Heterocyclic RBM39 modulators

Abstract

Provided herein are compounds of formula (I) that modulate RMB39 and methods of using the compounds in RMB39-associated disorders, such as cancer (eg, renal cell carcinoma). [Case 1] JPEG2025529797000173.jpg19154

Description

[Background technology]

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

[0002] RBM39 (59.4 kDa protein) is an essential serine / arginine-rich RNA-binding protein found in the nuclei of all organisms and is involved in pre-mRNA splicing, transcriptional co-regulation, and translation (Xu, et al., Cell Death Discov. 7, 214 (2021) (Non-Patent Document 1)).

[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), with genes containing RBM39-regulated alternative exons linked to a wide variety of biological processes, including G2 / M transition, cellular response to DNA damage, adherens junctions, and endocytosis (Mai, et al., Biochim Biophys Acta., 1859(8), 1014-1024 (2016)). RBM39 has also been implicated in the malignant progression of several solid and hematological cancers (Xu, et al., Cell Death Discov. 7, 214 (2021)).

[0004] Several arylsulfonamides (indisulam, tasisulam, CQS, and E7820) have been shown to act as molecular adhesive degraders of RBM39 by forming ternary complexes with RBM39 and the E3 ubiquitin ligase receptor DCAF15, with no detectable affinity for either species alone. These molecular adhesives promote the interaction of the RBM39 splicing factor with the CUL4-DCAF15 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of RBM39. In human cancer cell lines treated with arylsulfonamides, RBM39 degradation resulted in significant antiproliferative effects. Furthermore, using CRISPR-Cas9 to silence DCAF15 in cancer cells confers resistance to RBM39 degradation by arylsulfonamides, highlighting RBM39 degradation as the primary mechanism of the anticancer effects observed with these compounds (Han, et al., Science., 356(6336), (2017) (Non-Patent Document 3); Du, et al., Structure., 27, 1625-1633 (2019) (Non-Patent Document 4)). Furthermore, gene knockout experiments of RBM39-deficient human cancer cells injected into mice delayed the growth of leukemia progression and improved overall survival (Wang, et al., Cancer Cell., 35(3), 369-384 (2019) (Non-Patent Document 5)).

[0005] Arylsulfonamides have previously been shown to exhibit acceptable safety profiles in clinical trials, with some antitumor activity observed across a variety of cancers. However, overall response rates remain low, potentially due to a lack of understanding of the mechanism of action and potential response biomarkers. Therefore, for specific patient populations, RBM39 degraders have the potential to effectively treat certain types of human cancers, requiring further investigation (Wang, et al., Cancer Cell., 35(3), 369-384 (2019)). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Xu,et al.,Cell Death Discov.7,214(2021) [Non-patent document 2] Mai, et al., Biochim Biophys Acta., 1859(8), 1014-1024(2016) [Non-patent document 3] Han,et al.,Science.,356(6336),(2017) [Non-patent document 4] Du,et al.,Structure.,27,1625-1633(2019) [Non-patent document 5] Wang,et al.,Cancer Cell.,35(3),369-384(2019) Summary of the Invention [Means for solving the problem]

[0007] Provided herein are compounds of formula (I) and pharmaceutically acceptable salts thereof: [ka] (In the formula, R N1 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 alkyl; R N2 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; X 1 is CR 1 or N;X 2 is CR 3 or N;X 3 is CR 4 or N;R 1 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 5 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C1-6 each R N are independently H, 1, 2 or 3 R 7 C optionally substituted with 1-6 Alkyl, or C 3-10 Het is cycloalkyl; Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N; and R 6 each R is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl optionally substituted with 6 are independently halo, 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 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, 4-6 membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 6-10 aryl, 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, wherein C 3-10 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 An aryl or a 5- or 6-membered heteroaryl may have 1, 2, or 3 R 7 Each C may be substituted with 1-6 Alkyl, C 1-6 Alkylene, or C 1-6 Alkoxy is C 1-6Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 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 In some cases, R N1 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 alkyl; R N2 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; X 1 is CR 1 or N;X 2 is CR 3 or N;X 3 is CR 4 or N;R 1 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 3 is H, C 1-6 Alkyl, C 1-6Haloalkyl, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 5 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 and each R N are independently H or 1, 2 or 3 R 7 C optionally substituted with 1-6 alkyl; Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N, and 1, 2 or 3 R 6 each R is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl optionally substituted with 6 are independently halo, 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 or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 3-10 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 6-10 aryl or a 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, wherein C 3-10 Cycloalkyl, 5- or 6-membered heterocycloalkyl, C 6-10 An aryl or a 5- or 6-membered heteroaryl may have one, two, or three R 7 Each C may be substituted with 1-6 Alkyl or C 1-6 Alkylene is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 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.

[0008] Also provided are compositions comprising the compounds disclosed herein and a pharmaceutically acceptable excipient. Further provided are methods for modulating RBM39 protein by contacting RBM30 protein with a compound disclosed herein. Also provided are methods for treating a disease associated with aberrant RBM39 activity in a subject (e.g., cancer, such as renal cell carcinoma) by administering a therapeutically effective amount of a compound disclosed herein to the subject. DETAILED DESCRIPTION OF THE INVENTION

[0009] Provided herein are compounds and their uses in the treatment or prevention of diseases and disorders associated with aberrant RBM39 activity, such as cancer. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising such a compound or a pharmaceutically acceptable salt thereof, for treating or preventing diseases and disorders associated with aberrant RBM39 activity, such as cancer.

[0010] compound Provided herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R N1 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; R N2 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; X 1 is CR 1 or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 1 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 2 is H, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 5 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N are independently H, 1, 2 or 3 R 7C optionally substituted with 1-6 Alkyl, or C 3-10 is cycloalkyl; Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N, and 1, 2 or 3 R 6 is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl optionally substituted with Each R 6 are independently halo, 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 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, 4-6 membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 6-10 aryl, 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, wherein C 3-10 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, or one, two, or three R 7 and each C 1-6 Alkyl, C 1-6 Alkylene, or C 1-6 Alkoxy is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C1-6 optionally substituted with 1 or 2 substituents independently selected from 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).

[0011] In some cases, R N1 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; R N2 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; X 1 is CR 1 or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 1 is H, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 2 is H, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 3 is H, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 4 is H, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 5 is H, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N are independently H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N, and 1, 2 or 3 R 6 is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl optionally substituted with Each R 6 are independently halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, COOH, C(O)NR N R N , C 1-6 Alkylene-C(O)OR N , P(O)(R N )(R N ), C(O)-5 or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 3-10 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 6-10 aryl or a 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, wherein C 3-10 Cycloalkyl, 5- or 6-membered heterocycloalkyl, C 6-10 aryl, or one, two or three R 7 5- or 6-membered heteroaryl optionally substituted with each C 1-6 Alkyl or C 1-6 Alkylene is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 optionally substituted with 1 or 2 substituents independently selected from 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.

[0012] In some cases, Het contains 1, 2, or 3 ring heteroatoms selected from O, S, and N, and 1, 2, or 3 R 6 In some cases, Het contains 1, 2, or 3 ring heteroatoms selected from O, S, and N, and 1, 2, or 3 R 6In some cases, Het is a 5-membered heteroaryl optionally substituted with 1, 2, or 3 R 6 In some cases, Het is thiazolyl optionally substituted with [ka] and R 6 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 [ka] and R 6 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 selected from one, two, or three R 6 In some cases, Het is thiazolyl optionally substituted with [ka] and R 6 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 [ka] and R 6 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10cycloalkyl, P(O)(Me)2 or C(O)-morpholinyl.

[0013] In some cases, X 1 is CR 1 In some cases, X 2 is CR 3 In some cases, X 3 is CR 4 In some cases, X 1 is CR 1 and X 2 is CR 3 and X 3 is 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 the is N. In some cases, X 1 , X 2 , and X 3 Two of them are N. In some cases, X 1 is N. In some cases, X 2 is N. In some cases, X 3 is N.

[0014] In some cases, the compound has the structure of Formula (Ia): [ka]

[0015] In some cases, R N1 and R N2 One of the is H. In some cases, R N1 is H. In some cases, R N2 is H. In some cases, R N1 and R N2 are H. In some cases, R N1 is one, two, or three R 7 C optionally substituted with 1-6 In some cases, RN2 is one, two or three R 7 C optionally substituted with 1-6 It is alkyl.

[0016] In some cases, R 1 is H or C 1-6 alkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 In some cases, R 1 is H.

[0017] In some cases, R 2 is H, C 1-6 alkyl, halo, or CN, 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, 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 is CN.

[0018] In some cases, R 3 is H, C 1-6 alkyl or halo, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 In some cases, R 3 is H. In some cases, R 3 is C 1-6 alkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NRN R N and CO2C 1-6 In some cases, R 3 is methyl. In some cases, R 3 is a halo. In some cases, R 3 is fluoro.

[0019] In some cases, R 4 is H, C 1-6 alkyl or halo, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 In some cases, R 4 is H.

[0020] In some cases, R 5 is H, C 1-6 alkyl or halo, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 In some cases, R 5 is H.

[0021] In some cases, each R 6 are independently halo, 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 or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C3-5 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 6-10 aryl, or a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; C 3-5 cycloalkyl, 5- or 6-membered heterocycloalkyl, C 6-10 An aryl or a 5- or 6-membered heteroaryl may have one, two, or three R 7 Each C may be substituted with 1-6 Alkyl or C 1-6 Alkylene is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 and optionally substituted with 1 or 2 substituents independently selected from alkyl. In some cases, each R 6 are independently halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylene-C(O)OC 1-6 alkyl, 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; C 6-10 aryl, or a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; a 5- or 6-membered heterocycloalkyl, C 6-10 An aryl or a 5- or 6-membered heteroaryl may have one, two, or three R 7 Each C may be substituted with 1-6 Alkyl or C 1-6 Alkylene is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 In some cases, each R 6 independently, halo, C 1-6alkyl, or a 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 is selected from 1, 2, or 3 R 7 Each C may be substituted with 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 and optionally substituted with 1 or 2 substituents independently selected from alkyl. In some cases, at least one R 6 is a halo. In some cases, one R 6 is a halo. In some cases, at least one R 6 is chloro or bromo. In some cases, one R 6 is chloro or bromo. In some cases, R 6 is chloro. In some cases, R 6 is bromo. In some cases, at least one R 6 is C 1-6 alkyl, and each C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 and optionally substituted with 1 or 2 substituents independently selected from alkyl. In some cases, at least one R 6 is methyl, ethyl, or isopropyl. In some cases, one R 6 is methyl, ethyl, or isopropyl. In some cases, R 6 is methyl. In some cases, R 6 is ethyl. In some cases, R 6 is isopropyl. In some cases, each R 6 is a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R 7 In some cases, at least one R 6is pyrazolyl, pyridinyl, pyridazinyl, or pyrimidinyl, each of which may be selected from one, two, or three R 7 In some cases, one R 6 is pyrazolyl, pyridinyl, pyridazinyl, or pyrimidinyl, each of which may be selected from one, two, or three R 7 In some cases, R 6 is one, two or three R 7 In some cases, R 6 is one, two or three R 7 In some cases, R 6 is pyridazinyl, or one, two or three R 7 In some cases, R 6 is one, two or three R 7 and pyrimidinyl optionally substituted by.

[0022] In some cases, each R 7 independently, halo, C 1-6 Alkyl or C 1-6 In some cases, at least one R 7 is C 1-6 In some cases, at least one R 7 is methyl.

[0023] Specific contemplated compounds include those in Table A below or a pharmaceutically acceptable salt thereof. Compounds having a chiral center without exhibiting a specific stereoisomerism exhibit a mixture of stereogenicity at that chiral center. [ka] [ka] [ka] [ka]

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[0024] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) 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 disclosure unless only one of the isomers is specifically indicated. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomer" refers to a compound that differs in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein can exist as single stereoisomers or as a mixture of stereoisomers. The stereochemistry of the compounds depicted herein denotes relative, rather than absolute, stereochemistry, unless otherwise discussed. As used herein, a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least 50% or more of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.

[0025] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0026] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon by a C-rich carbon, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, particularly deuterium analogs, may also be therapeutically useful.

[0027] 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 its chemical structure and chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0028] The compounds disclosed herein can be useful as modulators of RBM39, such as inhibitors of RBM39. These compounds can also be useful for treating or preventing diseases and disorders associated with aberrant RBM39 activity, such as cancer, in patients.

[0029] definition As used herein, the term "alkyl" refers to straight-chain and branched saturated hydrocarbon groups containing 1 to 30 carbon atoms, for example, 1 to 20 carbon atoms, or 1 to 10 carbon atoms. n means that the alkyl group has "n" carbon atoms. For example, C6 alkyl refers to an alkyl group having 6 carbon atoms. C1-C6 alkyl refers to an alkyl group having a number of carbon atoms, including all ranges (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 t-butyl (1,1-dimethylethyl). Unless otherwise specified, alkyl groups can be unsubstituted or substituted alkyl groups.

[0030] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, substituted with one or more halogen atoms.

[0031] As used herein, the term "alkylene" refers to an alkyl group that has a substituent. For example, the term "alkylenehalo" refers to an alkyl group substituted with a halo group. For example, an alkylene group can be -CHCH- or -CH-. nThe term alkylene means that the group has "n" carbon atoms. For example, C 1-6 Alkylene refers to an alkylene group having a number of carbon atoms, including all ranges and subgroups as described above for the "alkyl" group. Unless otherwise indicated, an alkylene group can be an unsubstituted alkylene group or a substituted alkylene group.

[0032] As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms). n The term C5 cycloalkyl means that the cycloalkyl group has "n" carbon atoms. For example, C5 cycloalkyl refers to a cycloalkyl group having 5 carbon atoms in the ring. C3-C 10 Cycloalkyl refers to cycloalkyl groups having a number of carbon atoms inclusive of all ranges (e.g., 3 to 10 carbon atoms) and all subgroups (e.g., 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, 1 to 2, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified, a cycloalkyl group can be unsubstituted or substituted. The cycloalkyl groups described herein can be isolated or fused to another cycloalkyl group, a heterocycloalkyl group, an aryl group, and / or a heteroaryl group. When a cycloalkyl group is fused to another cycloalkyl group, each of the cycloalkyl groups can contain 3 to 8 carbon atoms, unless otherwise specified. Unless otherwise specified, a cycloalkyl group can be unsubstituted or substituted.

[0033] As used herein, the term "heterocycloalkyl" is defined similarly to cycloalkyl, except that the ring contains one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur. Specifically, the term "heterocycloalkyl" refers to a ring containing a total of five or six atoms, in which one, two, or three 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 groups include piperidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, and the like.

[0034] Cycloalkyl and heterocycloalkyl groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, 1 to 3 groups, independently selected from alkyl, alkylene-OH, C(O)NH, NH, oxo (=O), aryl, alkylene-halo, halo, and OH. Heterocycloalkyl groups can be further N-substituted with alkyl (e.g., methyl or ethyl), alkylene-OH, alkylene-aryl, and alkylene-heteroaryl. The heterocycloalkyl groups described herein can be isolated or fused to another heterocycloalkyl group, cycloalkyl group, aryl group, and / or heteroaryl group. When a heterocycloalkyl group is fused to another heterocycloalkyl group, each heterocycloalkyl group can contain 3 to 12 total ring atoms and 1 to 3 heteroatoms. Unless otherwise indicated, heterocycloalkyl groups can be unsubstituted or substituted.

[0035] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring having 5 to 12 total ring atoms and containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the aromatic ring. In particular, heteroaryls described herein contain 5 or 6 total ring atoms and 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur in the aromatic ring. Unless otherwise indicated, heteroaryl groups can be unsubstituted or substituted with one or more, particularly 1 to 3, substituents described herein. Examples of heteroaryl groups include thienyl, furyl, pyridyl, 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, indolizyl, 1H-indazolyl, benzimidazolyl, 7-azaindolyl, 5-azaindolyl, 6-azaindolyl, 1,2-benzyl, and the like. Examples include, but are not limited to, isoxazolyl, 1,2-benzothiazolyl, 2,1-benzisothiazolyl, benzoxazolyl, benzthiazolyl, benzo[c][1,2,5]thiadiazolyl, 1,2-benzisothiazol-3(2H)-onyl, adenyl, guanyl, quinolyl, isoquinolyl, quinoxalyl, phthalazyl, quinazolyl, cinnolyl, 1,8-naphthyridyl, pyrido[3,2-d]pyrimidyl, pyrido[4,3-d]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[3,2-b]pyrazyl, pteridyl, 2H-chromen-2-onyl, 2H-benzo[e][1,2]oxazyl, quinolin-2(1H)-onyl, and isoquinolin-1(2H)-onyl.

[0036] As used herein, the term "alkoxy" or "alkoxyl" refers to an "-O-alkyl" group. An alkoxy or alkoxyl group can be unsubstituted or substituted.

[0037] As used herein, the term "therapeutically effective amount" means an amount of a compound or combination of therapeutically active compounds that ameliorates, attenuates, 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.

[0038] As used herein, the terms "patient" and "subject" are used interchangeably and can refer to animals such as dogs, cats, cows, horses, and sheep (e.g., non-human animals) and humans. A particular patient or subject is a mammal (e.g., a human).

[0039] As used herein, the term "pharmaceutically acceptable" means that the compound of the present disclosure, or a formulation containing the compound, or a referenced substance, such as a particular 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 effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.

[0040] As used herein, the term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API).

[0041] pharmaceutically acceptable salts The compounds described herein can exist in free form or, where appropriate, as salts.Pharmaceutically acceptable salts are particularly interesting because they are useful for administering the compounds described below for medical purposes.Pharmaceutically unacceptable salts are useful in the manufacturing process for the purpose of isolation and purification, for use in separating the stereoisomeric forms of the compounds of the present disclosure or their intermediates.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue adverse effects, such as toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio.

[0043] Pharmaceutically acceptable salts are well known in the art. For example, S. M. 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 salts 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.

[0044] When a compound described herein contains a basic group or a sufficiently basic bioisostere, an acid addition salt can be prepared by 1) reacting the purified compound in its free base form with an appropriate organic or inorganic acid, and 2) isolating the salt thus formed. In practice, the acid addition salt may be a more convenient form for use and use than the free base form.

[0045] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or 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, hemisulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxybenzoate ... Examples of the salts include dimethylethanesulfonate, 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, and valerate.

[0046] When the compounds described herein contain a carboxy group or a sufficiently acidic bioisostere, a base addition salt 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 a base addition salt may be more convenient, and the use of the salt form essentially corresponds to the use of the free acid form. Salts derived from appropriate bases include alkali metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, and N +(C1-4 alkyl)4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0047] Base addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. Sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. 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, and the like. Suitable amine base addition salts are prepared from amines, which are frequently used in medicinal chemistry due to their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

[0048] Other acids and bases may be used in the preparation of salts which, while not themselves pharmaceutically acceptable, are useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0049] It is understood that the compounds disclosed herein can exist as mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of the free form of the compound and a pharmaceutically acceptable salt are also contemplated.

[0050] Pharmaceutical Formulations, Administration and Routes of Administration Further provided is a pharmaceutical formulation (also referred to throughout this specification as a composition) comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0051] The compounds described herein can be administered to a subject in a therapeutically effective amount either alone or as part of a pharmaceutically acceptable composition or formulation.Furthermore, the compounds can be delivered at once, multiple times, or substantially uniformly over a period of time.It should also be noted that the dose of the compound can be varied over time.

[0052] The specific dosing regimen for a particular subject depends in part on the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects. The amount of compound administered to a subject (e.g., a mammal such as a human) according to the present disclosure should be sufficient to affect the desired response over a reasonable time frame. The dosage typically depends on the route, timing, and frequency of administration. Thus, clinicians titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect, and conventional dose-setting techniques are known to those skilled in the art.

[0053] Purely by way of example, the present methods include administering, for example, about 0.1 mg / kg to about 100 mg / kg or more of the compound, depending on the factors discussed above. In other embodiments, the dosage ranges 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 administering lower doses of the compound over multiple administrations. If desired, the dose of the compound may be administered as two, three, four, five, six, or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. The duration of treatment depends on the specific condition and type of pain and may last from one day to several months.

[0054] Suitable methods for administering physiologically acceptable compositions, such as pharmaceutical compositions containing the compounds disclosed herein, are well known in the art. While more than one route can be used to administer a compound, certain routes may provide a more rapid and effective response than others. Depending on the situation, a pharmaceutical composition containing a compound may be applied or instilled into a body cavity, absorbed through the skin or mucous membrane, ingested, inhaled, and / or introduced into the circulation. For example, in certain situations, it may be desirable to deliver a pharmaceutical composition containing an agent by injection intravenously, intraperitoneally, intracerebrally (intraparenchymal), intracerebroventricularly, intramuscularly, intraocularly, intraarterially, intraportally, intralesionally, intramedullary, intrathecally, intracerebroventricularly, transdermally, subcutaneously, intraperitoneally, intranasally, enterally, topically, sublingually, via urethral, ​​vaginal, or rectal means, orally by sustained release systems, or by implanted devices. If desired, the compound may be administered locally by intrathecal administration, intracerebrally (intraparenchymal), intracerebroventricular administration, or intravenously or intraarterially supplying the region of interest. Alternatively, the compositions are administered locally via implantation of a membrane, sponge, or another suitable material into which the desired compound has been absorbed or encapsulated. When an implantation device is used, the device, in one aspect, is implanted into any suitable tissue or organ, and delivery of the desired compound is by, for example, diffusion, time-release bolus, or continuous administration.

[0055] To facilitate administration, compounds are, in various aspects, formulated into physiologically acceptable compositions containing carriers (e.g., vehicles, adjuvants, or diluents). The specific carriers used are limited only by physicochemical considerations, such as solubility and lack of reactivity with the compound, and the route of administration. Physiologically acceptable carriers are well known in the art. Exemplary pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (see, e.g., U.S. Pat. No. 5,466,468). Injectable formulations are further described, for example, in Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). Pharmaceutical compositions containing compounds are, in one aspect, placed in a container along with packaging material that provides instructions regarding the use of such pharmaceutical compositions. Generally, such instructions include tangible language describing the concentrations of reagents and, in certain embodiments, the relative amounts of excipient components or diluents (e.g., water, saline, or PBS) that may be required to reconstitute the pharmaceutical composition.

[0056] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0057] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Microbial contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0058] 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 starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retardants, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0059] 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 known in the art.Solid dosage forms can also contain opacifying agents.Furthermore, solid dosage forms can be embedded compositions that release active compound or compounds in a specific part of the intestinal tract in a delayed manner.Examples of embedding compositions that can be used are polymeric substances and waxes.Active compounds can also be in microencapsulated form, optionally with one or more excipients.

[0060] The liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compound, liquid dosage form can contain the inert diluent commonly used in this field, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, or the mixture of these substances.

[0061] In addition to such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. Suspensions can contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances.

[0062] Compositions for rectal administration are preferably suppositories and can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ordinary temperatures but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ingredient.

[0063] The compositions used in the methods 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 cells, delivering the entrapped contents to intracellular compartments.

[0064] Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulations are easily administered in a variety of dosage forms, such as injectable solutions, drug-release capsules, and the like. For parenteral administration in aqueous solution, for example, the solution should be suitably buffered if necessary, and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.

[0065] The frequency of administration depends on the pharmacokinetic parameters of the drug and the route of administration. The optimal pharmaceutical formulation is determined by those skilled in the art depending on the route of administration and the desired dosage. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, which are incorporated herein by reference. Such formulations can affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered drug. Depending on the route of administration, appropriate doses can be calculated according to body weight, body surface area, or organ size. Further refinement of the calculations necessary to determine appropriate therapeutic doses can be routinely performed by those skilled in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein and the pharmacokinetic data observed in animal or human clinical trials.

[0066] The exact dosage used will depend on several factors, including the host, the condition being treated, e.g., the nature and severity of the disease or disorder, the mode of administration, and the specific active substance being used, whether in veterinary or human medicine. The compound can be administered by any conventional route, particularly enterally, or in one aspect orally in the form of a tablet or capsule. The administered compound can be in free form or in pharmaceutically acceptable salt form, as appropriate, for use as a pharmaceutical, particularly for the preventive or curative treatment of the disease of interest. These measures slow the progression of the disease state and help the body reverse the process in a natural way.

[0067] It will be appreciated that the pharmaceutical compositions and treatment methods of the present invention are useful in the fields of human medicine and veterinary medicine. Thus, the subject to be treated is, in one aspect, a mammal. In another aspect, the mammal is a human.

[0068] In jurisdictions that prohibit patents on methods performed on the human body, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance that the human subject self-administers by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patents on methods performed on the human body, "administering" a composition includes both the method and the aforementioned activities performed on the human body.

[0069] How to use The compounds described herein can modulate RBM39. In some embodiments, the compounds inhibit RBM39. In various embodiments, the compounds induce RBM39 degradation, i.e., the compounds are RBM39 degraders.

[0070] As used herein, the term "RBM39 degrader" refers to a compound that has the ability to induce degradation of the RBM39 protein formed in a complex between the RBM39 protein and any part of an E3 ubiquitin ligase complex.

[0071] Although RBM39 has been identified as being associated with malignant progression in several solid and hematological cancers, there remains a great need and opportunity for 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 is involved in breast cancer progression by mediating VEGF alternative splicing (Mercier, et al., Am J Pathol. 174(4), 1172-1190 (2009)). It is also upregulated in human non-small cell lung cancer (NSCLC) tissue compared to normal lung tissue, promoting proliferation and migration (Chai, et al., Tumor Biol., 35, 6311-6317 (2014)). RBM39 protein is required for the maintenance of acute myeloid leukemia (AML) through mis-splicing of HOXA9 target genes and for the survival of neuroblastoma cells in vitro and in vivo (Wang, et al., Cancer Cell., 35(3), 369-384 (2019); Singh, et al., Sci Adv., 7(47), (2021)). RBM39 is an emerging cancer target (Yuewei et al., 2021). Other cancers that have shown promising therapeutic potential are neuroblastomas with MYC-N amplification and tumors with KRAS mutations, which are highlighted herein.

[0072] The compounds disclosed herein are particularly advantageous for the treatment or prevention of diseases or disorders caused by aberrant RBM39 activity.

[0073] As used herein, "abnormal RBM39 activity" refers to RBM39 activity associated with malignant progression in cancer. Such RBM39-related malignant progression is associated with various cancers (Xu, et al., Cell Death Discov. 7, 214 (2021)). One example of abnormal RBM39 activity is RBM39-induced splicing of proteins encoded by KRAS oncogenes, such as KRAS4A.

[0074] Given the important biological role of RBM39, the compounds of the present disclosure are useful in many applications in a variety of contexts. For example, most simply, active agents of the present disclosure are useful for inducing degradation of RBM39 in cells. In this regard, the present disclosure provides a method of inducing degradation of RBM39 in a cell. The method comprises contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to induce 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 an in vivo cell. In certain embodiments, the method is intended for research purposes, while in other embodiments, the method is intended for therapeutic purposes.

[0075] As shown herein, compounds that induce degradation of RBM39 increase tumor cell death. Accordingly, the present disclosure provides a method for increasing tumor cell death in a subject. The method includes administering to the subject an amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, effective to increase tumor cell death.

[0076] In accordance with the above, the present disclosure further provides a method of treating cancer in a subject, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to treat cancer in the subject.

[0077] As used herein, the term "treat" and related words do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that those skilled in the art recognize as having potential benefits or therapeutic effects. In this regard, the disclosed methods of treating cancer can provide any amount or level of cancer treatment. Furthermore, the treatment provided by the disclosed methods can include treatment of one or more conditions or symptoms of the cancer being treated. The treatment provided by the disclosed methods can also include slowing the progression of cancer. For example, the methods can treat cancer by reducing tumor or cancer growth, reducing metastasis of tumor cells, increasing cell death of tumor or cancer cells, etc.

[0078] Cancers treatable by the methods disclosed herein can be any cancer, for example, any malignant growth or tumor caused by abnormal and uncontrolled cell division that can spread to other parts of the body via the lymphatic system or bloodstream. In some embodiments, the cancer is one in which RBM39 is expressed by cells of the cancer. In some aspects, the cancer is one in which the RBM39 protein is overexpressed, the gene encoding RBM39 is amplified, and / or an RBM39 mutant protein (e.g., truncated RBM39, point-mutated RBM39) is expressed.

[0079] Neuroblastoma is the most common pediatric solid tumor, with high-risk cases having a poor prognosis despite the use of multimodal treatments. Neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation and spliceosome dependency, requires 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) demonstrated that aberrant alternative pre-mRNA splicing plays a critical role in MYC-driven cancers and that targeting the dysregulated spliceosome may be an effective therapeutic strategy in these cancers. Genetic depletion or indisulam-mediated degradation of RBM39 induced significant genome-wide splicing abnormalities and cell death in neuroblastoma, which resulted in significant 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 a therapeutic strategy for high-risk neuroblastoma") also confirmed that neuroblastoma lines are highly sensitive to indisulam. RNA-seq and proteomic analyses highlighted distinct disruptions to the cell cycle, metabolome, and mitochondrial function both in vitro and in vivo. Our studies also confirmed complete tumor regression without recurrence in both xenograft and Th-MYCN transgenic models of neuroblastoma with indisulam treatment.

[0080] The KRAS oncogene, which is mutated in many cancers, encodes two distinct proteins, KRAS4A and KRAS4B, generated by differential splicing. Wei-Ching Chen and colleagues recently (2021) demonstrated that coordinate regulation of both KRAS4A and KRAS4B isoforms through splicing control is essential for the development of Kras-mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells and responds to hypoxia, whereas the major KRAS4B is induced by ER stress. KRAS4A splicing is regulated by the DCAF15 / RBM39 pathway. The authors experimentally demonstrated that deletion of KRAS4A or pharmacological inhibition of RBM39 with indisulam resulted in the inhibition of cancer stem cells. Therefore, sulfonamides targeting KRAS4A splicing may have the potential to inhibit human tumors expressing the minor KRAS4A isoform. Low 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)).

[0081] 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 tumorigenesis, H3K4me3, and the expression of tumor suppressors and oncogenes in breast cancer cells. The authors demonstrated the therapeutic potential of RBM39 RRM3-derived peptides that disrupt the RBM39 / MLL1 complex and reduce H3K4me3 and cancer hallmarks in multiple breast cancer subtypes, while being non-toxic to normal cells.

[0082] The cancer, in some aspects, is selected from acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or rectum, eye cancer, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, leukemia (e.g., chronic lymphocytic leukemia), chronic myeloid carcinoma, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, The cancer is one selected from the group consisting of Hodgkin's lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, peritoneal cancer, omental cancer, and midgut 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 certain embodiments, 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, such as non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma. In certain aspects, the cancer is an 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.

[0083] Also provided herein is the use of the compounds 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.

[0084] The present disclosure will be more readily understood by reference to the following examples.

[0085] 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 construed as limiting the scope of the invention.

[0086] As used herein, the terms "treatment" or "treating" a disease or disorder refer to a method of reducing, delaying, or ameliorating such a condition before or after it occurs. Treatment may relate to one or more effects or symptoms of a disease and / or underlying pathology. Treatment is intended to obtain a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, such that an improvement is observed in a patient, even though the patient may still be affected by the underlying disease. For prophylactic benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or to patients who may not have been diagnosed with the disease but who report one or more physiological symptoms of the disease. Treatment can be any reduction, including, but not limited to, the complete elimination of a disease or a symptom of a disease. The degree of such reduction or prevention, as measured by any standard technique, is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%, as compared to comparable untreated controls.

[0087] As used herein, the term "therapeutic benefit" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0088] Synthesis of Compounds of the Present Disclosure The compounds disclosed herein can be prepared by using standard synthetic methods and procedures known to those skilled in the art, or in light of the teachings herein, by a variety of methods using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates. The synthesis of the compounds disclosed herein can generally be accomplished by following the synthetic schemes as described in the Examples section, with modifications for particular desired substituents.

[0089] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field, including, but not limited to, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley&Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd Classic texts, one or several of which are sources of information, such as the "Classical Texts of Organic Synthesis," ed., John Wiley & Sons: New York, 1999, are useful and recognized references for organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not limit, general procedures for preparing compounds of the present disclosure.

[0090] The synthetic process disclosed herein can tolerate a wide variety of functional groups. Thus, various substitution starting materials can be used. The method generally provides the desired final compound at or near the end of the overall method, although in certain cases it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0091] Embodiment The present disclosure may be further understood in view of the following non-limiting embodiments.

[0092] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R N1 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; R N2 is H or 1, 2 or 3 R 7 C optionally substituted with 1-6 is alkyl; X 1 is CR 1 or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 1 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 3 is H, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 5 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo, OH, or CN, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N are independently H, 1, 2 or 3 R 7 C optionally substituted with 1-6 Alkyl, or C 3-10 is cycloalkyl; Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N, and 1, 2 or 3 R 6 is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl optionally substituted with Each R 6 are independently halo, CN, C1-6 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 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, 4-6 membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 6-10 aryl, 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, wherein C 3-10 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, or one, two, or three R 7 and each C 1-6 Alkyl, C 1-6 Alkylene, or C 1-6 Alkoxy is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 optionally substituted with 1 or 2 substituents independently selected from 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).

[0093] Embodiment 2. Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N and 1, 2 or 3 R 6 The compound or salt of embodiment 1, wherein R is 5-membered heteroaryl optionally substituted with R.

[0094] Embodiment 3. Het is one, two or three R 6 The compound or salt of embodiment 2, wherein R is 1 or 2;

[0095] Embodiment 4. Het [ka] and R 6 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 The compound or salt of embodiment 1 or 2, which is cycloalkyl, P(O)(Me)2, or C(O)-morpholinyl.

[0096] Embodiment 5.X 1 is CR 1 and X 2 is CR 3 and X 3 is CR 4 5. The compound or salt of any one of embodiments 1 to 4, wherein:

[0097] Embodiment 6.X 1 , X 2 and X 3 The compound or salt of any one of embodiments 1 to 4, wherein one of: is N.

[0098] Embodiment 7.X 1 The compound or salt of embodiment 6, wherein

[0099] Embodiment 8.X 3 The compound or salt of embodiment 6, wherein

[0100] Embodiment 9. A compound or salt of embodiment 1 having the structure of formula (Ia): [ka]

[0101] Embodiment 10.R N1 The compound or salt of any one of embodiments 1 to 9, wherein is H.

[0102] Embodiment 11.R N2 The compound or salt of any one of embodiments 1 to 10, wherein is H.

[0103] Embodiment 12.R 1 is H or C 1-6 alkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 The compound or salt of any one of embodiments 1 to 6 and 8 to 11, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0104] Embodiment 13.R 1 The compound or salt of embodiment 12, wherein

[0105] Embodiment 14.R 2 is H or C 1-6 alkyl, halo, or CN, 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 14. The compound or salt of any one of embodiments 1 to 13, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0106] Embodiment 15.R 2 The compound or salt of embodiment 14, wherein is H, halo, or CN.

[0107] Embodiment 16.R 2 The compound or salt of embodiment 15, wherein is Cl.

[0108] Embodiment 17.R 2 The compound or salt of embodiment 16, wherein is CN.

[0109] Embodiment 18.R 3 is H or C 1-6 alkyl or halo, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 18. The compound or salt of any one of embodiments 1 to 17, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0110] Embodiment 19.R 3 The compound or salt of embodiment 18, wherein

[0111] Embodiment 20.R 3 or C 1-6 alkyl, C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 The compound or salt of embodiment 18, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0112] Embodiment 21.R 3 The compound or salt of embodiment 20, wherein is methyl.

[0113] Embodiment 22.R 3 The compound or salt of embodiment 18, wherein is halo.

[0114] Embodiment 23.R 3 The compound or salt of embodiment 22, wherein is fluoro.

[0115] Embodiment 24.R 4 The compound or salt of any one of embodiments 1-7 and 9-23, wherein is H.

[0116] Embodiment 25.R 5 The compound or salt of any one of embodiments 1-24, wherein is H.

[0117] Embodiment 26.X 1 is CH and R 2 is H or CN, and X 2 is CH or CMe, and X 3 is CH and R 5 is H, Het is thiazolyl, imidazolyl, isoxazolyl, 1,2,4-triazolyl or oxazolyl, Het is unsubstituted or has one or two R 6 2. The compound or salt of embodiment 1, substituted with:

[0118] Embodiment 27. Het is one R 6 27. The compound or salt of embodiment 26, optionally substituted with

[0119] Embodiment 28. Het is a group having two R 6 27. The compound or salt of embodiment 26, optionally substituted with

[0120] Embodiment 29. Each R 6 However, independently, halo, 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 or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C 3-5 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C6-10 aryl, or a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; C 3-5 cycloalkyl, 5- or 6-membered heterocycloalkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl is 1, 2, or 3 R 7 Each C may be substituted with 1-6 Alkyl or C 1-6 Alkylene is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 The compound or salt of any one of embodiments 1 to 28, optionally substituted with 1 or 2 substituents independently selected from alkyl.

[0121] Embodiment 30. Each R 6 However, independently, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylene-C(O)OC 1-6 alkyl, 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; C 6-10 aryl, or a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; a 5- or 6-membered heterocycloalkyl, C 6-10 An aryl or a 5- or 6-membered heteroaryl may have one, two, or three R 7 Each C may be substituted with 1-6 Alkyl or C 1-6 Alkylene is C 1-6 Alkoxy, OH, CN, COH, NR N R N , and CO2C 1-6 The compound or salt of embodiment 29, optionally substituted with 1 or 2 substituents independently selected from alkyl.

[0122] Embodiment 31. Each R 6 But independently, Halo, C 1-6alkyl, or a 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 is selected from 1, 2, or 3 R 7 Each C may be substituted with 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 The compound or salt of embodiment 30, optionally substituted with 1 or 2 substituents independently selected from alkyl.

[0123] Embodiment 32. At least one R 6 The compound or salt of embodiment 30, wherein is halo.

[0124] Embodiment 33. At least one R 6 The compound or salt of embodiment 32, wherein is chloro or bromo.

[0125] Embodiment 34. At least one R 6 C 1-6 alkyl, and each C 1-6 Alkyl is C 1-6 Alkoxy, OH, CN, COH, NR N R N and CO2C 1-6 The compound or salt of embodiment 30, optionally substituted with 1 or 2 substituents independently selected from alkyl.

[0126] Embodiment 35. At least one R 6 The compound or salt of embodiment 34, wherein is methyl, ethyl, or isopropyl.

[0127] Embodiment 36. Each R 6 is a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R 7 31. The compound or salt of embodiment 30, optionally substituted with:

[0128] Embodiment 37. At least one R 6 is pyrazolyl, pyridinyl, pyridazinyl, or pyrimidinyl, each of which is selected from the group consisting of one, two, or three R 7 37. The compound or salt of embodiment 36, optionally substituted with:

[0129] Embodiment 38. Each R 7 But independently, Halo, C 1-6 Alkyl or C 1-6 The compound or salt of any one of embodiments 1 to 37, wherein the compound or salt is haloalkyl.

[0130] Embodiment 39. At least one R 7 C 1-6 The compound or salt of embodiment 38, wherein R is alkyl.

[0131] Embodiment 40. At least one R 7 The compound or salt of embodiment 39, wherein is methyl.

[0132] Embodiment 41. A compound listed in Table A or a pharmaceutically acceptable salt thereof.

[0133] Embodiment 42. A pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 41 and a pharmaceutically acceptable excipient.

[0134] Embodiment 43. A method for modulating RBM39 protein, comprising contacting RBM39 protein with a compound or salt according to any one of embodiments 1 to 41 or a pharmaceutical composition according to embodiment 42.

[0135] Embodiment 44 The method of embodiment 43, wherein modulating RBM39 protein comprises degrading RBM39 protein.

[0136] Embodiment 45 The method of embodiment 43 or 44, wherein contacting the compound or salt comprises administering to the subject.

[0137] Embodiment 46 The method of embodiment 45, wherein the subject is a human.

[0138] Embodiment 47. A method for treating a disease associated with abnormal RBM39 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of Embodiments 1 to 41 or a pharmaceutical composition of Embodiment 42.

[0139] Embodiment 48. The method of embodiment 47, wherein the disease is cancer.

[0140] Embodiment 49. The method of embodiment 48, wherein the cancer is renal cell carcinoma. [Example]

[0141] Example 1 General method A [ka] Synthesis of 2-(benzylthio)-5-bromothiazole. To a stirred suspension of phenylmethanethiol (0.62 g, 5.03 mmol) and K2CO3 (1.39 g, 10.07 mmol) in DMF (10 mL) was added the compound 2-bromo-5-chlorothiazole (1.0 g, 5.03 mmol) at room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC and LCMS. (R of SM and product) f The values ​​were 0.3 and 0.5, respectively. TLC system: 20% EtOAc and petroleum ether). After completion of the reaction, the RM was quenched by adding ice-cold water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (3 × 30 mL), dried over NaSO, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography (using 100-200 silica, eluting with 15% EtOAc in petroleum ether) to give the product. [ka]

[0142] Synthesis of 5-bromothiazole-2-sulfonyl chloride. To a stirred solution of 2-(benzylthio)-5-chlorothiazole (0.5 g, 2.06 mmol) in acetic acid water (3:1) (10 mL) was added N-chlorosuccinimide (0.55 g, 4.13 mmol) at 0 °C and stirred at room temperature for 2 hours. After completion of 2 hours, the reaction mass was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with saturated aqueous NaHCO (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 further purification. [ka]

[0143] Synthesis of 5-bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide. To a stirred solution of 7-amino-4-methyl-1H-indole-3-carbonitrile (1 equivalent) and pyridine (5 equivalents) in DMF (7.0 mL) was added crude 5-chlorothiazole-2-sulfonyl chloride at 0° C. and stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC / achiral SFC to give the corresponding final compound.

[0144] LCMS: 369.16 [M+H]+ ion present. 1 H-NMR(400MHz,DMSO-d6):δ 12.11(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)

[0145] Example 2 General method B [ka] Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(morpholin-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), morpholine (98.7 mg, 1.13 mmol, 1.50 equiv.) and K2CO3 (209 mg, 1.51 mmol, 2.00 equiv.) were added, and the resulting mixture was stirred at 60 °C for 48 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography to give the title compound.

[0146] LCMS(ES) m / z:[M+H] + :404, 1 H NMR(300MHz,DMSO-d6,ppm)δ 11.99(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).

[0147] General method C [ka] 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 equiv.) and pyridin-3-ylboronic acid (185 mg, 1.51 mmol, 4 equiv.) in dioxane (2.4 mL) and HO (0.6 mL) was added NaCO (200 mg, 1.89 mmol, 5 equiv.) and Pd(dppf)Cl (27.6 mg, 0.0380 mmol, 0.1 equiv.). After stirring at 80 °C under a nitrogen atmosphere for 4 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the title compound.

[0148] LCMS(ES)m / z:[M+H]+:396.0,1H NMR(300MHz,DMSO-d6,ppm)δ 12.13(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).

[0149] General method D [ka] 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 equiv.) in DMF (5 mL) was added CuI (28.8 mg, 0.151 mmol, 0.3 equiv.) and Pd(PPh3)4 (116 mg, 0.101 mmol, 0.2 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 5 minutes under microwave irradiation. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography to provide the title compound.

[0150] LCMS(ES)m / z):[M+H] + :396.0, 1 H NMR(300MHz,DMSO-d6,ppm)δ 12.13(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).

[0151] General Procedure E [ka] 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 NaBH (11.5 mmol, 30 equiv.) at 0 °C, and the resulting mixture was stirred at room temperature for an additional 3 days. The residue was purified by preparative HPLC / achiral SFC to give the corresponding final compound.

[0152] LCMS: (LCMS(ES) m / z): [M+1] + :363, 1 H NMR(300MHz,DMSO-d6,ppm)δ 12.05(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),6.7 2(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).

[0153] General Procedure F [ka] Synthesis of 2-ethyl-1H-imidazole-4-sulfonyl chloride. To a solution of 2-ethyl-1H-imidazole (20 g, 208 mmol, 1 equiv.) in CHCl (1600 mL) was added chlorosulfonic acid (80 mL), and the resulting mixture was stirred overnight at reflux under a nitrogen atmosphere. SOCl (600 mL) was added to the mixture, and the resulting mixture was stirred at 100 °C for an additional 2 h and then concentrated under reduced pressure. The mixture was poured into ice water. The resulting mixture was extracted with DCM (4 × 150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. [ka]

[0154] Synthesis 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 (40.8 mmol, 1 equivalent) and pyridine (122 mmol, 3 equivalents) in DCM (100 mL) was added a solution of 2-ethyl-1H-imidazole-4-sulfonyl chloride (49.0 mmol, 1.2 equivalents) in DCM (20 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to provide the title compound.

[0155] LCMS (LCMS (ES) m / z): [M+1] + :330, 1 H NMR(400MHz,DMSO-d6,ppm)δ 12.41(s,1H),12.16 - 12.11(m,1H),9.77(s,1H),8.20(d,J=3.0Hz,1H),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).

[0156] General Procedure G [ka] Synthesis of ethyl 2-mercaptothiazole-4-carboxylate. To a stirred solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (2.5 g, 10.590 mmol, 1 equiv.) in EtOH (50.00 mL) was added dropwise a mixture of NaSH (2.97 g, 53.0 mmol, 5 equiv.) in EtOH (25 mL) at 80° C. The resulting mixture was stirred at 80° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and acidified to pH 3 with HCl (aq.). The precipitated solid was collected by filtration and washed with water (3×5 mL) to give the title compound, which was used in the next step without further purification. [ka]

[0157] 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 equiv.) in concentrated HCl (14 mL) was added NaClO (14.3 mL, 192 mmol, 26 equiv., 10% by weight in water) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 15 minutes. The precipitated solid was collected by filtration and washed with water (3×5 mL) to give the title compound, which was used in the next step without further purification. [ka]

[0158] 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 equiv.) and pyridine (1.15 g, 14.5 mmol, 3 equiv.) in DCM (25 mL) was treated with a solution of ethyl 2-(chlorosulfonyl)-1,3-thiazole-4-carboxylate (1.24 g, 4.85 mmol, 1 equiv.) (146-2) in DCM (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The residue was concentrated in vacuo and purified by silica gel chromatography to provide the title compound. [ka]

[0159] Synthesis of 2-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)thiazole-4-carboxylic acid. To a solution of ethyl 2-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-1,3-thiazole-4-carboxylate (200 mg, 0.51 mmol, 1 equiv) in THF (2 mL) was added 1 M aqueous LiOH (2 mL, 2.00 mmol, 3.90 equiv) dropwise at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was washed with DCM (1 × 10 mL), and the aqueous layer was acidified to pH 3 with 1 M HCl. The precipitated solid was collected by filtration and washed with water (3 × 3 mL). The material was purified by reverse-phase chromatography to provide the title compound.

[0160] LCMS: (LCMS(ES) m / z): [M+1] + :363, 1 H 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). [ka]

[0161] 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 equiv.) in DMF was added DIEA (2.07 mmol, 5.00 equiv.), ammonium chloride (5 equiv.), and HATU (0.62 mmol, 1.5 equiv.), and the resulting mixture was stirred at room temperature for an additional hour. The crude material was purified by reverse-phase chromatography to provide the title compound.

[0162] LCMS (LCMS (ES) m / z): [M+1] +:362, 1 H NMR(400MHz,DMSO-d6,ppm)δ 12.12(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).

[0163] General Procedure H [ka] Preparation of 2-ethyl-1H-imidazole-4-sulfonic acid. To a solution of 2-ethyl-1H-imidazole (2 g, 20.8 mmol, 1 equiv.) in CHCl (16.0 mL) was added HSOCl (8 mL), and the resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo and diluted with EtO (200 mL) and EtOH (20 mL) at room temperature, and the resulting mixture was stirred at room temperature for 0.5 h. The resulting mixture was filtered, and the filter cake was washed with EtO and dried under vacuum to give the crude product, which was used without further purification.

[0164] 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 equiv.) in DMF (66.0 mL) was added methyl 2-bromoacetate (3.44 g, 22.4 mmol, 1.2 equiv.) and KCO (7.77 g, 56.1 mmol, 3 equiv.), and the resulting mixture was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction mixture was diluted with MeOH, filtered, acidified with HCl in MeOH (4 M, 40 mL), and concentrated in vacuo to give the crude product, which was used without further purification.

[0165] 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 equiv.) 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 the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 267

[0166] 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 equiv.) and pyridine (0.62 g, 7.88 mmol, 3 equiv.) in DCM (14 mL) was added dropwise a solution of methyl 2-[4-(chlorosulfonyl)-2-ethylimidazol-1-yl]acetate (0.70 g, 2.62 mmol, 1 equiv.) in DCM (4 mL) at 0° C., and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1]+: 402

[0167] 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 equiv.) in MeOH (10 mL) and HO (10 mL) was added LiOH (0.03 g, 1.24 mmol, 1 equiv.), and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo, and the crude residue was purified by reverse-phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]: 388, 1H NMR(300MHz,DMSO-d6,ppm)δ 13.32(s,1H),12.15(s,1H),9.85(s,1H),8.20(d,J=3.1Hz,1H),7.63(s,1 H),6.81(s,2H),4.83(s,2H),2.59(d,J=7.4Hz,5H),1.21(t,J=7.5Hz,3H).

[0168] 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 equiv.) and aminocyclopropane (111 mg, 1.93 mmol, 5 equiv.) in THF (3 mL) was added T3P (185 mg, 0.58 mmol, 1.50 equiv.) and DIPEA (251 mg, 1.93 mmol, 5 equiv.), 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)δ 12.18(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).

[0169] General Procedure I [ka] 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 equiv.) in TFA (4 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography to give the title compound. LCMS (ES) m / z: [M+1]: 320, 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.87(d,J=3.1Hz,1H),10.01(s,1H),8.22(d,J=3.1Hz,1H),7.85(s,2H),7.4 7(d,J=7.9Hz,1H),7.30(s,1H),7.18(t,J=7.8Hz,1H),7.02(d,J=7.7Hz,1H).

[0170] General Procedure N Preparation of methyl 2-((5-(chlorosulfonyl)thiazol-2-yl)oxy)acetate [ka] 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 equiv.) in THF (40 mL) was added NaH (0.41 g, 17.2 mmol, 2.1 equiv.) and 2,5-dibromo-1,3-thiazole (2 g, 8.23 ​​mmol, 1 equiv.) 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 Na SO , 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

[0171] 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 equiv.) in dioxane (8 mL), Xantphos (91.8 mg, 0.159 mmol, 0.1 equiv.), Pd2(dba)3 (72.6 mg, 0.079 mmol, 0.05 equiv.), benzyl mercaptan (236 mg, 1.90 mmol, 1.2 equiv.), and DIPEA (615 mg, 4.76 mmol, 3 equiv.) were added, 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 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

[0172] 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 HO (7 mL) was added 1,3,5-trichloro-1,3,5-triazinane-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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :272

[0173] General Procedure J 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 [ka]

[0174] 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 equiv.) were reacted in the presence of pyridine in dichloromethane solution at 0° C. for 1 hour to form the sulfonamide intermediate. The intermediate was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give the title compound. LCMS (ES, m / z): [M+1] + :393, 1 H NMR(400MHz,DMSO-d6,ppm)δ 12(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).

[0175] The sulfonamide intermediate above for the preparation of N-(3-cyano-1H-indol-7-yl)-2-(2-hydroxy-2-methylpropoxy)thiazole-5-sulfonamide was reacted with MeMgCl in THF at 0°C for 2 hours to give the desired compound. The compound was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give the title compound.

[0176] LCMS(ES,m / z):[M+1] + :391, 1H NMR(400MHz,DMSO-d6,ppm)δ 11.99(d,J=3.1Hz,1H),10.38(s,1H),8.22(d,J=3.1Hz,1H),7.60 - 7.48(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).

[0177] Preparation of N-(3-cyano-1H-indol-7-yl)-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydrothiazole-5-sulfonamide [ka]

[0178] Methyl 2-(5-(chlorosulfonyl)-2-oxothiazol-3(2H)-yl)acetate and 7-amino-1H-indole-3-carbonitrile (100 mg, 0.636 mmol, 1 equiv.) were reacted in a similar manner as above. The intermediate was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give the desired compound. LCMS (ES, m / z): [M+1] + :391, 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.99(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).

[0179] Preparation of intermediate sulfonyl chlorides Preparation of 5-(2-hydroxy-2-methylpropyl)-1,3-thiazole-2-sulfonyl chloride [ka]

[0180] 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 equiv.) and CuBr (998 mg, 4.47 mmol, 1.1 equiv.) in MeCN (35 mL) was added t-BuONO (628 mg, 6.09 mmol, 1.5 equiv.) dropwise at −10° C., and the resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous NaSO 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

[0181] 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 equiv.) and benzyl mercaptan (224 mg, 1.81 mmol, 1.2 equiv.) in dioxane (7 mL), DIPEA (584 mg, 4.52 mmol, 3 equiv.), Xantphos (87.3 mg, 0.15 mmol, 0.1 equiv.), and Pd2(dba)3 (69.0 mg, 0.07 mmol, 0.05 equiv.) were added, 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

[0182] 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 equiv.) in THF (8 mL) was added CHCl (1.5 mL, 4.29 mmol, 3.0 equiv.) dropwise at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. The reaction was quenched with saturated NHCl 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. LCMS: (ES, m / z): [M+1] + :280

[0183] 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 equiv.) in AcOH (2 mL) and HO (2 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (285 mg, 1.44 mmol, 2 equiv.), and the resulting mixture was stirred at 40° C. under a nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification.

[0184] Preparation of oxazole-5-sulfonyl chloride [ka] Preparation of 2-(triisopropylsilyl)oxazole. To a solution of oxazole (1.0 g, 14.4 mmol, 1.0 equiv) in EtO (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. for 1 h under a nitrogen atmosphere. To the mixture was added triisopropylsilyl trifluoromethanesulfonate (4.44 g, 14.4 mmol, 1.0 equiv) 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :226

[0185] 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. for 1 h under a nitrogen atmosphere. SO and SOCl (2.39 g, 17.7 mmol, 2.0 equiv.) were added dropwise over 3 min at −40° C., 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :168

[0186] Preparation of 2-fluorothiazole-5-sulfonyl chloride [ka] Preparation of 5-(benzylsulfanyl)-1,3-thiazol-2-amine. To a solution of 5-bromo-1,3-thiazol-2-amine (30.0 g, 167 mmol, 1.0 equiv.) and benzyl mercaptan (25.0 g, 201 mmol, 1.2 equiv.) in DMF (300 mL) was added K2CO3 (34.7 g, 251 mmol, 1.5 equiv.), and the resulting mixture was stirred at room temperature for 3 hours. 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.

[0187] Preparation of 5-(benzylsulfanyl)-2-fluoro-1,3-thiazole. A solution of 5-(benzylsulfanyl)-1,3-thiazol-2-amine (10.0 g, 45.0 mmol, 1.0 equiv) in hydrogen fluoride pyridine (100 mL) was stirred at 0° C. for 1 hour under a nitrogen atmosphere. NaNO (3.7 g, 54.0 mmol, 1.2 equiv) was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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.

[0188] 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 equiv.) in AcOH (9 mL) and HO (4.5 mL) was added NCS (1600 mg, 12.0 mmol, 3.0 equiv.), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] +:202.

[0189] Preparation of 2-substituted 1,3-oxazole-4-sulfonyl chlorides [ka] Preparation of propanecarbonyl isothiocyanate. To a solution of propanoyl chloride (6.0 g, 64.9 mmol, 1.0 equiv.) in acetone (60 mL) was added potassium thiocyanate (6.3 g, 64.8 mmol, 1.0 equiv.), and the resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure to give the crude product, which was not further purified. LCMS (ES, m / z): [M+1] + :116.

[0190] 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 for 1 h under a nitrogen atmosphere. 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.

[0191] 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 equiv.) in AcOH (13 mL) and HO (6.5 mL) was added NCS (2.8 g, 20.7 mmol, 3.5 equiv.), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :196.

[0192] Preparation of 5-methylisoxazole-3-sulfonyl chloride [ka] 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 equiv.) in acetone (200 mL) was added benzyl bromide (19.0 g, 111 mmol, 1.1 equiv.) and K2CO3 (20.9 g, 151 mmol, 1.5 equiv.), 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 the crude product, which was used without further purification. LCMS (ES, m / z): [M-Cl]+: 190

[0193] 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 equiv.) in toluene (216 mL) and triphosgene (12.2 g, 41.1 mmol, 1 equiv.), DMF (1.20 g, 10% BTC by weight) was added, 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 the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :208

[0194] Preparation of 2-benzyl-5-methyl-1,2-oxazole-3-thione. To an aqueous solution of benzyl-3-chloro-5-methyl-1,2-oxazol-2-ium (6.80 g, 32.6 mmol, 1 equiv.) was added dropwise a solution of NaSH (3.65 g, 65.2 mmol, 2.0 equiv.) in HO (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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+ 1] + :206

[0195] 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 equiv.) in MeCN (110 mL) was added benzyl bromide (3.67 g, 21.4 mmol, 1 equiv.), and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1] + :206

[0196] Preparation of 5-methylisoxazole-3-sulfonyl chloride. To a solution of 3-(benzylsulfanyl)-5-methyl-1,2-oxazole (400 mg, 1.94 mmol, 1 equiv.) in DCM (2 mL) and HO (6 mL) was added trichloroisocyanuric acid (679 mg, 2.92 mmol, 1.5 equiv.), and the resulting mixture was stirred at 0° 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 NaSO, 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

[0197] Preparation of 1,3,4-oxadiazole-2-sulfonyl chloride [ka] Preparation of 2-(benzylthio)-1,3,4-oxadiazole. To a solution of N-formylhydrazine (5 g, 83.2 mmol, 1 equiv.) and KOH (5.14 g, 91.5 mmol, 1.1 equiv.) in EtOH (100 mL) was added CS2 (6.97 g, 91.5 mmol, 1.1 equiv.) dropwise at 0 °C, and the resulting mixture was stirred at 80 °C for 5 h under a nitrogen atmosphere. Benzyl bromide (4.98 g, 29.1 mmol, 0.35 equiv.) 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.

[0198] 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 equiv.) in HO (15 mL) and DCM (5 mL) was added trichloro-1,3,5-triazinane-2,4,6-trione (906 mg, 3.90 mmol, 1.5 equiv.) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. 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 to give the crude product, which was used without further purification.

[0199] Preparation of isoxazole-4-sulfonyl chloride [ka] Preparation of 2-(benzylsulfanyl)propanediol. To a solution of 2-chloropropanediol (8 g, 75.1 mmol, 1 equiv.) in DMF (160 mL) was added benzyl mercaptan (11.2 g, 90.1 mmol, 1.2 equiv.) and K2CO3 (31.1 g, 225 mmol, 3 equiv.), and the resulting mixture was stirred at 60 °C under a 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

[0200] Preparation of 4-(benzylsulfanyl)-1,2-oxazole. To a solution of 2-(benzylsulfanyl)propanediol (2.50 g, 12.9 mmol, 1 equiv.) in EtOH (50 mL), NH2OH.HCl (0.89 g, 12.9 mmol, 1 equiv.) was added, 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

[0201] Preparation of 1,2-oxazole-4-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)-1,2-oxazole (1.50 g, 7.84 mmol, 1 equiv.) in DCM (30 mL) and HO (90 mL) was added trichloroisocyanuric acid (2.73 g, 11.8 mmol, 1.5 equiv.), 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+aniline-Cl+1] + :225

[0202] Preparation of 1,2,5-oxadiazole-3-sulfonyl chloride [ka] Preparation of (1E,2E)-N-hydroxy-2-(hydroxyimino)acetimidoyl chloride. To a solution of NHOH.HCl (28.3 g, 407 mmol, 3 equiv.) in HO (300 mL) was added NaHCO (17.1 g, 203 mmol, 1.5 equiv.) in HO (300 mL) and 2,2,2-trichloroacetaldehyde (20.0 g, 135 mmol, 1 equiv.), and the resulting mixture was stirred at 0 °C for 4 h. To the mixture was added NaOH (21.7 g, 542 mmol, 4 equiv.) in HO (200 mL), and the resulting mixture was stirred at 0 °C for 5 h. The reaction mixture was quenched with HSO and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS(ES,m / z):[M+1]+:123

[0203] Preparation of (E)-N-[(2E)-2-(benzylsulfanyl)-2-(hydroxyimino)ethylidene]hydroxylamine. To a solution of (1E,2E)-N-hydroxy-2-(hydroxyimino)ethanecarbonimidoyl chloride (3 g, 24.4 mmol, 1 equiv.) in MeCN (60 mL) was added benzyl mercaptan (3.7 g, 29.3 mmol, 1.2 equiv.) and K2CO3 (10.1 g, 73.4 mmol, 3 equiv.), and the resulting mixture was stirred at room temperature under a 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

[0204] 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 equiv.) in THF (20 mL) was added SOCl (11.3 g, 95.1 mmol, 10 equiv.), and the resulting mixture was stirred at 50 °C overnight. The reaction was quenched with saturated NaHCO and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]: 193

[0205] 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 equiv.) in DCM (7 mL) and HO (22 mL) was added trichloroisocyanuric acid (1.45 g, 6.24 mmol, 1 equiv.), 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]: 169

[0206] Preparation of 3-cyclopropylisothiazole-5-sulfonyl chloride [ka] 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 equiv.) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (704 mg, 4.19 mmol, 3 equiv.) in dioxane (3 mL) and HO (1 mL) was added KPO (889 mg, 4.19 mmol, 3 equiv.) and Pd(dtbpf)Cl (273 mg, 0.419 mmol, 0.3 equiv.), 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

[0207] 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 equiv.) in DCM (1.8 mL) and HO (0.6 mL) was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (169 mg, 0.728 mmol, 1.5 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 anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :224

[0208] Preparation of 3-(difluoromethyl)isothiazole-5-sulfonyl chloride [ka] Preparation of 5-(benzylsulfanyl)-1,2-thiazole-3-carbaldehyde. To a solution of 5-bromo-1,2-thiazole-3-carbaldehyde (500 mg, 2.60 mmol, 1 equiv.) in DMF (10 mL) was added benzyl mercaptan (388 mg, 3.12 mmol, 1.2 equiv.), K2CO3 (1.07 g, 7.80 mmol, 3 equiv.), and the resulting mixture was stirred at room temperature for 1 hour. 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

[0209] 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 equiv.) in DCM (6 mL) was added DAST (226.0 mg, 1.40 mmol, 1.1 equiv.) 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

[0210] 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 equiv.) in DCM (1.5 mL) and HO (4.5 mL) was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (238 mg, 1.02 mmol, 1.1 equiv.) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :234

[0211] Preparation of 5-sulfamoylthiophene-2-sulfonyl chloride [ka] Preparation of 5-bromothiophene-2-sulfonamide. To a solution of 5-bromothiophene-2-sulfonyl chloride (500 mg, 1.91 mmol, 1 equiv.) in THF (10 mL) was added NH3·H2O (100 mg, 2.86 mmol, 1.5 equiv.) 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 to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 242.

[0212] Preparation of 5-(benzylsulfanyl)thiophene-2-sulfonamide. To a solution of 5-bromothiophene-2-sulfonamide (460 mg, 1.90 mmol, 1 equiv.) in dioxane (10 mL), DIPEA (736 mg, 5.70 mmol, 3 equiv.), benzyl mercaptan (283 mg, 2.28 mmol, 1.2 equiv.), Xantphos (109 mg, 0.19 mmol, 0.1 equiv.), and Pd2(dba)3 (86.9 mg, 0.09 mmol, 0.05 equiv.) were added, and the resulting mixture was stirred at 100 °C under a 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.

[0213] Preparation of 5-sulfamoylthiophene-2-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)thiophene-2-sulfonamide (320 mg, 1.12 mmol, 1 equiv.) 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 equiv.) at 0°C, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]: 262.

[0214] Preparation of 5-sulfamoylthiophene-3-sulfonyl chloride [ka]

[0215] Preparation of 4-bromothiophene-2-sulfonamide. To a solution of 4-bromothiophene-2-sulfonyl chloride (800 mg, 3.06 mmol, 1 equiv.) in THF (16 mL) was added NH3·H2O (78.1 mg, 4.59 mmol, 1.5 equiv.) 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 the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :242

[0216] Preparation of 4-(benzylsulfanyl)thiophene-2-sulfonamide. To a solution of 4-bromothiophene-2-sulfonamide (796 mg, 3.28 mmol, 1 equiv.) in dioxane (15 mL) was added benzyl mercaptan (490 mg, 3.94 mmol, 1.2 equiv.), Pd2(dba)3 (150 mg, 0.16 mmol, 0.05 equiv.), Xantphos (190 mg, 0.33 mmol, 0.1 equiv.), and DIPEA (1.27 g, 9.86 mmol, 3 equiv.), 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

[0217] Preparation of 5-sulfamoylthiophene-3-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)thiophene-2-sulfonamide (835 mg, 2.92 mmol, 1 equiv.) in HO (0.4 mL), AcOH (0.5 mL), and MeCN (12.5 mL) was added DCDMH (864 mg, 4.38 mmol, 1.2 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :262

[0218] Preparation of 2-sulfamoylthiazole-5-sulfonyl chloride [ka] 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 equiv.) and K2CO3 (4.67 g, 33.7 mmol, 2 equiv.) in DMF (82 mL) was added benzyl mercaptan (2.52 g, 20.2 mmol, 1.2 equiv.), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with EtOAc and extracted. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, 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

[0219] 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 equiv.) in DCM (12.5 mL) and HO (37.5 mL) was added trichloroisocyanuric acid (3.04 g, 13.1 mmol, 1.5 equiv.) at 0 °C, and the resulting mixture was stirred at room temperature under a 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]: 262

[0220] 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 equiv.) in THF (30 mL) was added NH3·H2O (0.92 g, 26.1 mmol, 4 equiv.), 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 the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]+: 243

[0221] 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 equiv.) in dioxane (16 mL) was added benzyl mercaptan (0.49 g, 3.94 mmol, 1.2 equiv.), DIPEA (1.28 g, 9.87 mmol, 3 equiv.), Xantphos (0.19 g, 0.329 mmol, 0.1 equiv.), and Pd2(dba)3 (0.15 g, 0.165 mmol, 0.05 equiv.), and the resulting mixture was stirred at 100 °C under a 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

[0222] 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 equiv.) in DCM (12 mL) and HO (38 mL) at 0 °C, trichloroisocyanuric acid (898 mg, 3.87 mmol, 1.5 equiv.) was added, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1]: 263

[0223] Preparation of 4-sulfamoylthiophene-2-sulfonyl chloride [ka] Preparation of 4-(benzylsulfanyl)-2-chlorothiophene. To a solution of 4-bromo-2-chlorothiophene (200 mg, 1.03 mmol, 1 equiv.) in dioxane (4 mL), benzyl mercaptan (151 mg, 1.21 mmol, 1.2 equiv.), DIPEA (392 mg, 3.04 mmol, 3 equiv.), Xantphos (58.6 mg, 0.101 mmol, 0.1 equiv.), and Pd2(dba)3 (46.4 mg, 0.051 mmol, 0.05 equiv.) were added, 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, filtered, 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

[0224] Preparation of 5-chlorothiophene-3-sulfonyl chloride. To a solution of 4-(benzylsulfanyl)-2-chlorothiophene (180 mg, 0.748 mmol, 1 equiv.) in AcOH (3 mL) and HO (1 mL) was added NCS (300 mg, 2.24 mmol, 3 equiv.) 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :217

[0225] 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

[0226] Preparation of 5-(benzylsulfanyl)thiophene-3-sulfonamide. To a solution of 5-chlorothiophene-3-sulfonamide (100 mg, 0.50 mmol, 1 equiv.) in dioxane (2 mL), benzyl mercaptan (75.4 mg, 0.607 mmol, 1.2 equiv.), DIPEA (196 mg, 1.52 mmol, 3 equiv.), Xantphos (29.3 mg, 0.051 mmol, 0.1 equiv.), and Pd2(dba)3 (23.2 mg, 0.025 mmol, 0.05 equiv.) were added, and the resulting mixture was stirred overnight at 100 °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, filtered, 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

[0227] Preparation of sulfamoylthiophene-2-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)thiophene-3-sulfonamide (55 mg, 0.19 mmol, 1 equiv.) in AcOH (1 mL) and HO (0.1 mL) was added NCS (77.2 mg, 0.58 mmol, 3 equiv.) 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :262

[0228] Preparation of 2-(2-hydroxy-2-methylpropyl)thiazole-5-sulfonyl chloride [ka] 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 equiv.) in THF (100 mL) was added LiHMDS (73.0 mL, 73.0 mmol, 1.3 equiv.), and the resulting mixture was stirred at −60° C. for 30 minutes under a nitrogen atmosphere. To the mixture was added acetone (3.91 g, 67.4 mmol, 1.2 equiv.) dropwise at −60° C., and the resulting mixture was stirred at 0° C. for 1 hour 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 NaSO, 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

[0229] 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 equiv.) in dioxane (3 mL), benzyl mercaptan (75.7 mg, 0.61 mmol, 1.2 equiv.), DIPEA (197 mg, 1.52 mmol, 3.00 equiv.), Xantphos (29.4 mg, 0.05 mmol, 0.10 equiv.), and Pd2(dba)3 (23.3 mg, 0.03 mmol, 0.05) were added, and the resulting mixture was stirred at 100 °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] + :280

[0230] 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 equiv.) in AcOH (1 mL) and HO (1 mL) was added NCS (196.2 mg, 1.23 mmol, 3.0 equiv.), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: [M+aniline-Cl+1] + :313

[0231] Preparation of tert-butyl (5-(chlorosulfonyl)thiazol-2-yl)carbamate [ka] 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 equiv.) in toluene (20 mL) was added iPrMgCl / LiCl (9 mL, 6.44 mmol, 1.8 equiv.) at −20° C., and the resulting mixture was stirred at room temperature for 1 h. SO2Cl2 (1.21 g, 8.96 mmol, 2.5 equiv.) 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

[0232] Preparation of tert-butyl (2-(chlorosulfonyl)thiazol-4-yl)carbamate [ka] Preparation of tert-butyl (2-(chlorosulfonyl)thiazol-4-yl)carbamate. To a solution of tert-butyl N-(2-bromo-1,3-thiazol-4-yl)carbamate (600 mg, 2.14 mmol, 1 equiv.) in toluene (12 mL) was added iPrMgCl.LiCl (2.98 mL, 3.86 mmol, 1.8 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 hour. SO2Cl2 (725 mg, 5.37 mmol, 2.5 equiv.) was added to the mixture, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. 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 the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :299

[0233] Preparation of 2-((dimethylamino)methyl)thiazole-5-sulfonyl chloride [ka] 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 equiv) 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 for 30 minutes under a nitrogen atmosphere. NaBHCN (392 mg, 6.24 mmol, 3 equiv) was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 9 with saturated NaHCO and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :221

[0234] 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 equiv) in dioxane (6 mL) was added DIPEA (526 mg, 4.07 mmol, 3 equiv), benzyl mercaptan (202 mg, 1.63 mmol, 1.2 equiv), Xantphos (78.5 mg, 0.136 mmol, 0.10 equiv), and Pd2(dba)3 (62.1 mg, 0.06 mmol, 0.05 equiv) and the resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :265

[0235] 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 equiv) in AcOH (4 mL) and HO (0.4 mL) was added NCS (303 mg, 2.26 mmol, 3 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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification.

[0236] Preparation of 2-(1,1-difluoroethyl)thiazole-5-sulfonyl chloride [ka] 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 equiv) in dioxane (10 mL) was added DIPEA (940 mg, 7.27 mmol, 3 equiv), benzyl mercaptan (331 mg, 2.66 mmol, 1.1 equiv), Xantphos (140 mg, 0.24 mmol, 0.10 equiv), and Pd2(dba)3 (111 mg, 0.12 mmol, 0.05 equiv) and the resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour. 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

[0237] 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 a nitrogen atmosphere for 24 hours. 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

[0238] 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 equiv) in MeCN (4.3 mL), AcOH (0.3 mL), and HO (0.2 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (473 mg, 2.40 mmol, 1.5 equiv), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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 to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :247

[0239] Preparation of 2-(3-hydroxyoxetan-3-yl)thiazole-5-sulfonyl chloride and 5-(3-hydroxyoxetan-3-yl)thiazole-2-sulfonyl chloride [ka] Preparation of 3-(5-bromo-1,3-thiazol-2-yl)oxetan-3-ol and 3-(2-bromothiazol-5-yl)oxetan-3-ol. To a solution of 2,5-dibromo-1,3-thiazole (3 g, 12.3 mmol, 1.0 equiv) in EtO (150 mL) was added n-BuLi (7.4 mL, 18.4 mmol, 1.5 equiv, 2.5 M in hexanes) at −100° C., and the resulting mixture was stirred at −100° C. for 1 h. To this solution was added a solution of oxetan-3-one (1.36 g, 18.4 mmol, 1.5 equiv) in EtO (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 [ka]

[0240] Preparation of 3-(5-(benzylthio)thiazol-2-yl)oxetan-3-ol. To a solution of 3-(5-bromo-1,3-thiazol-2-yl)oxetan-3-ol (750 mg, 3.17 mmol, 1.0 equiv) in dioxane (15 mL) was added DIPEA (1.23 g, 9.5 mmol, 3 equiv), Xantphos (183 mg, 0.31 mmol, 0.10 equiv), Pd2(dba)3 (145 mg, 0.15 mmol, 0.05 equiv), and benzyl mercaptan (473 mg, 3.81 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 crude residue was purified by reverse-phase flash chromatography to give the product. LCMS: (ES) m / z: [M+1] + :280

[0241] Preparation of 2-(3-hydroxyoxetan-3-yl)-1,3-thiazole-5-sulfonyl chloride. To a solution of 3-(5-(benzylthio)thiazol-2-yl)oxetan-3-ol (800 mg, 2.86 mmol, 1.0 equiv) in DCM (5 mL) and HO (15 mL) was added trichloroisocyanuric acid (732 mg, 3.15 mmol, 1.10 equiv) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the product, which was used without further purification.

[0242] Preparation of 5-(3-hydroxyoxetan-3-yl)thiazole-2-sulfonyl chloride [ka] Preparation of 3-(2-(benzylthio)thiazol-5-yl)oxetan-3-ol. To a solution of 3-(2-bromo-1,3-thiazol-5-yl)oxetan-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, 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] + :280

[0243] Preparation of 5-(3-hydroxyoxetan-3-yl)-1,3-thiazole-2-sulfonyl chloride. To a solution of 3-[2-(benzylsulfanyl)-1,3-thiazol-5-yl]oxetan-3-ol (1.05 g, 3.75 mmol, 1.0 equiv) in DCM (6.3 mL) and HO (18.9 mL) was added trichloroisocyanuric acid (0.96 g, 4.13 mmol, 1.1 equiv) at 0 °C, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the product, which was used without further purification.

[0244] Preparation of intermediate indoles and indazoles Preparation of 7-amino-4-methyl-1H-indole-3-carbonitrile [ka] Preparation of 7-bromo-4-methyl-1H-indole. To a solution of 1-bromo-4-methyl-2-nitrobenzene (100 g, 462 mmol, 1 equiv.) in THF (2 L) was added vinylmagnesium bromide (1.39 L, 1.39 mol, 1 M, 3 equiv.) at −45° C., and the resulting mixture was stirred at −45° C. for 1 hour. Saturated NH4Cl was added to the reaction mixture, which was then extracted with EtOAc. 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 crude residue was purified by silica gel column chromatography to give the product.

[0245] Preparation of 7-bromo-4-methyl-1H-indole-3-carbaldehyde. To a solution of POCl3 (26.7 mL, 286 mmol, 1.1 equiv.) in DMF (250 mL) was added 7-bromo-4-methyl-1H-indole (50 g, 238 mmol, 1 equiv.) 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 the crude product, which was used without further purification. LCMS (ES, m / z): 239.9 [M+1].

[0246] Preparation of (E)-7-bromo-4-methyl-1H-indole-3-carbaldehyde oxime. To a solution of 7-bromo-4-methyl-1H-indole-3-carbaldehyde (52 g, 218 mmol, 1 equiv.) in EtOH (1 L) was added NaCO (46.3 g, 437 mmol, 2 equiv.) in HO (130 mL) and NHOH.HCl (30.3 g, 437 mmol, 2 equiv.), 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 the crude product, which was used without further purification. LCMS (ES, m / z): 255.0 [M+2H] + .

[0247] 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 equiv.) in THF (50 mL) was added pyridine (33 mL, 403 mmol, 2 equiv.) and TFAA (143 mL, 403 mmol, 2 equiv.) 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): 232.9 [MH] -

[0248] Preparation of 7-amino-4-methyl-1H-indole-3-carbonitrile. To a solution of 7-bromo-4-methyl-1H-indole-3-carbonitrile (25 g, 106 mmol, 1 equiv.) in DMSO (125 mL) was added KCO (36.7 g, 266 mmol, 2.5 equiv.), CuI (4.05 g, 22 mmol, 0.2 equiv.), L-proline (2.45 g, 22 mmol, 0.2 equiv.), and aqueous NHOH (500 mL), and the resulting mixture was stirred at 120 °C for 3 h. The reaction mixture was filtered and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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] +

[0249] Preparation of 7-amino-1H-indole-3-carbonitrile [ka] Preparation of 7-nitro-1H-indole-3-carbaldehyde. To a solution of POCl3 (34.6 mL, 320 mmol, 1.1 equiv.) in DMF (50 mL) was added a solution of 7-nitro-1H-indole (50 g, 308 mmol, 1 equiv.) 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 the crude product, which was used without further purification. LCMS (ES, m / z): 190.98 [M+1] + .

[0250] 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 equiv.) in EtOH (1 L) was added NaCO (100 g, 945 mmol, 3 equiv.) in HO (240 mL), NHOH.HCl (54.7 g, 687 mmol, 2.5 equiv.), 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 the crude product, which was used without further purification. LCMS (ES, m / z): 205.98 [M+1] + .

[0251] 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 equiv.) in THF (1.2 L) was added pyridine (70 mL, 877 mmol, 3 equiv.) and TFAA (143 mL, 1024 mmol, 3.5 equiv.), 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): 185.97 [MH] - .

[0252] Preparation of 7-amino-1H-indole-3-carbonitrile. To a solution of 7-nitro-1H-indole-3-carbonitrile (50 g, 267 mmol, 1 equiv.) in EtOH (500 mL) and HO (500 mL), iron powder (37.24 g, 667 mmol, 3 equiv.) and NH4Cl (71.4 g, 1336 mmol, 5 equiv.) were added at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, 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] + .

[0253] Preparation of 7-amino-4-(trifluoromethyl)-1H-indole-3-carbonitrile [ka] 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 equiv.) (SM1) and EtN (19.9 g, 196 mmol, 3 equiv.) in DCM (270 mL) was added TFAA (27.5 g, 131 mmol, 2 equiv.) dropwise under a nitrogen atmosphere at 0° C., 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification.

[0254] 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 equiv.) in THF (450 mL) was added vinylmagnesium bromide (451 mL, 451 mmol, 6 equiv., 1 M in THF) dropwise at −40° C. under a nitrogen atmosphere, and the resulting mixture was stirred at −40° C. for 1 h. 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

[0255] 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 equiv.) in DMF (75 mL) was added chlorosulfonyl isocyanate (5.30 g, 37.5 mmol, 3 equiv.) dropwise under a nitrogen atmosphere at 0° C., and the resulting mixture was stirred at 0° C. for 1 hour. 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

[0256] 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 equiv.) 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 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product. LCMS (ES, m / z): [M+1]+ :226

[0257] Preparation of 3-(trifluoromethyl)-1H-indol-7-amine analogues [ka] 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 equiv.) in DMF (10 mL) was added NIS (875 mg, 3.88 mmol, 1.05 equiv.) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted 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.

[0258] 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 equiv.) and methyl 2,2-difluoro-2-sulfoacetate (3 g, 15.6 mmol, 5 equiv.) in DMF (20 mL) was added CuI (118 mg, 0.62 mmol, 0.2 equiv.), and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. 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.

[0259] 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 equiv.) in 50 mL of EtOAc was added Pd / C (10% wt.), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the product.

[0260] Preparation of 3-chloro-1H-indol-7-amine analogues [ka] 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 equiv.) in DMF (20 mL) was added NCS (815 mg, 6.10 mmol, 1.1 equiv.) in DMF (1 mL) dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 2 hours. 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.

[0261] 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 equiv.) in EtOH (55 mL), Rennie Ni (440 mg, 5.12 mmol, 1 equiv.) and hydrazine hydrate (330 mg, 10.2 mmol, 2 equiv.) were added at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with EtOH, and dried under vacuum to give the product, which was used without further purification.

[0262] Preparation of 7-amino-1H-indole-3-carbonitrile analogues [ka] 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 equiv.) in DMF (20 mL) was added NIS (1.4 g, 6.10 mmol, 1.1 equiv.), and the resulting mixture was stirred at room temperature for 8 hours. 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.

[0263] Preparation of 4-fluoro-7-nitro-1H-indole-3-carbonitrile. To a solution of 4-fluoro-3-iodo-7-nitro-1H-indole (1.5 g, 4.90 mmol, 1 equiv.) in DMF (20 mL) was added Zn(CN) (345 mg, 2.94 mmol, 0.6 equiv.) and Pd(PPh) (566 mg, 0.49 mmol, 0.1 equiv.), and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction was quenched with saturated NH Cl and extracted with DCM. The combined organic layers were washed with brine, dried over Na SO , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product.

[0264] 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 equiv.) and Pd / C (10% wt.) in EtOAc (10 mL V) was stirred under a hydrogen atmosphere at room temperature for 1 h. The resulting mixture was filtered and concentrated under reduced pressure to give the product, which was used without further purification.

[0265] Preparation of 7-amino-1H-indazole-3-carbonitrile analogues [ka] Preparation of 3-iodo-7-nitro-1H-indazole. To a solution of 7-nitroindazole (4 g, 24 mmol, 1 equiv.) in DMF (80 mL) was added NIS (6.6 g, 29 mmol, 1.2 equiv.), 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

[0266] 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 equiv.) in DMF (80 mL) was added Zn(CN) (1.02 g, 8.71 mmol, 0.6 equiv.) and XantPhos-Pd-G (1.29 g, 1.45 mmol, 0.1 equiv.), and the resulting mixture was stirred at 100 °C for 1 h under a nitrogen atmosphere. 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

[0267] 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 equiv.) in EtOH (70 mL) and HO (14 mL) was added NH4Cl (7.96 g, 148 mmol, 10 equiv.) and Fe (8.31 g, 148 mmol, 10 equiv.), 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 layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product. LCMS (ES, m / z): [M+1] + :159

[0268] Preparation of 3-chloro-1H-indazol-7-amine [ka] Preparation of 3-chloro-1H-indazol-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) under a hydrogen atmosphere at room temperature, and the resulting mixture was stirred at room temperature for 4 hours. 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

[0269] Preparation of 7-amino-4-ethyl-1H-indole-3-carbonitrile [ka] Preparation of N-(4-bromo-3-cyano-1H-indol-7-yl)-2,2,2-trifluoroacetamide. 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) was added chlorosulfonyl isocyanate (3.50 g, 24.4 mmol, 3 equiv.) dropwise 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

[0270] 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 equiv.) in THF (20 mL) was added diethylzinc (1.12 g, 9 mmol, 3 equiv.) and Pd(dppf)Cl (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, and the crude product was purified by reverse-phase flash chromatography to give the product. LCMS (ES, m / z): [M+1] + :282

[0271] Preparation of 7-amino-4-methyl-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 equiv.) in MeOH (5 mL) was added a solution of 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 in vacuo to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :186

[0272] Preparation of 7-amino-4-methoxy-1H-indole-3-carbonitrile [ka] 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 equiv.) in ACN (10 mL) and DMF (5 mL) was added chlorosulfonyl isocyanate (1.10 g, 7.81 mmol, 3 equiv.) dropwise at 0° C., and the resulting mixture was stirred at 0° C. for 3 hours under a nitrogen atmosphere. 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] + :218.

[0273] 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 equiv.) in MeOH (100 mL) was added Rennie Ni (500 mg, 100% wt.), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The residue was concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :188

[0274] Preparation of 7-amino-4-methoxy-1H-indole-3-carbonitrile [ka] Preparation of 7-bromo-5-methoxy-1H-indole. To a solution of 2-bromo-4-methoxy-1-nitrobenzene (10 g, 43 mmol, 1 equiv.) in THF (200 mL) was added vinylmagnesium bromide (57.3 mL, 172 mmol, 4 equiv., 3 M in THF) dropwise at −78° C. under a nitrogen atmosphere, and the resulting mixture was stirred at −78° 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 NaSO, 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

[0275] Preparation of 7-bromo-5-methoxy-1H-indole-3-carbonitrile. To a solution of 7-bromo-5-methoxy-1H-indole (5 g, 22.1 mmol, 1 equiv.) in DMF (100 mL) was added chlorosulfonyl isocyanate (6.26 g, 44.2 mmol, 2 equiv.) dropwise 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 NaSO, 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

[0276] Preparation of 7-((diphenylmethylene)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 equiv.) in THF (50 mL) under a nitrogen atmosphere was added diphenylmethanimine (3.75 g, 20.7 mmol, 2 equiv.), PEPPSI-iPr-Pd (1.01 g, 1.03 mmol, 0.1 equiv.), and LiHMDS (31 mL, 31.1 mmol, 3 equiv., 1 M in THF), 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

[0277] Preparation of 7-amino-5-methoxy-1H-indole-3-carbonitrile. To a solution of 7-((diphenylmethylene)amino)-5-methoxy-1H-indole-3-carbonitrile (3.5 g, 9.96 mmol, 1 equiv.) in THF (35 mL) was added HCl (35 mL, 70 mmol, 7 equiv., 2 M in THF) dropwise at room temperature under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. 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

[0278] Preparation of 7-amino-5-methyl-1H-indole-3-carbonitrile [ka] 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 equiv.) in THF (90 mL) was added NaH (0.49 g, 20.3 mmol, 1.2 equiv.) and SEM-Cl (3.67 g, 21.9 mmol, 1.3 equiv.) dropwise at 0° C. under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :396.

[0279] 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 equiv.) in dioxane (100 mL) and HO (25 mL) was added KPO (9.96 g, 46.9 mmol, 3 equiv.), RuPhos-Pd-G (650 mg, 0.8 mmol, 0.05 equiv.), and trimethyl-1,3,5,2,4,6-trioxatriborinane (5.89 g, 47 mmol, 3 equiv.), and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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.

[0280] 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 equiv) in MeOH (160 mL) at room temperature was added 10% Pd / C (0.63 g, 50% wt), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. 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.

[0281] 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 equiv.) in TFA (50 mL) was stirred at 40° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The crude residue was mixed with saturated NaHCO to pH 8, 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] + :172.

[0282] Preparation of 3,4-dichloro-1H-indol-7-amine [ka] 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 equiv.) in DMF (40 mL) was added NCS (1.49 g, 11.1 mmol, 1.1 equiv.) 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

[0283] Preparation of 3,4-dichloro-1H-indol-7-amine. To a solution of 3,4-dichloro-7-nitro-1H-indole (2.05 g, 8.87 mmol, 1 equiv.) in MeOH (50 mL) was added Rennie-Ni (20% wt.), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature 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

[0284] Preparation of 7-amino-3-chloro-1H-indole-4-carbonitrile [ka] 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 equiv.) in DMF (160 mL) was added Zn(CN) (5.81 g, 49.4 mmol, 1.2 equiv.) and XPhos-Pd-G (3.49 g, 4.12 mmol, 0.1 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :186

[0285] 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 equiv.) in DMF (10 mL) was added NCS (0.80 g, 6 mmol, 1.1 equiv.), and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :220

[0286] Preparation of 3-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 equiv.) in EtOH (18 mL) and HO (6 mL), NH4Cl (2.90 g, 54.2 mmol, 10 equiv.) and Fe (3.02 g, 54.2 mmol, 10 equiv.) were added at room temperature, and the resulting mixture was stirred at 80 °C under a 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 the crude product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :192

[0287] Preparation of 7-amino-3-methyl-1H-indole-4-carbonitrile [ka] 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 equiv.) in DMF (25 mL) was added NIS (1.32 g, 5.88 mmol, 1.1 equiv.) in portions at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :312

[0288] 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 equiv.) in dioxane (24 mL) and HO (6 mL), KPO (3.1 g, 15 mmol, 3 equiv.), Pd(PPh) (0.56 g, 0.48 mmol, 0.1 equiv.), and trimethyl-1,3,5,2,4,6-trioxatriborinane (6.14 g, 48.8 mmol, 10 equiv.) were added 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 the crude product, which was used without further purification. LCMS: (ES, m / z): [M-1] - :200

[0289] 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 equiv.) in MeOH (60 mL) was added Rennie Ni (0.48 g, 40% wt.) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. 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

[0290] Preparation of 3-amino-4H-thieno[3,2-b]pyrrole-6-carbonitrile [ka] 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 equiv.) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M-1] - :386

[0291] 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 equiv.) in DMF (40 mL) was added Zn(CN) (1.28 g, 10.8 mmol, 0.6 equiv.) and Xantphos-Pd-G (1.61 g, 1.81 mmol, 0.10 equiv.), and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction mixture was filtered and extracted with EtOAc. The combined organic layers were washed, dried over anhydrous NaSO, 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

[0292] 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 equiv.) in THF (28 mL) was added MeOH (14 mL) and HO (20 mL). LiOH-HO (8.01 g, 190 mmol, 16 equiv.) was added, and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature, washed with EtOAc, and brought to pH 3 with 2 M 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

[0293] 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 equiv.) in quinoline (40 mL) was added Cu (34.9 mg, 0.549 mmol, 0.2 equiv.), and the resulting mixture was stirred at 160° C. for 20 minutes under microwave irradiation. The reaction mixture was diluted with 2M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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] + :227

[0294] Preparation of 3-[(diphenylmethylidene)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 diphenylmethanimine (478 mg, 2.64 mmol, 2 equiv.), and the resulting mixture was stirred at 85 °C under a 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

[0295] Preparation of 3-amino-4H-thieno[3,2-b]pyrrole-6-carbonitrile. To a solution of 3-[3,2-b]-4H-thienopyrrole-6-carbonitrile (1.3 g, 3.97 mmol, 1.0 equiv.) in THF (13 mL) was added 2.0 M HCl (aq.) (13 mL, 26 mmol, 6.5 equiv.) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. 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.

[0296] Preparation of 2-(7-amino-1H-indol-3-yl)acetonitrile [ka] Preparation of N,N-dimethyl-1-(7-nitro-1H-indol-3-yl)methanamine. To a solution of [(dimethylamino)methyl]dimethylamine (1.39 g, 13.6 mmol, 1.1 equiv.) in AcOH (30 mL) was added 7-nitroindole (2.0 g, 12.3 mmol, 1.0 equiv.) in AcOH (30 mL), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3.5 hours. 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

[0297] 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 equiv) in DMF (0.3 mL), HO (0.3 mL), and THF (15 mL) was added MeI (485 mg, 3.42 mmol, 2.5 equiv), and the resulting mixture was stirred at 70° C. for 15 minutes under a nitrogen atmosphere. NaCN (335 mg, 6.84 mmol, 5 equiv) was added to the mixture, and the resulting mixture was stirred at 70° C. for 2 hours. 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

[0298] 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 HO (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 hours. 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

[0299] Example 3: Preparation of specific final compounds Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(dimethylphosphoryl)thiazole-2-sulfonamide (Compound 111) [ka] 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 equiv.) and (methylphosphonoyl)methane (197 mg, 2.51 mmol, 5 equiv.) in DMF (10 mL) was added Pd(OAc) (11.3 mg, 0.05 mmol, 0.10 equiv.), Xantphos (29.0 mg, 0.050 mmol, 0.1 equiv.), and KPO (160.29 mg, 0.754 mmol, 1.5 equiv.), and the resulting mixture was stirred at 95 °C for 1.5 min in a microwave oven. The residue was purified by reverse phase flash chromatography to give the product. LCMS (ES, m / z): [M+1]+: 395, 1H NMR(300MHz,DMSO-d6,ppm)δ 12.13(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).

[0300] Preparation of N-(3-cyano-1H-indol-7-yl)-2-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-imidazole-5-sulfonamide (compound 394) [ka] Preparation of 2-bromo-1-methylimidazole-4-sulfonyl chloride. A solution of 2-bromo-1-methylimidazole (2 g, 12.4 mmol, 1 equiv) 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, filtered, 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 H NMR(300MHz,DMSO-d6,ppm)δ 7.76(s,1H),3.69(s,3H).

[0301] Preparation of 2-bromo-N-(3-cyano-1H-indol-7-yl)-1-methylimidazole-4-sulfonamide. To a stirred mixture of 7-amino-1H-indole-3-carbonitrile (350 mg, 2.22 mmol, 1 equiv.) in THF (10 mL), 2-bromo-1-methylimidazole-4-sulfonyl chloride (636 mg, 2.45 mmol, 1.10 equiv.) and pyridine (528 mg, 6.70 mmol, 3 equiv.) were added, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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 [M+1] + :380

[0302] 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 equiv.) in THF (20.0 mL) was added NaH (158 mg, 6.58 mmol, 2.50 equiv.) under a nitrogen atmosphere at 0° C., and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. To the mixture was added SEM-Cl (965 mg, 5.79 mmol, 2.20 equiv.), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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

[0303] 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 equiv) in THF (10.0 mL) at 0° C. was added NaH (37.5 mg, 1.56 mmol, 2 equiv), and the resulting mixture was stirred at 80° C. under a 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 equiv.) in THF (1 mL), and the resulting mixture was stirred at 80° C. under a 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS [M+1] + :740

[0304] 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 equiv.) in TBAF (2 mL, 1 M in THF) was added 1,2-ethylenediamine (29.6 mg, 0.49 mmol, 1.50 equiv.), and the resulting mixture was stirred at 65° C. under a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. To the crude residue was added TFA (6 mL), and the resulting mixture was stirred at 75°C under a nitrogen atmosphere for 0.5 hours. 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, 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.92(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).

[0305] Preparation of methyl 2-(5-(chlorosulfonyl)-2-oxothiazol-3(2H)-yl)acetate [ka] 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 equiv.) in EtOAc (10 mL) was added 4 M HCl (10 mL, 40 mmol, 10 equiv.), 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

[0306] 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 equiv.) in acetone (20 mL), methyl 2-bromoacetate (706 mg, 4.62 mmol, 1.2 equiv.) and CsCO (1.88 g, 5.77 mmol, 1.5 equiv.) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :296

[0307] 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 equiv.) in DCM (5 mL) and HO (16 mL) was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (778 mg, 3.35 mmol, 1.5 equiv.) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. 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 to give the crude product, which was used without further purification. LCMS (ES, m / z): [M+1] + :272

[0308] Preparation of N-(3-cyano-1H-indol-7-yl)thiazole-5-sulfonamide (compound 50) [ka] Preparation of 5-(benzylsulfanyl)-1,3-thiazole. To a solution of 5-bromo-1,3-thiazole (30 g, 184 mmol, 1 equiv.) in dioxane (600 mL), benzyl mercaptan (27 g, 219 mmol, 1.2 equiv.), DIPEA (71 g, 552 mmol, 3 equiv.), Xantphos (10.6 g, 18.3 mmol, 0.10 equiv.), and Pd2(dba)3 (8.37 g, 9.15 mmol, 0.05 equiv.) were added, 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 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

[0309] Preparation of thiazole-5-sulfonyl chloride. To a solution of 5-(benzylsulfanyl)-1,3-thiazole (30 g, 145 mmol, 1 equiv.) in MeCN (300 mL), AcOH (17 mL), and HO (13 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (43 g, 217 mmol, 1.50 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 NaSO, and concentrated under reduced pressure to give the crude product, which was used without further purification. LCMS ES, m / z: [M+aniline+1] + :240

[0310] Preparation of N-(3-cyano-1H-indol-7-yl)-1,3-thiazole-5-sulfonamide. To a solution of 7-amino-1H-indole-3-carbonitrile (15 g, 95.4 mmol, 1 equiv.) in DCM (300 mL) was added pyridine (23 g, 286 mmol, 3 equiv.) and 1,3-thiazole-5-sulfonyl chloride (21 g, 115 mmol, 1.2 equiv.) in DCM (150 mL) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography to give the title compound (10 g, 34%). LCMS ES, m / z: [M+1] + :305, 1 H NMR-PH-ROP-2021-03-259-0:(300MHz,DMSO-d 6, ppm)δ 12.01(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)δ 161.28,147.82,136.72,135.54,131.25,129.04,122.52,122.33,119.33,117.69,116.35,85.42.

[0311] Preparation of N-(3-cyano-1H-indol-7-yl)-2-oxo-2,3-dihydrothiazole-5-sulfonamide (compound 353) [ka] 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 equiv.) and pyridine (301 mg, 3.81 mmol, 3 equiv.) in DCM (4 mL) was added 2-methoxy-1,3-thiazole-5-sulfonyl chloride (326 mg, 1.52 mmol, 1.2 equiv.) 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 NaSO, and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash to give the product. LCMS: (ES, m / z): [M+1] + :335, 1 H NMR(300MHz,DMSO-d6,ppm)δ 11.98(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).

[0312] 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 (150 mg, 0.449 mmol, 1 equiv) in concentrated HCl (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was neutralized to pH 7 with saturated Na2CO3 and extracted with EtOAc (2 x 5 mL). 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 to give the product. LCMS (ES, m / z): [M+1] + :319, 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.84-12.33(s,2H),10.30(s,1H),8.22(dd,J=3.1,1.7Hz,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).

[0313] 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) [ka] 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

[0314] 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 hour. 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

[0315] 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 (1 g, 2.73 mol, 1.0 equiv.) in DMF (20 mL) was added K2CO3 (1.13 g, 8.19 mmol, 3 equiv.) and 2,2-dimethyloxirane (0.39 g, 5.46 mmol, 2 equiv.), 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography to give the product.

[0316] LCMS: (ES) m / z: [M+1] + : 438, HNMR: (300MHz, DMSO-d 6, ppm)δ 11.93(s,1H),9.64(s,1H),8.20(s,1H),7.72(s,1H),7.41(dd,J=8.0,1.0Hz,1H),7.0 8(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).

[0317] 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 (460 mg, 1.05 mol, 1.0 equiv.) in DCM (20 mL) was added EtN (318 mg, 3.15 mmol, 3 equiv.) and SEM-Cl (524 mg, 3.15 mmol, 3 equiv.), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES) m / z: [M+1] + :568

[0318] 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 equiv) in THF (10 mL) was added NaH (135 mg, 5.63 mmol, 5 equiv) 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 equiv) in THF (10 mL) at 0° C., and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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] + :598

[0319] 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 minutes. The reaction mixture was concentrated in vacuo. 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)δ 11.97 - 11.92(m,1H),11.01(s,1H),9.89(s,1H),8.24(s,1H),7.47(d,J=8.0Hz,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).

[0320] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-2-ethyl-1H-imidazole-4-sulfonamide (compound 8) [ka] Preparation of 2-ethyl-1H-imidazole-4-sulfonyl chloride. To a solution of 2-ethyl-1H-imidazole (20 g, 208 mmol, 1.0 equiv) in CHCl (1.6 L) was added chlorosulfonic acid (80 mL), and the resulting mixture was stirred overnight at reflux under a nitrogen atmosphere. SOCl (600 mL) and DMF (3 drops, catalytic) were added to the mixture, and the resulting mixture was stirred at 100 °C for an additional 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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES, m / z): [M+1]+ :195

[0321] 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 (7 g, 40.9 mmol, 1 eq) and pyridine (7.32 g, 122 mmol, 3 eq) in DCM (100 mL) was added 2-ethyl-1H-imidazole-4-sulfonyl chloride (9.56 g, 49.0 mmol, 1.2 eq) in DCM (40 mL), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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)δ 12.41(s,1H),12.16 - 12.11(m,1H),9.77(s,1H),8.20(d,J=3.0Hz,1H),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).

[0322] Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-4-(trifluoromethyl)-1,3-thiazole-2-sulfonamide (compound 12) [ka] 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 equiv.) in DMF (300 mL) was added benzyl mercaptan (9.64 g, 77.5 mmol, 1.2 equiv.) and K2CO3 (13.4 g, 96.9 mmol, 1.5 equiv.), and the resulting mixture was stirred at room temperature for an additional hour. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, 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

[0323] 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 HO (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 an additional 2 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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

[0324] 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 (7 g, 40.9 mmol, 1.0 equiv.) in DCM (140 mL) was added a solution of pyridine (16.2 g, 204 mmol, 5.0 equiv.) and 4-(trifluoromethyl)-1,3-thiazole-2-sulfonyl chloride (11.3 g, 44.9 mmol, 1.1 equiv.) in DCM (5 mL) dropwise at 0° C., and the resulting mixture was stirred at room temperature for an additional 1 h. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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)δ 12.23(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).

[0325] Preparation of N-(3-chloro-4-fluoro-1H-indol-7-yl)-4-(trifluoromethyl)-1,3-thiazole-2-sulfonamide (Compound 159) [ka] 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 equiv.) in DMF (20 mL) was added NCS (815 mg, 6.10 mmol, 1.1 equiv.), and the resulting mixture was stirred at 65° C. under a nitrogen atmosphere for 3 hours. 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.

[0326] 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 equiv.) in EtOH (55 mL) was added Rennie Ni (1.1 g, 100% wt.) and hydrazine hydrate (0.40 g, 10.2 mmol, 2.0 equiv., 80% solution), and the resulting mixture was stirred at room temperature for 30 minutes. 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.

[0327] 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. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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).

[0328] Preparation of N-(3-cyano-4-ethyl-1H-indol-7-yl)-1,3-thiazole-2-sulfonamide (Compound 216) [ka] Preparation of N-(4-bromo-3-cyano-1H-indol-7-yl)-2,2,2-trifluoroacetamide. 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) was added chlorosulfonyl isocyanate (3.50 g, 24.4 mmol, 3.00 equiv) dropwise 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, filtered, 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

[0329] 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)Cl (0.11 g, 0.15 mmol, 0.05 equiv.), and the resulting mixture was stirred at 70° C. under a nitrogen atmosphere for 1 hour. 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

[0330] Preparation of 7-amino-4-ethyl-1H-indole-3-carbonitrile. N-(3-cyano-4-ethyl-1H-indol-7-yl)-2,2,2-trifluoroacetamide (750 mg, 2.66 mmol, 1.0 equiv.) and NH3 (g) were added to a solution of MeOH (8 mL) and the resulting mixture was stirred at room temperature for 3 days. The resulting mixture was concentrated in vacuo to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :186

[0331] 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 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) dropwise at 0° C., and the resulting mixture was stirred at room temperature for an additional 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] + :333, 1 H NMR(300MHz,DMSO-d6,ppm)δ 12.13(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).

[0332] Preparation of N-(3-cyano-1H-indazol-7-yl)-1,3-thiazole-5-sulfonamide (compound 244) [ka] 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), iPrMgCl-LiCl (9.1 mL, 11.9 mmol, 1.3 equiv., 1.3 M in THF) was added dropwise at -20 °C, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. To the reaction mixture, SO2Cl2 (1.11 mL, 13.7 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 30 minutes. 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.

[0333] Preparation of N-(3-cyano-1H-indazol-7-yl)-1,3-thiazole-5-sulfonamide. To a solution of 7-amino-1H-indazole-3-carbonitrile (150 mg, 0.94 mmol, 1.0 equiv) in DCM (3 mL) was added pyridine (225 mg, 2.84 mmol, 3.0 equiv) and 1,3-thiazole-5-sulfonyl chloride (348 mg, 1.89 mmol, 2.0 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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)δ 14.38(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).

[0334] Preparation of N-(3-cyano-1H-indol-7-yl)-3-methyl-1,2-thiazole-5-sulfonamide (Compound 256) [ka] 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), 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.) were added, 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, filtered, 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

[0335] 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 equiv.) in DCM (108 mL) and HO (324 mL) was added trichloroisocyanuric acid (29.9 g, 129 mmol, 1.5 equiv.) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. 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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification.

[0336] 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 hour. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, 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] + :319, 1 H NMR(300MHz,DMSO-d6,ppm)δ 12.07(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).

[0337] Preparation of N-(3-cyano-1H-indol-7-yl)-2-cyclopropyl-1,3-oxazole-5-sulfonamide (compound 107) [ka] 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, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :282

[0338] Preparation of S-benzyl 2-aminoethanethioate. 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

[0339] Preparation of N-[2-(benzylsulfanyl)-2-oxoethyl]cyclopropanecarboxamide. To a solution of S-benzyl 2-aminoethanethioate (98 g, 0.34 mol, 1.0 equiv.) in DCM (1 L) was added EtN (104 g, 1.03 mol, 3.0 equiv.) and cyclopropanecarbonyl chloride (42.7 g, 0.41 mol, 1.2 equiv.) 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

[0340] 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 POCl (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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :232

[0341] 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 equiv.) (450-2) in AcOH (265 mL) and HO (135 mL) was added NCS (40.4 g, 303 mol, 3.5 equiv.) 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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS (ES, m / z): [M+1] + :207

[0342] 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 a solution of 2-cyclopropyl-1,3-oxazole-5-sulfonyl chloride (12.7 g, 611 mmol, 1.2 equiv.) in DCM (20 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. 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, 1H NMR(400MHz,DMSO-d6,ppm)δ 12.09(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).

[0343] Preparation of N-(3-cyano-1H-indol-7-yl)-4-(hydroxymethyl)thiophene-2-sulfonamide (compound 306) [ka] Preparation of [5-(benzylsulfanyl)thiophen-3-yl]methanol. To a solution of (5-bromothiophen-3-yl)methanol (600 mg, 3.1 mmol, 1.0 equiv.) in dioxane (12 mL), Xantphos (179 mg, 0.311 mmol, 0.1 equiv.), dioxane (12 mL), DIPEA (1.20 g, 9.32 mmol, 3 equiv.), benzyl mercaptan (462 mg, 3.73 mol, 1.2 equiv.), and Pd2(dba)3 (142 mg, 0.155 mmol, 0.05 equiv.) were added, and the resulting mixture was stirred at 100 °C under a 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

[0344] Preparation of 4-(hydroxymethyl)thiophene-2-sulfonyl chloride. To a solution of [5-(benzylsulfanyl)thiophen-3-yl]methanol (500 mg, 2.1 mmol, 1.0 equiv.) in AcOH (10 mL) and HO (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. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :213

[0345] 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 hour. 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, 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.97 - 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).

[0346] Preparation of N-(3-cyano-4-fluoro-1H-indol-7-yl)-3-methyl-1,2-oxazole-5-sulfonamide (compound 354) [ka] 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), 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.) were added, 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

[0347] Preparation of 3-methylisoxazole-5-sulfonyl chloride. To a solution of 5-(benzylthio)-3-methylisoxazole (110 mg, 0.53 mmol, 1.0 equiv.) in MeCN (1.1 mL), AcOH (0.11 mL), and HO (0.11 mL) at 0 °C, NCS (85.8 mg, 0.64 mmol, 1.2 equiv.) was added, and the resulting mixture was stirred at room temperature 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 NaSO, and concentrated under reduced pressure to give the product, which was used without further purification. LCMS: (ES, m / z): [M+1] + :182

[0348] 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 hour. 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.

[0349] Preparation of N-(3-cyano-4-methyl-1H-indazol-7-yl)-1,3-thiazole-5-sulfonamide (compound 342) [ka] 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 hour. 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, 1H NMR(400MHz,DMSO-d6,ppm)δ 14.36(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).

[0350]

Table 1

[0351]

Table 2

[0352]

Table 3

[0353]

Table 4

[0354]

Table 5

[0355]

Table 6

[0356]

Table 7

[0357]

Table 8

[0358]

Table 9

[0359]

Table 10

[0360]

Table 11

[0361]

Table 12

[0362]

Table 13

[0363]

Table 14

[0364]

Table 15

[0365] Table 16

[0366] Table 17

[0367] Table 18

[0368] Table 19

[0369] Table 20

[0370] Table 21

[0371] Table 22

[0372] Table 23

[0373] Table 24

[0374] Table 25

[0375] Table 26

[0376] Table 27

[0377] Table 28

[0378] Table 29

[0379] Table 30

[0380] Table 31

[0381] Table 32

[0382]

Table 33

[0383] Table 34

[0384] Table 35

[0385] Table 36

[0386] Table 37

[0387] Table 38

[0388] Table 39

[0389] Table 40

[0390] [Table 41]

[0391] Example 3 - Targeted RBM39 Degradation Assay The molecular adhesive is thought to enhance the productive formation of a complex between the RBM39 protein and DCAF15, a substrate-recognition subunit of the E3 ubiquitin ligase complex, leading to subsequent ubiquitination and proteosomal degradation of the RBM39 protein. To confirm ubiquitin- and proteosomal-dependent degradation of RBM39 by the compounds disclosed herein, OVCAR3 cells were cultured for 6 hours with or without 1 μM of compound, 5 μM MG132 (a proteasome degrader), and 0.3 μM pevonedistat (MLN4924), a NEDDylation inhibitor. 50 μg of protein per sample was loaded per lane of an SDS-PAGE gel, and the proteins were transferred to a PVDF membrane using the iBlot2 Dry Blotting System High MW protocol: 2.5 A for 10 minutes, 25 V maximum. The membrane was blocked in TBST / 5% BSA for 1 hour at room temperature with shaking at 100 rpm. The membranes were probed with rabbit antibodies RBM39 and β-actin (1:1000 dilution) in TBST / 5% milk at 100 rpm with shaking, followed by fluorescent secondary antibodies conjugated to 800 nm and anti-β-actin (CST, #3700 mouse antibody at a dilution of 1:4000) as a loading control. The membranes were washed four times with 1x TBST for 5 min at room temperature and incubated with secondary antibodies anti-rabbit IgG antibody HRP-linked (1:10000 dilution) and IRDye 680 anti-mouse antibody (1:10000 dilution) in TBST / 5% milk for 1 h at room temperature. The membranes were washed four times for 5 min in TBST. After rinsing the membranes once with TBS, the loading control protein and target protein bands were analyzed, and the band signals were quantified.

[0392] Example 4 - CellTiter-Glo assay to assess the effect of RBM39 digests on cell viability and proliferation in vitro: The CellTiter-Glo assay was used to evaluate compound cytotoxicity against cell proliferation in OVCAR3, SK-N-SH, SK-N-AS, Kelly, IMR32, and SK-N-BE-2C cell lines. Cells were harvested in cell culture medium and counted. Cells were diluted with culture medium to the cell densities 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 control wells, which received 50 μL of phosphate-buffered saline.

[0393] [Table 42]

[0394] The plate was covered and incubated without shaking for 30 minutes at room temperature, then incubated overnight at 37°C and 5% CO2 for cell attachment. Test compounds were dissolved to make 10 mM DMSO stock solutions. A 10 μL aliquot of the stock solution was placed in a 384 LDV plate, and a 3-fold, 11-point dilution was performed by transferring 4 μL of compound to 8 μL of DMSO.

[0395] 50 nL of diluted compound was then transferred to the cell plate for a final concentration of 10 μM. A high control was prepared with 50 nL of DMSO. The plate was spun at 1,000 RPM for 1 minute at room temperature.

[0396] After 72 hours of compound treatment, plates were removed from the incubator and allowed to equilibrate at room temperature for 15 minutes. 40 μL of CellTiter-Glo reagent was then added to each well (1:1 with culture medium), and plates were incubated at room temperature for 30 minutes before reading.

[0397] Example 5 - DCAF15 RBM39 Complex Formation Assay: A TR-FRET assay was used to evaluate the effect of the compounds disclosed herein on the interaction between RBM39 and DCAF15 complex. Test compounds were dissolved to form 10 mM DMSO stock solutions. 45 μL aliquots of the stock solutions were transferred to a 384pp plate, and 8-point three-fold dilutions were performed by transferring 15 μL of compound solution to 30 μL of DMSO. The plate was then rotated at 1,000 RPM for 1 minute at room temperature.

[0398] A 30 nL aliquot of the diluted compound was transferred to a 384-well plate and incubated at room temperature for 15 minutes. Solutions 1, 2, and 3 were then 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 initiate the reaction. The final volume in each well was 10 μL. The plate was incubated at room temperature for 60 minutes before being read.

[0399] [Table 43]

[0400] [Table 44]

[0401] [Table 45]

[0402] Next, RBM39(R150-D331)3×Flag was prepared for use in the TR-FRET assay:

[0403] [Table 46]

[0404] The recombinant RBM39 protein consists of R1R2 (aa 150-331; UniProt: Q14498) of RBM39. The coding sequence was subcloned into the pGEX4T-1-RBM39-Flag vector, where it was expressed as a GST fusion protein with an N-terminal TEV protease cleavage site. A 3xFlag tag was added to the C-terminus of R1R2, which was used in the FRET assay. The results of the FRET assay are shown in the table below.

[0405] [Table 47]

[0406] [Table 48]

[0407] Example 6 - Western Blotting to assess the IC50 of compounds on RBM39 degradation: A Western blot assay was used to evaluate the effect of the compounds disclosed herein on RBM39 in the OVCAR3 cell line.

[0408] The cells were collected in cell culture medium and counted. The cells were diluted with culture medium to below cell density, and 2 mL of the cell suspension was added to each well of a 6-well cell culture plate. The plate was covered and incubated at room temperature without shaking for 30 minutes, and then incubated at 37°C and 5% CO2 overnight for cell attachment.

[0409] Test compounds were dissolved to form a 10 mM DMSO stock solution, and the compounds were diluted to 1000x the final concentration. 2 μL aliquots of diluted compounds were added to the cell plates. A 2 μL aliquot of DMSO was used for the vehicle control. The plates were gently shaken to mix.

[0410] After compound treatment, the medium was aspirated and the plate was 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 the cold plate, and the cells were lysed by pipetting. The plate was then incubated on ice for 5–15 minutes with shaking, then centrifuged at 4°C and 15,000 rpm for 10 minutes, and the supernatant was collected.

[0411] Cell lysates were mixed with loading dye and reducing agent, heated to 95°C for 10 minutes, and briefly spun down (10-15 seconds) at 13,000 rpm 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: 2.5 A for 10 minutes, max. 25 V.

[0412] Next, the membrane was blocked in TBST / 5% BSA with shaking at 100 rpm for 1 h at room temperature, followed by addition of primary antibodies (RBM39: 1 in 1000 dilution; β-actin: 1 in 4000 dilution) in TBST / 5% milk with shaking at 100 rpm for 16–20 h at 4°C. The membrane was washed four times with 1× TBST at room temperature for 5 min and then incubated with HRP-conjugated secondary antibodies anti-rabbit IgG (1 in 10000 dilution) and IRDye 680 anti-mouse (1 in 10000 dilution) in TBST / 5% milk for 1 h at room temperature.

[0413] The membrane was washed four times with TBST for 5 minutes and rinsed once with TBS, after which the loading control protein and target protein bands were detected and the band signals were quantified.

[0414] Example 7 - In vivo efficacy study on tumor growth in a subcutaneous xenograft model: Compounds are evaluated for their in vivo efficacy in a cell line-derived xenograft model of OVCAR3 (human ovarian cancer cell line, catalog number HTB#161 ATCC) to assess their in vivo efficacy. Compounds are formulated with 40% PEG400 / 5% Tween80 / 55% HP-b-CD (10% w / v). 1x10 6 cells in 0.1 ml PBS mixed with Matrigel (volume 1:1) are used. 7 OVCAR3 cells are inoculated subcutaneously into the right flank of 6-8 week-old female BALB / c nude mice for tumor development. Xenografts are approximately 100-150 mm 3 Once tumor-bearing mice reach a tumor size of 10 mm, they are randomly grouped into test groups (n=10). Randomization is performed based on the "matched distribution" method. The date of randomization is designated as day 0. Tumor-bearing mice are treated by oral gavage with vehicle (40% PEG400 / 5% Tween80 / 55% HP-b-CD (10% w / v)) or 10, 30, and 100 mg / kg BID of the compound for 25 days. Tumor size is measured in two dimensions twice a week using calipers, and volume is expressed in mm using the formula "V = (L x W x W) / 2". 3 where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Dosing and measurements of tumor volume and body weight are performed in a laminar flow cabinet.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, R Ｎ１ is H or 1, 2 or 3 R ７ C optionally substituted with １－６ is alkyl; R Ｎ２ is H or 1, 2 or 3 R ７ C optionally substituted with １－６ is alkyl; X １ is CR １ or N; X ２ is CR ３ or N; X ３ is CR ４ or N; R １ is H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ alkoxy, halo, OH, or CN; １－６ Alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ , and CO ２ C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R ２ is H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ alkoxy, halo, OH, or CN; １－６ Alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ , and CO ２ C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R ３ is H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ alkoxy, halo, OH, or CN; １－６ Alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ , and CO ２ C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ alkoxy, halo, OH, or CN; １－６ Alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ , and CO ２ C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R ５ is H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ alkoxy, halo, OH, or CN; １－６ Alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ , and CO ２ C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R Ｎ are independently H, 1, 2 or 3 R ７ C optionally substituted with １－６ Alkyl, or C ３－１０ is cycloalkyl; Het contains 1, 2 or 3 ring heteroatoms selected from O, S and N, and 1, 2 or 3 R ６ is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl optionally substituted with Each R ６ are independently halo, 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 , S.O. ２ NR Ｎ R Ｎ , P(O)(R Ｎ ) (R Ｎ ), O, S and N, C １－６ Alkylene-C ３－１０ C(O)-5 or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from cycloalkyl, O, S and N, C ６－１０ C containing 1, 2 or 3 ring heteroatoms selected from aryl ３－１０ cycloalkyl, 4-6 membered heterocycloalkyl, or 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; ３－１０ Cycloalkyl, 4-6 membered heterocycloalkyl, C ６－１０ aryl, or 5- or 6-membered heteroaryl is 1, 2, or 3 R ７ and each C １－６ Alkyl, C １－６ Alkylene, or C １－６ Alkoxy is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ optionally substituted with one or two substituents independently selected from alkyl, and Each R ７ are independently OH, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, NH ２ , NH(C １－６ alkyl) or N(C １－６ alkyl) ２ (It is).

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

3. Het is 1, 2 or 3 R ６ 3. The compound or salt of claim 2, which is thiazolyl optionally substituted with:

4. Het, 【Chemistry 2】 and R ６ But 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. X １ is CR １ and X ２ is CR ３ and X ３ is CR ４ The compound or salt according to any one of claims 1 to 4, wherein

6. X １ , X ２ and X ３ The compound or salt according to any one of claims 1 to 4, wherein one of

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

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

9. Formula (Ia): 【Chemistry 3】 2. The compound or salt of claim 1 having the structure:

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

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

12. R １ is H or C １－６ alkyl, C １－６ The alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 12. The compound or salt according to any one of claims 1 to 6 or 8 to 11, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl.

13. R １ 13. The compound or salt of claim 12, wherein is H.

14. R ２ H, C １－６ alkyl, halo, or CN, １－６ The alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 14. The compound or salt according to any one of claims 1 to 13, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl.

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

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

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

18. R ３ H, C １－６ alkyl or halo, C １－６ The alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 18. The compound or salt of any one of claims 1 to 17, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl.

19. R ３ 19. The compound or salt of claim 18, wherein is H.

20. R ３ or C １－６ alkyl, C １－６ The alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 19. The compound or salt of claim 18, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl.

21. R ３ 21. The compound or salt of claim 20, wherein is methyl.

22. R ３ 19. The compound or salt of claim 18, wherein is halo.

23. R ３ 23. The compound or salt of claim 22, wherein is fluoro.

24. R ４ The compound or salt of any one of claims 1 to 7 or 9 to 23, wherein is H.

25. R ５ The compound or salt of any one of claims 1 to 24, wherein is H.

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

27. Het is one R ６ 27. The compound or salt of claim 26, substituted with:

28. Het is two R ６ 27. The compound or salt of claim 26, substituted with:

29. Each R ６ But independently, halo, 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 or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C ３－５ cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from O, S and N, C ６－１０ aryl, or a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; ３－５ cycloalkyl, 5- or 6-membered heterocycloalkyl, C ６－１０ aryl, or 5- or 6-membered heteroaryl is 1, 2, or 3 R ７ and each C １－６ Alkyl or C １－６ Alkylene is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 29. The compound or salt according to any one of claims 1 to 28, optionally substituted with one or two substituents independently selected from alkyl.

30. Each R ６ But independently, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkylene-C(O)O-C １－６ alkyl, 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; C ６－１０ aryl, or a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from O, S, and N; a 5- or 6-membered heterocycloalkyl, C ６－１０ An aryl or a 5- or 6-membered heteroaryl may have one, two, or three R ７ and each C １－６ Alkyl or C １－６ The alkylene is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ , and CO ２ C １－６ 30. The compound or salt of claim 29, optionally substituted with one or two substituents independently selected from alkyl.

31. Each R ６ But independently, Halo, C １－６ alkyl, or a 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 is selected from 1, 2, or 3 R ７ and each C １－６ The alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 31. The compound or salt of claim 30, optionally substituted with one or two substituents independently selected from alkyl.

32. At least one R ６ 31. The compound or salt of claim 30, wherein is halo.

33. At least one R ６ 33. The compound or salt of claim 32, wherein is chloro or bromo.

34. At least one R ６ is C １－６ alkyl, and each C １－６ The alkyl is C １－６ Alkoxy, OH, CN, CO ２ H, N.R. Ｎ R Ｎ and CO ２ C １－６ 31. The compound or salt of claim 30, optionally substituted with one or two substituents independently selected from alkyl.

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

36. Each R ６ is a 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R ７ 31. The compound or salt of claim 30, optionally substituted with:

37. At least one R ６ is pyrazolyl, pyridinyl, pyridazinyl, or pyrimidinyl, each of which is selected from the group consisting of one, two, or three R ７ 37. The compound or salt of claim 36, optionally substituted with:

38. Each R ７ But independently, Halo, C １－６ Alkyl or C １－６ 38. The compound or salt of any one of claims 1 to 37, which is haloalkyl.

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

40. At least one R ７ 40. The compound or salt of claim 39, wherein is methyl.

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

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

43. 43. A method of modulating RBM39 protein, comprising contacting RBM39 protein with a compound or salt according to any one of claims 1 to 41 or a pharmaceutical composition according to claim 42.

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

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

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

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

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

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

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