minute at room temperature.

[0648] An aliquot of 30 nL of the diluted compound was transferred to a 384-well plate and incubated at room temperature for 15 minutes. Next, solutions 1, 2, and 3 were prepared as described in the table below. A 5 μL aliquot of solution 2 was added to each well, followed by 5 μL of solution 3 to start the reaction. The final volume in each well was 10 μL. The plate was incubated at room temperature for 60 minutes and then read.

[0649] Solution 1

[0650] serial number Components Final concentration 1 HEPES, pH 7.5 25mM 2 NaCl 100mM 3 BSA 0.1mg / ml 4 Tween 20 0.005％ 5 TCEP 0.5mM

[0651] Solution 2

[0652] serial number Components Final concentration 1 RBM39-Flag 50nM 2 APC-labeled anti-FLAG antibody 50nM

[0653] Solution 3

[0654] serial number Components Final concentration 1 His-DCAF15-DDA1-DDB1 10nM 2 Europium-labeled anti-His antibody 0.5nM

[0655] Next, prepare RBM39(R150-D331)3xFlag used in the TR-FRET assay:

[0656]

[0657] The recombinant RBM39 protein consists of R1R2 of RBM39 (aa 150 to 331; UniProt: Q14498). The coding sequence was subcloned into the pGEX4T-1-RBM39-flag vector and expressed as a GST fusion protein with an N-terminal TEV protease cleavage site. A 3x Flag tag was added to the C-terminus of R1R2 for FRET assay. The results of the FRET assay are shown in the table below.

[0658]

[0659]

[0660] Example 6- Western blot for evaluation of IC50 of compounds on RBM39 degradation:

[0661] A Western blot assay was used to evaluate the effects of compounds disclosed herein on RBM39 in the OVCAR3 cell line.

[0662] The cells were harvested into cell culture medium and counted. The cells were diluted with culture medium to below the cell density and 2 mL of the cell suspension was added to each well of a 6-well cell culture plate. The plates were covered and incubated at room temperature for 30 minutes without shaking and then incubated overnight at 37°C and 5% CO2 for cell attachment.

[0663] Dissolve the test compound to form a 10 mM DMSO stock solution and dilute the compound to 1000X final concentration. Add a 2 μL aliquot of the diluted compound to the cell plate. For vehicle control, use a 2 μL aliquot of DMSO. Gently shake the plate to mix.

[0664] After compound treatment, the culture medium was aspirated and the plates were washed with ice-cold phosphate buffered saline. Fresh, ice-cold 1x RIPA lysis buffer supplemented with protease and phosphatase inhibitors was added to the cells on ice or cold plates, and the cells were pipetted to lyse. The plates were then incubated on ice with shaking for 5-15 min, then centrifuged at 4°C and 15,000 rpm for 10 minutes, and the supernatant was collected.

[0665] The cell lysate was mixed with the loading dye and reducing agent, heated at 95°C for 10 min, and briefly centrifuged at 13000 rpm (10-15 seconds) at room temperature. Next, 50 μg of protein sample was loaded onto the gel in 1X MOPS buffer and the sample was run at 125 V for 120 minutes. The sample was transferred to a PVDF membrane using a dry blotting system. High MW protocol: 10 min at 2.5 A, up to 25 V.

[0666] Next, the membrane was blocked in TBST / 5% BSA for 1 h at room temperature with shaking at 100 rpm, and then hybridized with primary antibodies (RBM39: 1 to 1000 dilution; β-actin: 1 to 4000) at 4°C with shaking at 100 rpm. The membrane was washed 4X 5 mins at room temperature with 1x TBST and incubated with linked secondary antibodies anti-rabbit IgG antibody HRP (1 to 10000 dilution) and IRDye 680 anti-mouse antibody (1 to 10000 dilution) diluted in TBST / 5% milk for 1 h at room temperature.

[0667] The membrane was washed in TBST for 5 min × 4 times, and the loading control protein and target protein bands were detected after rinsing the membrane once with TBS, and the band signals were quantified.

[0668] Example 7- In vivo efficacy studies of tumor growth in subcutaneous xenograft models:

[0669] The compounds were evaluated for in vivo efficacy in a cell line derived xenograft model of OVCAR3 (human ovarian cancer cell line, catalog number HTB#161ATCC) to evaluate in vivo efficacy. The compounds were formulated with 40% PEG400 / 5% Tween80 / 55% HP-b-CD (10% w / v). 1 x 10 cells / ml of PBS mixed with Matrigel (volume ratio 1:1) were added to the mixture. 7 OVCAR3 cells were subcutaneously inoculated into the right flank of 6-8 week old female BALB / c nude mice for tumor development. When the size of the xenograft reached approximately 100-150 mm 3The tumor-bearing mice were randomly divided into study groups (n=10) at 1:00 pm. Randomization was based on the "matched over-distribution" method. The date of randomization was denoted as day 0. Tumor-bearing mice were treated with vehicle (40% PEG400 / 5% Tween80 / 55% HP-b-CD (10% w / v) or compound at 10, 30 and 100 mg / kg BID oral gavage for 25 days. Tumor size was measured twice a week in two dimensions using calipers and volume was expressed as mm. 3 The tumor volume was expressed using "V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension) and W is the tumor width (the longest tumor dimension perpendicular to L). Dosing and tumor volume and body weight measurements were performed in a laminar flow cabinet.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in R N1 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl; R N2 is H or optionally 1, 2, or 3 R 7 Substituted C 1-6 alkyl; X 1 Yes CR 1 or N; X 2 Yes CR 3 or N; X 3 Yes CR 4 or N; R 1 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; R 2 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; R 3 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; R 4 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; R 5 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halo, OH, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl; Each R N is independently H, optionally substituted by 1, 2, or 3 R 7 Substituted C 1-6 Alkyl, or C 3-10 Cycloalkyl; Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 replace; Each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR N R N ,COOH,C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , C 1-6 Alkylene-C(O)NR N R N , SO2NR N R N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl--containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, C 1-6 Alkylene-C 3-10 Cycloalkyl, C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the C 3-10 Cycloalkyl, 4-membered to 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl, C 1-6 Alkylene, or C 1-6 The alkoxy group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 Alkyl; and Each R 7 are independently OH, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, NH(C 1-6 alkyl), or N(C 1-6 Alkyl)2.

2. The compound or salt of claim 1, wherein Het is a 5-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N and optionally substituted by 1, 2, or 3 R 6 replace.

3. The compound or salt of claim 2, wherein Het is optionally substituted by 1, 2, or 3 R 6 Substituted thiazolyl.

4. The compound or salt of claim 1 or 2, wherein Het is And R 6 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, P(O)(Me)2, or C(O)-morpholinyl.

5. The compound or salt of any one of claims 1 to 4, wherein X 1 Yes CR 1 , X 2 Yes CR 3 , and X 3 Yes CR 4 .

6. The compound or salt of any one of claims 1 to 4, wherein X 1 , X 2 , and X 3 One of them is N.

7. The compound or salt of claim 6, wherein X 1 It is N.

8. The compound or salt of claim 6, wherein X 3 It is N.

9. The compound or salt according to claim 1, which has the structure of formula (Ia):

10. The compound or salt of any one of claims 1 to 9, wherein R N1 It's H.

11. The compound or salt of any one of claims 1 to 10, wherein R N2 It's H.

12. A compound or salt as claimed in any one of claims 1 to 6 and 8 to 11, wherein R 1 Is H or C 1-6 alkyl, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

13. The compound or salt of claim 12, wherein R 1 It's H.

14. The compound or salt of any one of claims 1 to 13, wherein R 2 It is H, C 1-6 alkyl, halo, or CN, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

15. The compound or salt of claim 14, wherein R 2 is H, halo, or CN.

16. The compound or salt of claim 15, wherein R 2 It is Cl.

17. The compound or salt of claim 16, wherein R 2 It is CN.

18. A compound or salt as claimed in any one of claims 1 to 17, wherein R 3 It is H, C 1-6 alkyl, or halogenated, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

19. The compound or salt of claim 18, wherein R 3 It's H.

20. The compound or salt of claim 18, wherein R 3 It is C 1-6 alkyl, and the C 1-6 The alkyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

21. The compound or salt of claim 20, wherein R 3 It's methyl.

22. The compound or salt of claim 18, wherein R 3 It is halogenated.

23. The compound or salt of claim 22, wherein R 3 It's fluorine.

24. A compound or salt as described in any one of claims 1 to 7 and 9 to 23, wherein R 4 It's H.

25. A compound or salt as described in any one of claims 1 to 24, wherein R 5 It's H.

26. The compound or salt of claim 1, wherein X 1 Yes CH, R 2 is H or CN, X 2 is CH or CMe, X 3 Yes CH, R 5 is H, and Het is thiazolyl, imidazolyl, isoxazolyl, 1,2,4-triazolyl, or oxazolyl, and Het is unsubstituted or substituted with 1 or 2 R 6 replace.

27. The compound or salt of claim 26, wherein Het is replaced by 1 R 6 replace.

28. The compound or salt of claim 26, wherein Het is replaced by 2 R 6 replace.

29. A compound or salt as described in any one of claims 1 to 28, wherein each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, COOH, C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , P(O)(R N )(R N ), C(O)-5-membered or 6-membered heterocycloalkyl--containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, C 3-5 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the C 3-5 Cycloalkyl, 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

30. The compound or salt of claim 29, wherein each R 6 are independently halogenated, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylene-C(O)OC 1-6 Alkyl, 5-membered or 6-membered heterocycloalkyl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the 5-membered or 6-membered heterocycloalkyl, C 6-10 Aryl, or 5-membered or 6-membered heteroaryl may be optionally substituted by 1, 2, or 3 R 7 Replace, and each C 1-6 Alkyl or C 1-6 The alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

31. The compound or salt of claim 30, wherein each R 6 are independently halogenated, C 1-6 alkyl, or 5- or 6-membered heteroaryl - containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the 5- or 6-membered heteroaryl may be optionally replaced by 1, 2, or 3 R 7 Replace, and each C 1-6 The alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

32. The compound or salt of claim 30, wherein at least one R 6 It is halogenated.

33. The compound or salt of claim 32, wherein at least one R 6 It is chlorine or bromine.

34. The compound or salt of claim 30, wherein at least one R 6 It is C 1-6 alkyl, and each C 1-6 The alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following: 1-6 Alkoxy, OH, CN, CO2H, NR N R N , and CO2C 1-6 alkyl.

35. The compound or salt of claim 34, wherein at least one R 6 It is methyl, ethyl, or isopropyl.

36. The compound or salt of claim 30, wherein each R 6 is independently a 5- or 6-membered heteroaryl group containing 1, 2, or 3 ring heteroatoms selected from O, S, and N, wherein the 5- or 6-membered heteroaryl group may be optionally replaced by 1, 2, or 3 R 7 replace.

37. The compound or salt of claim 36, wherein at least one R 6 is pyrazolyl, pyridyl, pyridazinyl, or pyrimidinyl, each of which may be optionally substituted by 1, 2, or 3 R 7 replace.

38. A compound or salt as described in any one of claims 1 to 37, wherein each R 7 are independently halogenated, C 1-6 Alkyl, or C 1-6 Halogenated alkyl.

39. The compound or salt of claim 38, wherein at least one R 7 It is C 1-6 alkyl.

40. The compound or salt of claim 39, wherein at least one R 7 It's methyl.

41. A compound listed in Table A, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1 to 41 and a pharmaceutically acceptable excipient.

43. A method for regulating RBM39 protein, the method comprising contacting the RBM39 protein with a compound or salt as described in any one of claims 1 to 41 or a pharmaceutical composition as described in claim 42.

44. The method of claim 43, wherein modulating the RBM39 protein comprises degrading the RBM39 protein.

45. The method of claim 43 or 44, wherein contacting of the compound or salt comprises administering to a subject.

46. ​​The method of claim 45, wherein the subject is a human.

47. A method of treating a disease associated with aberrant RBM39 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or salt as described in any one of claims 1 to 41 or a pharmaceutical composition as described in claim 42.

48. The method of claim 47, wherein the disease is cancer.

49. The method of claim 48, wherein the cancer is renal cell carcinoma.

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