Treatment of cancers via RNA-binding motif protein 39 (RBM39) degradation

Abstract

Disclosed herein are methods of treating a patient suffering from cancer whose tumor is characterized by microsatellite instability - high (MSI-H), microsatellite instability - low (MSI-L), or a mismatch repair deficient solid tumor or having a ARIDA1 mutation, comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

Description

TREATMENT OF CANCERS VIA RNA-BINDING MOTIF PROTEIN 39 (RBM39) DEGRADATIONFIELD

[0001] The present disclosure relates generally to the field of cancer therapeutics. More specifically, it provides methods of treating cancers characterized as microsatellite instability-high (MSI-H), microsatellite instability-low (MSI-L), or mismatch repair deficient (dMMR), including endometrial, colorectal, gastric, ovarian, rectal, and adrenal, cancers using inhibitors or degraders of RNA-binding motif protein 39 (RBM39). The present disclosure also provides methods of treating cancers characterized as harboring mutations in the AT-rich interaction domain (ARID1A) gene including endometrial, bladder, gastric, colorectal, ovarian, breast, pancreatic, hepatocellular, rectal, and adrenal, cancers using inhibitors or degraders of RBM39.BACKGROUND

[0002] The DNA mismatch repair (MMR) system is an evolutionarily conserved system that maintains genomic integrity by correcting errors during DNA replication, such as single nucleotide mismatches and insertions or deletions. Loss of function mutations can inactivate the MMR system and promote a hypermutable state within short, repetitive sequences in the DNA, called microsatellites (Ma, Jennifer, et al. Nat Comma., 2018, 9(1): 3292). This genomic signature, referred to as microsatellite instability (MSI), has been shown to occur frequently across a wide variety of cancers such as endometrial (—31 %), gastric (-19%), colorectal (—16%), and ovarian (-12%), and a subset of other solid tumors (Bonneville, R, et al. JOO Precis. Oncol., 2017, (1 ): 1 -15; Pal, T, et al. Clin Cancer Res., 2008, 14(21 ):6847-6854). While tumors with high MSI (MSI-H) harbor an immune-inflamed phenotype and can be clinically treated with immune checkpoint inhibitors, between 40 to 65% of patients do not respond to immune checkpoint inhibitors, and the use of these agents can be limited by toxicity. As a result, there is still a significant unmet medical need for treating MSI-H cancers (Chan, E, et al. Nature., 2019, 568, 551-556).

[0003] Alternative splicing and RNA-binding proteins (RBPs) have recently emerged as attractive therapeutic targets for cancer due to their critical roles in in the regulation of post-transcriptional modifications, impacts on DNA damage repair pathways, and modulation of cell cycle functions. Recent studies have revealed that RNA- binding motif protein 39 (RBM39) is an unexpected target of aryl sulfonamides, which can function as molecular glue degraders of by forming a ternary complex with RBM39 and the E3 ubiquitin ligase receptor DDB1 and CUL4 associated factor 15 (DCAF15). Additionally, clinical trials have shown that aryl sulfonamides were well tolerated with modest anti-tumor activity seen across a variety of cancers.

[0004] The switch / sucrose non-fermentable (SWI / SNF) chromatin remodeling complexes play a fundamental role in transcriptional regulation by modulating chromatin accessibility. Composed of over 15 subunits, these complexes assemble into three distinct forms: BRG1 / BRM-associated factor (BAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF) (Fontana, Beatrice, et al. Front Oncol., 2023, 13: 1136248). Among these, the AT-rich interacting domain-containing protein 1 A (ARID1 A) is a critical subunit that governs chromatin remodeling, transcriptional fidelity, and epigenetic regulation. Functioning as a tumor suppressor, ARID1 A is one of the most frequently mutated genes in cancer, with loss-of-function mutations identified in a range ofmalignancies, including ovarian clear-cell carcinoma (50%), endometrial (29%), gastric (29%), breast (35%), and hepatocellular (17%) cancers (Wu, Jennifer, et al. Cancer Discov., 2013, 3(1): 35-43). Given its central role in epigenetic control, ARID1 A-deficient cancers often exhibit aggressive phenotypes and remain a major area of unmet clinical need, necessitating the development of novel therapeutic strategies.

[0005] These findings suggest that RBM39 degraders may show promise as targeted cancer therapies, but the lack of predictive biomarkers and an inadequate understanding of RBM39 biology has limited their therapeutic potential (Xu, Y, et al. Br. J. Pharmacol., 2020, 179, 2795-2818).SUMMARY

[0006] Provided herein are methods of treating a patient suffering from a tumor which is characterized as microsatellite instability - high (MSI-H) microsatellite instability - low (MSI-L) or a mismatch repair deficient (dMMR), comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

[0007] Also provided are methods of treating an adult or pediatric patient with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumor, as determined by an FDA-approved test, comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

[0008] Further provided herein are methods of treating an SWI / SNF (e.g., ARID1 A) mutated cancer using a compound that increases degradation of RBM39.

[0009] In various embodiments, the compound that increases degradation of RBM39 is an aryl sulfonamide or a pharmaceutically acceptable salt thereof, such as an aryl sulfonamide as disclosed in PCT / US23 / 30294, PCT / US23 / 83478, or US 2022 / 0162193 or a pharmaceutically acceptable salt thereof. In some embodiments the compound that increases degradation of RBM39 is a compound disclosed herein, a compound of Formula (I) or (lb), or a compound as disclosed in Table A-1 or A2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound that increases degradation of RBM39 is indisulam, tasisulam, E7820, chloroquinoxaline sulfonamide, Compound 2A, Compound 215A, a pharmaceutically acceptable salt thereof, or a combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 A illustrates in vitro cell viability data for indisulam, tasisulam, E7280, and CQS from the Depmap for all human cancer cell lines characterized as MSI or MSS, and FIG. 1 B shows the comparisons for select tumor types where the frequency of MSI is enriched.

[0011] FIG. 2 illustrates in vitro cell viability data for Compound 2A using human MSI and MSS cell lines (A), and IC50 in MSI vs MSS cells (B).

[0012] FIG. 3 illustrates in vivo efficacy and tolerability of Compound 2A and E7820 in MSI human ovarian xenografts A2780 and OVK18.

[0013] FIG. 4 illustrates in vitro western blot data for Compound 2A and E7280 using human MSI and MSS cells.

[0014] FIG. 5 illustrates in vitro cell-cycle distribution data for Compound 2A and E7820 using human MSI and MSS cell lines.

[0015] FIG. 6 illustrates in vivo dose-dependent efficacy of Compound 215A in MSI human ovarian cancer xenograft A2780.

[0016] FIG. 7 illustrates in vitro cell viability data for Compound 2A using SWI / SNF mutant (e.g., ARIDA1 mutant) and SWI / SNF wildtype cell lines (A), and IC50 in SWI / SNF mutant vs wildtype cells (B).DETAILED DESCRIPTION

[0017] Provided herein are methods of treating cancer using a compound that increases degradation of RBM39 (also called an "RBM39 degrader”). In particular, it has been discovered that cancers that are microsatellite instable (MSI) are more sensitive to RBM39 degradation, compared to cancers that are microsatellite stable (MSS). Thus, patients that suffer from a MSI cancer benefit from a therapy comprising a compound that increases RBM39 degradation. Further, it has been discovered that cancers that are ARID1 A mutant are more sensitive to RBM39 degradation, compared to cancered that have wildtype ARID1A. Thus, patients that suffer from a ARID1 A mutant cancer benefit from a therapy comprising a compound that increases RBM39 degradation.Cancer and Microsatellite Instability and Tumor Mutational Burden-High (TMB-H)

[0018] Microsatellites (“MS(s)”) or microsatellite DNA are genomic regions containing tandem sequence repeats. Generally, microsatellites are tracts of variable-length repeats (generally repeated 5-50 times) of short DNA motifs (ranging in length from 1-6 or more base pairs). Microsatellites may encompass a variety of low complexity sequences, however, most MSs are mono- or di-nucleotide repeats. Microsatellites occur at thousands of locations within an organism's genome, which are distributed throughout the genome. MSs are abundant in nontranscribed regions of the human genome but may also occur in exons and untranslated regions. In the germline, rates of insertions and deletions (indels) in MSs are significantly higher than rates of singlenucleotide substitutions elsewhere in the genome (e.g., about 104to 103compared to about 108per locus per generation). The increased mutation rate within MS indels is thought to arise because of DNA polymerase slippage during replication, which leads to changes in the number of repeats. MS indels frequently result in frameshift mutations, which can be mutagenic by altering protein expression and / or function.

[0019] There are numerous ways in which to assess whether a cancer is MSI, e.g., by means of analyzing for the presence of one or more microsatellite markers. Testing of MSI can be accomplished by any means known in the art, and includes polymerase chain reaction (PGR), immunohistochemistry (IHC), or next generationsequencing (NGS) panels that are commercially available (Caris Life Sciences, Foundation Medicine, Guardant360, or Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK- IMPACT]).

[0020] Microsatellite instability can be performed by PCR to amplify a standard panel of DNA sequences containing nucleotide repeats, e.g. microsatellite markers. In some embodiments, the one or more microsatellite markers are selected from the group consisting of: BAT-25; BAT-26; MONO-27; NR-21; NR-24; and any combination thereof. In some embodiments, the one or more microsatellite markers are selected from the group consisting of: BAT-25; BAT-26; D5S346; D2S123; D17S250; and any combination thereof - often referred to as the core panel (Boland et al., 1998). In some embodiments, the one or more microsatellite markers are selected from the group consisting of BAT-25; BAT-26; MONO-27; NR-21; NR-24; D5S346; D2S123; D17S250; BAT40; and any combination thereof. Commercial kits for testing MSI are available, include one from Promega Corporation. Fragments are detected after amplification for assignment of genotype / phenotype. Samples that can be tested for MSI include tumor tissue as well as body fluids that contain nucleic acids shed from tumors. Testing for tumor DNA in such tissues and body fluids is well known.

[0021] A cancer, or sample, can be also classified as MSI-H if two or more of the five markers in the core panel show instability, or greater than 30% of markers show instability. Instability is well defined in the art and classically defined as expansion or contraction of the repetitive sequences in the cancer compared with normal tissue from the same patient. If one of the five markers in the core panel shows instability or fewer than 30% of markers tested shows instability, the cancer is classified as microsatellite instability-low (MSI-L). If none of the markers show instability in the core panel or other marker panels, the cancer is characters as microsatellite instability stable (MSI-S or MSS). Markers that can be tested for MSI status are discussed above.

[0022] The determination of MSI-H or deficient mismatch repair (dMMR) status can also be performed by IHC for loss of the various proteins in the mismatch repair proteins - e.g., mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MHS6), and / or postmeiotic segregation increased 2 (PMS2).

[0023] In some embodiments, a cancer that has MSI-H or defective or deficient mismatch repair (dMMR) comprises mutations in MLH1, MSH2, MHS6, PMS2, MSH3, MLH3, PMS1, EPCAM, ARID1A, ARID1 B, PTEN, KRAS, BRAF, NRAS, TP53, RB1, APC, ATM, SMAD4, PIK3CA, FBXW7, SYNE1, CHD7, RNF43, BRCA2, ACVR2A, MIKI67, RPL22, CASP5, MUC6, KMT2C, KMT2D, SETDB1, SGOL1, SEC31A, B2M, POLE, POLD1, SMARCA2, SMARCA4, SMARCB1, MEN1, MEN2, VHL, PBRM1, or any epigenetic silencing (e.g., promoter hypermethylation in MLH1), SWI / SNF complex genes, microsatellite fragile sites, or other genetic mutations that inactivate or reduce the amount of mismatch repair (Roudko, V, et al. Cell., 2020, 183(6), 1634-1649; Wu, RC, et al. Cancer Biol Then, 2014, 15(6), 655-664; Bonneville, R, et al. JCO Precis. Oncol., 2017, (1 ): 1 -15).

[0024] The MSI phenotype has been observed across many tumor types, e.g., solid tumors, including colon adenocarcinoma (COAD), esophageal adenocarcinoma (ESCA), stomach adenocarcinoma (STAD), uterine corpus endometrial carcinoma (UCEC) rectal adenocarcinoma (READ), adrenocortical carcinoma (ACC), breastcarcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), mesothelioma (MESO), uterine carcinoma (UCS), kidney renal clear cell carcinoma (KIRC), ovarian serous cysadenocarcinoma (OV) and other non-serous epithelial ovarian cancers (EOC), and cholangiocarcinoma (CHOL). MSI is present in Lynch Syndrome (LS) which is an inherited cancer syndrome that predisposes patients to colon, endometrial, gastric cancer, ovarian, small intestine, liver, hepatobiliary, upper urinary tract, brain, kidney, and prostate cancer. MSI is also present in Constitutional Mismatch Repair Deficiency (CMMRD) which is an inherited childhood cancer predisposition syndrome that predisposes patients to hematological malignancies, brain / CNS tumors, colorectal and other cancers described in LS patients. MSI is also present in colorectal, gastric, pancreatic, prostate, lung, ampullary, melanoma, bile duct, head and neck, sarcoma, and endometrial cancers. In various embodiments, the MSI cancer is colorectal cancer, gastric cancer, breast cancer, prostate cancer, cholangiocarcinoma, leukemia, bladder cancer, ovarian cancer, endometrial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), follicular thyroid cancer, or adrenocortical cancer.

[0025] In various embodiments, the cancer is MSI-L. In some specific cases of these embodiments, the MSI-L cancer is a tumor selected from colorectal, rectal, colon, ovarian, gastric, endometrial, prostate, uterine, cervical, esophageal, breast, renal, lung, and adrenal tumor. In some specific cases, the MSI-L cancer is a tumor selected from colorectal, gastric, endometrial, ovarian, adrenal, rectal, prostate, lung, and colon tumor.

[0026] Further disclosed are methods of treating an adult or pediatric patient with unresectable or metastatic tumor mutational burden-high (TMB-H) [>10 mutations / megabase (mut / Mb)] solid tumors, as determined by an FDA-approved test with a therapeutically effective amount of a compound that increases degradation of RBM39. Tumor mutational burden (TMB) is a measure of the total number of mutations per coding area of a tumor genome. The term "tumor mutation burden (TMB)” used herein refers to the total number of gene coding errors, base substitutions, gene insertion or deletion errors detected in a somatic cell per million bases. In some embodiments of the present disclosure, tumor mutation burden (TMB) is estimated by analysis of somatic mutations, including coding base substitutions and the megabase insertions of the panel sequences studied TMB can be measured with both tissue and blood-based comprehensive genomic tests. TMB-H is designated when 10 or more mutations per megabase (million base pairs) are measured (>10 mut / Mb).

[0027] In some cases, the patient has progressed following prior treatment and / or has no satisfactory alternative treatment options for the cancer from which they suffer.SWI / SNF (e.g., ARID1A) mutant cancers

[0028] The SWI / SNF subunits include ARID1 A, ARID1 B, ARID2, SMARCA4 and SMARCA2. In some cases, the SWI / SNF mutated cancer has a mutation in at least one (1, 2, 3, 4, or 5) of ARID1A, ARID1 B, ARID2, SMARCA4 and SMARCA2. In some cases, the cancer is mutated in 2, 3, 4, or 5 of ARID1 A, ARID1 B, ARID2, SMARCA4 and SMARCA2. In some cases, the cancer is mutated in ARID1A. In some cases, the cancer is mutated in ARID1 B. In some cases, the cancer is mutated in ARID2. In some cases, the cancer is mutated in SMARCA4. In some cases, the cancer is mutated in SMARCA2.

[0029] The AT-rich interaction domain (ARID) family is a superfamily belonging to switch / sucrose non- fermentable (SWI / SNF) chromatin remodeling complexes, a sub-family of ATP-dependent chromatin remodeling complexes found in eukaryotes (Zhu et al., Cancer Biology & Therapy, 2022, Vol. 23, No. 1, 104-111). The ARID family consists of a series of members associated with basic processes of cellular function, including the modification of chromatin structure and the regulation of targeted gene transcription. All ARID family members contain a DNA-binding domain through which they could bind targeted DNA and participate in the process of DNA replication, gene expression and cell growth, differentiation, and development.

[0030] The AT-rich interaction domain 1A (ARID1A, sometimes called BAF250a) is a non-catalytic, DNA- binding subunit of the human SWI / SNF complex (a chromatin remodeling complex). It is thought to play an important role in several cellular processes, including transcription, DNA replication, and DNA damage repair. A review by Mittal et al. (Mittal et al., 2020, Nat Rev Clin Oncol., 2020 Jul. 17 (7): 435-448) cites research showing that ATP-dependent chromatin remodeler SMARCA4 (also known as transcription activator BRG1) and ARID1 A are recruited to sites of DNA damage and assist in homologous recombination (HR)-mediated DNA repair and non-homologous end joining (NHEJ). ARID1 A is also thought to interact with DNA mismatch repair protein Msh2 (MutS homolog 2 or MSH2).

[0031] Mutation of ARID1 A induces changes in the expression of multiple genes (e.g. cyclin dependent kinase inhibitor 1 A (CDKN1 A), mothers against decapentaplegic homolog 3 (SMAD family member 3 or SMAD3), DNA mismatch repair protein Mlh1 (MutL protein homolog 1 or MLH1), and phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1 )) via chromatin remodeling dysfunction, which contributes to carcinogenesis and has been shown to cause transformation of cells associated with the phosphoinositide 3-kinases (PI3K) / protein kinase B (PKB or Akt) pathway (i.e. PI3K / Akt pathway) (Takeda et al., Oncology Reports, 2016, 35:607-613). Mutation of ARID1 A may compromise DNA mismatch repair, leading to increased tumor mutational burden (TMB), programmed death-ligand 1 (PD-L1) expression, infiltration of cytotoxic T lymphocytes (CTL), and increased and sensitivity to checkpoint inhibitors. For example, ARID1 A mutation has been linked to sensitivity to PARP inhibitors and ATR inhibitors.

[0032] ARID1 A is a frequently mutated tumor suppressor. Mutations in ARID1 A have been linked to various cancers, such as ovarian clear cell carcinoma (Mittal et al., 2020, Nat Rev Clin Oncol., 2020 Jul. 17 (7): 435- 448), endometriosis-associated ovarian carcinoma (Samartzis et al., Int. J. Mol. Sci., 2013, 14, 188824-18849), endometrial carcinoma (Takeda et al., Oncology Reports, 2016, 35:607-613), and cholangiocarcinoma (also known as bile duct cancer; via activation of the PI3K / Akt pathway; Tessiri et al., PeerJ, 2022, 10: e12750). In particular, ARID1A is mutated in 9% of colorectal cancers (Mullen et al., Cancer Treatment Reviews, 2021, 100, 102287), and ARID1A is mutated in more than 50% of all ovarian clear cell carcinomas and ovarian endometrial carcinomas. ARID1 A mutant breast and endometrial cancer is associated with increased PI-3K and Akt signaling and sensitivity to PI-3K and Akt inhibitors (Takeda et al., Oncology Reports, 2016, 35: 607-613). Co-occurrence of ARID1A alterations with PI3K / Akt pathway activation has been reported in ovarian clear cell carcinoma, breast cancer, and gastric cancer (Huang et al., Mod Pathol, 2014 July; 27(7):983-90; Samartzis et al., Oncotarget.2014 Jul. 30; 5(14):5295-303; Zhang et al., Oncotarget. 2016 Jul. 19; 7(29):46127-46141 ; De and Dey, Int J Mol Sci. 2019 Nov. 15; 20(22):5732).

[0033] ARID1 A loss is linked with activation of the PI-3K / Akt / mTOR pathway (Mullen et al., Cancer Treatment Reviews, 2021 , 100, 102287). ARID1A expression loss also leads to delayed mitosis and chromosomal segregation. Silencing of ARID1A in gastric, ovarian, glioma, and colon cancer cells has been shown to activate the phosphorylation of Akt and PI3K (Zeng et al., Head & Neck Oncology. 2013; 5(1):6; Xie et al., Tumour Biol. 2014 August; 35 (8): 7921-7; Takeda et al., Oncology Reports, 2016, 35:607-613; Zhang et al., Oncotarget. 2016 Jul. 19; 7(29):46127-46141), suggesting an interrelationship between ARID1 A deficiency and PI3K / Akt pathway activation.

[0034] Interestingly, rhabdoid tumors and ARID1 A mutant ovarian cell carcinoma are dependent on RTK signaling including platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors (FGFRs), and Met.

[0035] In various embodiments, an SWI / SNF mutant tumor or cancer can be a cancer of the brain, breast, bladder, bone, cartilage, cervix, colon, neural tissue, glia, esophagus, fallopian tube, pancreas, intestines, gallbladder, kidney, liver, lung, ovary, pancreas, parathyroid, pineal gland, pituitary gland, prostate, spinal cord, spleen, skeletal muscle, skin, muscle, stomach, testis, thymus, thyroid, urogenital tract, ureter, urethra, uterus, endometrium, vagina, or a combination thereof.Compounds that Increase Degradation of RBM39

[0036] Any compound that increases degradation of RBM39 can be used in the methods disclosed herein. Compounds used in the disclosed methods are understood to encompass pharmaceutically acceptable salts thereof. The term "compound that increases degradation of RBM39” as used herein may refer to one compound or a combination of two or more compounds. In various cases, the compound that increases degradation of RBM39 is an aryl sulfonamide.

[0037] Specifically contemplated compound that increases degradation of RBM39 include those disclosed in PCT / US23 / 30294, which include compounds of Formula (I) or (la), and pharmaceutically acceptable salts thereof:wherein RN1is H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; RN2is H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; X1is CR1or N; X2is CR3or N; X3is CR4or N; R1is H, C1-6al ky I, C1-6h aloal ky I, C1-6al koxy , halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; R2is H, C1-6alkyl, C1-6haloalkyl, Cvealkoxy, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; R3is H, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, halo, OH, or ON, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; R4is H, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, halo, OH, or ON, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; R5is H, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, halo, OH, or ON, and the Ci. ealkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; each RNis independently H, C1-6alkyl optionally substituted with 1 , 2, or 3 R7, or Ce-iocycloalkyl; Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl comprising 1, 2, or 3 ring heteroatoms selected from 0, S, and N and optionally substituted with 1 , 2, or 3 R6; each R6is independently halo, ON, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, NRNRN, COCH, C(O)NRNRN, Ci.ealkylene-C(O)ORN, Ci.6alkylene- C(O)NRNRN, S02NRNRN, P(O)(RN)(RN), C(0)-5- or 6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, C1-6alkylene- C3-10cycloalkyl, C3-10cycloalkyl, 4-6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, C6-10aryl, or 5- or 6-membered heteroaryl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, wherein the Cs-iocycloalkyl, 4-6- membered heterocycloalkyl, C6-10aryl, or 5- or 6-membered heteroaryl can optionally be substituted with 1 , 2, or 3 R7and each C1-6alkyl, C1-6alkylene, or C1-6alkoxy can be optionally substituted with 1 or 2 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; and; each R7is independently OH, halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, NH2, NH(C1-6alkyl), or N(C1-6alkyl)2.. In some cases, RN1is H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; RN2is H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; X1is CR1or N; X2is CR3or N; X3is CR4or N; R1is H, C1-6alkyl, C1-6haloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; R2is H, C1-6alkyl, C1-6haloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl; R3is H, C1-6alkyl, C1-6haloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; R4is H, C1-6alkyl, C1-6haloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; R5is H, C1-6alkyl, Ci. ehaloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; each RNis independently H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N and optionally substituted with 1 , 2, or 3 R6; each R6is independently halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, COOH, C(0)NRNRN, C1-6alkylene- C(0)0RN, P(O)(RN)(RN) , C(0)-5- or 6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, Cs-wcycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, C6-10aryl, or 5- or 6-membered heteroaryl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, wherein the Cs-wcycloalkyl, 5- or 6-membered heterocycloalkyl, C6-10aryl, or 5- or 6-membered heteroaryl can optionally be substituted with 1 , 2, or 3 R7and each C1-6alkyl or C1-6alkylenecan be optionally substituted with 1 or 2 substituents independently selected from Cvealkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; and each R7is independently OH, halo, ON, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, NH2, NH(Ci.6alkyl), or N(Ci.6alkyl)2.

[0038] Also contemplated in the disclosed methods are specific compounds in Table A-1 , or pharmaceutically acceptable salts thereof.

[0040] Other compound that increases degradation of RBM39 contemplated in the disclosed methods include those in PCT / US23 / 83478, e.g., compounds of Formula (I) or (la), or pharmaceutically acceptable salts thereof:wherein RN1is H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; RN2is H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; X1is OR1or N; X2is OR3or N; X3is OR4or N; R1is H, C1-6alkyl. Ci.6haloalky I, halo, OH, or ON, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; R2is H, C1-6alkyl, C1-6haloalkyl. halo, OH, or ON, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, ON, CO2H, NRNRN, and CO2C1-6alkyl; R3is H, C1-6alkyl, C1-6haloalkyl. halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; R4is H, C1-6alkyl, C1-6haloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; R5is H, C1-6alkyl, C1-6haloalkyl, halo, OH, or CN, and the C1-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; each RNis independently H or C1-6alkyl optionally substituted with 1 , 2, or 3 R7; Ar is a C6-10aryl or 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl comprising 1 , 2, or 3 ring heteroatoms selected from 0, S, and N, and Ar is optionally substituted with 1 , 2, or 3 R6; each R6is independently halo, OH, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C0-6alkylene-SRN, C0-6alkylene-NRNRN, O-C2-ealkylene-NRNRN, C0-6alkylene-C(O)ORN, C0-6alkylene-C(O)NRNRN, P(O)(RN)(RN) , Co- ealky lene-Cyc, C0-6alkylene-C(0)-Cyc, O- C0-6alkylene-Cyc, N(RN)-C0-6alkyene-Cyc, or N(RN)C(0)-C0-6alkyene- Cyc, and each C1-6alkyl or C1-6alkoxy can be optionally substituted with 1 or 2 substituents independently selected from C1-6alkoxy, OH, CN, CO2H, NRNRN, and CO2C1-6alkyl; Cyc is C3-10Cylcoalkyl, phenyl, 4-, 5-, 6-, 7-,8-, 9-, 10-, 11-, or 12-membered heterocycloalkyl comprising 1 , 2, 3, or 4 ring heteroatoms selected from 0, S, and N, or 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl comprising 1 , 2, 3, or 4 ring heteroatoms selected from 0, S, and N, and Cyc is substituted with 0, 1 , 2, or 3 R7; and each R7is independently OH, halo, ON, Ci. ealkyl, C1-6haloalkyl, C1-6alkyl-OH, C1-6alkoxy, NH2, NH(C1-6alkyl), or N(C1-6alkyl)2.

[0041] Also contemplated in the disclosed methods are specific compounds in Table A-2, or pharmaceutically acceptable salts thereof.

[0042] Table A-2

[0043] Other compound that increases degradation of RBM39 include those as disclosed in, e.g., US 2022 / 0162193, such as compounds of Formula (I), or pharmaceutically acceptable salts thereof,wherein X is N or CRe; Ri is hydrogen, C1 -C4 alkyl, 01-04 fluoroalkyl, or halo; R2 is hydrogen, halo or cyano; R3 is hydrogen, 01-04 alkyl, halo, cyano, 01-04 fluoroalkyl, -(01-04 alkyl)OH, or -NRaRb, wherein Raor Rbis independently hydrogen, 03-06 cycloalkyl, heterocycloalkyl or 01-04 alkyl, or Ra / Rband the nitrogen atom they are attached to form a 5 or 6-membered ring optionally independently substituted by one or more substituents selected from halo, 01-04 alkyl, cyano, hydroxy and -0(01-04 alkyl); R4 is hydrogen, 01-06 alkyl, 01- CWheteroalkyl, 01-04 fluoroalkyl, -(01-04 alkyl)NH2, 03-06 cycloalkyl, -(01-04 alkyl)(C3-C6 cycloalkyl), -(CI- 04 alkyl)phenyl, phenyl, heteroaryl, -(01-04 alkyl)heteroaryl, 02-05 alkenyl, -(01-04 alkyl)heterocycloalkyl,heterocycloalkyl, -C0-C4 alkylS(=O)2(C1 -C4 alkyl), -S(=O)2phenyl, -S(=O)2heteroaryl, -C0-C4 alkylC(=O)heterocycloalkyl, -C0-C4 alkyl C=O)NRaRb, -(C0-C4 alkyl)C(=O)O(C1-C4 alkyl), -(C0-C4 alkyl)C(=O)C1 -C4 alkyl, -(C0-C4 alkyl)C(=O)OH or -(C1-C8 alkyl)OH, wherein R4 is substituted with 0, 1 , 2, or 3 substituents selected from deuterium, halo, hydroxy, -(C0-C4alkyl)O(C1-C4 alkyl), -C1-C4 alkyl, -(C0- C4alkyl)cyano, -S(=O)2(C1-C4 alkyl), -C0-C4 alkylC(=O)NRaRb, -C(=O)O(C1-C4 alkyl), C1-C4 fluoroalkyl oxo, -(C1-C4 alkyl)OH, and -NH2, wherein each of Raand Rbis independently substituted with 0, 1 , 2, or 3 hydrogen, C3-C6 cycloalkyl, heterocycloalkyl or C1-C4 alkyl; R5 is hydrogen, halo, -NH2 or C1-C4 alkyl; Re is hydrogen, halo or C1-C4 alkyl; and Rz is hydrogen, halo, heteroalkyl, C1-C4 alkyl, -(C0-C4 alkyl)O(C1-C4 alkyl), -(C1-C4 alkyl)(C3-C6 cycloalkyl), C3-C6 cycloalkyl, -(C1-C4 alkyl)heterocycloalkyl, or heterocycloalkyl. In some cases, the compound, or pharmaceutically acceptable salt is selected from N-(3-chloro-1 H-indol-7-yl)-1 -methyl-pyrazole- 4-sulfonamide; N-(3-chloro-1 H-i ndol-7-y l)-1 , 3, 5-tri methy l-py razole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol- 7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; N-(3-chloro- 1 H-indol-7-yl)-1,3-dimethyl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(difluoromethyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1- tetrahydrofuran-3-yl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(2-methylsulfonylethyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1 H-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1- (difluoromethyl)pyrazole-4-sulfonamide; tert-butyl 3-[4-[(3-chloro-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]azetidine-1- carboxylate; N-(3-chloro-1 H-indol-7-yl)-1-(2-hydroxyethyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1- (cyanomethyl)pyrazole-4-sulfonamide; 1-(5-chloro-3-fluoro-2-pyridyl)-N-(3-chloro-1 H-indol-7-yl)pyrazole-4- sulfonamide; 2-[4-[(3-chloro-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]acetamide; 2-[4-[4-[(3-chloro-1 H-indol-7- yl)sulfamoyl]pyrazol-1-yl]sulfonylpyrazol-1-yl]acetamide; 1-(azetidin-3-yl)-N-(3-chloro-1 H-indol-7-yl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(1 H-pyrazol-4-ylsulfonyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol- 7-yl)-1-tetrahydropyran-4-yl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(5-fluoro-2-pyridyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]pyrazole-4-sulfonamide; N-(3-chloro- 1 H-indol-7-yl)-1-[2-(2-methoxyethoxy)ethyl]pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-[2-[2-(2- methoxyethoxy)ethoxy]ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2- hydroxyethyl)pyrazole-4-sulfonamide; tert-butyl 4-[4-[(3-chloro-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]piperidine-1- carboxylate; 1-(1-acetylazetidin-3-yl)-N-(3-chloro-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7- yl)-1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-tetrahydrofuran- 3-yl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-sulfonamide; N- (3-cyano-4-methyl-1 H-indol-7-yl)-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7- yl)-1-(2,2-dimethoxyethyl)pyrazole-4-sulfonamide; tert-butyl N-[2-[4-[(3-chloro-1 H-indol-7-yl)sulfamoyl]pyrazol-1- yl]ethyl]carbamate; 1-(2-aminoethyl)-N-(3-chloro-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7- yl)-1-(2-fluoroethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-fluoroethyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-phenyl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1 -(2,2,2- trifluoroethyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-isopropyl-pyrazole-4-sulfonamide; N-(3-chloro- 1 H-indol-7-yl)-1-(oxetan-3-yl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(4-piperidyl)pyrazole-4-sulfonamide; tert-butyl 3-[[4-[(3-chloro-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]methyl]azetidine-1 -carboxylate; 1- (azetidin-3-ylmethyl)-N-(3-chloro-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-[(3- methylthietan-3-yl)methyl]pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-[(3-methyl-1 ,1-dioxo-thietan-3- yl)methyl]pyrazole-4-sulfonamide; N-(3-cyano-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(3-chloro-1 H- indol-7-yl)-1-cyclobutyl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-N, 1-bis(cyclopropylmethyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(2-methoxyethyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)- N, 1-bis(2-methoxyethyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(cyclopropylmethyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-[(1-cyanocyclopropyl)methyl]pyrazole-4-sulfonamide; N-(3-chloro-1 H- indol-7-yl)-1-[(3,3-difluorocyclobutyl)methyl]pyrazole-4-sulfonamide; N-(3-chloro-4-fluoro-1 H-indol-7-yl)-1-methyl- pyrazole-4-sulfonamide;

[0112] N-(4-fluoro-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide;

[0113] N-(3-chloro- 1 H-indol-7-yl)-1-(fluoromethyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(3-fluoropropyl)pyrazole-4- sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(1 , 1-dioxothietan-3-yl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7- yl)-1-(2-cyanoethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2,2,2-trifluoroethyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-cyclobutyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H- indol-7-yl)-1 H-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-isopropyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(oxetan-3-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1- methyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-methylsulfonylethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H- indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(cyclopropylmethyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 -(fluoromethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl- 1 H-indol-7-yl)-1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(3- fluorooxetan-3-yl)methyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3-fluoropropyl)pyrazole- 4-sulfonamide; 1-methyl-N-(4-methyl-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-chloro-4-methyl-1 H-indol-7-yl)- 1-methyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-cyano-2-methyl-propyl)pyrazole-4- sulfonamide; 1 -(2-cyanoethyl)-N-(3-cyano-4-methyl-1 H-i ndol-7-y I) py razol e-4-sulfon ami de; N-(3-cyano-4-methyl- 1 H-indol-7-yl)-1-(cyclobutylmethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(2,2- difluorocyclopropyl)methyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[1- (fluoromethyl)vinyl]pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(4- chloro-3-cyano-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(3- hydroxycyclobutyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-methyl-2-methylsulfonyl- propyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(4,4-difluorocyclohexyl)pyrazole-4-sulfonamide; N-(3-cyano-4- methyl-1 H-indol-7-yl)-1-[1-(2,2,2-trifluoroethyl)-4-piperidyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol- 7-yl)-1-cyclopentyl-pyrazole-4-sulfonamide; 1-benzyl-N-(3-cyano-4-methyl-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-propyl-pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2,2- difluoroethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 -methylsulfonyl-pyrazole-4-sulfonamide; 1 -tert-buty l-N-(3-cy ano-4-methy I - 1 H-i ndol-7-y l)py razol e-4-su Ifon ami de; 1 -tert-buty l-N-(3-chloro- 1 H-i ndol-7-y I )py razol e-4- sulfonamide; 1-methyl-N-[4-(trifluoromethyl)-1 H-indol-7-yl]pyrazole-4-sulfonamide; N-[3-chloro-4-(trifluoromethyl)- 1 H-indol-7-yl]-1-methyl-pyrazole-4-sulfonamide; N-(3-chloro-4-methyl-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole- 4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[[1-(trifluoromethyl)cyclopropyl]methyl]pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 - (fl uoromethy I sulfonyl ) py razol e-4-su Ifon am ide ; 1 - (benzenesulfonyl)-N-(3-cyano-4-methyl-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7- yl)-1-ethyl-5-fluoro-pyrazole-4-sulfonamide; N-[3-chloro-4-(trifluoromethyl)-1 H-indol-7-yl]-1-(2,2- difluoroethyl)pyrazole-4-sulfonamide; N-[3-cyano-4-(trifluoromethyl)-1 H-indol-7-yl]-1-(2,2-difluoroethyl)pyrazole-4- sulfonamide; N- [3-cy ano-4-(trifl uoromethy I )- 1 H-i ndol-7-y l]-1 -methyl-pyrazole-4-sulfonamide; N-(3-cyano-4- methyl-1 H-indol-7-yl)-1-[[3-(hydroxymethyl)oxetan-3-yl]methyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H- indol-7-yl)-1-(3-methyloxetan-3-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-hydroxy-2- methyl-propyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3,3-difluorocyclobutyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 -(trideuteriomethyl)pyrazole-4-sulfonamide; N-(3-cyano-4- methyl-1 H-indol-7-yl)-1-(3-fluorocyclobutyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-5-fluoro-1-methyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1 ,5-dimethyl-pyrazole-4-sulfonamide; N-(3- cyano-4-methyl-1 H-indol-7-yl)-1 ,3-dimethyl-pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1-(3- methyloxetan-3-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[3-(hydroxymethyl)oxetan-3- yl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[3-(fluoromethyl)oxetan-3-yl]pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3-methyloxetan-3-yl)pyrazole-4-sulfonamide; N-(4-chloro-3- cyano-1 H-indol-7-yl)-1-(difluoromethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1 -(2,2,2- trifl uoroethy l)py razole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1 H-pyrazole-4-sulfonamide; N-(4- chloro-3-cyano-1 H-indol-7-yl)-5-fluoro-1-methyl-pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1- (cyclopropylmethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(fluoromethyl)pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(oxetan-3-yl)pyrazole-4-sulfonamide; N-(3-fluoro-4-methyl-1 H- indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide;

[0185] N-(3-cyano-4-methyl-1 H-indol-7-yl)-5-fluoro-1-(3-methyloxetan-3-yl)pyrazole-4-sulfonamide; N-(3-chloro-2-fluoro-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-5-fluoro-1-(3- methyloxetan-3-yl)pyrazole-4-sulfonamide; 5-cyano-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-methyl-pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-5-cyano-1-methyl-pyrazole-4-sulfonamide; methyl 2-[4-[(3- cyano-4-methyl-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]acetate; 2-[4-[(3-cyano-4-methyl-1 H-indol-7- yl)sulfamoyl]pyrazol-1-yl]acetic acid; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(trideuteriomethyl)pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; 2-[4-[(3- cyano-4-methyl-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]-N-(3,3-difluorocyclobutyl)acetamide; N-(3-cyano-4-methyl- 1 H-indol-7-yl)-1-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]pyrazole-4-sulfonamide; 2-[4-[(3-cyano-4- methyl-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]-N-methyl-acetamide; 2-[4-[(3-cyano-4-methyl-1 H-indol-7- yl)sulfamoyl]pyrazol-1-yl]-N,N-dimethyl-acetamide; 2-[4-[(3-cyano-4-methyl-1 H-indol-7-yl)sulfamoyl]pyrazol-1- yl]acetamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)pyrazole-4-sulfonamide; N-(3,4-dichloro- 1 H-indol-7-yl)-1-(oxetan-3-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-5-fluoro-1- (oxetan-3-yl)pyrazole-4-sulfonamide; 1 -[(1 -cyanocyclopropyl)methyl]-N-(3-cyano-4-methyl-1 H-i ndol-7- yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-oxopyrrolidin-3-yl)pyrazole-4-sulfonamide; N- (4-chloro-3-cyano-1 H-indol-7-yl)-1-(2-oxopyrrolidin-3-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7- yl)-3-fluoro-1-methyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-5-(difluoromethyl)-1-methyl- pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-5-(difluoromethyl)-1-methyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(3S,4R)-4-fluoropyrrolidin-3-yl]pyrazole-4-sulfonamide; N-(4-chloro-3- cyano-1 H-indol-7-yl)-1-[(3S,4R)-4-fluoropyrrolidin-3-yl]pyrazole-4-sulfonamide; tert-butyl (3S,4R)-3-[4-[(3-cyano- 4-methyl-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]-4-fluoro-pyrrolidine-1 -carboxylate; 2-[4-[(4-chloro-3-cyano-1 H- indol-7-yl)sulfamoyl]pyrazol-1-yl]-2-methyl-propanamide; 5-chloro-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-methyl- pyrazole-4-sulfonamide; 5-chloro-N-(4-chloro-3-cyano-1 H-i ndol-7-y l)-1 -methyl-pyrazole-4-sulfonamide; N-(3- cyano-4-methyl-1 H-indol-7-yl)-1-[3-(cyanomethyl)oxetan-3-yl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H- indol-7-yl)-1-[3-(cyanomethyl)oxetan-3-yl]pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1 H-pyrazole-4- sulfonamide; 1-[3-(cyanomethyl)oxetan-3-yl]-N-(3,4-dichloro-1 H-indol-7-yl)pyrazole-4-sulfonamide; 5-amino-N-(3- cyano-4-methyl-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2- hydroxyethyl)pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1-(2-hydroxyethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[1-(chloromethyl)-2-hydroxy-1-(hydroxymethyl)ethyl]pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[3-(hydroxymethyl)oxetan-3-yl]pyrazole-4-sulfonamide; 1-[1- (chloromethyl)-2-hydroxy-1-(hydroxymethyl)ethyl]-N-(3,4-dichloro-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3,4- dichloro-1 H-indol-7-yl)-1-[3-(hydroxymethyl)oxetan-3-yl]pyrazole-4-sulfonamide; methyl 2-[4-[(3,4-dichloro-1 H- indol-7-yl)sulfamoyl]pyrazol-1-yl]-2-methyl-propanoate; methyl 2-[4-[(4-chloro-3-cyano-1 H-indol-7- yl)sulfamoyl]pyrazol-1-yl]-2-methyl-propanoate; N-(3,4-dichloro-1 H-indol-7-yl)-1-(2-hydroxy-1 ,1-dimethyl- ethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4- sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1-(2-hydroxy-1-methyl-ethyl)pyrazole-4-sulfonamide; N-(3,4-dichloro- 1 H-indol-7-yl)-1-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H- indol-7-yl)-1-(3-hydroxycyclobutyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3- hydroxycyclobutyl)pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1-[2-hydroxy-1- (hydroxymethyl)ethyl]pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1-(2-hydroxy-2-methyl- propyl)pyrazole-4-sulfonamide; 1-(2-amino-2-methyl-propyl)-N-(4-chloro-3-cyano-1 H-indol-7-yl)pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1-hydroxycyclobutyl)methyl]pyrazole-4-sulfonamide; 5- amino-N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(3,4-dichloro-1 H-indol-7-yl)-1- (methylsulfonylmethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1- (methylsulfonylmethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1- cyanocyclopropyl)methyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(4- hydroxytetrahydropyran-4-yl)methyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-5-fluoro-1-(2- hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-i ndol-7-y I )-1 -(3- methoxycyclobutyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(3-methoxycyclobutyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[1-(hydroxymethyl)cyclobutyl]pyrazole-4-sulfonamide; N-(3- cyano-4-fluoro-1 H-indol-7-yl)-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H- indol-7-yl)-1-(3-hydroxycyclobutyl)pyrazole-4-sulfonamide; N-(3-chloro-1 H-indol-7-yl)-1-(3- hydroxycyclobutyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[[1-(hydroxymethyl)cyclopropyl]methyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(2S)-2- hydroxypropyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(2R)-2-hydroxypropyl]pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 - (2-hy d roxy- 1 , 1 -d i methy l-ethy I) py razol e-4-su Ifon amide; N-(4- chloro-3-cyano-1 H-indol-7-yl)-3-fluoro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; N-(3-cyano-4- methyl-1 H-indol-7-yl)-3-fluoro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H- indol-7-yl)-3-fluoro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1- [(1 R)-2-hydroxy-1-methyl-ethyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 R)-2-hydroxy-1- methyl-ethyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3-hydroxypropyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 -(3-hydroxypropyl)pyrazole-4-sulfonamide; N-(3-cyano-4- fluoro-1 H-indol-7-yl)-1-(3-hydroxypropyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-[(1R)-2- hydroxy-1-methyl-ethyl]pyrazole-4-sulfonamide; (2R)-2-[4-[(4-chloro-3-cyano-1 H-indol-7-yl)sulfamoyl]pyrazol-1- yl]propenamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1 H-pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7- yl)-1-(difluoromethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(2,2,2-trifluoroethyl)pyrazole-4- sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; 1-(3-bicyclo[1.1.1]pentanyl)-N- (3-cyano-4-methyl-1 H-i ndol-7-y I) py razole-4-sulfon ami de; 1 - (3-bicycl o[1.1 .1 ]pentanyl)-N-(3-cyano-4-fluoro-1 H- indol-7-yl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3-hydroxy-3-methyl-butyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 -(3-hydroxy-3-methyl-butyl)pyrazole-4-sulfonamide; N-(3- cyano-4-fluoro-1 H-indol-7-yl)-1-(3-hydroxy-3-methyl-butyl)pyrazole-4-sulfonamide; 1-(3-bicyclo[1.1.1]pentanyl)-N- (4-chloro-3-cyano-1 H-indol-7-yl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(2-hydroxy-1 ,1- dimethyl-ethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-[(1 R)-2-fluoro-1-methyl- ethyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 S)-2,2-difluoro-1- (hydroxymethyl)ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(1 S)-2,2-difluoro-1- (hydroxymethyl)ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-[(1 S)-2,2-difluoro-1- (hydroxymethyl)ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3-hydroxy-1 , 1-dimethyl- propyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3-hydroxy-1 , 1-dimethyl-propyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 - (3-hy d roxy- 1 , 1 , 3-tri methy I -butyl )pyrazole-4-su Ifon ami de; N-(4- chloro-3-cyano-1 H-indol-7-yl)-1-[(1 S,2R)-2-hydroxy-1-methyl-propyl]pyrazole-4-sulfonamide; N-(3-cyano-4- fluoro-1 H-indol-7-yl)-1-[(1 S,2R)-2-hydroxy-1-methyl-propyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H- indol-7-yl)-1-[(1 S,2R)-2-hydroxy-1-methyl-propyl]pyrazole-4-sulfonamide; N-(3-cyano-1 H-indol-7-yl)-1-(2- hydroxy-1 ,1-dimethyl-ethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3-hydroxy-1-methyl- propyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3-hydroxy-1-methyl-propyl)pyrazole-4- sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 S)-1-(fluoromethyl)-2-hydroxy-ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-5-(2-hydroxyethyl)-1-methyl-pyrazole-4-sulfonamide; 2-[4-[(3-cyano-4-fluoro-1 H-indol-7-yl)sulfamoyl]pyrazol-1-yl]-2-methyl-propanamide; 2-[4-[(3-cyano-4-methyl-1 H-indol-7- yl)sulfamoyl]pyrazol-1-yl]-2-methyl-propanamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3-hydroxy-1 ,3-dimethyl- butyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(3-hydroxy-1 ,3-dimethyl-butyl)pyrazole-4- sulfonamide; 5-chloro-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4- sulfonamide; 5-chloro-N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(1 S)-1-(fluoromethyl)-2-hydroxy-ethyl]pyrazole-4- sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-[(1 S)-1-(fluoromethyl)-2-hydroxy-ethyl]pyrazole-4-sulfonamide; 1-[(2S)-2-amino-3,3,3-trifluoro-propyl]-N-(4-chloro-3-cyano-1 H-indol-7-yl)pyrazole-4-sulfonamide; 1-[(2S)-2- amino-3,3,3-trifluoro-propyl]-N-(3-cyano-4-methyl-1 H-indol-7-yl)pyrazole-4-sulfonamide; 5-chloro-N-(4-chloro-3- cyano-1 H-indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4-sulfonamide; 5-chloro-N-(3-cyano-1 H-indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4-sulfonamide; 3-chloro-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2- hydroxy-1 ,1-dimethyl-ethyl)pyrazole-4-sulfonamide; 3-chloro-N-(3-cyano-1 H-indol-7-yl)-1-(2-hydroxy-1 ,1- dimethyl-ethyl)pyrazole-4-sulfonamide; tert-butyl 3-[[4-[(4-chloro-3-cyano-1 H-indol-7-yl)sulfamoyl]pyrazol-1- yl]methyl]-3-fluoro-azetidine-1 -carboxylate; tert-butyl 3-[[4-[(3-cyano-4-methyl-1 H-indol-7-yl)sulfamoyl]pyrazol-1- yl]methyl]-3-fluoro-azetidine-1 -carboxylate; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(3-fluoroazetidin-3- yl)methyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(3-fluoroazetidin-3-yl)methyl]pyrazole-4- sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3-hydroxy-2,2-dimethyl-propyl)pyrazole-4-sulfonamide; N-(4- chloro-3-cyano-1 H-indol-7-yl)-1-(3-hydroxy-2,2-dimethyl-propyl)pyrazole-4-sulfonamide; 3-chloro-N-(4-chloro-3- cyano-1 H-indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4-sulfonamide; 3-chloro-N-(3-cyano-4-fluoro-1 H- indol-7-yl)-1-(2-hydroxy-1 , 1-dimethyl-ethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[1- (hydroxymethyl)-2-methoxy-ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[1- (hydroxymethyl)-2-methoxy-ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(2R)-3-hydroxy-2-methyl-propyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(2R)-3-hydroxy-2-methyl- propyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 S)-2-hydroxy-1-methyl-ethyl]pyrazole-4- sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-[(1 S)-2-hydroxy-1-methyl-ethyl]pyrazole-4-sulfonamide; N-(3- cyano-4-methyl-1 H-indol-7-yl)-1-[1-(hydroxymethyl)cyclopropyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H- indol-7-yl)-1-[1-(hydroxymethyl)cyclopropyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(3- hydroxybutyl)pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-ethyl-pyrazole-4- sulfonamide; 5-amino-N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; 5-amino-N-(4-chloro-3- cyano-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(1 R,2S)-2-hydroxy-1- methyl-propyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 R,2S)-2-hydroxy-1-methyl- propyl]pyrazole-4-sulfonamide; 5-chloro-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-hydroxy-2-methyl- propyl)pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole-4- sulfonamide; 5-amino-N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole-4-sulfonamide; 5-amino- N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(2,2-difluoroethyl)pyrazole-4-sulfonamide; 5-chloro-N-(3-cyano-4-fluoro-1 H- indol-7-yl)-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(1 R)-2- fluoro-1-methyl-ethyl]pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(difluoromethyl)pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4- fluoro-1 H-indol-7-yl)-1-(difluoromethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 R,2R)-2- hydroxy-1-methyl-propyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(1 R,2R)-2-hydroxy-1- methyl-propyl]pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-[(1 R,2R)-2-hydroxy-1-methyl- propyl]pyrazole-4-sulfonamide; 5-amino-N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2-hydroxy-2-methyl- propyl)pyrazole-4-sulfonamide; 3-amino-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; 3- amino-N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-ethyl-pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-1 H-indol-7-yl)-1- (difluoromethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(1-fluoro-2-hydroxy-1-methyl- ethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(1-fluoro-2-hydroxy-1-methyl-ethyl)pyrazole-4- sulfonamide; 3-amino-N-(3-cyano-4-methyl-1 H-indol-7-y I)- 1 H-pyrazole-4-sulfonamide; 3-amino-N-(4-chloro-3- cyano-1 H-indol-7-yl)-1 H-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(1-fluoro-2-hydroxy- ethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(1-fluoro-2-hydroxy-ethyl)pyrazole-4- sulfonamide; 5-amino-N-(3-cyano-1 H-indol-7-yl)-1-methyl-pyrazole-4-sulfonamide; 3-amino-N-(3-cyano-4-fluoro- 1 H-i ndol-7-y I )- 1 H-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-i ndol-7-y l)-1 -(1,1 -d if I uoro-2-hy d roxy- ethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-fluoro-1 H-indol-7-yl)-1-(fluoromethyl)pyrazole-4-sulfonamide; 5- amino-N-(3-cyano-4-methyl-1H-indol-7-yl)-1-[(1R)-2-hydroxy-1-methyl-ethyl]pyrazole-4-sulfonamide; 5-amino-N- (3-cyano-4-methyl-1 H-indazol-7-yl)-1-methyl-pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indazol-7-yl)-1- (fluoromethyl)pyrazole-4-sulfonamide; 5-amino-N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1 R)-2-hydroxy-1 -methyl- ethyl]pyrazole-4-sulfonamide; 5-amino-N-(4-chloro-3-cyano-1 H-indazol-7-yl)-1-methyl-pyrazole-4-sulfonamide; 5- amino-N-(3-cyano-4-methyl-1H-indol-7-yl)-1-(fluoromethyl)pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-fluoro- 1 H-indol-7-yl)-1-(fluoromethyl)pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indazol-7-yl)-1-[(1 R)-1- (fluoromethyl)-2-hydroxy-ethyl]pyrazole-4-sulfonamide; N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-[(1R)-1- (fluoromethyl)-2-hydroxy-ethyl]pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-1 H-indol-7-yl)-1- (fluoromethyl)pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-[(1 R)-1-(fluoromethyl)-2-hydroxy- ethyl]pyrazole-4-sulfonamide; N-(3-cyano-4-methyl-1 H-indazol-7-yl)-1-[(1 R)-1-(fluoromethyl)-2-hydroxy- ethyl]pyrazole-4-sulfonamide; 5-amino-N-(3-cyano-4-methyl-1 H-indol-7-yl)-1-(2-hydroxy-1 ,1-dimethyl- ethyl)pyrazole-4-sulfonamide; and 5-amino-N-(4-chloro-3-cyano-1 H-indol-7-yl)-1-(2-hydroxy-1 ,1-dimethyl- ethyl)pyrazole-4-sulfonamide.

[0044] In some cases, the compound that increases degradation of RBM39 is indisulam, tasisulam, E7820, chloroquinoxaline sulfonamide, Compound 2A, Compound 215A, or any combination thereof. Compound 2A canbe prepared as described in PCT / US23 / 30294 and has a structure of . Insome cases, the compound that increases degradation of RBM39 is Compound 215A, which has a structure of can be prepared as described in PCT / US23 / 30294.Single Agent

[0045] The compound that increases degradation of RBM39 may be administered as a single agent for the treatment of the cancer disclosed herein. In this embodiment, an additional treatment for the cancer is not administered. However, treatment may still be administered as a pharmaceutical composition, which will generally comprise a suitable pharmaceutically acceptable excipient, diluent or carrier.EXAMPLESExample 1- Method for evaluating drug sensitivity for RBM39 degraders

[0046] Drug sensitivity data for RBM39 degraders indisulam, tasisulam, CQS, and E7820 for a panel of ceil lines was accessed from the DeμMap portal and integrated with the MSI / MSS annotation from Chan et al. , Nature. 2019, 568:561-556 - see Figure 1 . All data was obtained from the PRISM Repurposing single point screen with cells treated with compounds at 2.5 pi M for 5 days. Cell line Iog2 fold changes between RBM39 degraders indisulam, tasisulam, CQS, or E7820 in the MSI (n =65) and MSS (n=668) cell lines were analyzed and tested for significance using a Wilcoxon Rank Sum Test.

[0047] RBM39 degraders indisulam (p=0.0011), tasisulam (p=0.0009), and CQS (p=0.0113) displayed significant differences in treatment effect between MSI and MSS cell lines, providing evidence that MSI-H cancers are vulnerable to RBM39 degradation, and can be therapeutically targeted with RBM39 degraders (Figure 1 A). The cell line Iog2 fold change after 5 days for each of indisulam, tasisulam, CQS or E7820 in cell lines coming from tissues that are most commonly enriched in MSI tumors (colon / bowel, uterus, ovary / fallopian tube, esophagus / stomach and adrenal gland) were assessed, and similar effects were observed (Figure 1B). While several reports have identified E7820 as a potent RBM39 degrader, it is also potent modulator of integrin alpha 2 and RBM23, among other targets, suggesting that E7820 may be less specific to RBM39 versus indisulam, tasisulam, and CQS.Example 2 - Method for evaluating cell viability for Compound 2A in human MSI and MSS cancer cell lines

[0048] Cell lines were obtained from ATCC with media and culture conditions as recommended by ATCC. The assay was conducted at Pharmaron. Cells were seeded 100 - 3,200 cells per well 384-well plates in 40μL of media on Day 0. Compound 2A was dissolved in a 10mM DMSO stock solution, targeting a top concentration of 30μM. On the same day (Day 0), 120nL of diluted compound was transferred from the compound source plate into the cell plates employing an ECHO automated liquid handler. After seven days of compound treatment, the plates were taken out from the incubators, and an equilibration process at roomtemperature was performed for 25 minutes. Prior to initiating the experiment, the CeilTiterGlo reagent was also equilibrated to room temperature to ensure optimal performance. 30 μL of the equilibrated CellTiterGlo reagent was added into each well. Subsequently, the plates were kept at room temperature for 30 minutes in a light-free environment to prevent light interference. Data acquisition was conducted using the Envision multi-label reader. Compound 2A concentrations that provoked a response equal to 50% (IC50) of the inhibition in ceil viability were calculated using GraphPad Prism 10.1.1 by fitting an inhibitor vs normalized response curve where Y=100 / (1 +(IC50 / X)AHillSlope). Top (100%) and Bottom (0%) were defined by control data of untreated wells with DMSO, and compound treated wells at the top concentration of 30μM. Cell lines was analyzed and tested for significance using a Wilcoxon Rank Sum Test in GraphPad Prisim 10.1.1.

[0049] Figure 2A shows the individual IC50 values for Compound 2A across a wide variety of MSI and MSS human cancer cell lines. Treatment with Compound 2A led to a significantly more reduced IC50 in human cancer cells classified as MSI versus those that are classified as MSS (p<0.0001). These data suggest that RBM39 degraders such as Compound 2A may be therapeutically beneficial for patients whose cancers are characterized as MSI.Example 3 - Evaluation of Compound 2A and E7820 efficacy and tolerability in MSI human cancer ovarian xenografts A2780 and OVK18

[0050] A2780 and OVK18 cells were grown in the respective media conditions, DMEM + 10% FBS and MEM + 10% FBS. Cell inoculations were prepared in 1 :1 (Media:Matrigel) and a subcutaneous flank injection of 100 μl per female BALB / c nude mouse. The groups were randomized when the mean tumor volume reached approximately 128 mm3(A2780) or 170 mm3(OVK18) Post inoculation, mice were randomized according to tumor volume into 3 treatment groups (n= 8 per group) on Day 0. Test agents were administered for 12 days (A278) or 17 days (OVK18) at the dose levels, route, and schedules indicated in Table 1 (A2780), Table 2 (OVK18), and Figure 3. Tumor volumes were measured three per week after randomization in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). %TGI was calculated using the formula %TGI = (TV vehicle - TV treatment) I (TV vehicle - TV initial) *100 for all mice (Wong, H, et al. Clin Cancer Res., 2012, 18(14): 3846-3855). Body weights were also measured three times per week at the same time that tumor volumes were recorded.TABLE 1 - A2780PO- oral; QD- once daily; BID- twice daily; %TGI - calculated based on tumor volume on Day 10TABLE 2 - OVK18P0- oral; QD- once daily; BID- twice daily; %TGI - calculated based on tumor volume on Day 11Example 4- Method for evaluating pharmacodynamic markers and mechanism of action for RBM39 degraders

[0051] Assay Condition:Cell line: OVCAR3, A2780Compounds: Vehicle (DMSO), E7820, Compound 2ATreatment Time: 48 hoursLoading amount: 25 pig sample per lane

[0052] Detection antibody information:Phospho-Chk2 (Thr68) (C13C1) Rabbit mAb (Cell Signaling Technology, 2197) Phospho-Chk1 (Ser345) (133D3) Rabbit mAb (Cell Signaling Technology, 2348) Anti-ATM (phospho S1981) antibody [EP1890Y] (Abeam, ab81292) Anti-KAP1 (phospho S824) antibody (Abeam, ab70369)Phospho-Histone H2A.X (Seri 39) (20E3) Rabbit mAb (Cell Signaling Technology, 9718) Cyclin H antibody (Cell Signaling Technology, 2927)Phospho-Histone H3 (Seri 0) (D7N8E) XP Rabbit mAb (Cell Signaling Technology, 55348) RBM39 antibody (Sigma, HPA001591 )Rad51 (D4B10) Rabbit mAb (Cell Signaling Technology, 8875)

[0053] Detection Method: Li-COR

[0054] Sample Preparation: Cells were seeded at 4 x 105per well in a 6-well plate and incubated overnight. Cells were then treated with E7820, DMSO, and Compound 2A. Cells were treated at two compound concentrations - 300nM and 1000nM. Post-treatment, the culture medium was discarded, and cells were rinsed with ice-cold PBS. Lysis was performed using 50piL 1 x RIPA lysis buffer supplemented with Halt™ Protease and Phosphatase Inhibitor Cocktail, EDTA-free (100X) (Thermofisher, 78447). The lysis step was conducted on an ice-cold plate, followed by a 30-minute incubation on ice, shaking with intermittent vortexing every 10 minutes. Samples were then centrifuged at 12,000 rpm for 10 minutes at 4°C, and the supernatant was subsequently collected. Protein concentration was determined using the BCA protein assay. The cell lysate was then combined with loading dye and reducing agent and heated for 10 minutes at 95°C. The treated lysate was briefly spun (10 - 15 seconds) at room temperature at 13,000 rpm.

[0055] Western Blot Assay: Samples were loaded in loaded into gels in a 1X MOPS buffer before being run at 125V for 120 minutes. Samples were then transferred to a nitrocellulose membrane using an IBIot2 dry blotting as per the high MW Protocol which involved a 10-minute process at 2.5A up to 25V.

[0056] Subsequently, the membranes were blocked with TBST / 5% BSA for 60 minutes at room temperature with shaking at 100 rpm. Membranes were hybridized for 16-20 hours at 4°C with primary antibodies in TBST / 5%BSA, with shaking at 100 rpm. Membranes were washed with 1x TBST for 10 minutes three times, and each time at room temperature. Membranes were then probed with secondary antibodies diluted 1 :10000 in TBST / 5% BSA and incubated for 60 minutes at room temperature, with shaking at 100 rpm. Membranes were then washed with 1x TBST for 10 minutes three times, and each time at room temperature followed by PBS rinse. Membranes were then imaged at 800nm channel.

[0057] Results

[0058] Treatment with Compound 2A and E7820 resulted in dose-dependent changes in key proteins that regulate DNA damage repair and cell-cycle progression (Figure 4). Phosphorylation of H2AX and KAP1 are well established as biologically relevant markers of DNA double-strand breaks (DSBs) (Bonner, W, et al. Nat Rev Cancer., 2008, 8(12): 957-67, White, D, et al. Mol Cancer Res., 2012, 10(3): 401-414). Without wishing to be bound by any particular theory, increases in the expression of these proteins suggest activation of DDR and cellcycle regulatory checkpoints. In MSS CV90 cells (Figure 4B), treatment with RBM39 degraders Compound 2A and E7820 did not induce meaningful changes in these pharmacodynamic markers, compared to the MSI-H A2780 cells (Figure 4A). Importantly, RBM39 degradation is seen in both A2780 and CV90 cells; however, changes in DDR proteins such as RAD51 and Cyclin H are reduced only in the A2780 treated cells. It is also relevant to highlight that A2780 harbors ARID1 A and PTEN mutations, whilst the CV90 cell line is CCNE1- amplified, as indicated by elevated RAD51 levels in the DMSO-treated wells. Overall, these results suggest that RBM39 degraders may be more biologically active in cell lines characterized by high genomic instability and MSI- H signatures.Example 5 - Evaluation of Compound 2A modulation of cell-cycle checkpoints in MSI and MSS human cell lines

[0059] Assay Condition:Cell line: OVCAR3, A2780, SW48, HT29, TOV21G, MFE280 Compounds: Vehicle (DMSO), E7820, Compound 2A, Palbociclib Treatment Time: 48 hours

[0060] Reagent: FITC BrdU Flow Kit (BD, 559619)

[0061] Instrument: iQue3

[0062] Sample Preparation: Cells were seeded at a density of 2 x 105per well in 2mL media in 6-well plates on day 0. Compounds were diluted with DMSO (1 :1000) and 2piL of diluted compounds were added to media on day 1 . Cells were treated with Vehicle (DMSO), E7820, Compound 2A, and Palbociclib. Cells were treated at twocompound concentrations for E7820 and Compound 2A - 300nM and 1000nM and at one concentration for palbociclib - 1000nM. Cells were treated for 46 hours. Following treatment, BrdU solution (1mM BrdU in 1XDPBS, 1 :100) was added for each mL in of the culture medium. Cells were incubated for 2 hours. Following incubation, the supernatant was collected in 15mL tubes, and cells were rinsed with PBS. A lysis step was performed using 500pil of trypsin, followed by termination of the digestion with 1mL of culture medium. Cells were harvested in the same 15mL tube and centrifuged at 4500rpm for 5 minutes, with subsequent supernatant discarded. Cells were then washed once with PBS. The cells were then resuspended in 10OpiL of BD Cytofix / Cytoperm Buffer in a 1 ,5mL tube and incubated at room temperature for 20 minutes. Cells were then washed with 1mL of cell staining buffer and centrifuged at 4500rpm for 5 minutes, with subsequent supernatant discarded. Cells were then washed once with PBS. Cells were resuspended in 600pil of BD Cytoperm Permeabilization Buffer Plus, with incubation occurring for 10 minutes on ice. Cells were washed with 1mL 1XBD Perm / Wash Buffer, centrifuged at 4500rpm for 5 minutes, and supernatant discarded. Cells were then resuspended with 10OpiL of diluted DNase and incubated for 1 hour at 37°C. After additional wash and centrifugation cycles, cell resuspension took place in 50piL of BD Perm / Wash Buffer containing diluted fluorescent anti-BrdU, followed by a 20-minute incubation at room temperature. After a final wash and centrifugation cycles, cells were then resuspended in 300piL of 7-AAD solution for a 10-minute incubation at room temperature. Data was acquired on IQue3.

[0063] Gating Strategy: Measuring the proportion of cell cycle distribution after compound treatment consisted of (I) noise filter to remove clutter, (II) removal of sticky cells to obtain single cell population and (ill) gating %dead (7-AAD-BrdU-), %G0 / G1 (7-AAD+BrdU-), %S (7-AAD +-++B rd U+), %G2 / M (7-AAD++BrdU-) in cells by fluorescence intensity.

[0064] Results

[0065] Examination of cell-cycle distributions by flow cytometric analysis in human cancer cells demonstrated that a larger proportion of MSI cells treated with Compound 2A and E7820 remain in the G2 / M phase of the cell cycle versus compound treated MSS cells (Figure 5). This is in contrast to palbociclib, which is an approved CDK4 / 6 inhibitor for breast cancer and known to cause G1 cell cycle arrest, which demonstrated no correlation in sensitivity for MSI versus MSS cells. Overall, these results indicate that RBM39 degradation may leads to G2 / M arrest followed by cell death or a halted proliferation in MSI cells preferentially over MSS cells. This suggests that RBM39 degradation may be selectively therapeutic in cancers characterized as MSI, which are rapidly proliferating due to the large genomic instability seen in these tumors as a result of deficient or defective mismatch repair, and thus more vulnerable to G2 / M activation and cell cycle arrest. Moreover, previous western blot analysis data from Figure 4 suggests this mechanism is CHK2 mediated.Example 6- Evaluation of Compound 215A efficacy in MSI human cancer ovarian xenograft A2780

[0066] A2780 cells were grown in the media condition consisting of DMEM + 10% FBS. Cell inoculations were prepared in 1 :1 (Media:Matrigel) and a subcutaneous flank injection of 100 l per female BALB / c nude mouse.The groups were randomized when the mean tumor volume reached approximately 128 mm3. Post inoculation, mice were randomized according to tumor volume into 4 treatment groups (n= 8 per group) on Day 0. Test agents were administered for 11 days at the dose levels, route, and schedules indicated in Table 3 and Figure 6. Tumor volumes were measured three per week after randomization in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). %TGI was calculated using the formula %TGI = (TV vehicle - TV treatment) I (TV vehicle - TV initial) *100 for all mice (Wong, H, et al. Clin Cancer Res., 2012, 18(14): 3846-3855).

[0067] Compound 215A demonstrated dose-dependent efficacy and tumor stasis was observed at 10 mg / kgBID with clear reductions in efficacy at 3 mg / kg BID and 1 mg / kg BID.TABLE 3 - A2780DO- oral; QD- once daily; BID- twice daily; %TGI - calculated based on tumor volume on Day 10Example 7 - Method for evaluating cell viability for Compound 2A in SWI / SNF Mutant Cancers

[0068] Cell lines were obtained from ATCC with media and culture conditions as recommended by ATCC. Cells were seeded 100 - 3,200 cells per well 384-well plates in 40μL of media on Day 0. Compound 2A was dissolved in a 10mM DMSO stock solution, targeting a top concentration of 30μM. On the same day (Day 0), 120nL of diluted compound was transferred from the compound source plate into the cell plates employing an ECHO automated liquid handler. After seven days of compound treatment, the plates were taken out from the incubators, and an equilibration process at room temperature was performed for 25 minutes. Prior to initiating the experiment, the CellTiterGlo reagent was also equilibrated to room temperature to ensure optimal performance. 30 μL of the equilibrated CellTiterGlo reagent was added into each well. Subsequently, the plates were kept at room temperature for 30 minutes in a light-free environment to prevent light interference. Data acquisition was conducted using the Envision multi-label reader. Compound 2A concentrations that provoked a response equal to 50% (IC50) of the inhibition in cell viability were calculated using GraphPad Prism 10.1 .1 by fitting an inhibitor vs normalized response curve where Y=100 / (1 +(IC50 / X)AHillSlope). Top (100%) and Bottom (0%) were defined by control data of untreated wells with DMSO, and compound treated wells at the top concentration of 30μM. Cell lines was analyzed and tested for significance using a Wilcoxon Rank Sum Test in GraphPad Prism 10.1.1.

[0069] Figure 7A shows the individual IC50 values for Compound 2A across a wide variety of SWI / SNF mutant human cancer cell lines. Treatment with Compound 2A led to a significantly more reduced IC50 in human cancer cells with an SWI / SNF mutation versus those that are SWI / SNF wild type (Figure 7B). These data suggest that RBM39 degraders such as Compound 2A may be therapeutically beneficial for patients whose cancers that are SWI / SNF mutated.

[0070] The mutation status of the cells tested across different subunits of SWI / SNF are shown in Table 4

Claims

What is claimed is:1 . A method of treating a patient suffering from a tumor which is characterized as microsatellite instability - high (MSI-H) microsatellite instability - low (MSI-L) or a mismatch repair deficient (dMMR), comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

2. A method of treating an adult or pediatric patient whose cancer is characterized as microsatellite-instability high (MSI-H), microsatellite instability - low (MSI-L), or mismatch repair deficient (dMMR), as determined by any FDA-approved test or NCCN guideline recommended test, comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

3. The method of claim 1 or 2, wherein the patient has a MSI-L tumor.

4. The method of claim 3, wherein the MSI-L tumor is selected from colorectal, rectal, colon, ovarian, gastric, endometrial, prostate, uterine, cervical, esophageal, breast, renal, mesothelioma, lung, pancreatic, head and neck, bile duct, liver, CNS, hematological, sarcoma, thyroid, soft tissue, large intestine, small intestine, neuroendocrine, and adrenal tumor.

5. The method of claim 3, wherein MSI-L tumor is selected from colorectal, gastric, endometrial, ovarian, adrenal, rectal, and colon tumors.

6. The method of claim 1 or 2, wherein the patient has a MSI-H tumor.

7. The method of claim 1 or 2, wherein the patient has a dMMR tumor.

8. The method of any one of claims 1 to 7, wherein the MSI tumor is a solid tumor.

9. The method of any one of claims 1 to 7, wherein the MSI tumor is a liquid tumor.

10. The method of any one of claims 1 to 9, wherein the patient has Lynch syndrome.11 . The method of any one of claims 1 to 9, wherein the patient has Constitutional mismatch repair deficiency.

12. The method of any one of claims 1 to 4 or 6 to 9, wherein the tumor is a neuroendocrine tumor.

13. A method of treating an adult or pediatric patient with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumor, as determined by an FDA-approved test, comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

14. The method of claim 13, wherein the solid tumor progressed following prior treatment, the patient has no satisfactory alternative treatment option, or both.

15. A method of treating a patient suffering from a cancer having a SWI / SNF mutation, comprising administering to the patient a therapeutically effective amount of a compound that increases degradation of RBM39.

16. The method of claim 15, wherein the SWI / SNF mutation is in ARID1A.

17. The method of claim 15 or 16, wherein the SWI / SNF mutation is in ARID1B.

18. The method of any one of claims 15 to 17, wherein the SWI / SNF mutation is in ARID2.

19. The method of any one of claims 15 to 18, wherein the SWI / SNF mutation is in SMARCA2.

20. The method of any one of claims 15 to 19, wherein the SWI / SNF mutation is in SMARCA4.21 . The method of any one of claims 1 to 20, wherein the compound that increases RBM39 degradation is an aryl sulfonamide or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 , wherein the aryl sulfonamide is as disclosed in PCT / US23 / 30294, PCT / US23 / 83478, or US 2022 / 0162193, or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 1 to 20, wherein the compound that increases RBM39 degradation is indisulam, tasisulam, E7820, chloroquinoxaline sulfonamide, Compound 2A, Compound 215A, a pharmaceutically acceptable salt thereof, or a combination thereof.

24. The method of claim 23, wherein the compound that increases RBM39 degradation is Compound 2A, or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the compound that increases RBM39 degradation is Compound 215A, or a pharmaceutically acceptable salt thereof.

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